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1.
Ann Rheum Dis ; 80(3): 402-403, 2021 03.
Article in English | MEDLINE | ID: covidwho-1909670
2.
Clin Rheumatol ; 40(10): 4179-4189, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1384475

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a new clinical condition characterized by signs of inflammation and multiorgan dysfunction due to cytokine storm associated with SARS-CoV-2. The clinical spectrum of MIS-C ranges from mild to severe, and even to mortal multisystem involvement. To guide clinicians, we evaluated detailed demographic characteristics, clinical features, laboratory findings, and outcomes of MIS-C cases. METHODS: We performed a retrospective study of patients with MIS-C who were managed in the Department of Pediatric Infectious Disease in the Selcuk University Faculty of Medicine, Konya, Turkey. MIS-C patients were divided into three clinical severity groups (mild, moderate, and severe) and separated into three age groups (< 5 years, 5-10 years, > 10 years). We compared the characteristics of MIS-C cases according to the severity of the disease and by age groups. RESULT: Thirty-six children with MIS-C were evaluated (52.8% male, median age of 7.8 years). A clinical spectrum overlapping with Kawasaki disease (KD) was the most common presentation (69.4%) in all age groups. The most common clinical symptoms were fever (100%), mucocutaneous rash (69.4%), and gastrointestinal symptoms (66.6%). There was no statistically significant difference in echocardiographic abnormality between KD-like and the other clinical spectra (p > 0.05). All life-threatening rhythm disturbances were observed in severe cases. No patients died. CONCLUSION: It is important to increase the awareness of physicians about the MIS-C disease, which can present with different combinations of different systemic findings, so that patients can be diagnosed and treated in a timely manner. Key Points • A single tertiary centre study shows that children with MIS-C can present with different clinic spectra other than Kawasaki diseases. • Electrocardiographic and echocardiographic evaluation is important in early diagnosis of children with MIS-C. • Pro-BNP can be used as a screening test in the emergency room for children with prolonged and unexplained fever for determine early cardiac involvement of MIS-C. • The lack of require biological agents and favourable outcomes in children with MIS-C may be related with administration of steroid therapy with IVIG in early stage of disease.


Subject(s)
COVID-19 , Child , Child, Preschool , Female , Humans , Male , Retrospective Studies , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , Turkey/epidemiology
3.
Front Physiol ; 12: 649604, 2021.
Article in English | MEDLINE | ID: covidwho-1268279

ABSTRACT

Conventional smoking is known to both increase susceptibility to infection and drive inflammation within the lungs. Recently, smokers have been found to be at higher risk of developing severe forms of coronavirus disease 2019 (COVID-19). E-cigarette aerosol inhalation (vaping) has been associated with several inflammatory lung disorders, including the recent e-cigarette or vaping product use-associated lung injury (EVALI) epidemic, and recent studies have suggested that vaping alters host susceptibility to pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the impact of vaping on lung inflammatory pathways, including the angiotensin-converting enzyme 2 (ACE2) receptor known to be involved in SARS-CoV-2 infection, mice were exposed to e-cigarette aerosols for 60 min daily for 1-6 months and underwent gene expression analysis. Hierarchical clustering revealed extensive gene expression changes occurred in the lungs of both inbred C57BL/6 mice and outbred CD1 mice, with 2,933 gene expression changes in C57BL/6 mice, and 2,818 gene expression changes in CD1 mice (>abs 1.25-fold change). Particularly, large reductions in IgA and CD4 were identified, indicating impairment of host responses to pathogens via reductions in immunoglobulins and CD4 T cells. CD177, facmr, tlr9, fcgr1, and ccr2 were also reduced, consistent with diminished host defenses via decreased neutrophils and/or monocytes in the lungs. Gene set enrichment (GSE) plots demonstrated upregulation of gene expression related to cell activation specifically in neutrophils. As neutrophils are a potential driver of acute lung injury in COVID-19, increased neutrophil activation in the lungs suggests that vapers are at higher risk of developing more severe forms of COVID-19. The receptor through which SARS-CoV-2 infects host cells, ACE2, was found to have moderate upregulation in mice exposed to unflavored vape pens, and further upregulation (six-fold) with JUUL mint aerosol exposure. No changes were found in mice exposed to unflavored Mod device-generated aerosols. These findings suggest that specific vaping devices and components of e-liquids have an effect on ACE2 expression, thus potentially increasing susceptibility to SARS-CoV-2. In addition, exposure to e-cigarette aerosols both with and without nicotine led to alterations in eicosanoid lipid profiles within the BAL. These data demonstrate that chronic, daily inhalation of e-cigarette aerosols fundamentally alters the inflammatory and immune state of the lungs. Thus, e-cigarette vapers may be at higher risk of developing infections and inflammatory disorders of the lungs.

4.
Blood Transfus ; 20(3): 198-205, 2022 05.
Article in English | MEDLINE | ID: covidwho-1249632

ABSTRACT

BACKGROUND: We investigated the presence of anti-SARS-CoV-2 antibodies in Italian plasma pools and intravenous immunoglobulins sent to our Institute (Italian National Institute of Health - Istituto Superiore di Sanità) in the context of the Official Control Authority Batch Release. The plasma pools were made up from donations collected in several different Italian regions from May 2017 to October 2020, i.e. in the pre-pandemic and pandemic periods. MATERIALS AND METHODS: All plasma pools were initially tested for the qualitative detection of anti-SARS-CoV-2 antibodies against the nucleocapsid protein using the Roche Elecsys® Anti-SARS-CoV-2 test kit. Plasma pools positive for these antibodies were further tested using the Roche Elecsys® Anti-SARS-CoV-2 S test kit for the quantitative detection of antibodies against SARS-CoV-2 spike receptor binding domain. All plasma pools showing reactivity to these antibodies were tested undiluted for the presence of SARS-CoV-2 RNA using the Grifols Procleix SARS-CoV-2 transcription-mediated amplification assay. Intravenous immunoglobulins were tested using both test kits to determine the presence of anti-SARS-CoV-2 antibodies. RESULTS: All plasma pools made up from donations collected in the pre-pandemic period were negative for anti-SARS-CoV-2 antibodies against the nucleocapsid protein. Of the plasma pools made up from donations collected from December 2018 to March 2020, only 1 pool out of 68 (1.4%), that was made up from donations from the Lombardy region, was reactive for these antibodies. Interestingly, 105 out of 174 (60.3%) of the plasma pools made up from donations collected from November 2018 to October 2020 showed the presence of these antibodies. All plasma pools positive for these antibodies were tested for antibodies against SARS-CoV-2 spike receptor binding domain and were confirmed positive. DISCUSSION: None of these plasma pools tested were reactive for SARS-CoV-2 RNA. In the case of intravenous immunoglobulins, 20 out of 25 (80%) batches showed the presence of both anti-SARS-CoV-2 antibodies, reflecting the concentration in the plasma pools used for their production.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/diagnosis , COVID-19/epidemiology , Humans , Immunoglobulins, Intravenous , Nucleocapsid Proteins , Pandemics , RNA, Viral
5.
Virol J ; 18(1): 101, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1238724

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a major challenge facing the world. Certain guidelines issued by National Health Commission of the People's Repubilic of China recommend intravenous immunoglobulin (IVIG) for adjuvant treatment of COVID-19. However, there is a lack of clinical evidence to support the use of IVIG. METHODS: This single-center retrospective cohort study included all adult patients with laboratory-confirmed severe COVID-19 in the Respiratory and Critical Care Unit of Dabie Mountain Regional Medical Center, China. Patient information, including demographic data, laboratory indicators, the use of glucocorticoids and IVIG, hospital mortality, the application of mechanical ventilation, and the length of hospital stay was collected. The primary outcome was the composite end point, including death and the use of mechanical ventilation. The secondary outcome was the length of hospital stay. RESULTS: Of the 285 patients with confirmed COVID-19, 113 severely ill patients were included in this study. Compared to the non-IVIG group, more patients in the IVIG group reached the composite end point [12 (25.5%) vs 5 (7.6%), P = 0.008] and had longer hospital stay periods [23.0 (19.0-31.0) vs 16.0 (13.8-22.0), P < 0.001]. After adjusting for confounding factors, differences in primary outcomes between the two groups were not statistically significant (P = 0.167), however, patients in the IVIG group had longer hospital stay periods (P = 0.041). CONCLUSION: Adjuvant therapy with IVIG did not improve in-hospital mortality rates or the need for mechanical ventilation in severe COVID-19 patients. Our study does not support the use of immunoglobulin in patients with severe COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Immunoglobulins, Intravenous/therapeutic use , SARS-CoV-2 , Adult , Aged , COVID-19/mortality , Female , Hospital Mortality , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index
6.
Cochrane Database Syst Rev ; 5: CD013600, 2021 05 20.
Article in English | MEDLINE | ID: covidwho-1235649

ABSTRACT

BACKGROUND: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required.  OBJECTIVES: Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence. SEARCH METHODS: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events. MAIN RESULTS: We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract). Effectiveness of convalescent plasma We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone.  Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences.  We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence).  Safety of convalescent plasma We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group.  We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence).  A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline).  Effectiveness of convalescent plasma We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence).  We identified no study reporting quality of life.  Safety of convalescent plasma We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence). This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. AUTHORS' CONCLUSIONS: We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.


Subject(s)
COVID-19/therapy , Bias , COVID-19/mortality , Cause of Death , Humans , Immunization, Passive/adverse effects , Immunization, Passive/methods , Immunization, Passive/mortality , Immunization, Passive/statistics & numerical data , Non-Randomized Controlled Trials as Topic/statistics & numerical data , Pandemics , Randomized Controlled Trials as Topic/statistics & numerical data , Respiration, Artificial/statistics & numerical data , Treatment Outcome , Ventilator Weaning/statistics & numerical data
7.
Vaccine X ; 8: 100098, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1203207

ABSTRACT

Patients who recover from SARS-CoV-2 infections produce antibodies and antigen-specific T cells against multiple viral proteins. Here, an unbiased interrogation of the anti-viral memory B cell repertoire of convalescent patients has been performed by generating large, stable hybridoma libraries and screening thousands of monoclonal antibodies to identify specific, high-affinity immunoglobulins (Igs) directed at distinct viral components. As expected, a significant number of antibodies were directed at the Spike (S) protein, a majority of which recognized the full-length protein. These full-length Spike specific antibodies included a group of somatically hypermutated IgMs. Further, all but one of the six COVID-19 convalescent patients produced class-switched antibodies to a soluble form of the receptor-binding domain (RBD) of S protein. Functional properties of anti-Spike antibodies were confirmed in a pseudovirus neutralization assay. Importantly, more than half of all of the antibodies generated were directed at non-S viral proteins, including structural nucleocapsid (N) and membrane (M) proteins, as well as auxiliary open reading frame-encoded (ORF) proteins. The antibodies were generally characterized as having variable levels of somatic hypermutations (SHM) in all Ig classes and sub-types, and a diversity of VL and VH gene usage. These findings demonstrated that an unbiased, function-based approach towards interrogating the COVID-19 patient memory B cell response may have distinct advantages relative to genomics-based approaches when identifying highly effective anti-viral antibodies directed at SARS-CoV-2.

8.
J Clin Microbiol ; 59(5)2021 04 20.
Article in English | MEDLINE | ID: covidwho-1195818

ABSTRACT

In this study, we comprehensively analyzed multispecific antibody kinetics of different immunoglobulins in hospitalized patients with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Three hundred fifty-four blood samples longitudinally obtained from 81 IgG-seroconverting progressed coronavirus disease 2019 (CoVID-19) patients were quantified for spike 1 (S1), S2, and nucleocapsid protein (NCP)-specific IgM, IgA, IgG, and total Ig antibodies using a microarray, 11 different enzyme-linked immunosorbent assays (ELISAs)/chemiluminescence immunoassays (CLIAs), and 1 rapid test by seven manufacturers. The assays' specificity was assessed in 130 non-CoVID-19 pneumonia patients. Using the microarray, NCP-specific IgA and IgG antibodies continuously displayed higher detection rates during acute CoVID-19 than S1- and S2-specific ones. S1-specific IgG antibodies, however, reached higher peak values. Until the 26th day post-symptom onset, all patients developed IgG responses against S1, S2, and NCP. Although detection rates by ELISAs/CLIAs generally resembled those of the microarray, corresponding to the target antigen, sensitivities and specificities varied among all tests. Notably, patients with more severe CoVID-19 displayed higher IgG and IgA levels, but this difference was mainly observed with S1-specific immunoassays. In patients with high SARS-CoV-2 levels in the lower respiratory tract, we observed high detection rates of IgG and total Ig immunoassays with a particular rise of S1-specific IgG antibodies when viral concentrations in the tracheal aspirate subsequently declined over time. In summary, our study demonstrates that differences in sensitivity among commercial immunoassays during acute SARS-CoV-2 infection are only partly related to the target antigen. Importantly, our data indicate that NCP-specific IgA and IgG antibodies are detected earlier, while higher S1-specific IgA antibody levels occur in severely ill patients.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Immunoassay/methods , Coronavirus Nucleocapsid Proteins/immunology , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Kinetics , Phosphoproteins/immunology , SARS-CoV-2 , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology
9.
N Engl J Med ; 384(22): 2092-2101, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1174739

ABSTRACT

BACKGROUND: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder. METHODS: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay. RESULTS: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation. CONCLUSIONS: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).


Subject(s)
Autoantibodies/blood , COVID-19 Vaccines/adverse effects , Platelet Factor 4/immunology , Thrombocytopenia/etiology , Thrombosis/etiology , Adult , Autoimmune Diseases/etiology , Blood Chemical Analysis , Disseminated Intravascular Coagulation/etiology , Enzyme-Linked Immunosorbent Assay , Fatal Outcome , Female , Humans , Intracranial Hemorrhages/etiology , Male , Middle Aged , Platelet Activation , Thrombocytopenia/immunology , Thrombosis/immunology , Young Adult
10.
Int J Environ Res Public Health ; 18(7)2021 04 02.
Article in English | MEDLINE | ID: covidwho-1167581

ABSTRACT

Dentists have been supposed to be among the healthcare workers at greatest risk of SARS-CoV-2 infection. However, scant data are available on the issue. The aim of this study is to quantify the SARS-CoV-2 antibody prevalence and determinants in a sample of dentists, dental hygienists, and other personnel employed among the dental staff in Lombardy region. We used an accurate rapid diagnostic test kit detecting immunoglobulins (Ig) in 504 adults. Of the 499 participants who obtained a valid antibody test, 54 (10.8%) had a SARS-CoV-2 positive test (0.4% IgM+, 1.8% both IgM+ and IgG+, and 8.6% IgG+). A statistically significant association with infection was found for geographic area (compared to Milan, adjusted odds ratio was 2.79, 95% confidence interval, CI: 1.01-7.68 for eastern and 2.82, 95% CI: 1.34-5.94, for southern Lombardy). The clinical staff did not result positive to SARS-CoV-2 more frequently than the administrative staff. This is the first study using antibody test in the dental staff personnel. It shows that the prevalence of SARS-CoV-2 infection in Lombardy region was around 10%, in line with estimates on other healthcare professionals. Despite the close physical contact with the patient, dentists have been able to scrupulously manage and effectively use protective devices.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Viral , Dental Staff , Health Personnel , Humans , Italy/epidemiology
11.
Front Immunol ; 12: 627285, 2021.
Article in English | MEDLINE | ID: covidwho-1120044

ABSTRACT

Introduction: Cross-reactivity to SARS-CoV-2 antigenic peptides has been detected on T-cells from pre-pandemic donors due to recognition of conserved protein fragments within members of the coronavirus's family. Further, preexisting antibodies recognizing SARS-CoV-2 with conserved epitopes in the spike region have been now seen in uninfected individuals. High-dose Intravenous Immunoglobulin (IVIg), derived from thousands of healthy donors, contains natural IgG antibodies against various antigens which can be detected both within the IVIg preparations and in the serum of IVIg-receiving patients. Whether IVIg preparations from pre-pandemic donors also contain antibodies against pre-pandemic coronaviruses or autoreactive antibodies that cross-react with SARS-CoV-2 antigenic epitopes, is unknown. Methods: 13 samples from 5 commercial IVIg preparations from pre-pandemic donors (HyQvia (Baxalta Innovations GmbH); Privigen (CSL Behring); Intratect (Biotest AG); IgVena (Kedrion S.p.A); and Flebogamma (Grifols S.A.) were blindly screened using a semi-quantitative FDA-approved and validated enzyme-linked immunosorbent assay (ELISA) (Euroimmun, Lubeck, Germany). Results: Nine of thirteen preparations (69.2%), all from two different manufactures, were antibody-positive based on the defined cut-off positivity (index of sample OD to calibrator OD > 1.1). From one manufacturer, 7/7 lots (100%) and from another 2/3 lots (67%), tested positive for cross-reacting antibodies. 7/9 of the positive preparations (77%) had titers as seen in asymptomatically infected individuals or recent COVID19-recovered patients, while 2/9 (23%) had higher titers, comparable to those seen in patients with active symptomatic COVID-19 infection (index > 2.2). Conclusion: Pre-pandemic IVIg donors have either natural autoantibodies or pre-pandemic cross-reactive antibodies against antigenic protein fragments conserved among the "common cold" - related coronaviruses. The findings are important in: (a) assessing true anti-SARS-CoV-2-IgG seroprevalence avoiding false positivity in IVIg-receiving patients; (b) exploring potential protective benefits in patients with immune-mediated conditions and immunodeficiencies receiving acute or chronic maintenance IVIg therapy, and (c) validating data from a recent controlled study that showed significantly lower in-hospital mortality in the IVIg- treated group.


Subject(s)
Antibodies, Viral/immunology , Autoimmunity , COVID-19/immunology , Immunoglobulins, Intravenous/immunology , SARS-CoV-2/immunology , Seasons , COVID-19/epidemiology , Cross Reactions , Epitopes/immunology , Humans , Spike Glycoprotein, Coronavirus/immunology
12.
JMIR Public Health Surveill ; 7(2): e22483, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1105949

ABSTRACT

BACKGROUND: The COVID-19 pandemic presents a great public health challenge worldwide, especially given the urgent need to identify effective drugs and develop a vaccine in a short period of time. Globally, several drugs and vaccine candidates are in clinical trials. However, because these drugs and vaccines are still being tested, there is still no definition of which ones will succeed. OBJECTIVE: This study aimed to assess the opinions of over 1000 virus researchers with knowledge on the prevention and treatment of coronavirus-related human diseases to determine the most promising drug and vaccine candidates to address COVID-19. METHODS: We mapped the clinical trials related to COVID-19 registered at ClinicalTrials.gov. These data were used to prepare a survey questionnaire about treatments and vaccine candidates for COVID-19. In May 2020, a global survey was conducted with authors of recent scientific publications indexed in the Web of Science Core Collection related to viruses, severe acute respiratory syndrome coronavirus, coronaviruses, and COVID-19. RESULTS: Remdesivir, immunoglobulin from cured patients, and plasma were considered to be the most promising treatments in May 2020, while ChAdOx1 and mRNA-1273 were considered to be the most promising vaccine candidates. Almost two-thirds of the respondents (766/1219, 62.8%) believed that vaccines for COVID-19 were likely to be available in the next 18 months. Slightly fewer than 25% (289/1219, 23.7%) believed that a vaccine was feasible, but probably not within 18 months. CONCLUSIONS: The issues addressed in this study are constantly evolving; therefore, the current state of knowledge has changed since the survey was conducted. However, for several months after the survey, the respondents' expectations were in line with recent results related to treatments and vaccine candidates for COVID-19.


Subject(s)
COVID-19 Vaccines , COVID-19/drug therapy , Expert Testimony , Pandemics , Research Personnel , COVID-19/epidemiology , Clinical Trials as Topic , Cross-Sectional Studies , Global Health , Humans
13.
Immunotherapy ; 13(5): 397-407, 2021 04.
Article in English | MEDLINE | ID: covidwho-1073248

ABSTRACT

Background: This study assesses the feasibility of producing hyperimmune anti-COVID-19 intravenously administrable immunoglobulin (C-IVIG) from pooled convalescent plasma (PCP) to provide a safe and effective passive immunization treatment option for COVID-19. Materials & methods: PCP was fractionated by modified caprylic acid precipitation followed by ultrafiltration/diafiltration to produce hyperimmune C-IVIG. Results: In C-IVIG, the mean SARS-CoV-2 antibody level was found to be threefold (104 ± 30 cut-off index) that of the PCP (36 ± 8.5 cut-off index) and mean protein concentration was found to be 46 ± 3.7 g/l, comprised of 89.5% immunoglobulins. Conclusion: The current method of producing C-IVIG is feasible as it uses locally available PCP and simpler technology and yields a high titer of SARS-CoV-2 antibody. The safety and efficacy of C-IVIG will be evaluated in a registered clinical trial (NCT04521309).


Subject(s)
Antibodies, Viral/isolation & purification , COVID-19/blood , Immunoglobulins, Intravenous/isolation & purification , SARS-CoV-2/immunology , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , COVID-19/therapy , Caprylates/chemistry , Chemical Fractionation , Humans , Immunization, Passive , Immunoglobulins, Intravenous/immunology , Immunoglobulins, Intravenous/therapeutic use
14.
Pediatr Pulmonol ; 55(2): 330-337, 2020 02.
Article in English | MEDLINE | ID: covidwho-1064414

ABSTRACT

BACKGROUND: Long-term effects of sulfur dioxide (SO2 ) exposure on children, a vulnerable population, are largely unknown. Further, how long-term SO2 affects Puerto Rican children living in the island of Puerto Rico, a group with high asthma prevalence, is unclear. We evaluated the effects of annual average 1-hour daily maximum SO2 average on asthma, atopy, total immunoglobulin E (IgE), and lung function in Puerto Rican children. METHODS: A cohort of 678 children (351 with asthma, 327 without asthma) was recruited in Puerto Rico from 2009 to 2010. Annual average 1-hour daily maximum SO2 exposure was interpolated utilizing publicly available monitoring data. Multivariable logistic and linear regression was used for the analysis of asthma, atopy (defined as an IgE ≥0.35 IU/mL to at least one of five common aero-allergens), total IgE, and lung function measures (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1], and FEV1/FVC ratio). RESULTS: Annual SO2 exposure (per 1 ppb) was significantly associated with asthma (odds ratio [OR] = 1.42; 95% confidence interval [CI] = 1.05-1.91) and atopy (OR = 1.35; 95% CI = 1.02-1.78). Such exposure was also significantly associated with lower FEV1/FVC in all children (ß = -1.42; 95% CI = -2.78 to -0.08) and in children with asthma (ß = -2.39; 95% CI= -4.31 to -0.46). Annual SO2 exposure was not significantly associated with total IgE, FEV1, or FVC. CONCLUSIONS: Among Puerto Rican children in Puerto Rico, long-term SO2 exposure is linked to asthma and atopy. In these children, long-term SO2 exposure is also associated with reduced FEV1/FVC, particularly in those with asthma.


Subject(s)
Air Pollution/statistics & numerical data , Asthma/epidemiology , Inhalation Exposure/statistics & numerical data , Sulfur Dioxide/analysis , Adolescent , Allergens , Asthma/physiopathology , Child , Cohort Studies , Female , Humans , Hypersensitivity, Immediate , Lung/physiopathology , Male , Odds Ratio , Prevalence , Puerto Rico/epidemiology , Respiratory Function Tests , Vital Capacity
15.
Mult Scler Relat Disord ; 49: 102725, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1002925

ABSTRACT

BACKGROUND: There are limited data on the impact of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on people with multiple sclerosis (MS). OBJECTIVE: To better understand SARS-CoV-2 infection in ocrelizumab-treated people with MS. METHODS: Internal Roche/Genentech data sources: Cases of COVID-19 from ongoing Roche/Genentech clinical trials and from post-marketing use of ocrelizumab until July 31, 2020 were identified and assessed using descriptive statistics. External real-world data (RWD) source: An MS COVID-19 cohort and an ocrelizumab-treated MS COVID-19 cohort were identified and assessed from the OPTUMⓇ de-identified COVID-19 electronic health record (EHR) database. RESULTS: Roche/Genentech clinical trial data: There were 51 (1.3%) suspected or confirmed cases of COVID-19 identified from 4,000 patients ongoing in 10 Roche/Genentech clinical trials. Of these, 26 (51%) were confirmed COVID-19 and 25 (49%) were suspected COVID-19. Sixteen (31.4%) patients were hospitalized. COVID-19 severity was mild to moderate in most patients (35, 68.6%). Ten (19.6%) patients had severe disease and there were three (5.9%) fatal cases. Most patients (43, 84.3%) recovered or were recovering. There was no association apparent between duration of exposure to ocrelizumab and COVID-19. Among COVID-19 patients with previous serum immunoglobulin status (27/51, 52.9%), all (27/27, 100%) had IgG levels within the normal range. Roche/Genentech post-marketing safety database data: There were 307 post-marketing cases of COVID-19 in the Roche/Genentech global safety database. Of these, 263 (85.7%) were confirmed and 44 (14.3%) were suspected COVID-19. 100 (32.6%) patients were hospitalized. COVID-19 was asymptomatic, mild or moderate in 143 (46.6%) patients, severe in 52 (16.9%) patients, and critical in 15 (4.9%) patients. There were 17 (5.5%) fatal cases. Information on severity was not reported in 80 (26.1%) cases. Most patients (211, 68.7%) recovered or were recovering at the time of the report. External RWD data source: As of July 13, 2020, the OPTUMⓇ database included EHRs for almost 1.2 million patients with suspected COVID-19, 130,500 of whom met the criteria for confirmed/clinically diagnosed COVID-19. A total of 357 patients with MS with confirmed COVID-19 were identified. Forty-eight (13.4%) were treated with ocrelizumab, of whom 12 (25.0%) were hospitalized and one died (2.1%). Similar rates of hospitalization, invasive ventilation, and death were observed in the ocrelizumab-treated and non-ocrelizumab-treated MS cohorts. Across the Roche/Genentech and RWD sources assessed, age, male sex, and the presence of comorbidities such as hypertension were associated with a more severe disease course of COVID-19. There was a higher number of comorbidities present in hospitalized versus non-hospitalized patients. CONCLUSIONS: This assessment provides evidence that COVID-19 in ocrelizumab-treated people with MS is predominantly mild to moderate in severity with most patients not requiring hospitalization; in line with data reported from the general population and MS datasets. Risk factors known to be associated with severe COVID-19 outcomes in the general population also appear to influence COVID-19 severity in ocrelizumab-treated people with MS. Case fatality rates for ocrelizumab-treated people with MS were within published ranges for the general population and other MS cohorts.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Multiple Sclerosis , Adolescent , Adult , Aged , Aged, 80 and over , Electronic Health Records , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Risk Factors , Young Adult
16.
Antibodies (Basel) ; 9(4)2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-965211

ABSTRACT

Intravenous immune globulin (IVIG) is made after processing plasma from healthy donors. It is composed mainly of pooled immunoglobulin and has clinical evidence-based applications in adult and pediatric populations. Recently, several clinical applications have been proposed for managing conditions in the neonatal population, such as hemolytic disease of the newborn, treatment, and prophylaxis for sepsis in high-risk neonates, enterovirus parvovirus and COVID-19 related neonatal infections, fetal and neonatal immune-induced thrombocytopenia, neonatal hemochromatosis, neonatal Kawasaki disease, and some types of immunodeficiency. The dosing, mechanism of action, effectiveness, side effects, and adverse reactions of IVIG have been relatively well studied in adults but are not well described in the neonatal population. This review aims to provide the most recent evidence and consensus guidelines about the use of IVIG in the fetus and neonate.

17.
Med Sci Monit ; 26: e928755, 2020 Dec 02.
Article in English | MEDLINE | ID: covidwho-954198

ABSTRACT

BACKGROUND This retrospective study aimed to describe the effects of convalescent plasma therapy in 24 patients diagnosed with coronavirus disease 2019 (COVID-19) pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during February and March 2020 in Wuhan, China. MATERIAL AND METHODS The confirmation of SARS-CoV-2 infection was made by the reverse transcription-polymerase chain reaction test. We retrospectively analyzed the clinical data and laboratory test reports of patients with severe COVID-19 pneumonia who received a convalescent plasma transfusion. RESULTS A total of 24 patients with COVID-19 pneumonia who were transfused with ABO-compatible convalescent plasma were enrolled in the study. Convalescent plasma transfusion showed an effective clinical outcome in 14 of 24 patients (an effective rate of 58.3%). No patients had an adverse reaction to the transfusion. Compared with before convalescent plasma transfusion, the lymphocyte count after convalescent plasma transfusion increased to a normal level (median: 0.80×109/L vs. 1.12×109/L, P=0.004). Other laboratory indicators such as white blood cells, high-sensitivity C-reactive protein, procalcitonin, alanine aminotransferase, and aspartate transaminase showed a decreasing trend after transfusion. CONCLUSIONS This retrospective observational clinical study showed that convalescent plasma therapy could have beneficial effects on patient outcomes. Recently, regulatory authorization has been given for the use of convalescent plasma therapy, and clinical guidelines have been developed for the collection and use of convalescent plasma and hyperimmune immunoglobulin in patients with COVID-19.


Subject(s)
Blood Component Transfusion/methods , COVID-19/therapy , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , COVID-19 Nucleic Acid Testing , China , Female , Humans , Immunization, Passive/methods , Male , Middle Aged , RNA, Viral/isolation & purification , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome
18.
Crit Care Explor ; 2(11): e0280, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-939583

ABSTRACT

Dysregulated neutrophil and platelet interactions mediate immunothrombosis and cause lung injury in coronavirus disease 2019. IV immunoglobulin modulates neutrophil activation through FcγRIII binding. We hypothesized that early therapy with IV immunoglobulin would abrogate immunothrombosis and improve oxygenation and reduce progression to mechanical ventilation in coronavirus disease 2019 pneumonia. DESIGN: Prospective randomized open label. SETTING: Inpatient hospital. PATIENTS AND INTERVENTION: Hypoxic subjects with coronavirus disease 2019 pneumonia were randomized 1:1 to receive standard of care plus IV immunoglobulin 0.5 g/kg/d with methylprednisolone 40 mg 30 minutes before infusion for 3 days versus standard of care alone. MAIN RESULTS: Sixteen subjects received IV immunoglobulin and 17 standard of care. Median ages were 51 and 58 years for standard of care and IV immunoglobulin, respectively. Acute Physiology and Chronic Health Evaluation II and Charlson comorbidity scores were similar for IV immunoglobulin and standard of care. Seven standard of care versus two IV immunoglobulin subjects required mechanical ventilation (p = 0.12, Fisher exact test). Among subjects with A-a gradient of greater than 200 mm Hg at enrollment, the IV immunoglobulin group showed: 1) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p = 0.038 Fisher exact test), 2) shorter median hospital length of stay (11 vs 19 d, p = 0.01 Mann Whitney U test), 3) shorter median ICU stay (2.5 vs 12.5 d, p = 0.006 Mann Whitey U test), and 4) greater improvement in Pao2/Fio2 at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44·5 [-115 to +157], p = 0.01, Mann Whitney U test) than standard of care. Pao2/Fio2 improvement at day 7 was significantly less for the standard of care patients who received glucocorticoid therapy than those in the IV immunoglobulin arm (p = 0.0057, Mann Whiney U test). CONCLUSIONS: This pilot study showed that IV immunoglobulin significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in coronavirus disease 2019 patients with A-a gradient greater than 200 mm Hg. A phase 3 multicenter randomized double-blinded clinical trial is under way to validate these findings.

19.
Int J Clin Pharmacol Ther ; 58(12): 678-686, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-902836

ABSTRACT

Although medication treatment in COVID-19 patients would have no direct effect on the spread of the disease, a shortening of the period of hospitalization by only a few days would release 25 - 30% of critical-care resources. However, there appears to be no well-established medication treatment available that can do this reliably at the present time. Anti-malarials currently being evaluated, i.e., chloroquine and hydroxychloroquine, are not yet established as effective medications, and antiviral agents, including remdesivir, are only weakly active. This position paper report is focused on the modulation of the cytokine storm since it appears to be a major cause of the multi-organ failure in COVID-19. Whereas corticosteroids are not recommended in patients not on mechanical ventilation, immunotherapy with convalescent plasma and intravenous immunoglobulin (IVIG) have been used with some success in COVID-19. There is emerging new evidence that polyvalent immunoglobulins (PVIG) from bovine colostrum given orally can also modulate the immune response. Research using lipopolysaccharide-stimulated peripheral blood mononuclear cells from colorectal cancer patients (a so called micro-cytokine storm) has shown that PVIG block the expression of pro-inflammatory cytokines and stimulate the expression of anti-inflammatory cytokines. We have been able to confirm these results in a similar model using mononuclear cells from healthy subjects and could demonstrate that the modulations produced by PVIG are quantitatively and qualitatively similar to those obtained using human immunoglobulin (IVIG). Both immunoglobulins reduce the lipopolysaccharide-induced increase in inflammatory cytokines, interleukin (IL-) 12/23p40 (-90%), IL-6 (-75%) and TNF-α (-60%) and increased the levels of the anti-inflammatory cytokine, IL-10 (+75%). Evidence is presented that PVIG can produce anti-inflammatory effects similar to these after oral application in patients. Its use is contraindicated in patients with lactose intolerance but is otherwise safe and free of complications in clinical studies including the treatment of infants with gastrointestinal disorders. Conclusion: PVIG appears to be a potential and safe anti-inflammatory agent and can be recommended as a candidate medication for studies in COVID-19 patients.


Subject(s)
Coronavirus Infections/therapy , Cytokine Release Syndrome/therapy , Pneumonia, Viral/therapy , Animals , Betacoronavirus , COVID-19 , Cattle , Cells, Cultured , Cytokine Release Syndrome/virology , Cytokines , Humans , Immunization, Passive , Immunoglobulins, Intravenous/therapeutic use , Leukocytes, Mononuclear , Pandemics , SARS-CoV-2
20.
Trials ; 21(1): 905, 2020 Nov 02.
Article in English | MEDLINE | ID: covidwho-901916

ABSTRACT

OBJECTIVES: The aim of this trial is to investigate the safety and clinical efficacy of passive immunization therapy through Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG: 5% liquid formulation), on severe and critically ill patients with COVID-19. TRIAL DESIGN: This is a phase I/II single centre, randomised controlled, single-blinded, superiority trial, through parallel-group design with sequential assignment. Participants will be randomised either to receive both C-IVIG and standard care or only standard care (4:1). PARTICIPANTS: The study is mono-centric with the participants including COVID19 infected individuals (positive SARS-CoV-2 PCR on nasopharyngeal and/or oropharyngeal swabs) admitted in institute affiliated with Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan. Consenting patients above 18 years that are classified by the treating physician as severely ill i.e. showing symptoms of COVID-19 pneumonia; dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93%, PaO2/FiO2 <300, and lung infiltrates >50% on CXR; or critically ill i.e. respiratory failure, septic shock, and multiple organ dysfunction or failure. Patients with reported IgA deficiency, autoimmune disorder, thromboembolic disorder, and allergic reaction to immunoglobulin treatment were excluded from study. Similarly, pregnant females, patients requiring two or more inotropic agents to maintain blood pressure and patients with acute or chronic kidney injury/failure, were also excluded from the study. INTERVENTION AND COMPARATOR: The study consists of four interventions and one comparator arm. All participants receive standard hospital care which includes airway support, anti-viral medication, antibiotics, fluid resuscitation, hemodynamic support, steroids, painkillers, and anti-pyretics. Randomised test patients will receive single dose of C-IVIG in following four dosage groups: Group 1: 0.15g/Kg with standard hospital care Group 2: 0.2g/Kg with standard hospital care Group 3: 0.25g/Kg with standard hospital care Group 4: 0.3g/Kg with standard hospital care Group 5 (comparator) will receive standard hospital care only MAIN OUTCOMES: The primary outcomes are assessment and follow-up of participants to observe 28-day mortality and, • the level and duration of assisted ventilation during hospital stay, • number of days to step down (shifting from ICU to isolation ward), • number of days to hospital discharge, • adverse events (Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)) during hospital stay, • change in C-Reactive Protein (CRP) levels, • change in neutrophil lymphocyte ratio to monitor inflammation. RANDOMISATION: Consenting participants who fulfill the criteria are allocated to either intervention or comparator arm with a ratio of 4:1, using sequentially numbered opaque sealed envelope simple randomization method. The participant allocated for intervention will be sequentially assigned dosage group 1-4 in ascending order. Participants will not be recruited in the next dosage group before a set number of participants in one group (10) are achieved. BLINDING (MASKING): Single blinded study, with participants blinded to allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Total 50 patients are randomised. The intervention arms consist of 40 participants divided in four groups of 10 participants while the comparator group consists of 10 patients. TRIAL STATUS: Current version of the protocol is "Version 2" dated 29th September, 2020. Participants are being recruited. Recruitment started on June, 2020 and is estimated to primarily end on January, 2021. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, NCT04521309 on 20 August 2020 and is retrospectively registered. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).


Subject(s)
Coronavirus Infections/therapy , Immunization, Passive/methods , Immunoglobulins, Intravenous , Pneumonia, Viral/therapy , Adult , Betacoronavirus/isolation & purification , COVID-19 , Critical Illness/therapy , Female , Humans , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/adverse effects , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Male , Pandemics , Randomized Controlled Trials as Topic , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
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