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Lancet Infect Dis ; 21(9): 1246-1256, 2021 09.
Article in English | MEDLINE | ID: covidwho-1180123


BACKGROUND: Emergence of variants with specific mutations in key epitopes in the spike protein of SARS-CoV-2 raises concerns pertinent to mass vaccination campaigns and use of monoclonal antibodies. We aimed to describe the emergence of the B.1.1.7 variant of concern (VOC), including virological characteristics and clinical severity in contemporaneous patients with and without the variant. METHODS: In this cohort study, samples positive for SARS-CoV-2 on PCR that were collected from Nov 9, 2020, for patients acutely admitted to one of two hospitals on or before Dec 20, 2020, in London, UK, were sequenced and analysed for the presence of VOC-defining mutations. We fitted Poisson regression models to investigate the association between B.1.1.7 infection and severe disease (defined as point 6 or higher on the WHO ordinal scale within 14 days of symptoms or positive test) and death within 28 days of a positive test and did supplementary genomic analyses in a cohort of chronically shedding patients and in a cohort of remdesivir-treated patients. Viral load was compared by proxy, using PCR cycle threshold values and sequencing read depths. FINDINGS: Of 496 patients with samples positive for SARS-CoV-2 on PCR and who met inclusion criteria, 341 had samples that could be sequenced. 198 (58%) of 341 had B.1.1.7 infection and 143 (42%) had non-B.1.1.7 infection. We found no evidence of an association between severe disease and death and lineage (B.1.1.7 vs non-B.1.1.7) in unadjusted analyses (prevalence ratio [PR] 0·97 [95% CI 0·72-1·31]), or in analyses adjusted for hospital, sex, age, comorbidities, and ethnicity (adjusted PR 1·02 [0·76-1·38]). We detected no B.1.1.7 VOC-defining mutations in 123 chronically shedding immunocompromised patients or in 32 remdesivir-treated patients. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value (mean 28·8 [SD 4·7] vs 32·0 [4·8]; p=0·0085) and genomic read depth (1280 [1004] vs 831 [682]; p=0·0011). INTERPRETATION: Emerging evidence exists of increased transmissibility of B.1.1.7, and we found increased virus load by proxy for B.1.1.7 in our data. We did not identify an association of the variant with severe disease in this hospitalised cohort. FUNDING: University College London Hospitals NHS Trust, University College London/University College London Hospitals NIHR Biomedical Research Centre, Engineering and Physical Sciences Research Council.

COVID-19/virology , Genome, Viral , SARS-CoV-2/genetics , Severity of Illness Index , Whole Genome Sequencing , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , London , Male , Middle Aged , Phylogeny , United Kingdom , Viral Load , Virus Shedding
Br J Haematol ; 191(2): 194-206, 2020 10.
Article in English | MEDLINE | ID: covidwho-966626


Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.

Antineoplastic Agents/therapeutic use , COVID-19/complications , Hematologic Diseases/complications , Immunotherapy , Adult , Age Factors , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Black People , COVID-19/mortality , COVID-19/therapy , Comorbidity , Cross Infection/complications , Female , Hematologic Diseases/drug therapy , Hematologic Diseases/mortality , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation , Humans , Leukemia/complications , Leukemia/drug therapy , Leukemia/mortality , London/epidemiology , Lymphoma/complications , Lymphoma/drug therapy , Lymphoma/mortality , Male , Middle Aged , Respiration, Artificial , Retrospective Studies , Risk Factors , SARS-CoV-2 , Thrombophilia/drug therapy , Thrombophilia/etiology , Treatment Outcome , Young Adult
Science ; 370(6522): 1339-1343, 2020 12 11.
Article in English | MEDLINE | ID: covidwho-913669


Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

Antibodies, Viral/blood , COVID-19/immunology , Immunity, Humoral , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Animals , COVID-19/blood , Epitope Mapping , Female , HEK293 Cells , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Viral Zoonoses/blood , Viral Zoonoses/immunology , Young Adult