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.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. ...JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T‐cell (CAR‐T) therapy. We describe successful treatment of PML with Programmed death‐1 (PD‐1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel. Radiological features of immune reconstitution inflammatory syndrome without clinical deterioration were seen. Evidence of anti‐viral immune reconstitution by in vitro detection of JC‐specific T‐cells and sustained neurological recovery in this patient suggest PD‐1 blockade may be an effective treatment approach for PML post‐CAR‐T.
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.
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.
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).
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.
University College London Hospitals NHS Trust, University College London/University College London Hospitals NIHR Biomedical Research Centre, Engineering and Physical Sciences Research Council.
Cet article étudie la relation entre la vie professionnelle et la vie familiale en privilégiant une entrée par la profession afin de mettre en avant l’impact des spécificités de l’appartenance ...professionnelle sur la manière de vivre et de gérer cette relation et les tensions sous-jacentes. Pour ce faire, les auteurs prennent appui sur une enquête par questionnaire réalisée en Belgique francophone auprès de 314 infirmières-parents et de 284 policiers-parents. Ils montrent qu’au côté des différences entre les hommes et les femmes, l’appartenance professionnelle induit tendanciellement des ressentis et des modes d’atténuation de la tension en matière d’articulation de la vie professionnelle avec la vie familiale (APF) différents. Les différences observées permettent d’opposer au final deux grands modes de régulation de cette APF : l’un à caractère séquentiel dans le milieu infirmier ; l’autre à caractère intégratif dans le milieu policier.
Health-care workers (HCWs) are at high risk of developing COVID-19, and may themselves contribute to transmission.1 To evaluate these risks, we enrolled 200 patient-facing HCWs between March 26 and ...April 8, 2020, in SARS-CoV-2 Acquisition in Frontline Healthcare Workers—Evaluation to inform Response (SAFER), a prospective cohort study in high-risk frontline HCWs in an acute National Health Service hospital trust in London. Of the 42 HCWs that ever tested positive for SARS-CoV-2 by RT-PCR, 20 (48%) reported symptoms within 7 days of the positive test that were consistent with Public Health England's COVID-19 case definition,2 and 16 (38%) did not report any symptoms in the same time frame. CS is funded by a Royal Society Napier Professorship, the Rosetrees Trust, and the Breast Cancer Research Foundation; receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana, Boehringer Ingelheim, and Ono Pharmaceutical; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute; is a shareholder of Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options in and is co-founder of Achilles Therapeutics.
Summary
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.
Abstract
Background/Aims
Haemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory condition that is characterised by excessive macrophage activation in response to a wide range of ...triggers, including infections, rheumatological and haematological conditions. HLH is associated with high morbidity and mortality, and treatment requires significant immunosuppression. University College London Hospitals (UCLH) operates an HLH service; we were keen to understand the burden of infective complications in our cohort of patients and establish specific guidelines.
Methods
A retrospective descriptive analysis was performed of all adults with secondary HLH over a two-year time-frame (1stApril 2019 to 1st April 2021) at UCLH. UCLH has a designated HLH multi-disciplinary team (MDT) supported by rheumatology, infectious diseases, tropical medicine, virology, haematology and critical care. This work was registered as a service evaluation project by the Medical Specialities Division. Data was collated from electronic health records into REDCap, and processed in R version 1.4.1103 and Microsoft Excel by two independent authors.
Results
40 patients were identified, with a median age of 37. 14 patients had an identified haematological trigger (35%), 12 an infectious one (30%) and 5 a rheumatological (12.5%). 24 patients (60%) were admitted to intensive care and 13 died during admission (32.5%). 35 patients (87.5%) received steroids at some time during their admission, with 24 (60%) receiving a long course. Four patients (10%) had prolonged neutropaenia during admission. Twenty-four patients (60%) developed an infection during their admission; with 33 bacterial, 7 viral and 12 fungal infections (5 proven, 2 probable and 5 possible) identified. Sixteen patients had >1 infection. Those who did not have a diagnosed infection during their admission were more likely to survive than those who did (93% vs 44%, p = 0.047). The mortality rate of those with fungal infections was 89%, compared to 43% for bacterial and viral infections. Of the 24 patients who received a long course of steroids, 14 (58%) did not receive anti-fungal prophylaxis during their admission and three of these patients were diagnosed with fungal infections during their admission. Of the 4 patients with prolonged neutropenia, 1 (25%) did not receive antifungal prophylaxis and did suffer from a confirmed fungal infection. One patient with confirmed PCP had not previously been taking PCP prophylaxis. Of the seven patients with viral infections, 2 had HSV-1 infections and neither had received anti-viral prophylaxis before their infection start date.
Conclusion
We demonstrate that a high proportion of patients with HLH develop infective complications, which is associated with increased mortality. Prior to this analysis, the use of antimicrobial prophylaxis was variable. We have since written a specific guideline for the routine use of antimicrobial prophylaxis for patients with HLH, with a view to auditing future care against this guideline.
Disclosure
P. Saha: None. N. McCann: None. M. Brown: None. N. Stone: None. E. Sanchez: None. B. Carpenter: None. A. Laurence: None. M. Hutchinson: None. A. Jones: None. S.H. Gohil: None. J. Manson: None.
Abstract
Background/Aims
Haemophagocytic lymphohistiocytosis (HLH) is a devastating condition caused by uncontrolled activation of the immune system. If left untreated, the condition leads to ...multi-organ failure and death. Even with treatment, recent UK data has shown a mortality rate of 50%. In 2019, a group of clinicians from University College London Hospital (UCLH) came together with the aim of improving outcomes for patients with HLH. The UCLH HLH multi-disciplinary meeting (MDM) has been running since that time and includes representation from rheumatology, haematology, infectious diseases, tropical medicine, virology, neurology, and critical care. Clinicians from any UK trust are invited to join and present patients. As part of a service evaluation project, we aimed to assess the scope of this meeting with regards to the number, demographics and primary diagnoses of patients discussed and the geographical location of the referring clinical team.
Methods
This is a retrospective descriptive analysis of all patients discussed at the UCLH HLH MDT from 2nd September 2020 to 20th July 2022. Data were obtained from electronic health records and analysed in Prism version 9.4.1. This work has been registered as a service evaluation project within the Division of Medical Specialities at UCLH.
Results
93 patients were discussed. 38 were female. 55 were male. The median age was 38 years. Triggers for HLH were haematological malignancy (38.0%), infection (29.3%) rheumatological (14.1%) primary HLH (6.5%) and unknown (7.6%). In 4 patients, HLH was not felt to be the underlying diagnosis. 40 patients were managed as inpatients at UCLH, 37 of whom were transferred from other trusts. Geographical data were obtained on 81 patients. Patients were referred from all 9 regions of England: London (34), North East (1), North West (2), Yorkshire (2), East Midlands (1), West Midlands (3) South East (11), East of England (11), South West (11) as well as Wales (2), Scotland (2) and Ireland (1). Haemophagocytosis was confirmed on bone marrow biopsy in 66.7% of patients. Mortality data showed that 32 (34%) patients died following their diagnosis.
Conclusion
A multi-disciplinary approach is essential in the management of HLH. Our data show that patients with HLH are young, have a high mortality and broad range of pathology. The UCLH HLH MDT currently serves a wide geographical area across the UK and UCLH acts as a tertiary referral centre for patients with the condition.
Disclosure
N.S. Shah: None. M. Hutchinson: None. S. Clark: None. E. Sanchez: None. M. Brown: None. N. Stone: None. A.S. Carr: None. B. Carpenter: None. A. Laurence: None. S.H. Gohil: None. R.S. Tattersall: None. J.J. Manson: None. A. Jones: None.
PDF
