Response to COVID-19 booster vaccinations in seronegative people with MS.

BackgroundUncertainties remain about the benefit of a 3rd COVID-19 vaccine for people with attenuated response to earlier vaccines. This is of particular relevance for people with multiple sclerosis (pwMS) treated with anti-CD20 therapies and fingolimod, who have substantially reduced antibody responses to initial vaccine course. MethodsPwMS taking part in a seroprevalence study without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/-venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. The relationship between evidence of prior COVID-19 infection and immune response to COVID-19 vaccine 3 was evaluated using Fishers exact test. ResultsOf 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There no association between laboratory evidence of prior COVID-19 infection and anti-spike seroconversion following COVID-19 vaccine 3. ConclusionsApproximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine. Key messagesO_ST_ABSWhat is already knownC_ST_ABSThe benefits of COVID vaccination are well described. It is unknown whether there is additional benefit afforded from a third COVID-19 vaccination in those people who have failed to mount a serological response to their initial vaccine course. What this study addsApproximately one third of people with MS in our study, all of whom had failed to response to initial vaccine course, developed anti-spike antibodies following a third COVID-19 vaccine. Two-thirds of participants had T cell response to vaccination. No people taking fingolimod appeared to mount a T cell response to vaccination. How this study might influence practiceThese findings highlight potential benefits of booster vaccinations to a substantial proportion of immunosuppressed people who have failed to respond to initial vaccination course. The clinical correlates of antibody and T-cell responses to COVID-19 remain uncertain but they are almost certainly associated with milder subsequent disease in the general population.

Mechanically ventilated patients shed high titre live SARS-CoV2 for extended periods from both the upper and lower respiratory tract

BackgroundSARS-CoV-2 infection can lead to severe acute respiratory distress syndrome needing intensive care admission and may lead to death. As a virus that transmits by respiratory droplets and aerosols, determining the duration of viable virus shedding from the respiratory tract is critical for patient prognosis, and informs infection control measures both within healthcare settings and the public domain. MethodsWe examined upper and lower airway respiratory secretions for both viral RNA and infectious virions in mechanically ventilated patients admitted to the intensive care unit of the University Hospital of Wales. Samples were taken from the oral cavity (saliva), oropharynx (sub-glottic aspirate), or lower respiratory tract (non-directed bronchoalveolar lavage (NBL) or bronchoalveolar lavage (BAL)) and analyzed by both qPCR and plaque assay. Results117 samples were obtained from 25 patients. qPCR showed extremely high rates of positivity across all sample types, however live virus was far more common in saliva (68%) than in BAL/NBAL (32%). Average titres of live virus were higher in subglottic aspirates (4.5x107) than in saliva (2.2x106) or BAL/NBAL (8.5x106), and reached >108 PFU/ml in some samples. The longest duration of shedding was 98 days, while the majority of patients (14/25) shed live virus for 20 days or longer. ConclusionsIntensive care unit patients infected with SARS-CoV-2 can shed high titres of virus both in the upper and lower respiratory tract, and tend to be prolonged shedders. This information is important for decision making around cohorting patients, de-escalation of PPE, and undertaking potential aerosol generating procedures. SummaryPatients on intensive therapy infected with SARS-CoV-2 tend to be prolonged shedders, excreting virus for far beyond the time periods specified in current guidelines, and live virus titres can be extremely high in both the upper and lower respiratory tracts.

COVID-19 vaccine response in people with multiple sclerosis

ObjectiveTo investigate the effect of disease modifying therapies on serological response to SARS-CoV2 vaccines in people with multiple sclerosis Methods473 people with multiple sclerosis from 5 centres provided one or more dried blood spot samples and questionnaires about COVID-19. Information about disease and drug history was extracted from their medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV2 receptor binding domain. Seropositivity was expressed according to validated cut-off indices. Antibody titers were partitioned into tertiles using data from people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (Univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following SARS-CoV2 vaccine according to disease modifying therapy. We used regression modelling to explore the effect of factors including vaccine timing, treatment duration, age, vaccine type and lymphocyte count on vaccine response. ResultsCompared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio 0.03; 95% confidence interval 0.01-0.06, p<0.001) and fingolimod (odds ratio 0.41; 95% confidence interval 0.01-0.12) were associated with lower seroconversion following SARS-CoV2 vaccine. All other drug groups did not differ significantly from the untreated cohort. Time since last anti-CD20 treatment and total time on treatment were significantly related with response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. InterpretationSome disease modifying therapies carry a risk of attenuated response to SARS-CoV2 vaccination in people with MS. We provide recommendations for the practical management of this patient group.

A systematic review and meta-analysis of inpatient mortality associated with nosocomial and community COVID-19 exposes the vulnerability of immunosuppressed adults

BackgroundLittle is known about the mortality of hospital-acquired (nosocomial) COVID-19 infection globally. We investigated the risk of mortality and critical care admission in hospitalised adults with nosocomial COVID-19, relative to adults requiring hospitalisation due to community-acquired infection. MethodsWe systematically reviewed the peer-reviewed and pre-print literature from 1/1/2020 to 9/2/2021 without language restriction for studies reporting outcomes of nosocomial and community-acquired COVID-19. We performed a random effects meta-analysis (MA) to estimate the 1) relative risk of death and 2) critical care admission, stratifying studies by patient cohort characteristics and nosocomial case definition. Results21 studies were included in the primary MA, describing 8,246 admissions across 8 countries during the first wave, comprising 1517 probable or definite nosocomial COVID-19, and 6729 community-acquired cases. Across all studies, the risk of mortality was 1.31 times greater in patients with nosocomial infection, compared to community-acquired (95% CI: 1.01 to 1.70). Rates of critical care admission were similar between groups (Relative Risk, RR=0.74, 95% CI: 0.50 to 1.08). Immunosuppressed patients diagnosed with nosocomial COVID-19 were twice as likely to die in hospital as those admitted with community-acquired infection (RR=2.14, 95% CI: 1.76 to 2.61). ConclusionsAdults who acquire SARS-CoV-2 whilst already hospitalised are at greater risk of mortality compared to patients admitted following community-acquired infection; this finding is largely driven by a substantially increased risk of death in individuals with malignancy or who had undergone transplantation. These findings inform public health and infection control policy, and argue for individualised clinical interventions to combat the threat of nosocomial COVID-19, particularly for immunosuppressed groups. Systematic review registration: PROSPERO CRD42021249023

Fatigue symptoms associated with COVID-19 in convalescent or recovered COVID-19 patients; a systematic review and meta-analysis

BackgroundThe prevalence and prognosis of post-acute stage SARS-CoV-2 infection fatigue symptoms remain largely unknown. AimsWe performed a systematic review to evaluate the prevalence of fatigue in post-recovery from SARS-CoV-2 infection. MethodMedline, Embase, PsycINFO, CINAHL, Web of Science, Scopus, trial registries, Cochrane Central Register of Controlled Trials and Google Scholar were searched for studies on fatigue in samples that recovered from PCR diagnosed COVID-19. English, French and Spanish studies were included. Meta-analyses were conducted separately for each recruitment setting. ResultsWe identified 41 studies with 9362 patients that recovered from COVID-19. Post-COVID-19 patients self-report of fatigue was higher compared to healthy controls (RR = 3.688, 95%CI [2.502, 5.436], p < 0.001). Over 50% of patients discharged from inpatient care reported symptoms of fatigue during the first (ER = 0.517, 95%CI [0.278, 0.749]) and second month following recovery (ER = 0.527, 95%CI [0.337, 0.709]). 10% of the community patients reported fatigue in the first-month post-recovery. Patient setting moderated the association between COVID-19 recovery and fatigue symptoms (R2 = 0.11, p < 0.001). Female patients recovering from COVID-19 had a greater self-report of fatigue (OR = 1.782, 95%CI [1.531, 2.870]). Patients recruited through social media had fatigue above 90% across multiple time points. Fatigue was highest in studies from Europe. ConclusionFatigue is a symptom associated with functional challenges which could have economic and social impacts. Developing long-term planning for fatigue management amongst patients beyond the acute stages of SARS-CoV-2 infection is essential to optimizing patient care and public health outcomes. Further studies should examine the impact of sociodemographic, pandemic-related restrictions and pre-existing conditions on fatigue.

The burden of nosocomial covid-19: results from the Wales multi-centre retrospective observational study of 2518 hospitalised adults.

ObjectivesTo define the burden of nosocomial (hospital-acquired) novel pandemic coronavirus (covid-19) infection among adults hospitalised across Wales. DesignRetrospective observational study of adult patients with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection between 1st March - 1st July 2020 with a recorded hospital admission within the subsequent 31 days. Outcomes were collected up to 20th November using a standardised online data collection tool. SettingService evaluation performed across 18 secondary or tertiary care hospitals. Participants4112 admissions with a positive SARS-CoV-2 PCR result between 1st March to 1st July 2020 were screened. Anonymised data from 2518 participants were returned, representing over 60% of adults hospitalised across the nation of Wales. Main outcome measuresThe prevalence and outcomes (death, discharge) for nosocomial covid-19, assessed across of a range of possible case definitions. ResultsInpatient mortality rates for nosocomial covid-19 ranged from 38% to 42% and remained consistently higher than participants with community-acquired infection (31% to 35%) across a range of case definitions. Participants with nosocomial-acquired infection were an older, frailer, and multi-morbid population than those with community-acquired infection. Based on the Public Health Wales case definition, 50% of participants had been admitted for 30 days prior to diagnostic testing. ConclusionsThis represents the largest assessment of clinical outcomes for patients with nosocomial covid-19 in the UK to date. These findings suggest that inpatient mortality rates from nosocomial-infection are likely higher than previously reported, emphasizing the importance of infection control measures, and supports prioritisation of vaccination for covid-19 negative admissions and trials of post-exposure prophylaxis in inpatient cohorts. Trial registrationThis project was approved and sponsored by the Welsh Government, as part of a national audit and quality improvement scheme for patients hospitalised covid-19 across Wales. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSWe searched PubMed and ISI Web of Science up until 31-December-2020 for studies reporting on patient outcomes following hospital-acquired infection due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We identified a range of case-definitions for hospital-acquired infection, based on timing of diagnostic testing 5 to 15 days following admission. The largest and only multi-centre study concluded individuals with nosocomial infection are at a lower risk of death from SARS-CoV-2 than those infected in the community, however, was performed early in the pandemic and utilised a conservative definition of nosocomial infection. What this study addsOur multi-centre observational study represents the largest assessment of clinical outcomes for patients with nosocomial covid-19 in the UK to date, and suggests the burden of nosocomial SARS-CoV-2 infection has been underestimated. Nosocomial-infection occurred in older, frailer, and multi-morbid individuals, and was consistently associated with greater inpatient mortality than amongst those who were infected in the community across a spectrum of case-definitions. Our findings support implementation of enhanced infection control measures to reduce this burden during future waves, especially given the recent emergence of novel viral variants with enhanced transmissibility. Furthermore, roughly half of the patients meeting the Public Health Wales definition of definite nosocomial SARS-CoV-2 infection had been admitted for 30 days prior to diagnosis, highlighting a potential window of opportunity for inpatient pre-exposure and/or post-exposure prophylaxis.

Extended laboratory panel testing in the Emergency Department for risk-stratification of patients with COVID-19: a single centre retrospective service evaluation

BackgroundThe role of specific blood tests to predict poor prognosis in patients admitted with infection from SARS-CoV2 virus remains uncertain. During the first wave of the global pandemic, an extended laboratory testing panel was integrated into the local pathway to guide triage and healthcare resource utilisation for emergency admissions. We conducted a retrospective service evaluation to determine the utility of extended tests (D-dimer, ferritin, high-sensitivity troponin I, lactate dehydrogenase, procalcitonin) compared to the core panel (full blood count, urea & electrolytes, liver function tests, C-reactive protein). MethodsClinical outcomes for adult patients with laboratory-confirmed COVID-19 admitted between 17th March to 30st June 2020 were extracted, alongside costs estimates for individual tests. Prognostic performance was assessed using multivariable logistic regression analysis with 28-day mortality used as the primary endpoint, and a composite of 28-day intensive care escalation or mortality for secondary analysis. ResultsFrom 13,500 emergency attendances we identified 391 unique adults admitted with COVID-19. Of these, 113 died (29%) and 151 (39%) reached the composite endpoint. "Core" test variables adjusted for age, gender and index of deprivation had a prognostic AUC of 0.79 (95% Confidence Interval, CI: 0.67 to 0.91) for mortality and 0.70 (95% CI: 0.56 to 0.84) for the composite endpoint. Addition of "extended" test components did not improve upon this. ConclusionOur findings suggest use of the extended laboratory testing panel to risk stratify community-acquired COVID-19-positive patients on admission adds limited prognostic value. We suggest laboratory requesting should be targeted to patients with specific clinical indications.

Detection of antibodies to the SARS-CoV-2 spike glycoprotein in both serum and saliva enhances detection of infection

BackgroundDetecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. MethodsWe systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects. ResultsUsing trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting. ConclusionsDetecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection. FundingThis work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.