How much did the Covid-19 shielding policy cost in Wales? A Retrospective Cost analysis within the EVITE Immunity study (preprint)

Background: The EVITE Immunity study investigates the effects of shielding Clinically Extremely Vulnerable (CEV) people during the COVID-19 pandemic on health outcomes and healthcare costs in Wales, UK, to help prepare for future pandemics. Shielding was intended to protect those at highest risk of serious harm from COVID-19. We report the cost of implementing shielding in Wales. Methods: The number of people shielding was extracted from the Secure Anonymised Information Linkage Databank. Resources supporting shielding between March and June 2020 were mapped using published reports, web pages, freedom of information requests to Welsh Government and personal communications (e.g. the office of the Chief Medical Officer for Wales). Results: At the beginning of shielding, 117,415 people were on the shielding list. The total additional cost to support those advised to stay home during the initial 14 weeks of the pandemic was £13,307,654 (£113 per person shielded). This included the new resources required to compile the shielding list, inform CEV people of the shielding intervention and provide medicine and food deliveries. The list was adjusted weekly over the 3-month period (130,000 people identified by June 2020) therefore the cost per person shielded lies between £102 and £113. Conclusion: This is the first evaluation of the cost of the measures put in place to support those identified to shield in Wales. However, no data on opportunity cost was available. The true cost of shielding including its budget impact and opportunity costs need to be investigated to decide whether shielding is a worthwhile policy for future health emergencies.

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

Importance: Uncertainties 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. Objective: To report humoral and T-cell responses following COVID-19 vaccine 3 in pwMS who were seronegative after COVID-19 vaccines 1&2. Design, setting and participants: PwMS 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. Data on demographics, MS treatment, and COVID-19 infection/vaccine dates were derived from the medical notes. Methods: 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. Results: Of 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. Conclusions: Approximately 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.

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

Background SARS-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. Methods We 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. Results 117 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 (4.5x10^7) than in saliva (2.2x10^6) or BAL/NBAL (8.5x10^6), and reached >10^8 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. Conclusions Intensive 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.

Outcomes Following SARS-CoV-2 Infection in Patients With Primary and Secondary Immunodeficiency in The United Kingdom (preprint)

Purpose: To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

COVID-19 vaccine response in people with multiple sclerosis (preprint)

Objective: To investigate the effect of disease modifying therapies on serological response to SARS-CoV2 vaccines in people with multiple sclerosis Methods: 473 people with multiple sclerosis from 5 centres provided one or more dried blood spot samples and a questionnaire about COVID-19 and vaccine history. 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. Results: Compared 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. Both time since last anti-CD20 treatment and total time on treatment were significantly related with serological response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Interpretation: Some 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 (preprint)

Background: Little 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. Methods: We 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. Results: 21 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). Conclusions: Adults 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 (preprint)

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. Results We 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.

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

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. (preprint)

Objectives: To define the burden of nosocomial (hospital-acquired) novel pandemic coronavirus (covid-19) infection among adults hospitalised across Wales. Design: Retrospective observational study of adult patients with polymerase chain reaction (PCR) confirmed SARS-CoV-2 infection between 1st March to 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. Setting: Service evaluation performed across 18 secondary or tertiary care hospitals. Participants: 4112 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 measures: The prevalence and outcomes (death, discharge) for nosocomial covid19, assessed across of a range of possible case definitions. Results: Inpatient mortality rates for nosocomial covid19 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. Conclusions: This 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 registration: This 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.

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

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 (preprint)

Background: Detecting 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. Methods: We systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects. Results: Using 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. Conclusions. Detecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection. Funding. This 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.