Real-life experience with remdesivir for treatment of COVID-19 among older adults: a multicentre retrospective study.

INTRODUCTION: The effect of remdesivir on COVID-19 mortality remains conflicting. Elderly individuals are at risk for poor COVID-19 outcomes. We aimed to assess the effect of remdesivir on COVID-19 mortality among elderly individuals, using real-world data. METHODS: Retrospective multinational cohort of individuals aged ≥65 years, hospitalized with COVID-19 in six medical centres between January 2020 and May 2021. Associations with in-hospital mortality were evaluated using a multivariable logistic regression model with propensity score adjustment for remdesivir therapy and while implementing generalized estimating equations to control for centre effect. Sensitivity analysis was performed by stratification according to the degree of respiratory support. RESULTS: Of 3010 individuals included, 2788 individuals required either oxygen supplementation or non-invasive/invasive mechanical ventilation, 489 (16%) were treated with remdesivir, and 836 (28%) died. Median age was 77 (IQR 70-84) years and 42% were women. Remdesivir was the only therapeutic intervention associated with decreased mortality [adjusted OR (aOR) 0.49, 95% CI 0.37-0.66, P < 0.001]. This protective effect was shown for individuals requiring oxygen support and non-invasive mechanical ventilation, while no association was found among individuals necessitating invasive mechanical ventilation.Risk factors for mortality included invasive ventilation (aOR 5.18, 95% CI 2.46-10.91, P < 0.001), higher serum creatinine (aOR 1.25, 95% CI 1.09-1.43, P = 0.001) and dyspnoea (aOR 1.40, 95% CI 1.07-1.84, P = 0.015) on presentation, and other non-modifiable factors, such as comorbidities. CONCLUSIONS: Among elderly individuals hospitalized with COVID-19, remdesivir carries survival benefit for those with moderate to severe disease. Its role among individuals with critical illness should be further assessed.

Exclusion of older adults and immunocompromised individuals in influenza, pneumococcal and COVID-19 vaccine trials before and after the COVID-19 pandemic.

BACKGROUND: Older adults and immunocompromised individulas are often excluded from vaccine trials. AIM: We hypothesised that during the coronavirus disease 2019 (COVID-19) pandemic, the proportion of trials excluding these patients decreased. METHODS: Using the US Food and Drug Administration and and European Medicines Agency search engines, we identified all vaccines approved against pneumococcal disease, influenza (quadrivalent vaccines), and COVID-19 from 2011 to 2021. Study protocols were screened for direct and indirect age exclusion criteria and exclusion of immunocompromised individuals. In addition, we reviewed the studies with no explicit exclusion criteria and investigated the actual inclusion of those individuals. RESULTS: We identified 2024 trial records; 1702 were excluded (e.g., use of other vaccine or risk group); and 322 studies were eligible for our review. Among the pneumococcal and influenza vaccine trials (n = 193), 81 (42%) had an explicit direct age exclusion, and 150 (78%) had an indirect age-related exclusion. In total, 163 trials (84%) trials were likely to exclude older adults. Among the COVID-19 vaccine trials (n = 129), 33 (26%) had direct age exclusion and 82 (64%) had indirect age exclusion; in total, 85 (66%) trials were likely to exclude older adults. Therefore was a 18% decrease in the proportion of trials with age-related exclusion between 2011 and 2021 (only influenza and pneumococcal vaccine trials) and 2020-2021 (only COVID-19 vaccine trials) (p = 0.014). In a sub-analysis assessing observational and randomised trials, the decrease was 25% and 9%, respectively. Immunocompromised individuals were included in 87 (45%) of the pneumococcal and influenza vaccine trials compared with 54 (42%) of the COVID-19 vaccine trials (p = 0.058). CONCLUSIONS: During the COVID-19 pandemic, we found a decrease in the exclusion of older adults from vaccine trials but no significant change in the inclusion of immunocompromised individulas.

Assessment of Exercise Capacity of Individuals with Long COVID: A Cross-sectional Study.

BACKGROUND: Clinical investigations of long-term effects of coronavirus disease 2019 (COVID-19) are rarely translated to objective findings. OBJECTIVES: To assess the functional capacity of individuals reported on deconditioning that hampered their return to their pre-COVID routine. METHODS: Assessment included the 6-minute walk test (6MWT) and the 30-second sit-to-stand test (30-STST). We compared the expected and observed scores using the Wilcoxon signed-rank test. Predictors of test scores were identified using linear regression models. RESULTS: We included 49 individuals, of whom 38 (77.6%) were recovering from mild COVID-19. Twenty-seven (55.1%) individuals had a 6MWT score lower than 80% of expected. The average 6MWT scores were 129.5 ± 121.2 meters and 12.2 ± 5.0 repeats lower than expected scores, respectively (P < 0.001 for both). The 6MWT score was 107.3 meters lower for individuals with severe COVID-19 (P = 0.013) and rose by 2.7 meters per each 1% increase in the diffusing capacity of carbon monoxide (P = 0.007). The 30-STST score was 3.0 repeats lower for individuals who reported moderate to severe myalgia (P = 0.038). CONCLUSIONS: Individuals with long COVID who report on deconditioning exhibit significantly decreased physical capacity, even following mild acute illness. Risk factors include severe COVID-19 and impaired diffusing capacity or myalgia during recovery.

Predictors of survival in elderly patients with coronavirus disease 2019 admitted to the hospital: derivation and validation of the FLAMINCOV score.

OBJECTIVE: To identify predictors of 30-day survival in elderly patients with coronavirus disease 2019 (COVID-19). METHODS: Retrospective cohort study including patients with COVID-19 aged ≥65 years hospitalized in six European sites (January 2020 to May 2021). Data on demographics, comorbidities, clinical characteristics, and outcomes were collected. A predictive score (FLAMINCOV) was developed using logistic regression. Regression coefficients were used to calculate the score. External validation was performed in a cohort including elderly patients from a major COVID-19 centre in Israel. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in the derivation and validation cohorts. Survival risk groups based on the score were derived and applied to the validation cohort. RESULTS: Among 3010 patients included in the derivation cohort, 30-day survival was 74.5% (2242/3010). The intensive care unit admission rate was 7.6% (228/3010). The model predicting survival included independent functional status (OR, 4.87; 95% CI, 3.93-6.03), a oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio of >235 (OR, 3.75; 95% CI, 3.04-4.63), a C-reactive protein level of <14 mg/dL (OR, 2.41; 95% CI, 1.91-3.04), a creatinine level of <1.3 (OR, 2.02; 95% CI, 1.62-2.52) mg/dL, and absence of fever (OR, 1.34; 95% CI, 1.09-1.66). The score was validated in 1174 patients. The FLAMINCOV score ranges from 0 to 15 and showed good discrimination in the derivation (AUC, 0.79; 95% CI, 0.77-0.81; p < 0.001) and validation cohorts (AUC, 0.79; 95% CI, 0.76-0.81; p < 0.001). Thirty-day survival ranged from 39.4% (203/515) to 95.3% (634/665) across four risk groups according to score quartiles in the derivation cohort. Similar proportions were observed in the validation set. DISCUSSION: The FLAMINCOV score identifying elderly with higher or lower chances of survival may allow better triage and management, including intensive care unit admission/exclusion.

Risk Factors and Multidimensional Assessment of Long Coronavirus Disease Fatigue: A Nested Case-Control Study.

BACKGROUND: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology. METHODS: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue. RESULTS: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P = .038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P = .036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR: .79 per 10 beats/minute; 95% CI: .65-.96; P = .019) and long-COVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P = .003). CONCLUSIONS: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04851561.

Characteristics of long COVID among older adults: a cross-sectional study.

OBJECTIVE: To describe long-COVID symptoms among older adults, and to assess risk factors for two common long-COVID symptoms: fatigue and dyspnea. METHODS: Multicenter prospective cohort study, conducted in Israel, Switzerland, Spain, and Italy. Included were individuals at least 30 days since COVID-19 diagnosis. We compared long-COVID symptoms between elderly individuals (age>65 years) and younger population (18-65 years); and conducted univariate and multivariable analyses for predictors of long-COVID fatigue and dyspnea. RESULTS: 2333 individuals were evaluated at an average of 5 months [146 days (95% CI 142-150)] following COVID-19 onset. Mean age was 51 and 20.5% were>65 years. Older adults were more likely to be symptomatic, with most common symptoms being fatigue (38%) and dyspnea (30%). They were more likely to complain of cough and arthralgia, and have abnormal chest imaging and pulmonary function tests. Independent risk factors for long-COVID fatigue and dyspnea included female gender, obesity, and closer proximity to COVID-19 diagnosis; older age was not an independent predictor. CONCLUSIONS: Older individuals with long-COVID, have different persisting symptoms, with more pronounced pulmonary impairment. Women and individuals with obesity are at risk. Further research is warranted to investigate the natural history of long-COVID among the elderly population and to assess possible interventions aimed at promoting rehabilitation and well-being.

BNT162b2 vaccine effectiveness in chronic kidney disease patients-an observational study.

Background: Chronic kidney disease (CKD) is a risk factor for severe coronavirus disease 2019 (COVID-19). We aimed to evaluate the real-life effectiveness of the BNT162b2 messenger RNA vaccine for a range of outcomes in patients with CKD compared with matched controls. Methods: Data from Israel's largest healthcare organization were retrospectively used. Vaccinated CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2] and maintenance dialysis patients were matched to vaccinated controls without CKD (eGFR ≥60 ml/min/1.73 m2) according to demographic and clinical characteristics. Study outcomes included documented infection with severe acute respiratory syndrome coronavirus 2, symptomatic infection, COVID-19-related hospitalization, severe disease and death. Vaccine effectiveness was estimated as the risk ratio (RR) at days 7-28 following the second vaccine dose, using the Kaplan-Meier estimator. Effectiveness measures were also evaluated separately for various stages of CKD. Results: There were 67 861 CKD patients not treated with dialysis, 2606 hemodialysis (HD) patients and 70 467 matched controls. The risk of severe disease {RR 1.84 [95% confidence interval (CI) 0.95-2.67]} and death [RR 2.00 (95% CI 0.99-5.20)] was increased in nondialysis CKD patients compared with controls without CKD following vaccination. For the subgroup of patients with eGFR <30 ml/min/1.73 m2, the risk of severe disease and death was increased compared with controls [RR 6.42 (95% CI 1.85-17.51) and RR 8.81 (95% CI 1.63-13.81), respectively]. The risks for all study outcomes were increased in HD patients compared with controls. Conclusion: Two doses of the BNT162b2 vaccine were found to be less efficient for patients with eGFR <30 ml/min/1.73 m2. Risk in HD patients is increased for all outcomes. These results suggest prioritizing patients with eGFR <30 ml/min/1.73 m2 for booster shots, pre- and post-exposure prophylaxis and early COVID-19 therapy.

BNT162b2 vaccine effectiveness in chronic kidney disease patients – an observational study

Background chronic kidney disease (CKD) is a risk factor for severe COVID-19. We aimed to evaluate real-life effectiveness of the BNT162b2 mRNA vaccine for a range of outcomes in patients with CKD compared to matched controls. Methods Data from Israel's largest healthcare organization were retrospectively used. Vaccinated CKD (eGFR<60ml/min/1.73m2) and maintenance dialysis patients were matched to vaccinated controls without CKD (eGFR> = 60ml/min/1.73m2) according to demographic and clinical characteristics. Study outcomes included documented infection with SARS-CoV-2, symptomatic infection, COVID-19 related hospitalization, severe disease, and death. Vaccine effectiveness was estimated as the risk ratio [RR] at days 7-28 following the second vaccine dose, using the Kaplan–Meier estimator. Effectiveness measures were also evaluated separately for various stages of CKD. Results There were 67,861 CKD patients not treated with dialysis, 2,606 hemodialysis patients, and 70,467 matched controls. The risk of sever disease (RR1.84, 95% CI 0.95-2.67) and death (RR 2.00, 95% CI 0.99-5.20) was increased in non-dialysis CKD patients compared with controls without CKD following vaccination. For the subgroup of patients with eGFR below 30 ml/min/1.73m2, the risk of severe disease and death was increased compared to controls (RR 6.42, 95% CI 1.85-17.51 and RR 8.81, 95% CI 1.63-13.81, respectively). The risks for all study outcomes was increased in hemodialysis patients, compared with controls. Conclusion Two doses of the BNT162b2 vaccine were found less efficient for patients with eGFR<30ml/min/1.73m2. Risk in hemodialysis patients is increased for all outcomes. These results suggest prioritizing patients with eGFR<30ml/min/1.73m2 for booster shots, pre and post exposure prophylaxis, and early COVID-19 therapy. Graphical Graphical

Immunosuppression reduction when administering a booster dose of the BNT162b2 mRNA SARS-CoV-2 vaccine in kidney transplant recipients without adequate humoral response following two vaccine doses: protocol for a randomised controlled trial (BECAME study)

IntroductionInadequate antibody response to mRNA SARS-CoV-2 vaccination has been described among kidney transplant recipients. Immunosuppression level and specifically, use of antimetabolite in the maintenance immunosuppressive regimen, are associated with inadequate response. In light of the severe consequences of COVID-19 in solid organ transplant recipients, we believe it is justified to examine new vaccination strategies in these patients.Methods and analysisBECAME is a single-centre, open-label, investigator-initiated randomised controlled, superiority trial, aiming to compare immunosuppression reduction combined with a third BNT162b2 vaccine dose versus third dose alone. The primary outcome will be seropositivity rate against SARS-CoV-2. A sample size of 154 patients was calculated for the seropositivity endpoint assuming 25% seropositivity in the control group and 50% in the intervention group. A sample of participants per arm will be also tested for T-cell response. We also plan to perform a prospective observational study, evaluating seropositivity among ~350 kidney transplant recipients consenting to receive a third vaccine dose, who are not eligible for the randomised controlled trial.Ethics and disseminationThe trial is approved by local ethics committee of Rabin Medical Center (RMC-0192-21). All participants will be required to provide written informed consent. Results of this trial will be published;trial data will be available. Protocol amendments will be submitted to the local ethics committee.Trail registration numberNCT04961229.

Immune Response to Third Dose BNT162b2 COVID-19 Vaccine Among Kidney Transplant Recipients-A Prospective Study.

Immune response to two SARS-CoV-2 mRNA vaccine doses among kidney transplant recipients (KTRs) is limited. We aimed to evaluate humoral and cellular response to a third BNT162b2 dose. In this prospective study, 190 KTRs were evaluated before and ∼3 weeks after the third vaccine dose. The primary outcomes were anti-spike antibody level >4160 AU/ml (neutralization-associated cutoff) and any seropositivity. Univariate and multivariate analyses were conducted to identify variables associated with antibody response. T-cell response was evaluated in a subset of participants. Results were compared to a control group of 56 healthcare workers. Among KTRs, we found a seropositivity rate of 70% (133/190) after the third dose (37%, 70/190, after the second vaccine dose); and 27% (52/190) achieved levels above 4160 AU/ml after the third dose, compared to 93% of controls. Variables associated with antibody response included higher antibody levels after the second dose (odds ratio [OR] 30.8 per log AU/ml, 95% confidence interval [CI]11-86.4, p < 0.001); and discontinuation of antimetabolite prior to vaccination (OR 9.1,95% CI 1.8-46.5, p = 0.008). T-cell response was demonstrated in 13% (7/53). In conclusion, third dose BNT162b2 improved immune response among KTRs, however 30% still remained seronegative. Pre-vaccination temporary immunosuppression reduction improved antibody response.

SARS-CoV-2 antibody dynamics among kidney transplant recipients 3 months after BNT162b2 vaccination: a prospective cohort study.

Data regarding immunogenicity of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among kidney transplant recipients in the months following vaccination are lacking. We aimed to investigate humoral immune response at 3-4 months post-vaccination among a cohort of kidney transplant recipients, compared with a control group of dialysis patients. Anti-spike antibodies were tested at 1 and 3-4 months after vaccination. Of 259 kidney transplant recipients tested at a median time of 110 days from second vaccine dose, 99 (38%) were seropositive, compared with 83% (101/122) of control patients. Younger age, better renal function and lower immunosuppression levels were associated with seropositivity. A total of 14% (13/94) of participants seropositive at 1 month became seronegative at follow-up and 11% (18/165) became seropositive. The latter were mainly individuals with higher antibody levels at 1 month. Antibody levels at 3-4 months were significantly reduced in both study groups, although the decline was more pronounced in the control group. Kidney transplant recipients present poor antibody response to mRNA SARS-CoV-2 vaccination, with only 38% seropositive at 3-4 months. Nevertheless, the decay in antibody response over time is modest, and some patients may present delayed response, reaching adequate antibody levels at 3-4 months. Low seropositivity rates in this group call for investigating other immunization strategies.

Longevity of Humoral Response Six Months Following BNT162b2 Vaccine in Dialysis Patients.

Background: End-stage kidney disease substantially increases the risk of severe COVID-19. However, despite early robust immunogenicity of the mRNA-SARS-CoV-2 vaccination in patients with hemodialysis, the longevity of humoral response in this high-risk population is still unknown. Methods: A prospective cohort study aimed to evaluate the longevity of serologic response in patients with hemodialysis, compared with a control group, 6 months following the second dose of the BNT162b2 vaccine. We assessed antibody response by quantitative measurement of IgG antibodies against the receptor-binding domain of the Spike protein (anti-S1-RBD IgG). Study outcomes were defined as a seropositivity rate and log-transformed anti-S1-RBD IgG levels at 6 months, and the change in antibody levels between 3 and 6 months. Findings: The cohort included 104 patients with hemodialysis and 84 controls. At a median time of 184 days (IQR, 183-188) following the second dose of the vaccine, 83/104 (79.8%) patients with hemodialysis maintained seropositivity for the anti-S1-RBD IgG level compared to 83/84 (98.8%) in the control group (p < 0.001). The log-transformed antibody level was significantly lower in the hemodialysis group (2.23 ± 0.39 log AU/ml vs. 2.69 ± 0.65 log AU/ml, respectively, p < 0.001). Older age and hypoalbuminemia were the only variables that were found to be associated with reduced log-transformed antibody levels in univariate and multivariate analysis. There was no interaction between dialysis status and an antibody-level decline rate (p = 0.972). Conclusion: Among patients with hemodialysis, a seropositivity rate and anti-S1-RBD antibody titers were substantially reduced compared with a control group, at 6 months following the second dose of the BNT162b2 vaccine. These findings support the prioritization of patients with hemodialysis for a third "booster" dose.

Vaccination for SARS-CoV-2 in Hematological Patients.

Patients with specific hematological malignancies (HM) are at increased risk for severe disease and death from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy subjects, vaccination against SARS-CoV-2 has been demonstrated to be highly effective in disease prevention; however, immunocompromised patients were largely excluded from vaccine randomized controlled trials. In this review, we overview available non-randomized studies addressing effectiveness and safety of several coronavirus disease 2019 (COVID-19) vaccines in patients with HM. Overall, COVID-19 vaccines are safe in patients with HM, with adverse events similar to those in the general population. Though serology testing is not recommended as a test to evaluate vaccine effectiveness, a correlation between higher antibody levels and protection against infection has been reported. Studies evaluating humoral response to COVID-19 vaccine in HM patients demonstrate low immunogenicity, mainly in patients with lymphoproliferative disorders, as well as with certain drugs, including mainly anti-CD20 antibodies, Bruton tyrosine kinase inhibitors, and also ruxolitinib and venetoclax. Seropositivity rates of patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia following mRNA vaccination reach 40%-50%. T-cell responses to vaccination are also impaired among these patients. Better humoral response rates are reported in multiple myeloma patients and hematopoietic stem-cell transplant, reaching ∼75%-80%, but not in patients following chimeric antigen receptor T-cell therapy. Patients with chronic myeloid leukemia and myeloproliferative diseases have high response rate to vaccination. Third mRNA vaccine dose is currently recommended to all HM patients. Alternative approaches for vaccination and prevention in patients unable to mount an immune response following full vaccination are provided in the review.

ESCMID rapid guidelines for assessment and management of long COVID.

SCOPE: The aim of these guidelines is to provide evidence-based recommendations for the assessment and management of individuals with persistent symptoms after acute COVID-19 infection and to provide a definition for this entity, termed 'long COVID'. METHODS: We performed a search of the literature on studies addressing epidemiology, symptoms, assessment, and treatment of long COVID. The recommendations were grouped by these headings and by organ systems for assessment and treatment. An expert opinion definition of long COVID is provided. Symptoms were reviewed by a search of the available literature. For assessment recommendations, we aimed to perform a diagnostic meta-analysis, but no studies provided relevant results. For treatment recommendations we performed a systematic review of the literature in accordance with the PRISMA statement. We aimed to evaluate patient-related outcomes, including quality of life, return to baseline physical activity, and return to work. Quality assessment of studies included in the systematic review is provided according to study design. RECOMMENDATIONS: Evidence was insufficient to provide any recommendation other than conditional guidance. The panel recommends considering routine blood tests, chest imaging, and pulmonary functions tests for patients with persistent respiratory symptoms at 3 months. Other tests should be performed mainly to exclude other conditions according to symptoms. For management, no evidence-based recommendations could be provided. Physical and respiratory rehabilitation should be considered. On the basis of limited evidence, the panel suggests designing high-quality prospective clinical studies/trials, including a control group, to further evaluate the assessment and management of individuals with persistent symptoms of COVID-19.