Safety and effectiveness of vaccines against COVID-19 in children aged 5-11 years: a systematic review and meta-analysis.

BACKGROUND: To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years. METHODS: In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L·OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822. FINDINGS: Of 5272 screened records, we included 51 (1·0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41·6% (95% CI 28·1-52·6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36·2% (21·5-48·2; six NRSIs; CoE low) against symptomatic COVID-19, 75·3% (68·0-81·0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0·83 [95% CI 0·21-3·33]; two randomised controlled trials; CoE low), with approximately 0·23-1·2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1]; one NRSI; CoE low), with 0·13-1·04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2·07 (1·80-2·39; two RCTs; CoE moderate) after one dose and 2·06 (1·70-2·49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1·09 (1·04-1·16; two RCTs; CoE moderate) after one dose and 1·49 (1·34-1·65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1·21 [1·07-1·38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children. INTERPRETATION: In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years. FUNDING: German Federal Joint Committee.

Interventions for palliative symptom control in COVID-19 patients.

BACKGROUND: Individuals dying of coronavirus disease 2019 (COVID-19) may experience distressing symptoms such as breathlessness or delirium. Palliative symptom management can alleviate symptoms and improve the quality of life of patients. Various treatment options such as opioids or breathing techniques have been discussed for use in COVID-19 patients. However, guidance on symptom management of COVID-19 patients in palliative care has often been derived from clinical experiences and guidelines for the treatment of patients with other illnesses. An understanding of the effectiveness of pharmacological and non-pharmacological palliative interventions to manage specific symptoms of COVID-19 patients is required. OBJECTIVES: To assess the efficacy and safety of pharmacological and non-pharmacological interventions for palliative symptom control in individuals with COVID-19. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), medRxiv); Web of Science Core Collection (Science Citation Index Expanded, Emerging Sources); CINAHL; WHO COVID-19 Global literature on coronavirus disease; and COAP Living Evidence on COVID-19 to identify completed and ongoing studies without language restrictions until 23 March 2021. We screened the reference lists of relevant review articles and current treatment guidelines for further literature. SELECTION CRITERIA: We followed standard Cochrane methodology as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We included studies evaluating palliative symptom management for individuals with a confirmed diagnosis of COVID-19 receiving interventions for palliative symptom control, with no restrictions regarding comorbidities, age, gender, or ethnicity. Interventions comprised pharmacological as well as non-pharmacological treatment (e.g. acupressure, physical therapy, relaxation, or breathing techniques). We searched for the following types of studies: randomized controlled trials (RCT), quasi-RCTs, controlled clinical trials, controlled before-after studies, interrupted time series (with comparison group), prospective cohort studies, retrospective cohort studies, (nested) case-control studies, and cross-sectional studies. We searched for studies comparing pharmacological and non-pharmacological interventions for palliative symptom control with standard care. We excluded studies evaluating palliative interventions for symptoms caused by other terminal illnesses. If studies enrolled populations with or exposed to multiple diseases, we would only include these if the authors provided subgroup data for individuals with COVID-19. We excluded studies investigating interventions for symptom control in a curative setting, for example patients receiving life-prolonging therapies such as invasive ventilation.  DATA COLLECTION AND ANALYSIS: We used a modified version of the Newcastle Ottawa Scale for non-randomized studies of interventions (NRSIs) to assess bias in the included studies. We included the following outcomes: symptom relief (primary outcome); quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We rated the certainty of evidence using the GRADE approach.  As meta-analysis was not possible, we used tabulation to synthesize the studies and histograms to display the outcomes.  MAIN RESULTS: Overall, we identified four uncontrolled retrospective cohort studies investigating pharmacological interventions for palliative symptom control in hospitalized patients and patients in nursing homes. None of the studies included a comparator. We rated the risk of bias high across all studies. We rated the certainty of the evidence as very low for the primary outcome symptom relief, downgrading mainly for high risk of bias due to confounding and unblinded outcome assessors. Pharmacological interventions for palliative symptom control We identified four uncontrolled retrospective cohort studies (five references) investigating pharmacological interventions for palliative symptom control. Two references used the same register to form their cohorts, and study investigators confirmed a partial overlap of participants. We therefore do not know the exact number of participants, but individual reports included 61 to 2105 participants. Participants received multimodal pharmacological interventions: opioids, neuroleptics, anticholinergics, and benzodiazepines for relieving dyspnea (breathlessness), delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms.  Primary outcome: symptom relief All identified studies reported this outcome. For all symptoms (dyspnea, delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms), a majority of interventions were rated as completely or partially effective by outcome assessors (treating clinicians or nursing staff). Interventions used in the studies were opioids, neuroleptics, anticholinergics, and benzodiazepines.  We are very uncertain about the effect of pharmacological interventions on symptom relief (very low-certainty evidence). The initial rating of the certainty of evidence was low since we only identified uncontrolled NRSIs. Our main reason for downgrading the certainty of evidence was high risk of bias due to confounding and unblinded outcome assessors. We therefore did not find evidence to confidently support or refute whether pharmacological interventions may be effective for palliative symptom relief in COVID-19 patients. Secondary outcomes We planned to include the following outcomes: quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events. We did not find any data for these outcomes, or any other information on the efficacy and safety of used interventions. Non-pharmacological interventions for palliative symptom control None of the identified studies used non-pharmacological interventions for palliative symptom control. AUTHORS' CONCLUSIONS: We found very low certainty evidence for the efficacy of pharmacological interventions for palliative symptom relief in COVID-19 patients. We found no evidence on the safety of pharmacological interventions or efficacy and safety of non-pharmacological interventions for palliative symptom control in COVID-19 patients. The evidence presented here has no specific implications for palliative symptom control in COVID-19 patients because we cannot draw any conclusions about the effectiveness or safety based on the identified evidence. More evidence is needed to guide clinicians, nursing staff, and caregivers when treating symptoms of COVID-19 patients at the end of life. Specifically, future studies ought to investigate palliative symptom control in prospectively registered studies, using an active-controlled setting, assess patient-reported outcomes, and clearly define interventions. The publication of the results of ongoing studies will necessitate an update of this review. The conclusions of an updated review could differ from those of the present review and may allow for a better judgement regarding pharmacological and non-pharmacological interventions for palliative symptom control in COVID-19 patients.

A Comparison and Evaluation of International Guidelines on the Treatment of Severe SARS-CoV-2 Infection.

BACKGROUND: When the SARS-CoV-2 pandemic began, no uniform treatment and care strategies for critically ill COVID-19 patients were yet available. National and international treatment recommendations were formulated under time pressure, initially on the basis of indirect evidence from the treatment of similar diseases. In this article, we give an overview of the content, currency, and methodological quality of the existing national and international guidelines, with special attention to the care of critically ill patients. METHODS: Guidelines were identified by a comprehensive search, the included guidelines were assessed in standardized fashion with the AGREE II guideline assessment instrument and according to the AMWF rulebook criteria, and the core recommendations of the included and methodologically high-quality guidelines were compared. RESULTS: Nine of the 97 guidelines that were identified fulfilled the content criteria for inclusion, and 6 of these fulfilled the qualitative criteria; these 6 guidelines still differed, however, in the topics to which they devoted the most attention, as well as in their methodological quality and currency. The treatment strategies for patients with severe respiratory failure (lung-protective ventilation strategies and rescue measures) deviated little from established standards. Uniform recommendations were made, among other things, for the administration of dexamethasone, which was recommended in all of the guidelines for patients requiring oxygen treatment, as well as for antithrombotic drug prophylaxis and for the prone positioning of ventilated patients. Many recommendations were based on insufficient evidence, and some were contradictory, e.g., those regarding antibiotic treatment or the choice between high-flow oxygen administration via nasal canula (HFNC) and noninvasive ventilation (NIV). CONCLUSION: The consultation of multiple high-quality international guidelines and guideline recommendations shared in online portals such as MagicApp are helpful sources of information for clinicians. In view of the continuing lack of strong evidence, further research on intensive care treatments is needed (aspects of ventilation, positioning therapy, and the role of extracorporeal membrane oxygenation [ECMO]).