Abstract

BACKGROUND Clinical practice guidelines (CPGs) are statements that should be rigorously developed to guide clinicians' decision-making. However, given the scarce evidence for certain vulnerable groups like children, CPGs' recommendations formulation could be challenging. METHODS We conducted a scoping review of CPGs for COVID-19 management in children. Documents were included if they claimed to be a "clinical practice guideline", published between January and October 2021, and described the process followed to issue their recommendations. We assessed the quality using the "Appraisal of Guidelines for Research and Evaluation II" (AGREE-II) and described how the recommendations were reached. RESULTS We found five CPGs that fulfilled our inclusion criteria. The median score on the overall AGREE-II evaluation was 61% (range: 49%-72%), and the score on the third domain referred to the rigor of methodological development was 52% (range: 25%-88%). Recommendations for remdesivir, tocilizumab, and intravenous immunoglobulin were heterogeneous across CPGs (in favor, against, no recommendation), as well as the methodologies used to present the evidence, perform the benefits/harms balance, and issue the recommendation. CONCLUSIONS Heterogeneous recommendations and justifications across CPGs were found in the three assessed topics. Future CPGs should describe in detail their evidence-to-decision process to issue reliable and transparent recommendations.

Abstract

BACKGROUND The exact prevalence of Multisystem Inflammatory Syndrome in Adults (MIS-A) is largely unknown. Vague and multiple definitions and treatment options often add to the confusion on how to label the diagnosis with certainty. OBJECTIVES The objective of the study was to determine the demographic profile, clinical presentation, laboratory findings and outcomes of MIS-A in COVID-19. METHODS A systematic review was conducted after registering with PROSPERO. Multiple databases were systematically searched to encompass studies characterizing MIS-A from 1st January 2020 up to 31st August 2021. The inclusion criteria were- to incorporate all published or in press peer-reviewed articles reporting cases of MIS-A. We accepted the following types of studies: case reports, case-control, case series, cross-sectional studies and letters to the editors that incorporated clinical, laboratory, imaging, as well as the hospital course of MIS-A patients. The exclusion criteria for the review were- articles not in English, only abstracts published, no data on MIS-A and articles which have focus on COVID-19, and not MIS-A. Two independent authors screened the articles, extracted the data, and assessed the risk of bias. RESULTS A total of 53 articles were included in this review with a sample size of 79 cases. Majority of the patients were males (73.4%) with mean age of 31.67±10.02 years. Fever (100%) and skin rash (57.8%) were the two most common presenting symptoms. Echocardiographic data was available for 73 patients of whom 41 (73.2%) had reduced left ventricular ejection fraction. Cardiovascular system was most frequently involved (81%) followed by gastrointestinal (73.4%) and mucocutaneous (51.9%) involvement. Anti-inflammatory therapies used in treatment included steroids (60.2%), intravenous immunoglobulin (37.2%) and biologics (10.2%). Mean duration of the hospital stay was 11.67±8.08 days. Data regarding the outcomes was available for all 79 subjects of whom 4 (5.1%) died during course of hospital stay. CONCLUSIONS Emergence of MIS-A calls for further large-scale studies to establish standard case definitions and definite treatment guidelines.

Abstract

The aim of this randomized, controlled trial is to determine whether anti-SARS-CoV-2 hyperimmune globulin protects against severe COVID-19 in severely immunocompromised, hospitalized, COVID-19 patients. Patients were randomly assigned to receive anti-SARS-CoV-2 hyperimmune globulin (COVIG) or intravenous immunoglobulin without SARS-CoV-2 antibodies. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven out of eight (88%) in the IVIG control group (p = 0.015, Fisher's exact test). COVIG may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available. The trial was registered at www.trialregister.nl (#NL9436).

Abstract

INTRODUCTION Since COVID-19 outbreak, various studies mentioned the occurrence of neurological disorders. Of these, encephalitis is known as a critical neurological complication in COVID-19 patients. Numerous case reports and case series have found encephalitis in relation to COVID-19, which have not been systematically reviewed. This study aims to evaluate the clinical symptoms, diagnosis, treatment, and outcome of COVID-19-associated encephalitis. METHODS We used the Pubmed/Medline, Embase, and Web of Science databases to search for reports on COVID-19-associated encephalitis from January 1, 2019, to March 7, 2021. The irrelevant studies were excluded based on screening and further evaluation. Then, the information relating diagnosis, treatment, clinical manifestations, comorbidities, and outcome was extracted and evaluated. RESULTS From 4455 initial studies, 45 articles met our criteria and were selected for further evaluation. Included publications reported an overall number of 53 COVID-19-related encephalitis cases. MRI showed hyperintensity of brain regions including white matter (44.68%), temporal lobe (17.02%), and thalamus (12.76%). Also, brain CT scan revealed the hypodensity of the white matter (17.14%) and cerebral hemorrhages/hemorrhagic foci (11.42%) as the most frequent findings. The IV methylprednisolone/oral prednisone (36.11%), IV immunoglobulin (27.77%), and acyclovir (16.66%) were more preferred for COVID-19 patients with encephalitis. From the 46 patients, 13 (28.26%) patients were died in the hospital. CONCLUSION In this systematic review, characteristics of COVID-19-associated encephalitis including clinical symptoms, diagnosis, treatment, and outcome were described. COVID-19-associated encephalitis can accompany with other neurological symptoms and involve different brain. Although majority of encephalitis condition are reversible, but it can lead to life-threatening status. Therefore, further investigation of COVID-19-associated encephalitis is required.

Abstract

OBJECTIVES The potential benefit of convalescent plasma (CP) therapy for COVID-19 is highest when given early after symptom onset. Our objective was to determine the effectiveness of CP in improving the disease course of COVID-19 in high-risk outpatients. METHODS A multicentre double blind randomized trial was conducted comparing 300mL of CP with non-CP. Patients were 50 years or older, symptomatic for <8 days, had PCR or antigen-test confirmed COVID-19 and at least 1 risk factor for severe COVID-19. The primary endpoint was the highest score on a 5-point ordinal scale ranging from fully recovered (score=1) or not (2) on day 7, over hospital admission (3), ICU admission (4) and death (5) in the 28 days following randomization. Secondary endpoints were hospital admission, symptom duration and viral RNA excretion. RESULTS After enrolment of 421 patients and the transfusion of 416, recruitment was discontinued when the countrywide vaccination uptake in those aged >50 years was 80%. Patients had a median age of 60, symptoms for 5 days and 207 of 416 received CP. During the 28 days of follow-up, 28 patients were hospitalized and 2 died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95%credible interval 0.59-1.22). The OR was 0.58 (95%confidence interval 0.33-1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95%confidence interval 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms. CONCLUSIONS In patients with early COVID-19, CP did not improve the 5-point disease severity score. CLINICAL REGISTRY NUMBER NCT04589949.

Abstract

INTRODUCTION This study evaluated the use of platelet-rich plasma (PRP), an autologous blood product with supraphysiologic concentrations of growth factors, in the treatment of prolonged COVID-19 related smell loss. METHODS This multi-institutional, randomized controlled trial recruited COVID-19 patients with objectively measured smell loss (University of Pennsylvania's Smell Identification Test, UPSIT≤33) between 6-12 months. Subjects were randomized to 3 intranasal injections of either PRP or sterile saline into their olfactory clefts. Primary outcome measure was change in Sniffin' sticks score (TDI) from baseline. Secondary endpoint measures included responder rate (achievement of a clinically significant improvement, ≥5.5 point TDI), change in individual TDI olfaction scores, and change in subjective olfaction via a visual analogue scale. RESULTS 35 subjects were recruited and 26 completed the study. PRP treatment resulted in a 3.67 point (95% CI: 0.05-7.29, p = 0.047) greater improvement in olfaction compared to the placebo group at 3-months and a higher response rate (57.1% versus 8.3%, odds ratio 12.5, 95% exact bootstrap CI 2.2-116.7). There was a greater improvement in smell discrimination following PRP treatment compared to placebo, but no difference in smell identification or threshold. There was no difference in subjective scores between PRP and placebo. No adverse effects were reported. CONCLUSION Olfactory function following COVID-19 can improve spontaneously after 6 months and can improve to a greater extent with PRP injection. This data builds on the promise of PRP to be a safe potential treatment option for patients with COVID-19 smell loss, and larger-powered studies will help further assess efficacy. This article is protected by copyright. All rights reserved.

Abstract

Introduction; Pulmonary fibrosis is a frequently reported COVID-19 sequela in which the exact prevalence and risk factors are yet to be established. This meta-analysis aims to investigate the prevalence of post-COVID-19 pulmonary fibrosis (PCPF) and the potential risk factors. Methods; CINAHL, PubMed/MEDLINE, Cochrane Library, Web of Science, and EMBASE databases were searched to identify English language studies published up to December 3, 2021. Results; The systematic search initially revealed a total of 618 articles - of which only 13 studies reporting 2018 patients were included in this study. Among the patients, 1047 (51.9%) were male and 971 (48.1%) were female. The mean age was 54.5 years (15-94). The prevalence of PCPF was 44.9%. The mean age was 59 years in fibrotic patients and 48.5 years in non-fibrotic patients. Chronic obstructive pulmonary disease was the only comorbidity associated with PCPF. Fibrotic patients more commonly suffered from persistent symptoms of dyspnea, cough, chest pain, fatigue, and myalgia (p-value < 0.05). Factors related to COVID-19 severity that were associated with PCPF development included computed tomography score of ≥18, ICU admission, invasive/non-invasive mechanical ventilation, longer hospitalization period, and steroid, antibiotic and immunoglobulin treatments (p-value < 0.05). Parenchymal bands (284/341), ground-glass opacities (552/753), interlobular septal thickening (220/381), and consolidation (197/319) were the most common lung abnormalities found in fibrotic patients. Conclusion, About 44.9% of COVID-19 survivors appear to have developed pulmonary fibrosis. Factors related to COVID-19 severity were significantly associated with PCPF development.

Abstract

BACKGROUND Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77-1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66-1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14-4·29); for patients who were antibody negative, the OR was 0·51 (0·29-0·90; p(interaction)=0·001). INTERPRETATION When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING US National Institutes of Health.

Abstract

BACKGROUND There is limited information available regarding the management of multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2. We performed a systematic review and meta-analysis to evaluate the optimal treatment using IVIG alone versus IVIG plus glucocorticoids. METHODS PubMed, Google Scholar, EMBASE, and Cochrane databases were searched along with other secondary searches. Studies published within the time frame of January 2020 to August 2021 were included. We screened records, extracted data, and assessed the quality of the studies using NOS. Studies that directly compare the two treatment groups were included. Analyses were conducted using the random-effects model (DerSimonian-Laird analysis) if I (2) > 50% and fixed-effects model was used if I (2) < 50%. RESULTS We included three studies in the final quantitative analysis. The initial therapy with the IVIG plus glucocorticoids group significantly lowered the risk of treatment failure (OR 0.57, 95% CI (0.42, 0.79), I (2) 45.36%) and the need for adjunctive immunomodulatory therapy (OR 0.27, 95% CI (0.20, 0.37), I (2) 0.0%). The combination therapy showed no significant reduction in occurrence of left ventricular dysfunction (OR 0.79, 95% CI (0.34, 1.87), I (2) 58.44%) and the need for inotropic support (OR 0.83, 95% CI (0.35, 1.99), I (2) 75.40%). CONCLUSION This study supports the use of IVIG with glucocorticoids compared to IVIG alone, as the combination therapy significantly lowered the risk of treatment failure and the need for adjunctive immunomodulatory therapy.

Abstract

Intravenous immunoglobulin (IVIg) therapy has been suggested as a potential treatment option for hospitalised COVID-19 patients. The aim of this systematic review and meta-analysis was to investigate the potential impact of IVIg on mortality and length of hospitalisation in adult COVID-19 patients. PubMed, Scopus, Web of Science and medRxiv were searched in the week of 20.12.2021 for English language, prospective trials, and retrospective studies with control groups, reporting on the use of intravenous immunoglobulin therapy in adult hospitalised COVID-19 patients. Exclusion criteria were: studies evaluating the use of IVIg in paediatric COVID-19 cases, trials using convalescent anti-SARS-CoV-2 plasma or immunoglobulins derived from convalescent anti-SARS-CoV-2 plasma. A random effects meta-analysis with subgroup analyses regarding study design and patient disease severity according to WHO criteria was also performed. A total of 13 studies were included, of which 6 were prospective, on a total of 2313 (IVIg = 1104, control = 1209) patient outcomes. Meta-analysis results indicated that IVIg therapy had no statistically significant effect on mortality (RR 0.91 [0.59; 1.39], p = 0.65, I(2) = 69% [46%; 83%]) or length of hospital stay (MD 0.51 [-2.80; 3.81], p = 0.76, I(2) = 96% [94%; 98%]). Subgroup analyses indicated no statistically significant impact on either outcome, but prospective studies' results suggested that IVIg may increase the length of hospitalisation in the severe COVID-19 patient group (MD 2.66 [1.43; 3.90], p < 0.01, I(2) = 0% [0%; >90%]). The results of this meta-analysis do not support use of IVIg in hospitalised adult COVID-19 patients.