Impact of SARS-CoV-2 Infection on the Association Between Laboratory Tests and Severe Outcomes Among Hospitalized Children.

Background: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations. Methods: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations. Results: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 109/L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 109/L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts. Conclusions: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative.

Post-COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection.

Importance: Little is known about the risk factors for, and the risk of, developing post-COVID-19 conditions (PCCs) among children. Objectives: To estimate the proportion of SARS-CoV-2-positive children with PCCs 90 days after a positive test result, to compare this proportion with SARS-CoV-2-negative children, and to assess factors associated with PCCs. Design, Setting, and Participants: This prospective cohort study, conducted in 36 emergency departments (EDs) in 8 countries between March 7, 2020, and January 20, 2021, included 1884 SARS-CoV-2-positive children who completed 90-day follow-up; 1686 of these children were frequency matched by hospitalization status, country, and recruitment date with 1701 SARS-CoV-2-negative controls. Exposure: SARS-CoV-2 detected via nucleic acid testing. Main Outcomes and Measures: Post-COVID-19 conditions, defined as any persistent, new, or recurrent health problems reported in the 90-day follow-up survey. Results: Of 8642 enrolled children, 2368 (27.4%) were SARS-CoV-2 positive, among whom 2365 (99.9%) had index ED visit disposition data available; among the 1884 children (79.7%) who completed follow-up, the median age was 3 years (IQR, 0-10 years) and 994 (52.8%) were boys. A total of 110 SARS-CoV-2-positive children (5.8%; 95% CI, 4.8%-7.0%) reported PCCs, including 44 of 447 children (9.8%; 95% CI, 7.4%-13.0%) hospitalized during the acute illness and 66 of 1437 children (4.6%; 95% CI, 3.6%-5.8%) not hospitalized during the acute illness (difference, 5.3%; 95% CI, 2.5%-8.5%). Among SARS-CoV-2-positive children, the most common symptom was fatigue or weakness (21 [1.1%]). Characteristics associated with reporting at least 1 PCC at 90 days included being hospitalized 48 hours or more compared with no hospitalization (adjusted odds ratio [aOR], 2.67 [95% CI, 1.63-4.38]); having 4 or more symptoms reported at the index ED visit compared with 1 to 3 symptoms (4-6 symptoms: aOR, 2.35 [95% CI, 1.28-4.31]; ≥7 symptoms: aOR, 4.59 [95% CI, 2.50-8.44]); and being 14 years of age or older compared with younger than 1 year (aOR, 2.67 [95% CI, 1.43-4.99]). SARS-CoV-2-positive children were more likely to report PCCs at 90 days compared with those who tested negative, both among those who were not hospitalized (55 of 1295 [4.2%; 95% CI, 3.2%-5.5%] vs 35 of 1321 [2.7%; 95% CI, 1.9%-3.7%]; difference, 1.6% [95% CI, 0.2%-3.0%]) and those who were hospitalized (40 of 391 [10.2%; 95% CI, 7.4%-13.7%] vs 19 of 380 [5.0%; 95% CI, 3.0%-7.7%]; difference, 5.2% [95% CI, 1.5%-9.1%]). In addition, SARS-CoV-2 positivity was associated with reporting PCCs 90 days after the index ED visit (aOR, 1.63 [95% CI, 1.14-2.35]), specifically systemic health problems (eg, fatigue, weakness, fever; aOR, 2.44 [95% CI, 1.19-5.00]). Conclusions and Relevance: In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.

Outcomes of SARS-CoV-2-Positive Youths Tested in Emergency Departments: The Global PERN-COVID-19 Study.

Importance: Severe outcomes among youths with SARS-CoV-2 infections are poorly characterized. Objective: To estimate the proportion of children with severe outcomes within 14 days of testing positive for SARS-CoV-2 in an emergency department (ED). Design, Setting, and Participants: This prospective cohort study with 14-day follow-up enrolled participants between March 2020 and June 2021. Participants were youths aged younger than 18 years who were tested for SARS-CoV-2 infection at one of 41 EDs across 10 countries including Argentina, Australia, Canada, Costa Rica, Italy, New Zealand, Paraguay, Singapore, Spain, and the United States. Statistical analysis was performed from September to October 2021. Exposures: Acute SARS-CoV-2 infection was determined by nucleic acid (eg, polymerase chain reaction) testing. Main Outcomes and Measures: Severe outcomes, a composite measure defined as intensive interventions during hospitalization (eg, inotropic support, positive pressure ventilation), diagnoses indicating severe organ impairment, or death. Results: Among 3222 enrolled youths who tested positive for SARS-CoV-2 infection, 3221 (>99.9%) had index visit outcome data available, 2007 (62.3%) were from the United States, 1694 (52.6%) were male, and 484 (15.0%) had a self-reported chronic illness; the median (IQR) age was 3 (0-10) years. After 14 days of follow-up, 735 children (22.8% [95% CI, 21.4%-24.3%]) were hospitalized, 107 (3.3% [95% CI, 2.7%-4.0%]) had severe outcomes, and 4 children (0.12% [95% CI, 0.03%-0.32%]) died. Characteristics associated with severe outcomes included being aged 5 to 18 years (age 5 to <10 years vs <1 year: odds ratio [OR], 1.60 [95% CI, 1.09-2.34]; age 10 to <18 years vs <1 year: OR, 2.39 [95% CI 1.38-4.14]), having a self-reported chronic illness (OR, 2.34 [95% CI, 1.59-3.44]), prior episode of pneumonia (OR, 3.15 [95% CI, 1.83-5.42]), symptoms starting 4 to 7 days prior to seeking ED care (vs starting 0-3 days before seeking care: OR, 2.22 [95% CI, 1.29-3.82]), and country (eg, Canada vs US: OR, 0.11 [95% CI, 0.05-0.23]; Costa Rica vs US: OR, 1.76 [95% CI, 1.05-2.96]; Spain vs US: OR, 0.51 [95% CI, 0.27-0.98]). Among a subgroup of 2510 participants discharged home from the ED after initial testing and who had complete follow-up, 50 (2.0%; 95% CI, 1.5%-2.6%) were eventually hospitalized and 12 (0.5%; 95% CI, 0.3%-0.8%) had severe outcomes. Compared with hospitalized SARS-CoV-2-negative youths, the risk of severe outcomes was higher among hospitalized SARS-CoV-2-positive youths (risk difference, 3.9%; 95% CI, 1.1%-6.9%). Conclusions and Relevance: In this study, approximately 3% of SARS-CoV-2-positive youths tested in EDs experienced severe outcomes within 2 weeks of their ED visit. Among children discharged home from the ED, the risk was much lower. Risk factors such as age, underlying chronic illness, and symptom duration may be useful to consider when making clinical care decisions.

Belimumab for systemic lupus erythematosus.

BACKGROUND: Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help control disease activity. OBJECTIVES: To assess the benefits and harms of belimumab (alone or in combination) in systematic lupus erythematosus. SEARCH METHODS: An Information Specialist carried out the searches of CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, the World Health Organization (WHO) International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to 25 September 2019. There were no language or date restrictions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of belimumab (alone or in combination) compared to placebo/control treatment (immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil or another biologic), in adults with SLE. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. MAIN RESULTS: Six RCTs (2917 participants) qualified for quantitative analyses. All included studies were multicenter, international or US-based. The age range of the included participants was 22 to 80 years; most were women; and study duration ranged from 84 days to 76 weeks. The risk of bias was generally low except for attrition bias, which was high in 67% of studies. Compared to placebo, more participants on belimumab 10 mg/kg (Food and Drug Administration (FDA)-approved dose) showed at least a 4-point improvement (reduction) in Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, a validated SLE disease activity index: (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.22 to 1.45; 829/1589 in belimumab group and 424/1077 in placebo; I2= 0%; 4 RCTs; high-certainty evidence). Change in health-related quality of life (HRQOL), assessed by Short Form-36 Physical Component Summary score improvement (range 0 to 100), showed there was probably little or no difference between groups (mean difference 1.6 points, 95% CI 0.30 to 2.90; 401 in belimumab group and 400 in placebo; I2= 0%; 2 RCTs; moderate-certainty evidence). The belimumab 10 mg/kg group showed greater improvement in glucocorticoid dose, with a higher proportion of participants reducing their dose by at least 50% compared to placebo (RR 1.59, 95% CI 1.17 to 2.15; 81/269 in belimumab group and 52/268 in placebo; I2= 0%; 2 RCTs; high-certainty evidence). The proportion of participants experiencing harm may not differ meaningfully between the belimumab 10 mg/kg and placebo groups: one or more serious adverse event (RR 0.87, 95% CI: 0.68 to 1.11; 238/1700 in belimumab group and 199/1190 in placebo; I2= 48%; 5 RCTs; low-certainty evidence; ); one or more serious infection (RR 1.01, 95% CI: 0.66 to 1.54; 44/1230 in belimumab group and 40/955 in placebo; I2= 0%; 4 RCTs; moderate-certainty evidence); and withdrawals due to adverse events (RR 0.82, 95% CI: 0.63 to 1.07; 113/1700 in belimumab group and 94/1190 in placebo; I2= 0%; 5 RCTs; moderate-certainty evidence). Mortality was rare, and may not differ between belimumab 10 mg/kg and placebo (Peto odds ratio 1.15, 95% CI 0.41 to 3.25; 9/1714 in belimumab group and 6/1203 in placebo; I2= 4%; 6 RCTs; low-certainty evidence). AUTHORS' CONCLUSIONS: The six studies that provided evidence for benefits and harms of belimumab were well-designed, high-quality RCTs. At the FDA-approved dose of 10 mg/kg, based on moderate to high-certainty data, belimumab was probably associated with a clinically meaningful efficacy benefit compared to placebo in participants with SLE at 52 weeks. Evidence related to harms is inconclusive and mostly of moderate to low-certainty evidence. More data are needed for the longer-term efficacy of belimumab.

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis.

BACKGROUND: This is an update of the 2009 Cochrane overview and network meta-analysis (NMA) of biologics for rheumatoid arthritis (RA). OBJECTIVES: To assess the benefits and harms of nine biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX/DMARD-IR). METHODS: We searched for randomized controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (via The Cochrane Library Issue 6, June 2015), MEDLINE (via OVID 1946 to June 2015), and EMBASE (via OVID 1947 to June 2015). Data extraction, risk of bias and GRADE assessments were done in duplicate. We calculated both direct estimates using standard meta-analysis and used Bayesian mixed treatment comparisons approach for NMA estimates to calculate odds ratios (OR) and 95% credible intervals (CrI). We converted OR to risk ratios (RR) which are reported in the abstract for the ease of interpretation. MAIN RESULTS: This update included 73 new RCTs for a total of 90 RCTs; 79 RCTs with 32,874 participants provided usable data. Few trials were at high risk of bias for blinding of assessors/participants (13% to 21%), selective reporting (4%) or major baseline imbalance (8%); a large number had unclear risk of bias for random sequence generation (68%) or allocation concealment (74%).Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a statistically significant and clinically meaningful improvement in ACR50 versus comparator (RR 2.71 (95% confidence interval (CI) 2.36 to 3.10); absolute benefit 24% more patients (95% CI 19% to 29%), number needed to treat for an additional beneficial outcome (NNTB) = 5 (4 to 6). NMA estimates for ACR50 in tumor necrosis factor (TNF) biologic+MTX/DMARD (RR 3.23 (95% credible interval (Crl) 2.75 to 3.79), non-TNF biologic+MTX/DMARD (RR 2.99; 95% Crl 2.36 to 3.74), and anakinra + MTX/DMARD (RR 2.37 (95% Crl 1.00 to 4.70) were similar to the direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with a clinically and statistically important improvement in function measured by the Health Assessment Questionnaire (0 to 3 scale, higher = worse function) with a mean difference (MD) based on direct evidence of -0.25 (95% CI -0.28 to -0.22); absolute benefit of -8.3% (95% CI -9.3% to -7.3%), NNTB = 3 (95% CI 2 to 4). NMA estimates for TNF biologic+MTX/DMARD (absolute benefit, -10.3% (95% Crl -14% to -6.7%) and non-TNF biologic+MTX/DMARD (absolute benefit, -7.3% (95% Crl -13.6% to -0.67%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), biologic+MTX/DMARD was associated with clinically and statistically significantly greater proportion of participants achieving remission in RA (defined by disease activity score DAS < 1.6 or DAS28 < 2.6) versus comparator (RR 2.81 (95% CI, 2.23 to 3.53); absolute benefit 18% more patients (95% CI 12% to 25%), NNTB = 6 (4 to 9)). NMA estimates for TNF biologic+MTX/DMARD (absolute improvement 17% (95% Crl 11% to 23%)) and non-TNF biologic+MTX/DMARD (absolute improvement 19% (95% Crl 12% to 28%) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for inconsistency), radiographic progression (scale 0 to 448) was statistically significantly reduced in those on biologics + MTX/DMARDs versus comparator, MD -2.61 (95% CI -4.08 to -1.14). The absolute reduction was small, -0.58% (95% CI -0.91% to -0.25%) and we are unsure of the clinical relevance of this reduction. NMA estimates of TNF biologic+MTX/DMARD (absolute reduction -0.67% (95% Crl -1.4% to -0.12%) and non-TNF biologic+MTX/DMARD (absolute reduction, -0.68% (95% Crl -2.36% to 0.92%)) were similar to respective direct estimates.Based on direct evidence of moderate quality (downgraded for imprecision), results for withdrawals due to adverse events were inconclusive, with wide confidence intervals encompassing the null effect and evidence of an important increase in withdrawals, RR 1.11 (95% CI 0.96 to 1.30). The NMA estimates of TNF biologic+MTX/DMARD (RR 1.24 (95% Crl 0.99 to 1.57)) and non-TNF biologic+MTX/DMARD (RR 1.20 (95% Crl 0.87 to 1.67)) were similarly inconclusive and downgraded to low for both imprecision and indirectness.Based on direct evidence of high quality, biologic+MTX/DMARD was associated with clinically significantly increased risk (statistically borderline significant) of serious adverse events on biologic+MTX/DMARD (Peto OR [can be interpreted as RR due to low event rate] 1.12 (95% CI 0.99 to 1.27); absolute risk 1% (0% to 2%), As well, the NMA estimate for TNF biologic+MTX/DMARD (Peto OR 1.20 (95% Crl 1.01 to 1.43)) showed moderate quality evidence of an increase in the risk of serious adverse events. The other two NMA estimates were downgraded to low quality due to imprecision and indirectness and had wide confidence intervals resulting in uncertainty around the estimates: non-TNF biologics + MTX/DMARD: 1.07 (95% Crl 0.89 to 1.29) and anakinra: RR 1.06 (95% Crl 0.65 to 1.75).Based on direct evidence of low quality (downgraded for serious imprecision), results were inconclusive for cancer (Peto OR 1.07 (95% CI 0.68 to 1.68) for all biologic+MTX/DMARD combinations. The NMA estimates of TNF biologic+MTX/DMARD (Peto OR 1.21 (95% Crl 0.63 to 2.38) and non-TNF biologic+MTX/DMARD (Peto OR 0.99 (95% Crl 0.58 to 1.78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence that the use of biologic+MTX/DMARD in people with rheumatoid arthritis who have failed to respond to MTX or other DMARDs results in clinically important improvement in function and higher ACR50 and remission rates, and increased risk of serious adverse events than the comparator (MTX/DMARD/PL; high quality evidence). Radiographic progression is slowed but its clinical relevance is uncertain. Results were inconclusive for whether biologics + MTX/DMARDs are associated with an increased risk of cancer or withdrawals due to adverse events.