December 22, 2022

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Clinical Reports

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection
- A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5–81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.
Clinical Features and Burden of Post-Acute Sequelae of SARS-CoV-2 Infection in Children and Adolescents
- Among 659,286 children in the study sample, 59,893 (9.1%) tested positive by PCR for SARS-CoV-2. Most were tested in outpatient testing facility (50.3%) or office (24.6%) settings (Table 1). The most common syndromic, systemic, and medication features were loss of taste or smell (aHR 1.96 [95% CI 1.16–3.32), myocarditis (aHR 3.10 [95% CI 1.94–4.96]) (Figures 1 and 2), and cough and cold preparations (aHR 1.52 [95% CI 1.18–1.96]). The incidence of at least one systemic/syndromic/medication feature of PASC was 42.0% among PCR-positive children versus 38.2% among PCR-negative children, with an incidence proportion difference of 3.8% (95% CI 3.3–4.3%). A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5 years-old, and individuals with complex chronic conditions. In this large-scale, exploratory study, the burden of PASC in children appeared to be lower than earlier reports. Acute illness severity, young age, and comorbid complex chronic disease increased the risk of PASC.
Demonstration of stable clusters of symptoms in long COVID
- While symptoms within clusters were similar across both periods, in the cardiorespiratory cluster, the frequency of palpitations decreased (56% vs 16%) and cough increased (14% vs 45%) between reporting periods (both P< 0.01). Furthermore, a greater proportion of palpitations were reported in those with COVID-19 from waves 1 and 2 (35% and 28%) compared to 3 and 4 (both 12%, P< 0.001), and a greater proportion of chest pain in waves 1, 2 and 4 compared to wave 3. There were no differences in other symptoms (Table 3). Additionally there were significantly less palpitations reported in those vaccinated at the time of review (17% vs 31% P=0.002), but not chest pain (30% vs 39% P=0.13). In multivariate analysis, infection in wave 3 and 4 but not vaccination status remained significantly associated with lower reported palpitations (OR (95% CI) 0.28 (0.13–0.97) and 0.5 (0.06–0.87) for waves 3 and 4, both P< 0.05), and wave 3 infection remained independently associated with lower reported chest pain (OR 0.3 (0.25–0.7)). Three symptom clusters define long COVID across the two cohorts, but characteristics of the cardiorespiratory phenotype have evolved over time with evolution of SARS-CoV-2 variants.

Longitudinal Analysis of T cells in COVID-19 Survivors with Post-Acute Sequelae of COVID-19 Reveals Associations between Individual Symptoms and Inflammatory Indexes
- Participants who reported persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of CD8+Ki67+ cells. Those with dyspnea also had significantly higher levels of CD8+CD38+, CD8+Granzyme B+, and CD8+IL10+ cells. Those who suffered from forgetfulness, chest pain, and joint pain had significantly higher levels of CD4+CD25+ cells. These findings suggest continued CD8+ T cell and CD4+CD25+ T cell activation and response following SARS-CoV-2 infection in patients with PASC. An increase in T regulatory cells suggests an ongoing attempt to control host inflammation in a subset of these patients. These results shed further light on continued immune system activation and chronic inflammation as a link to symptoms in COVID-19 survivors suffering from PASC.

Antiviral Therapeutics and Vaccines

Reconsideration of anti-nucleocapsid IgG antibody as a marker of SARS-CoV-2 infection post-vaccination for mild COVID-19 patients
- Anti-nucleocapsid (N) IgG antibody responses were lower in plasma and oral fluid after SARS-CoV-2 infection in vaccinated patients compared to patients infected prior to vaccination or infected without vaccination. This raises questions about the long-term use of anti-N antibodies as a marker for natural infection for surveillance.

Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19–Associated Emergency Department or Urgent Care Encounters and Hospitalizations Among Immunocompetent Adults — VISION Network, Nine States, September–November 2022.
- Bivalent mRNA COVID-19 booster doses containing an Omicron BA.4/BA.5 sublineage component were recommended on September 1, 2022. The effectiveness of these updated vaccines against COVID-19–associated medical encounters has not been established. Bivalent booster doses provided additional protection against COVID-19–associated emergency department/urgent care encounters and hospitalizations in persons who previously received 2, 3, or 4 monovalent vaccine doses. Because of waning of monovalent vaccine-conferred immunity, relative effectiveness of bivalent vaccines was higher with increased time since the previous monovalent dose. All persons should stay up to date with recommended COVID-19 vaccinations, including receiving a bivalent booster dose if eligible.
Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19–Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years — IVY Network, 18 States, September 8–November 30, 2022
- Immunity from monovalent COVID-19 mRNA vaccination wanes over time. A bivalent COVID-19 mRNA booster dose is recommended for all eligible persons; however, little is known about its effectiveness against COVID-19 hospitalization. Among immunocompetent adults aged ≥65 years hospitalized in the multistate IVY Network, a bivalent booster dose provided 73% additional protection against COVID-19 hospitalization compared with past monovalent mRNA vaccination only. To maximize protection against severe COVID-19 this winter season, all eligible persons, especially adults aged ≥65 years, should receive a bivalent booster dose and consider additional prevention strategies, including masking in indoor public spaces.
Effect of Nirmatrelvir/Ritonavir versus Placebo on COVID-19─Related Hospitalizations and Other Medical Visits
- Of the 2246 patients (pts) enrolled globally from Jul to Dec2021, 2085 (nirmatrelvir/r, n=1039; PBO, n=1046) started treatment and met criteria for the modified intent-to-treat population (mITT1; ≤ 5 d of symptom onset, did not/not expected to receive a mAb). Fewer overall COVID-19-related medical visits were reported with nirmatrelvir/r vs PBO (Table 1). In addition to fewer hospitalizations being reported with nirmatrelvir/r (n=8 [0.8%]) vs PBO (n=65 [6.2%]), pts receiving nirmatrelvir/r had fewer hospitalized d (Table 2), with mean durations of 9.6 (range, 5.0, 16.0) d with nirmatrelvir/r and 11.2 (range, 2.0, 57.0) d with PBO in hospitalized pts. No pts in the nirmatrelvir/r group and 9 pts (0.9%) in PBO group were admitted to the ICU. No pts in the nirmatrelvir/r group received mechanical ventilation vs 3 pts in the PBO group. Fewer other COVID-19─related nonhospital medical visits were reported with nirmatrelvir/r vs PBO (Table 3). In the full analysis set, fewer pts required oxygen therapy for COVID-19 with nirmatrelvir/r (n=9/1120 [0.8%]) vs PBO (n=54/1126 [4.8%]). High-risk adults with symptomatic COVID-19 treated with nirmatrelvir/r within 5 d of symptom onset had fewer COVID-19─related medical visits and reduced healthcare utilization (no ICU visits, no mechanical ventilation, fewer days in hospital) vs pts receiving PBO. Clinical Trial: NCT04960202.
COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials
- Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher.
Bacterial Co-infection and Empirical Antibiotic Therapy in Patients with COVID-19
- Of 367 adult patients, 300 (81.7%) patients having sputum culture results were included in the analysis. Of these, 127 (42.3%) had a history of antibiotic exposure within 1 month before hospitalization. The coinfection rate within 48 hours of hospitalization was confirmed in 8.3% (25/300): 6.4% (11/163) of patients without prior antibiotic exposure and 11% (14/127) of patients with prior antibiotic exposure. In the group without prior antibiotic exposure, pathogens responsible for community-onset infections were isolated, whereas nosocomial pathogens were predominantly isolated in the antibiotic-exposed group. Empirical antibiotics were used in 144 (66%) of 275 patients without positive results for microbiological tests. Empirical antibiotic use in patients without positive results for microbiological tests was not significantly associated with 30-day mortality or in-hospital mortality after adjusting covariates including age, sex, comorbidity, anti-inflammatory treatment, and COVID-19 severity. In this study with a high rate of microbiological testing, bacterial co-infection was not frequent, and the results varied depended on previous exposure to antibiotics. Given the rarity of bacterial co-infection and the lack of potential benefits of empirical antibiotic therapy, the antibiotic use in patients with COVID-19 should be restricted as an important target of antibiotic stewardship.

Diagnostics

Similar SARS-CoV-2 Ct value distributions in anterior nares versus nasopharyngeal samples from symptomatic children during Delta and Omicron surges
- In symptomatic children tested for COVID-19 by PCR during both Delta and Omicron surges, Cycle threshold value medians and distributions in anterior nares (AN) and nasopharyngeal (NP) samples were very similar, suggesting similar yield of NP and AN sampling for SARS-CoV-2 PCR testing in symptomatic children.

Epidemiology

Prevalence of SARS-CoV-2 and Influenza Coinfection and Clinical Characteristics Among Children and Adolescents Aged <18 Years Who Were Hospitalized or Died with Influenza — United States, 2021–22 Influenza Season
- Influenza and SARS-CoV-2 viruses individually contribute to pediatric morbidity. The prevalence and severity of coinfection with influenza and SARS-CoV-2 are less well understood. During the 2021–22 influenza season, 6% of hospitalized pediatric influenza patients had SARS-CoV-2 coinfection; a higher percentage of patients with coinfection required invasive or noninvasive respiratory support compared with those with influenza only. Among influenza-associated pediatric deaths, 16% had SARS-CoV-2 coinfection; only one coinfected decedent received influenza antivirals, and none had been fully vaccinated against influenza. The public should adopt prevention strategies, including influenza and COVID-19 vaccination, and consider mask use during high respiratory virus circulation.
The WHO estimates of excess mortality associated with the COVID-19 pandemic
- The World Health Organization has a mandate to compile and disseminate statistics on mortality, and has been tracking the progression of the COVID-19 pandemic since the beginning of 2020. Reported statistics on COVID-19 mortality are problematic for many countries owing to variations in testing access, differential diagnostic capacity and inconsistent certification of COVID-19 as cause of death. Beyond what is directly attributable to it, the pandemic has caused extensive collateral damage that has led to losses of lives and livelihoods. Here researchers report a comprehensive and consistent measurement of the impact of the COVID-19 pandemic by estimating excess deaths, by month, for 2020 and 2021. They predict the pandemic period all-cause deaths in locations lacking complete reported data using an overdispersed Poisson count framework that applies Bayesian inference techniques to quantify uncertainty. Researchers estimate 14.83 million excess deaths globally, 2.74 times more deaths than the 5.42 million reported as due to COVID-19 for the period. There are wide variations in the excess death estimates across the six World Health Organization regions. Researchers describe the data and methods used to generate these estimates and highlight the need for better reporting where gaps persist. Researchers discuss various summary measures, and the hazards of ranking countries’ epidemic responses.
Impact of SARS-CoV-2 variants on inpatient clinical outcome
- Inpatients with COVID-19 at five hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. Severe disease or death within 28 days occurred for 977 (29%) of 3,369 unvaccinated patients and 269 (22%) of 1,230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared to ancestral lineages was 1.30 (95% confidence interval [CI] 1.11-1.49). Compared to Delta, this risk for Omicron patients was 0.72 (95% CI 0.59-0.88) and compared to ancestral lineages was 0.94 (95% CI 0.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio 0.40, 95% CI 0.30-0.54), but no significant outcome difference by variant. Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.
Association of Time to Surgery After COVID-19 Infection With Risk of Postoperative Cardiovascular Morbidity
- A total of 3997 patients (2223 [55.6%]; median age, 51.3 years [IQR, 35.1-64.4 years]; 667 [16.7%] African American or Black; 2990 [74.8%] White; and 340 [8.5%] other race) were included in the study. The median time from COVID-19 diagnosis to surgery was 98 days (IQR, 30-225 days). Major postoperative adverse cardiovascular events were identified in 485 patients (12.1%). Increased time from COVID-19 diagnosis to surgery was associated with a decreased rate of the composite outcome (adjusted odds ratio, 0.99 [per 10 days]; 95% CI, 0.98-1.00; P = .006). This trend persisted for the 1552 patients who had received at least 1 dose of COVID-19 vaccine (adjusted odds ratio, 0.98 [per 10 days]; 95% CI, 0.97-1.00; P = .04). This study suggests that increased time from COVID-19 diagnosis to surgery was associated with a decreased odds of experiencing major postoperative cardiovascular morbidity. This information should be used to better inform risk-benefit discussions concerning optimal surgical timing and perioperative outcomes for patients with a history of COVID-19 infection.