August 31, 2023

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Clinical Reports

Human Neural Larva Migrans Caused by Ophidascaris robertsi Ascarid
Ophidascaris species are nematodes exhibiting an indirect lifecycle; various genera of snakes across the Old and New Worlds are definitive hosts. O. robertsi nematodes are native to Australia, where the definitive hosts are carpet pythons (Morelia spilota). The adult nematodes inhabit the python’s esophagus and stomach and shed their eggs in its feces. Eggs are ingested by various small mammals, in which larvae establish, serving as intermediate hosts. Larvae migrate to thoracic and abdominal organs where, particularly in marsupials, the third-stage larvae may reach a considerable length (7–8 cm), even in small hosts. The lifecycle concludes when pythons consume the infected intermediate hosts. Humans infected with O. robertsi larvae would be considered accidental hosts, although human infection with any Ophidascaris species has not previously been reported. Researchers report a case of human neural larva migrans caused by O. robertsi infection.
The public health significance of finding autochthonous melioidosis cases in the continental United States
Recently, the pathogen that causes melioidosis, Burkholderia pseudomallei, was found in the Gulf Coast region of Mississippi, United States of America, associated with human cases and as bacteria in the soil of affected areas. Therefore, the Centers for Disease Control and Prevention has declared the pathogen as endemic in the continental United States for the first time. This viewpoint discusses some issues that the research, public health communities, and government agencies need to address.
Clinical Outcomes Associated With Overestimation of Oxygen Saturation by Pulse Oximetry in Patients Hospitalized With COVID-19
In this cohort study of 24,504 patients with concurrently measured pulse oximetry and arterial oxygen saturation, pulse oximeters more commonly overestimated arterial oxygen saturation in patients from minority racial and ethnic groups and led to delayed recognition of need for COVID-19 therapy among Black patients compared with White patients. In a subset of 8635 patients without immediate need for COVID-19 therapy on admission, overestimation of oxygen saturation by pulse oximetry was associated with delayed delivery of COVID-19 therapy and increased risk of hospital readmission, irrespective of patient race. These results suggest that although racial and ethnic disparities exist in measurement of oxygen saturation by pulse oximetry, overestimation may increase the risk of hospital readmission regardless of patient race.

Antiviral Therapeutics and Vaccines

Project NextGen Awards Over $1.4 Billion to Develop the Future of COVID-19 Vaccines and Therapeutics
The U.S. Department of Health and Human Services (HHS), through the Administration for Strategic Preparedness and Response (ASPR), awarded more than $1.4 billion for Project NextGen to support the development of a new generation of tools and technologies to protect against COVID-19 for years to come. The awards announced today follow extensive coordination with industry partners and include support for clinical trials that will enable the rapid development of even more effective and longer-lasting coronavirus vaccines, a new monoclonal antibody, and transformative technologies to streamline manufacturing processes.
Differences in SARS-CoV-2 specific humoral and cellular immune responses after contralateral and ipsilateral COVID-19 vaccination
In an observational study, 303 previously naive individuals were recruited, who received the second dose of the COVID-19 vaccine BNT162b2 on either the ipsilateral (n = 147) or the contralateral side (n = 156). Spike-specific IgG, IgG-avidity, and neutralizing antibodies were quantified using ELISA and a surrogate assay 2 weeks after dose 2. A subgroup of 143 individuals (64 ipsilateral, 79 contralateral) was analysed for spike-specific CD4 and CD8 T-cells using flow-cytometry. Median spike-specific IgG-levels did not differ after ipsilateral (4590 (IQR 3438) BAU/ml) or contralateral vaccination (4002 (IQR 3524) BAU/ml, p = 0.106). IgG-avidity was also similar (p = 0.056). However, neutralizing activity was significantly lower after contralateral vaccination (p = 0.024). Likewise, median spike-specific CD8 T-cell levels were significantly lower (p = 0.004). Consequently, the percentage of individuals with detectable CD8 T-cells was significantly lower after contralateral than after ipsilateral vaccination (43.0% versus 67.2%, p = 0.004). Spike specific CD4 T-cell levels were similar in both groups, but showed significantly higher CTLA-4 expression after contralateral vaccination (p = 0.011). These effects were vaccine-specific, as polyclonally stimulated T-cell levels did not differ. Both ipsilateral and contralateral vaccination induce a strong immune response, but secondary boosting is more pronounced when choosing vaccine administration-routes that allows for drainage by the same lymph nodes used for priming. Higher neutralizing antibody activity and higher levels of spike-specific CD8 T-cells may have implications for protection from infection and severe disease and support general preference for ipsilateral vaccination.
Pfizer and BioNTech Receive Positive CHMP (Committee for Medicinal Products for Human Use) Opinion for Omicron XBB.1.5-adapted COVID-19 Vaccine in the European Union
Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing authorization for the companies’ Omicron XBB.1.5-adapted monovalent COVID-19 vaccine (COMIRNATY® Omicron XBB.1.5) administered as a single dose for individuals 5 years of age and older, regardless of prior COVID-19 vaccination history. The Committee has also recommended the updated vaccine for children 6 months through 4 years of age as part or all of the primary three-dose vaccination series, depending on how many prior doses they received, or as single dose for those with a history of completion of a COVID-19 primary vaccination course or prior SARS-CoV-2 infection.
Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV)
Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0–7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%–73%). Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.
Optimal Duration of Systemic Corticosteroids in Coronavirus Disease 2019 Treatment: A Systematic Review and Meta-analysis
Corticosteroids confer a survival benefit in individuals hospitalized with coronavirus disease 2019 (COVID-19) who require oxygen. This meta-analysis seeks to determine the duration of corticosteroids needed to optimize this mortality benefit. Electronic databases were searched to 9 March 2022, for studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. Researchers estimated the effect of corticosteroids on mortality by random-effects meta-analyses. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment while adjusting for the severity of disease, age, duration of symptoms, and proportion of control group given steroids. Researchers identified 27 eligible studies consisting of 13 404 hospitalized COVID-19 patients. Seven randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy. Pooled analysis of 18 studies showed the greatest survival benefit for a treatment duration up to 6 days. Survival benefit was 0.65 up to 7 days, and no additional survival benefit was observed beyond 7 days of treatment. The survival benefit was not confounded by severity of disease, age, duration of symptoms, or proportion of control group given steroids. In this meta-analysis, optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with >7 days of treatment.

Epidemiology

Excess All-Cause Mortality in China After Ending the Zero COVID Policy
This cohort study analyzed published obituary data from 3 universities in China (2 in Beijing and 1 in Heilongjiang) and search engine data from the Baidu index (BI; weighted frequency of unique searches for a given keyword relative to the total search volume on the Baidu search engine) in each region of China from January 1, 2016, to January 31, 2023. Using an interrupted time-series design, analyses estimated the relative change in mortality among individuals 30 years and older in the universities and the change in BI for mortality-related terms in each region of China from December 2022 to January 2023. Analysis revealed a strong correlation between Baidu searches for mortality-related keywords and actual mortality burden. Using this correlation, the relative increase in mortality in Beijing and Heilongjiang was extrapolated to the rest of China, and region-specific excess mortality was calculated by multiplying the proportional increase in mortality by the number of expected deaths. Data analysis was performed from February 10, 2023, to March 5, 2023. An estimated 1.87 million (95% CI, 0.71 million-4.43 million; 1.33 per 1000 population) excess deaths occurred among individuals 30 years and older in China during the first 2 months after the end of the zero COVID policy. Excess deaths predominantly occurred among older individuals and were observed across all provinces in mainland China except Tibet. In this cohort study of the population in China, the sudden lifting of the zero COVID policy was associated with significant increases in all-cause mortality. These findings provide valuable insights for policy makers and public health experts and are important for understanding how the sudden propagation of COVID-19 across a population may be associated with population mortality.
International Pediatric COVID-19 Severity Over the Course of the Pandemic
Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.
Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study
Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. Researchers aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association. A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs. The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves' disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis. These findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.