Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label,randomized controlled trial

ObjectiveRandomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need.MethodsTo determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10.ResultsWe assigned 251 patients with COVID-19 and a PaO_2/FiO₂ ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56–1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61–1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0–0.0] vs. 0.0 [95% CI, 0.0–1.0]; p 0.83).DiscussionIn the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.     

An Outbreak of Breakthrough Infections by the SARS-CoV-2 Delta Variant in a Psychiatric Closed Ward

BackgroundA rapid decline in immunity and low neutralizing activity against the delta variant in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees has been observed. This study describes an outbreak of coronavirus disease 2019 (COVID-19) breakthrough infections caused by the SARS-CoV-2 delta variant in a psychiatric closed ward.MethodsData from epidemic intelligence service officers were utilized to obtain information regarding demographic, vaccination history, and clinical data along with SARS-CoV-2 PCR test results for a COVID-19 outbreak that occurred in a closed psychiatric ward.ResultsAmong the 164 residents, 144 (87.8%) received two doses of vaccines and 137 (95.1%) of them received ChAdOx1 nCoV-19 vaccine. The mean interval between the second vaccination and COVID-19 diagnosis was 132.77 ± 40.68 days. At the time of detection of the index case, SARS-CoV-2 had spread throughout the ward, infecting 162 of 164 residents. The case-fatality ratio was lower than that in the previously reported outbreak before the vaccination (1.2%, 2/162 vs. 6.9%, P = 0.030). Prolonged hospitalization occurred in 17 patients (11.1%) and was less prevalent in the vaccinated group than in the unvaccinated group (8.5% vs. 25.0%, P = 0.040).ConclusionThe findings of this study highlight that while vaccination can reduce mortality and the duration of hospitalization, it is not sufficient to prevent an outbreak of the SARS-CoV-2 delta variant in the present psychiatric hospital setting.     

Signals were broadly positive for months,but never definitive: the tocilizumab story

BackgroundMost treatment guidelines for coronavirus disease 2019 (COVID-19) currently recommend tocilizumab in combination with dexamethasone in critically ill patients who are exhibiting rapid respiratory decompensation.AimsTo produce a critical review and summary of the pathway which led to the repurposing of tocilizumab for COVID-19 treatment, from in vitro observations to guidelines recommendations.SourcesAll studies evaluating the effectiveness of tocilizumab to treat COVID-19 disease published between July 2020 and July 2021.ContentTwo large and methodologically well conducted observational studies, the TESEO and the STOP COVID cohorts, showed a reduction in the risk of invasive mechanical ventilation or death in patients treated with tocilizumab as compared to standard of care in 2020. Concomitantly, and up to February 2021, a number of randomized trials (RCTs) with small sample sizes were showing discrepant results. These RCTs had a number of issues: small sample size, various designs and inclusion criteria, and different dosages of tocilizumab used. The confidence interval of the meta-analytic estimate for the RCT results was consistent with the hypothesis of no efficacy of tocilizumab. In our opinion, this was mainly because the meta-analysis included small and heterogeneous studies. These results led to a delay in the inclusion of tocilizumab in guidelines which occurred only in the summer of 2021.ImplicationsAlthough observational studies are unable to control for unmeasured confounding, they can be put together quickly during a pandemic and promptly provide important information. The large sample size allows us to investigate effect measure modifiers and to better target interventions. It is key that the effect size is somewhat large (RR > 2), all sources of bias are properly accounted for, and the direct evidence is weighted against these factors. It appears to us that for tocilizumab, not having dismissed the results of carefully designed and analysed observational studies in 2020 could have prevented many deaths over those months.     

Impact of dexamethasone on SARS-CoV-2 concentration kinetics and antibody response in hospitalized COVID-19 patients: results from a prospective observational study

ObjectivesDexamethasone has become the standard of care for severe coronavirus disease 2019 (COVID-19), but its virological impact is poorly understood. The objectives of this work were to characterize the kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) concentration in the upper respiratory tract (URT) and the antibody response in patients with (D⁺) and without (D^–) dexamethasone treatment.MethodsData and biosamples from hospitalized patients with severe COVID-19, enrolled between 4th March and 11th December 2020 in a prospective observational study, were analysed. SARS-CoV-2 virus concentration in serial URT samples was measured using RT-PCR. SARS-CoV-2-specific immunoglobulins A and G (IgA and IgG) were measured in serum samples using S1-ELISA.ResultsWe compared 101 immunocompetent patients who received dexamethasone (according to the inclusion criteria and dosage determined in the RECOVERY trial) to 93 immunocompetent patients with comparable disease severity from the first months of the pandemic, who had not been treated with dexamethasone or other glucocorticoids. We found no inter-group differences in virus concentration kinetics, duration of presence of viral loads >10⁶ viral copies/mL (D⁺ median 17 days (IQR 13–24), D^– 19 days (IQR 13–29)), or time from symptom onset until seroconversion (IgA: D⁺ median 11.5 days (IQR 11–12), D^– 14 days (IQR 11.5–15.75); IgG: D⁺ 13 days (IQR 12–14.5), D^– 12 days (IQR 11–15)).ConclusionDexamethasone does not appear to lead to a change in virus clearance or a delay in antibody response in immunocompetent patients hospitalized with severe COVID-19.     

Upper respiratory tract SARS-CoV-2 RNA loads in symptomatic and asymptomatic children and adults

ObjectivesStudies comparing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA load in the upper respiratory tract (URT) between children and adults—who either presented with coronavirus disease 2019 (COVID-19) or were asymptomatic—have yielded inconsistent results. Here, we conducted a retrospective, single-centre study to address this issue.Patients and methodsIncluded were 1184 consecutive subjects (256 children and 928 adults) testing positive for SARS-CoV-2 RNA in nasopharyngeal exudates (NPs); of these, 424 (121 children and 303 adults) had COVID-19 and 760 (135 children and 625 adults) were asymptomatic close contacts of COVID-19 patients. SARS-CoV-2 RNA testing was carried out using the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, MS, USA). The AMPLIRUN® TOTAL SARS-CoV-2 RNA Control (Vircell SA, Granada, Spain) was used for estimating SARS-CoV-2 RNA loads (in copies/mL). SARS-CoV-2 RNA loads at the time of laboratory diagnosis (single specimen/patient) were used for comparison purposes.ResultsMedian initial SARS-CoV-2 RNA load was lower (p 0.094) in children (6.98 log₁₀ copies/mL, range 3.0–11.7) than in adults (7.14 log₁₀ copies/mL, range 2.2–13.4) with COVID-19. As for asymptomatic individuals, median SARS-CoV-2 RNA load was comparable (p 0.97) in children (6.20 log₁₀ copies/mL, range 1.8–11.6) and adults (6.48 log₁₀ copies/mL, range 1.9–11.8). Children with COVID-19 symptoms displayed SARS-CoV-2 RNA loads (6.98 log₁₀ copies/mL, range 3.0–11.7) comparable to those of their asymptomatic counterparts (6.20 log₁₀ copies/mL, range 1.8–11.6) (p 0.61). Meanwhile in adults, median SARS-CoV-2 RNA load was significantly higher in symptomatic (7.14 log₁₀ copies/mL, range 2.2–13.4) than in asymptomatic subjects (6.48 log₁₀ copies/mL, range 1.9–11.8) (p < 0.001). Overall, the observed URT SARS-CoV-2 RNA clearance rate was faster in children than in adults.ConclusionsBased on viral load data at the time of diagnosis, our results suggest that SARS-CoV-2-infected children, with or without COVID-19, may display NP viral loads of comparable magnitude to those found in their adult counterparts. However, children may have shorter viral shedding than adults.     

Effect of hydroxychloroquine pre-exposure on infection with SARS-CoV-2 in rheumatic disease patients: a population-based cohort study

ObjectivesEarly in vitro studies have suggested that hydroxychloroquine (HCQ) is a potentially useful drug against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. This study was conducted to determine whether HCQ had a preventive effect on coronavirus disease 2019 (COVID-19) in rheumatic disease patients who were taking HCQ.MethodsWe conducted a population-based retrospective cohort study using the records of the Korean Health Insurance Review and Assessment (HIRA) claim records. The clinical data of patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) who were tested for SARS-CoV-2 were investigated. We compared the attack rate of COVID-19 between those who underwent HCQ therapy within 14 days before the test for SARS-CoV-2 (HCQ users) and HCQ non-users. Data were analysed using logistic regression models, χ², and Student's t-tests.ResultsAs of 15th May 2020, 2066 patients with RA or SLE were tested for COVID-19. Among them, 31.4% (649/2066) were treated with HCQ. Most HCQ users (93.7%, 608/649) were taking 200–400 mg/day recommended for the treatment of rheumatic diseases. The attack rate of COVID-19 in the HCQ users (2.3%, 15/649) did not differ from that in the HCQ non-users (2.2%, 31/1417) (p 0.86).ConclusionsHCQ prophylactic use at a usual dose did not prevent COVID-19 in patients with rheumatic disease.     

COVID-19, SARS and MERS: are they closely related?

BackgroundThe 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries; cases have also been reported worldwide. This novel coronavirus disease (COVID-19) is associated with a respiratory illness that may lead to severe pneumonia and acute respiratory distress syndrome (ARDS). Although related to the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiological and clinical features which to date are not completely understood.AimsTo provide a review of the differences in pathogenesis, epidemiology and clinical features of COVID-19, SARS and MERS.SourcesThe most recent literature in the English language regarding COVID-19 has been reviewed, and extracted data have been compared with the current scientific evidence about SARS and MERS epidemics.ContentCOVID-19 seems not to be very different from SARS regarding its clinical features. However, it has a fatality rate of 2.3%, lower than that of SARS (9.5%) and much lower than that of MERS (34.4%). The possibility cannot be excluded that because of the less severe clinical picture of COVID-19 it can spread in the community more easily than MERS and SARS. The actual basic reproductive number (R₀) of COVID-19 (2.0–2.5) is still controversial. It is probably slightly higher than the R₀ of SARS (1.7–1.9) and higher than that of MERS (<1). A gastrointestinal route of transmission for SARS-CoV-2, which has been assumed for SARS-CoV and MERS-CoV, cannot be ruled out and needs further investigation.ImplicationsThere is still much more to know about COVID-19, especially as concerns mortality and its capacity to spread on a pandemic level. Nonetheless, all of the lessons we learned in the past from the SARS and MERS epidemics are the best cultural weapons with which to face this new global threat.     

Transplacental transmission of SARS-CoV-2 immunoglobulin G antibody to infants from maternal COVID-19 vaccine immunization before pregnancy

The coronavirus disease 2019 (COVID-19) vaccine generates functional antibodies in maternal circulation that are detectable in infants, while the information is restricted to the usage of COVID-19 vaccine during pregnancy. In this study, we aimed to evaluate the effect of maternal COVID-19 vaccines before pregnancy. Infants were included from mothers with no inactivated COVID-19 vaccine, 1-, 2-, and 3-dose before pregnancy, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibodies were tested. Comparative analysis was done between the groups. A total of 130 infants were enrolled in the study. Significantly higher levels of SARS-CoV-2 IgG antibodies in infants born to mothers with 3-dose COVID-19 vaccine before pregnancy compared with 1- and 2-dose groups (p < 0.0001). The levels of antibodies decreased significantly with age in infants born to mothers with the 3-dose COVID-19 vaccine before pregnancy (r = −0.338, p = 0.035), and it was still higher than that 2-dose COVID-19 vaccine group. The maternal SARS-CoV-2 antibodies produced from the inactivated COVID-19 vaccine before pregnancy can be transferred to newborns via the placenta. Maternal immunization with 3-dose of the COVID-19 vaccine before pregnancy could be more beneficial for both mothers and infants.     

Clinical features of neonates born to mothers with coronavirus disease-2019: A systematic review of 105 neonates

BackgroundDespite the increasingly recognized impact of novel coronavirus disease (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), on many aspects of health in adults and children, its effects on neonates born to infected mothers remain unclear. We conducted this study to investigate the outcomes of neonates born to mothers with COVID-19.MethodsWe searched the medical databases from inception to March 31, 2020 to perform a systematic review of outcomes in neonates born to mothers with COVID-19. Data were pooled using a random effects regression model. Primary and secondary outcomes were neonatal clinical outcomes and infectious status, respectively.ResultsFourteen studies involving 105 neonates fulfilling the study criteria were identified. The rates of preterm neonates and those small for gestational age (SGA) were 25 (23.8%) and 10 (11.2%), respectively. Among 91 neonates who were tested, 8 (8.8%) were positive for nucleic acids or antibodies for SARS-CoV-2. Additionally, 28 (26.7%) of the neonates were symptomatic and two test-negative neonates died, including one stillbirth. Between test-positive and test-negative groups, the rates of SGA, preterm delivery, duration between maternal symptom onset and delivery, and perinatal complication were not significantly different; but the rate of symptomatic after birth reached significant difference (62.5% vs 20.5%, p = 0.008).ConclusionsMost neonates born to infected mothers had favorable outcomes. Although direct evidences of intrauterine infection were scarce, the risk of intrauterine infection should be considered based on a positive test in 8.8% of the neonates. Symptomatic neonates born to infected mothers should receive tests for SARS-CoV-2 to initiate appropriate treatment and quarantine. Further studies are warranted to assess the outcomes of COVID-19 in neonates.     

The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses

BackgroundBoth humoral and cell-mediated responses are associated with immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although our understanding of the potential role of T-cell responses in the context of coronavirus disease 2019 (COVID-19) is rapidly increasing, more information is still needed.ObjectivesTo provide an overview of the role of T-cell immunity in COVID-19, in the context of natural infection and post-vaccination, and discuss the potential utility of measuring SARS-CoV-2-specific T-cell responses, drawing on experience of the use of interferon-γ release assays (IGRAs) in tuberculosis (TB).SourcesPubMed articles up to 16 April 2021.ContentT-cell responses can be detected very early in the course of COVID-19, earlier than the detection of antibody responses, and are correlated with COVID-19 outcome. Lower CD4⁺ and CD8⁺ T-cell counts are markers of more severe disease, longer duration of viral RNA positivity and increased mortality. In line with natural infection, SARS-CoV-2 vaccination stimulates robust T-cell responses, which probably play an important role in protection; data on long-term T-cell responses are currently limited. The utility of measuring T-cell responses is already well established in both aiding the diagnosis of TB infection using IGRAs, and evaluation of T-cell responses to TB vaccine candidates. A variety of assays have already been developed to measure SARS-CoV-2-specific T-cell responses, including IGRAs, intracellular cytokine staining and activation-induced markers. IGRAs based on SARS-CoV-2 antigens can distinguish between convalescent and uninfected healthy blood donors.ImplicationsSimple assays for measuring the quantity and function of T-cell responses may have utility in the prognostication of COVID-19, and for monitoring immune responses to SARS-CoV-2 vaccination and population-based immunity to SARS-CoV-2 variants of interest.     

Severe acute respiratory syndrome coronavirus 2 causes lung inflammation and injury

BackgroundAs of 14 October 2021, coronavirus disease 2019 (COVID-19) has affected more than 246 million individuals and caused more than 4.9 million deaths worldwide. COVID-19 has caused significant damage to the health, economy and lives of people worldwide. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not as lethal as SARS coronavirus or Middle East respiratory syndrome coronavirus, its high transmissibility has had disastrous consequences for public health and health-care systems worldwide given the lack of effective treatment at present.ObjectivesTo clarify the mechanisms by which SARS-CoV-2 caused lung inflammation and injury, from the molecular mechanism to lung damage and tissue repair, from research to clinical practice, and then presented clinical requirements.SourcesReferences for this review were identified through searches ‘(COVID-19 [Title]) OR (SARS-CoV-2 [Title])’ on PubMed, and focused on the pathological damage and clinical practice of COVID-19.ContentWe comprehensively reviewed the process of lung inflammation and injury during SARS-CoV-2 infection, including pyroptosis of alveolar epithelial cells, cytokine storm and thrombotic inflammatory mechanisms.ImplicationsThis review describes SARS-CoV-2 in comparison to SARS and explores why most people have mild inflammatory responses, even asymptomatic infections, and only a few develop severe disease. It suggests that future therapeutic strategies may be targeted antiviral therapy, the pathogenic pathways in the lung inflammatory response, and enhancing repair and regeneration in lung injury.     

Outbreak of SARS-CoV-2 B.1.617.2 (delta) variant in a nursing home 28 weeks after two doses of mRNA anti-COVID-19 vaccines: evidence of a waning immunity

ObjectivesTo describe a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.617.2 (Delta) variant outbreak among residents (n = 69) and health workers (n = 69) of a small nursing home in northeastern Italy, with full vaccination coverage of 91% and 82%, respectively. Evaluation of the anti-Spike IgG titres 28 weeks after the mRNA vaccine booster dose against SARS-CoV-2 infection and severe coronavirus disease 2019 (COVID-19).Materials and methodsSera were collected within 48 hours from the index case; anti-Spike IgG was determined (expressed as WHO binding antibody units (BAU)/mL) through a commercial quantitative assay; SARS-CoV-2 was diagnosed using RT-PCR, and full-genome sequencing was performed for lineage characterization. Residents were grouped according to anti-Spike IgG titres (≤50, 51–1000 and > 1000 BAU/mL) and the resulting protection against infection and severe disease was measured.ResultsNone of the health workers and 14 of the 59 (24%) residents fully vaccinated and without a previous SARS-CoV-2 infection showed anti-Spike IgG ≤50 BAU/mL (one-sided Fisher exact test, p 0.011). Among these residents, a level of anti-Spike IgG ≤50 BAU/mL resulted in a higher risk of SARS-CoV-2 infection (relative risk 1.55, 95% CI 1.17–2.05) and severe COVID-19 (relative risk 5.33, 95% CI 1.83–15.57).ConclusionLow levels of SARS-CoV-2 neutralizing anti-Spike IgG in serum 28 weeks after the administration of the second dose parallel the waning of vaccine protection.     

Non-alcoholic Fatty Liver Disease and COVID-19 Susceptibility and Outcomes: a Korean Nationwide Cohort

BackgroundEvidence for the association between underlying non-alcoholic fatty liver disease (NAFLD), the risk of testing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive, and the clinical consequences of coronavirus disease 2019 (COVID-19) is controversial and scarce. We aimed to investigate the association between the presence of NAFLD and the risk of SARS-CoV-2 infectivity and COVID-19-related outcomes.MethodsWe used the population-based, nationwide cohort in South Korea linked with the general health examination records between January 1, 2018 and July 30, 2020. Data for 212,768 adults older than 20 years who underwent SARS-CoV-2 testing from January 1 to May 30, 2020, were obtained. The presence of NAFLDs was defined using three definitions, namely hepatic steatosis index (HSI), fatty liver index (FLI), and claims-based definition. The outcomes were SARS-CoV-2 test positive, COVID-19 severe illness, and related death.ResultsAmong 74,244 adults who completed the general health examination, there were 2,251 (3.0%) who were SARS-CoV-2 positive, 438 (0.6%) with severe COVID-19 illness, and 45 (0.06%) COVID-19-related deaths. After exposure-driven propensity score matching, patients with pre-existing HSI-NAFLD, FLI-NAFLD, or claims-based NAFLD had an 11–23% increased risk of SARS-CoV-2 infection (HSI-NAFLD 95% confidence interval [CI], 1–28%; FLI-NAFLD 95% CI, 2–27%; and claims-based NAFLD 95% CI, 2–31%) and a 35–41% increased risk of severe COVID-19 illness (HSI-NAFLD 95% CI, 8–83%; FLI-NAFLD 95% CI, 5–71%; and claims-based NAFLD 95% CI, 1–92%). These associations are more evident as liver fibrosis advanced (based on the BARD scoring system). Similar patterns were observed in several sensitivity analyses including the full-unmatched cohort.ConclusionPatients with pre-existing NAFLDs have a higher likelihood of testing SARS-CoV-2 positive and severe COVID-19 illness; this association was more evident in patients with NAFLD with advanced fibrosis. Our results suggest that extra attention should be given to the management of patients with NAFLD during the COVID-19 pandemic.     

Low prevalence of active COVID-19 in Slovenia: a nationwide population study of a probability-based sample

ObjectivesAccurate population-level assessment of the coronavirus disease 2019 (COVID-19) burden is fundamental for navigating the path forward during the ongoing pandemic, but current knowledge is scant. We conducted the first nationwide population study using a probability-based sample to assess active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, combined with a longitudinal follow-up of the entire cohort over the next 6 months. Baseline SARS-CoV-2 RNA testing results and the first 3-week follow-up results are presented.MethodsA probability-based sample of the Slovenian population comprising data from 2.1 million people was selected from the Central Population Register (n = 3000). SARS-CoV-2 RNA was detected in nasopharyngeal samples using the cobas 6800 SARS-CoV-2 assay. Each participant filled in a detailed baseline questionnaire with basic sociodemographic data and detailed medical history compatible with COVID-19. After 3 weeks, participants were interviewed for the presence of COVID-19–compatible clinical symptoms and signs, including in household members, and offered immediate testing for SARS-CoV-2 RNA if indicated.ResultsA total of 1368 individuals (46%) consented to participate and completed the questionnaire. Two of 1366 participants tested positive for SARS-CoV-2 RNA (prevalence 0.15%; posterior mean 0.18%, 95% Bayesian confidence interval 0.03–0.47; 95% highest density region (HDR) 0.01–0.41). No newly diagnosed infections occurred in the cohort during the first 3-week follow-up round.ConclusionsThe low prevalence of active COVID-19 infections found in this study accurately predicted the dynamics of the epidemic in Slovenia over the subsequent month. Properly designed and timely executed studies using probability-based samples combined with routine target-testing figures provide reliable data that can be used to make informed decisions on relaxing or strengthening disease mitigation strategies.     

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review

BackgroundTocilizumab is a monoclonal antibody that interrupts interleukin-6 signalling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical coronavirus disease 2019 (COVID-19). Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear.ObjectivesTo synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab's use in these populations with COVID-19.SourcesPubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. The US Food and Drug Administration and the European Medicines Agency guidance for the industry and regulatory approval documents were reviewed.ContentPublished data on tocilizumab in pregnancy include 610 cases (n = 20 with COVID-19) together with seven mother–infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared with the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow up was limited. Tocilizumab appears to be compatible with breastfeeding.ImplicationsAlthough the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.     

Role of the early short-course corticosteroids treatment in ARDS caused by COVID-19: A single-center,retrospective analysis

PurposeSevere coronavirus disease 2019 (COVID-19) is strongly related to interstitial pneumonia with frequent development of acute respiratory distress syndrome (ARDS). The role of corticosteroids (CS) treatment in these patients is still controversial. Some studies evidenced a possible role of an early short-term course of CS treatment in the treatment of severe pneumonia.Patients and methodsThis is a single-center, retrospective study considering the patients with confirmed COVID-19 pneumonia admitted to our hospital between 9th March and 15^th June 2020. Two groups were considered: early high-dose of methyl-prednisolone (eHDM; n ​= ​31) and the control group (n ​= ​52). Patients in the eHDM group received the dose of 5-8 ​mg/kg/day of methyl-prednisolone for 2 consecutive days. Primary outcome was the mortality evaluation; secondary outcomes were clinical improvement, side-effects and laboratory/radiographic changes.ResultsSignificant differences between the two groups were: length of hospitalization (21.5 vs 28.4 days, p ​= ​0.026), length of non-invasive ventilation (NIV) or mechanical ventilation (11.5 vs 14.5 days, p ​= ​0.031), death (5 vs 12, p ​= ​0.006) and clinical improvement (16 vs 11, p=0.018). The following factors were related to in-hospital mortality in the multivariate analysis: comorbidities (OR ​= ​2.919; 95%CI ​= ​1.515-16.705; p<0.001), days from the onset of symptoms and the hospital admission (OR ​= ​1.404; 95%CI ​= ​1.069-12.492; p ​= ​0.011), PaO₂/FiO₂ (P/F) ratio (OR ​= ​3.111; 95%CI ​= ​2.334-16.991; p ​= ​0.009) and eHDM treatment (OR ​= ​0.741; 95%CI ​= ​0.129-0.917; p ​= ​0.007).ConclusionThe eHDM is an interesting and promising approach in the ARDS related to COVID-19 pneumonia, which reduces mortality, length of hospitalization and the need for mechanical ventilation.     

Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19

PurposeHost genetic variants may contribute to severity of COVID-19. NKG2C⁺ NK cells are potent antiviral effector cells, potentially limiting the extent of SARS-CoV-2 infections. NKG2C is an activating NK cell receptor encoded by the KLRC2 gene, which binds to HLA-E on infected cells leading to NK cell activation. Heterozygous or homozygous KLRC2 deletion (KLRC2^del) may naturally occur and is associated with a significantly lower or absent NKG2C expression level. In addition, HLA-E*0101/0103 genetic variants occur, caused by a single-nucleotide polymorphism. We therefore investigated whether the severity of COVID-19 is associated with these genetic variants.MethodsWe investigated the distribution of KLRC2 deletion and HLA-E*0101/0103 allelic variants in a study cohort of 361 patients with either mild (N = 92) or severe (N = 269) COVID-19.ResultsEspecially the KLRC2^del, and at a lower degree the HLA-E*0101, allele were significantly overrepresented in hospitalized patients (p = 0.0006 and p = 0.01), particularly in patients requiring intensive care (p < 0.0001 and p = 0.01), compared with patients with mild symptoms. Both genetic variants were independent risk factors for severe COVID-19.ConclusionOur data show that these genetic variants in the NKG2C/HLA-E axis have a significant impact on the development of severe SARS-CoV-2 infections, and may help to identify patients at high-risk for severe COVID-19.     

Neurologic manifestations associated with COVID-19: a multicentre registry

ObjectivesTo provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.MethodsWe conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March–April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible.ResultsWe included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53–72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19–associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3–8) days in COVID-19–associated encephalopathy, 7 (5–10) days in encephalitis, 12 (7–18) days in acute ischaemic cerebrovascular syndrome and 18 (15–28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17–34) days with a high short-term mortality rate (28/222, 12.6%).ConclusionsClinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.