The neurobiology of long COVID.

Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID-19 syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impact on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.

Optimal control strategies to tailor antivirals for acute infectious diseases in the host: a study case of COVID-19

Several mathematical models in SARS-CoV-2 have shown how the target cell model can help to understand the spread of the virus in the host and how potential antiviral treatments can help to control the virus. Concepts as equilibrium and stability have shown to be crucial to qualitatively determine the best alternatives to schedule drugs, based on their effectiveness in reducing the viral infection and replication rates. Important biological events such as rebounds of the infections (when antivirals are incorrectly interrupted) can also be explained by means of a dynamic study of the target cell model. In this work a full characterization of the dynamical behavior of the target cell models under control actions is given and, based on this characterization, the optimal fixed-dose antiviral schedule that produces the smallest amount of dead cells (without viral load rebounds) is computed. The results of several simulations – performed by considering real patient data – show the potential benefits of both the model characterization and the control strategy. © 2022 Elsevier Inc. All rights reserved.

Clinical characteristics of patients with a severe course of acute SARS-CoV-2 infection hospitalised in the Department of Paediatrics, University Hospital Motol

Objective: Although the SARS-CoV-2 infection (COVID-19) is highly contagious, paediatric patients represent only a small proportion of all diagnosed patients. The aim of this study was to assess the clinical characteristics of patients hospitalised with a serious course of acute SARS-CoV-2 infection at the Department of Paediatrics, University Hospital Motol in Prague, Czech Republic. Methods: We performed a retrospective observational study based on patients hospitalised with acute SARS-CoV-2 infection who were admitted to our department between 1st January 2020 and 1st April 2021. The anonymised data were obtained by medical record review. Serious course criterion was defined as respiratory failure when at least oxygen therapy was needed. Results: A total of ten patients were hospitalised in our department during the monitored period. The median age was 15 years (range 2-17), predominantly boys (60%). All patients had associated chronic conditions, the most common (60%) being overweight or obesity. Conclusion: In our experience, comorbid children, especially ones who are obesity or overweight, are at risk of a serious course of acute SARS-CoV-2 infection. This highlights the importance of vaccination for this part of paediatric population as well. © 2022, Czech Medical Association J.E. Purkyne. All rights reserved.

Distinguishing Incubation and Acute Disease Stages of Mild-to-Moderate COVID-19.

While numerous studies have already compared the immune responses against SARS-CoV-2 in severely and mild-to-moderately ill COVID-19 patients, longitudinal trajectories are still scarce. We therefore set out to analyze serial blood samples from mild-to-moderately ill patients in order to define the immune landscapes for differently progressed disease stages. Twenty-two COVID-19 patients were subjected to consecutive venipuncture within seven days after diagnosis or admittance to hospital. Flow cytometry was performed to analyze peripheral blood immune cell compositions and their activation as were plasma levels of cytokines and SARS-CoV-2 specific immunoglobulins. Healthy donors served as controls. Integrating the kinetics of plasmablasts and SARS-CoV-2 specific antibodies allowed for the definition of three disease stages of early COVID-19. The incubation phase was characterized by a sharp increase in pro-inflammatory monocytes and terminally differentiated cytotoxic T cells. The latter correlated significantly with elevated concentrations of IP-10. Early acute infection featured a peak in PD-1+ cytotoxic T cells, plasmablasts and increasing titers of virus specific antibodies. During late acute infection, immature neutrophils were enriched, whereas all other parameters returned to baseline. Our findings will help to define landmarks that are indispensable for the refinement of new anti-viral and anti-inflammatory therapeutics, and may also inform clinicians to optimize treatment and prevent fatal outcomes.

Acute Infection of Viral Pathogens and Their Innate Immune Escape.

Viral infections can cause rampant disease in human beings, ranging from mild to acute, that can often be fatal unless resolved. An acute viral infection is characterized by sudden or rapid onset of disease, which can be resolved quickly by robust innate immune responses exerted by the host or, instead, may kill the host. Immediately after viral infection, elements of innate immunity, such as physical barriers, various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, provide the first line of defense for viral clearance. Innate immunity not only plays a critical role in rapid viral clearance but can also lead to disease progression through immune-mediated host tissue injury. Although elements of antiviral innate immunity are armed to counter the viral invasion, viruses have evolved various strategies to escape host immune surveillance to establish successful infections. Understanding complex mechanisms underlying the interaction between viruses and host's innate immune system would help develop rational treatment strategies for acute viral infectious diseases. In this review, we discuss the pathogenesis of acute infections caused by viral pathogens and highlight broad immune escape strategies exhibited by viruses.

A 29-mRNA host response test from blood accurately distinguishes bacterial and viral infections among emergency department patients.

BACKGROUND: Whether or not to administer antibiotics is a common and challenging clinical decision in patients with suspected infections presenting to the emergency department (ED). We prospectively validate InSep, a 29-mRNA blood-based host response test for the prediction of bacterial and viral infections. METHODS: The PROMPT trial is a prospective, non-interventional, multi-center clinical study that enrolled 397 adult patients presenting to the ED with signs of acute infection and at least one vital sign change. The infection status was adjudicated using chart review (including a syndromic molecular respiratory panel, procalcitonin and C-reactive protein) by three infectious disease physicians blinded to InSep results. InSep (version BVN-2) was performed using PAXgene Blood RNA processed and quantified on NanoString nCounter SPRINT. InSep results (likelihood of bacterial and viral infection) were compared to the adjudicated infection status. RESULTS: Subject mean age was 64 years, comorbidities were significant for diabetes (17.1%), chronic obstructive pulmonary disease (13.6%), and severe neurological disease (6.8%); 16.9% of subjects were immunocompromised. Infections were adjudicated as bacterial (14.1%), viral (11.3%) and noninfected (0.25%): 74.1% of subjects were adjudicated as indeterminate. InSep distinguished bacterial vs. viral/noninfected patients and viral vs. bacterial/noninfected patients using consensus adjudication with AUROCs of 0.94 (95% CI 0.90-0.99) and 0.90 (95% CI 0.83-0.96), respectively. AUROCs for bacterial vs. viral/noninfected patients were 0.88 (95% CI 0.79-0.96) for PCT, 0.80 (95% CI 0.72-89) for CRP and 0.78 (95% CI 0.69-0.87) for white blood cell counts (of note, the latter biomarkers were provided as part of clinical adjudication). To enable clinical actionability, InSep incorporates score cutoffs to allocate patients into interpretation bands. The Very Likely (rule in) InSep bacterial band showed a specificity of 98% compared to 94% for the corresponding PCT band (> 0.5 µg/L); the Very Unlikely (rule-out) band showed a sensitivity of 95% for InSep compared to 86% for PCT. For the detection of viral infections, InSep demonstrated a specificity of 93% for the Very Likely band (rule in) and a sensitivity of 96% for the Very Unlikely band (rule out). CONCLUSIONS: InSep demonstrated high accuracy for predicting the presence of both bacterial and viral infections in ED patients with suspected acute infections or suspected sepsis. When translated into a rapid, point-of-care test, InSep will provide ED physicians with actionable results supporting early informed treatment decisions to improve patient outcomes while upholding antimicrobial stewardship. Registration number at Clinicaltrials.gov NCT03295825.

Using body temperature and variables commonly available in the EHR to predict acute infection: a proof-of-concept study showing improved pretest probability estimates for acute COVID-19 infection among discharged emergency department patients.

OBJECTIVES: Obtaining body temperature is a quick and easy method to screen for acute infection such as COVID-19. Currently, the predictive value of body temperature for acute infection is inhibited by failure to account for other readily available variables that affect temperature values. In this proof-of-concept study, we sought to improve COVID-19 pretest probability estimation by incorporating covariates known to be associated with body temperature, including patient age, sex, comorbidities, month, and time of day. METHODS: For patients discharged from an academic hospital emergency department after testing for COVID-19 in March and April of 2020, we abstracted clinical data. We reviewed physician documentation to retrospectively generate estimates of pretest probability for COVID-19. Using patients' COVID-19 PCR test results as a gold standard, we compared AUCs of logistic regression models predicting COVID-19 positivity that used: (1) body temperature alone; (2) body temperature and pretest probability; (3) body temperature, pretest probability, and body temperature-relevant covariates. Calibration plots and bootstrap validation were used to assess predictive performance for model #3. RESULTS: Data from 117 patients were included. The models' AUCs were: (1) 0.69 (2) 0.72, and (3) 0.76, respectively. The absolute difference in AUC was 0.029 (95% CI -0.057 to 0.114, p=0.25) between model 2 and 1 and 0.038 (95% CI -0.021 to 0.097, p=0.10) between model 3 and 2. CONCLUSIONS: By incorporating covariates known to affect body temperature, we demonstrated improved pretest probability estimates of acute COVID-19 infection. Future work should be undertaken to further develop and validate our model in a larger, multi-institutional sample.

The Effect of Proinflammatory Cytokines on the Proliferation, Migration and Secretory Activity of Mesenchymal Stem/Stromal Cells (WJ-MSCs) under 5% O2 and 21% O2 Culture Conditions.

Treatment with Mesenchymal Stem/Stromal Cells (MSCs) in clinical trials is becoming one of the most-popular and fast-developing branches of modern regenerative medicine, as it is still in an experimental phase. The cross-section of diseases to which these cells are applied is very wide, ranging from degenerative diseases, through autoimmune processes and to acute inflammatory diseases, e.g., viral infections. Indeed, now that first clinical trials applying MSCs against COVID-19 have started, important questions concern not only the therapeutic properties of MSCs, but also the changes that might occur in the cell features as a response to the "cytokine storm" present in the acute phase of an infection and capable of posing a risk to a patient. The aim of our study was thus to assess changes potentially occurring in the biology of MSCs in the active inflammatory environment, e.g., in regards to the cell cycle, cell migration and secretory capacity. The study using MSCs derived from Wharton's jelly (WJ-MSCs) was conducted under two aerobic conditions: 21% O2 vs. 5% O2, since oxygen concentration is one of the key factors in inflammation. Under both oxygen conditions cells were exposed to proinflammatory cytokines involved significantly in acute inflammation, i.e., IFNγ, TNFα and IL-1ß at different concentrations. Regardless of the aerobic conditions, WJ-MSCs in the inflammatory environment do not lose features typical for mesenchymal cells, and their proliferation dynamic remains unchanged. Sudden fluctuations in proliferation, the early indicator of potential genetic disturbance, were not observed, while the cells' migration activity increased. The presence of pro-inflammatory factors was also found to increase the secretion of such anti-inflammatory cytokines as IL-4 and IL-10. It is concluded that the inflammatory milieu in vitro does not cause phenotype changes or give rise to proliferation disruption of WJ-MSCs, and nor does it inhibit the secretory properties providing for their use against acute inflammation.

Early impact of school closure and social distancing for COVID-19 on the number of inpatients with childhood non-COVID-19 acute infections in Japan.

Many countries have implemented school closures as part of social distancing measures intended to control the spread of coronavirus disease 2019 (COVID-19). The aim of this study was to assess the early impact of nationwide school closure (March-May 2020) and social distancing for COVID-19 on the number of inpatients with major childhood infectious diseases in Japan. Using data from the Diagnosis Procedure Combination system in Japan, we identified patients aged 15 years or younger with admissions for a diagnosis of upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI), influenza, gastrointestinal infection (GII), appendicitis, urinary tract infection (UTI), or skin and soft tissue infection (SSTI) between July 2018 and June 2020. Changes in the trend of the weekly number of inpatients between the two periods were assessed using interrupted time-series analysis. A total of 75,053 patients in 210 hospitals were included. The overall weekly number of inpatients was decreased by 52.5%, 77.4%, and by 83.4% in the last week of March, April, and May 2020, respectively, when compared on a year-on-year basis. The estimated impact was a reduction of 581 (standard error 42.9) inpatients per week in the post-school-closure period (p < 0.001). The main part of the reduction was for pre-school children. Remarkable decreases in the number of inpatients with URI, LRTI, and GII were observed, while there were relatively mild changes in the other groups.Conclusion: We confirmed a marked reduction in the number of inpatients with childhood non-COVID-19 acute infections in the post-school-closure period. What is Known: • Most countries have implemented social distancing measures to limit the spread of the novel coronavirus disease 2019 (COVID-19). • A large decrease in pediatric emergency visits has been reported from several countries after the social distancing. What is New: • Based on administrative claims data, a marked reduction in the number of inpatients for childhood non-COVID-19 acute infections was found in the post-school-closure period in Japan. • The magnitude of the reduction was different between the disease groups.

Surveillance of Acute SARS-CoV-2 Infections in School Children and Point-Prevalence During a Time of High Community Transmission in Switzerland.

Background: Switzerland had one of the highest incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Europe during the second wave. Schools were open as in most of Europe with specific preventive measures in place. However, the frequency and transmission of acute unrecognized, asymptomatic or oligosymptomatic infections in schools during this time of high community transmission is unknown. Thereof, our aim was to pilot a surveillance system that detects acute SARS-CoV-2 infections in schools and possible transmission within classes. Methods: Fourteen out of the randomly selected sample of the Ciao Corona cohort study participated between December 1 and 11, a time when incidence rate for SARS-CoV-2 infections was high for the canton of Zurich. We determined point-prevalence of acute SARS-CoV-2 infections of school children attending primary and secondary school. A buccal swab for polymerase chain reaction (PCR) and a rapid diagnostic test (RDT) to detect SARS-CoV-2 were taken twice 1 week apart (T1 and T2) in a cohort of children from randomly selected classes. A questionnaire assessed demographics and symptoms compatible with a SARS-CoV-2 infection during the past 5 days. Results: Out of 1,299 invited children, 641 (49%) 6- to 16-year-old children and 66 teachers from 14 schools and 67 classes participated in at least one of two testings. None of the teachers but one child had a positive PCR at T1, corresponding to a point-prevalence in children of 0.2% (95% CI 0.0-1.1%), and no positive PCR was detected at T2. The child with positive PCR at T1 was negative on the RDT at T1 and both tests were negative at T2. There were 7 (0.6%) false positive RDTs in children and 2 (1.7%) false positive RDTs in teachers at T1 or T2 among 5 schools (overall prevalence 0.7%). All 9 initially positive RDTs were negative in a new buccal sample taken 2 h to 2 days later, also confirmed by PCR. Thirty-five percent of children and 8% of teachers reported mild symptoms during the 5 days prior to testing. Conclusion: In a setting of high incidence of SARS-CoV-2 infections, unrecognized virus spread within schools was very low. Schools appear to be safe with the protective measures in place (e.g., clearly symptomatic children have to stay at home, prompt contact tracing with individual and class-level quarantine, and structured infection prevention measures in school). Specificity of the RDT was within the lower boundary of performance and needs further evaluation for its use in schools. Given the low point prevalence even in a setting of very high incidence, a targeted test, track, isolate and quarantine (TTIQ) strategy for symptomatic children and school personnel adapted to school settings is likely more suitable approach than surveillance on entire classes and schools. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04448717, ClinicalTrials.gov NCT04448717.

Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses.

The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.