Host-directed-therapy strategies are warranted to fight tuberculosis. Here we assess the safety and immunogenicity of adjunctive vaccination with the H56:IC31 candidate and cyclooxygenase-2-inhibitor ...treatment (etoricoxib) in pulmonary and extra-pulmonary tuberculosis patients in a randomized open-label phase I/II clinical trial (TBCOX2, NCT02503839). A total of 222 patients were screened, 51 enrolled and randomized; 13 in the etoricoxib-group, 14 in the H56:IC31-group, 12 in the etoricoxib+H56:IC31-group and 12 controls. Three Serious Adverse Events were reported in the etoricoxib-groups; two urticarial rash and one possible disease progression, no Serious Adverse Events were vaccine related. H56:IC31 induces robust expansion of antigen-specific T-cells analyzed by fluorospot and flow cytometry, and higher proportion of seroconversions. Etoricoxib reduced H56:IC31-induced T-cell responses. Here, we show the first clinical data that H56:IC31 vaccination is safe and immunogenic in tuberculosis patients, supporting further studies of H56:IC31 as a host-directed-therapy strategy. Although etoricoxib appears safe, our data do not support therapy with adjunctive cyclooxygenase-2-inhibitors.
Background
A high proportion of COVID‐19 patients have cardiac involvement, even those without known cardiac disease. Downregulation of angiotensin converting enzyme 2 (ACE2), a receptor for ...SARS‐CoV‐2 and the renin‐angiotensin system, as well as inflammatory mechanisms have been suggested to play a role. ACE2 is abundant in the gut and associated with gut microbiota composition. We hypothesized that gut leakage of microbial products, and subsequent inflammasome activation could contribute to cardiac involvement in COVID‐19 patients.
Methods
Plasma levels of a gut leakage marker (LPS‐binding protein, LBP), a marker of enterocyte damage (intestinal fatty acid binding protein, IFABP), a gut homing marker (CCL25, ligand for chemokine receptor CCR9) and markers of inflammasome activation (IL‐1β, IL‐18 and their regulatory proteins) were measured at three time points (day 1, 3–5 and 7–10) in 39 hospitalized COVID‐19 patients and related to cardiac involvement.
Results
Compared to controls, COVID‐19 patients had elevated plasma levels of LBP and CCL25 but not IFABP, suggesting impaired gut barrier function and accentuated gut homing of T cells without excessive enterocyte damage. Levels of LBP were twice as high at baseline in patients with elevated cardiac markers compared with those without and remained elevated during hospitalization. Also, markers of inflammasome activation were moderately elevated in patients with cardiac involvement. LBP was associated with higher NT‐pro‐BNP levels, whereas IL‐18, IL‐18BP and IL‐1Ra were associated with higher troponin levels.
Conclusion
Patients with cardiac involvement had elevated markers of gut leakage and inflammasome activation, suggestive of a potential gut‐heart axis in COVID‐19.
Background
Although coronavirus disease 2019 (COVID‐19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier ...dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long‐term respiratory dysfunction remains unknown.
Methods
Plasma was collected during hospital admission and after 3 months from the NOR‐Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3‐month follow‐up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene.
Results
Gut microbiota diversity was reduced in COVID‐19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide‐binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low‐grade inflammation and respiratory dysfunction after 3 months.
Conclusion
Respiratory dysfunction after COVID‐19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut–lung axis that should be further investigated in relation to long‐term pulmonary dysfunction and long COVID.
Background
The complement system, an upstream recognition system of innate immunity, is activated upon SARS‐CoV‐2 infection. To gain a deeper understanding of the extent and duration of this ...activation, we investigated complement activation profiles during the acute phase of COVID‐19, its persistence post‐recovery and dynamic changes in relation to disease severity.
Methods
Serial blood samples were obtained from two cohorts of hospitalized COVID‐19 patients (n = 457). Systemic complement activation products reflecting classical/lectin (C4d), alternative (C3bBbP), common (C3bc) and terminal pathway (TCC and C5a) were measured during hospitalization (admission, days 3–5 and days 7–10), at 3 months and after 1 year. Levels of activation and temporal profiles during hospitalization were related to disease severity defined as respiratory failure (PO2/FiO2 ratio <26.6 kPa) and/or admission to intensive care unit, 60‐day total mortality and pulmonary pathology after 3 months.
Findings
During hospitalization, TCC, C4d, C3bc, C3bBbP and C5a were significantly elevated compared to healthy controls. Severely ill patients had significantly higher levels of TCC and C4d (p < 0.001), compared to patients with moderate COVID‐19. Escalated levels of TCC and C4d during hospitalization were associated with a higher risk of 60‐day mortality (p < 0.001), and C4d levels were additionally associated with chest CT changes at 3 months (p < 0.001). At 3 months and 1 year, we observed consistently elevated levels of most complement activation products compared to controls.
Conclusion
Hospitalized COVID‐19 patients display prominent and long‐lasting systemic complement activation. Optimal targeting of the system may be achieved through enhanced risk stratification and closer monitoring of in‐hospital changes of complement activation products.
Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key ...player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO₂/FiO₂ ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.
New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, ...but the antiviral effects of these drugs are not known.
To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx.
NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616).
23 hospitals in Norway.
Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection.
Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (
= 42), HCQ (
= 52), or standard of care (SoC) (
= 87).
In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables.
No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance.
The trial had no placebo group.
Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.
National Clinical Therapy Research in the Specialist Health Services, Norway.
Serum ACE as a prognostic biomarker in COVID‐19: a case series Kolberg, Espen Skarstein; Wickstrøm, Kristin; Tonby, Kristian ...
APMIS : acta pathologica, microbiologica et immunologica Scandinavica,
April 2021, 2021-04-00, 20210401, Letnik:
129, Številka:
4
Journal Article
Myeloid‐derived suppressor cells (MDSCs) increase in tuberculosis (TB) and may be targets for host‐directed therapy (HDT). In this study, we use flow cytometry to analyze the effects of ...cyclooxygenase‐2 inhibitors (COX‐2i) on monocytic (M)‐MDSCs in blood from TB patients attending a clinical trial of COX‐2i. The effects of COX‐2i on M‐MDSCs and mycobacterial uptake were also studied by an in vitro mycobacterial infection model. We found that M‐MDSC frequencies correlated with TB disease severity. Reduced M‐MDSC (P = 0.05) and IDO (P = 0.03) expression was observed in the COX‐2i group. We show that peripheral blood‐derived M‐MDSCs successfully internalized Mycobacterium bovis and that in vitro mycobacterial infection increased COX‐2 (P = 0.002), PD‐L1 (P = 0.01), and Arginase‐1 (P = 0.002) expression in M‐MDSCs. Soluble IL‐1β, IL‐10, and S100A9 were reduced in COX‐2i‐treated M‐MDSCs cultures (P < 0.05). We show novel data that COX‐2i had limited effect in vivo but reduced M‐MDSC cytokine production in vitro. The relevance of COX‐2i in a HDT strategy needs to be further explored.
Graphical
Study of Cyclooxygenase‐2 inhibitors effects on monocytic Myeloid‐derived suppressor cells in host directed therapy clinical trial supported by in‐vitro data with reduction of suppressive soluble markers.
Objective
To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve ...as biomarkers for disease severity in COVID-19 patients.
Methods
Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects.
Results
In total, 21% (
n
= 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (
n
= 6). Non-survivors had higher serum concentrations of NfL (
p
< 0.001) upon admission than patients who were discharged alive both in adjusted analyses (
p
= 2.6 × 10
–7
) and unadjusted analyses (
p
= 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (
p
= 0.02).
Conclusion
Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.
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