Coordinated local mucosal and systemic immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either protect against coronavirus disease 2019 (COVID-19) ...pathologies or fail, leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct patients with COVID-19 during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. By contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microorganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
Background
Coronavirus disease-2019 (COVID-19), a respiratory disease has been associated with ischemic complications, coagulation disorders, and an endotheliitis.
Objectives
To explore endothelial ...damage and activation-related biomarkers in COVID-19 patients with criteria of hospitalization for referral to intensive care unit (ICU) and/or respiratory worsening.
Methods
Analysis of endothelial and angiogenic soluble markers in plasma from patients at admission.
Results
Study enrolled 40 consecutive COVID-19 patients admitted to emergency department that fulfilled criteria for hospitalization. Half of them were admitted in conventional wards without any ICU transfer during hospitalization; whereas the 20 others were directly transferred to ICU. Patients transferred in ICU were more likely to have lymphopenia, decreased SpO2 and increased D-dimer, CRP and creatinine levels. In those patients, soluble E-selectin and angiopoietin-2 were significantly increased (
p
value at 0.009 and 0.003, respectively). Increase in
SELE
gene expression (gene coding for E-selectin protein) was confirmed in an independent cohort of 32 patients using a whole blood gene expression profile analysis. In plasma, we found a strong association between angiopoetin-2 and CRP, creatinine and D-dimers (with
p
value at 0.001, 0.001 and 0.003, respectively). ROC curve analysis identified an Angiopoietin-2 cut-off of 5000 pg/mL as the best predictor for ICU outcome (Se = 80.1%, Sp = 70%, PPV = 72.7%, NPV = 77%), further confirmed in multivariate analysis after adjustment for creatinine, CRP or D-dimers.
Conclusion
Angiopoietin-2 is a relevant predictive factor for ICU direct admission in COVID-19 patients. This result showing an endothelial activation reinforces the hypothesis of a COVID-19-associated microvascular dysfunction.
The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with ...COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.
Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of ...50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated ...with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.
Background
Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation ...remain unclear.
Methods
We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes.
Results
We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67,
p
= 0.028 and AUC = 0.74,
p
= 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified
ITG2AB
,
GP1BB
,
PPBP
and
SELPLG
to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for
SELPLG
and
PPBP
(AUC = 0.8,
p
= 0.046 for both). An optimal cutoff value for
PBPP
was predictive of intubation with 100% NPV and 45% PPV, and for
SELPLG
with 100% NPV and 50% PPV.
Conclusion
We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified
PPBP/CXCL7
and
SELPLG
as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.
Abstract
Background
Coronavirus disease 2019 (COVID-19) is a global public health problem that has already caused more than 662 000 deaths worldwide. Although the clinical manifestations of COVID-19 ...are dominated by respiratory symptoms, some patients present other severe damage such as cardiovascular, renal and liver injury, and/or multiple organ failure, suggesting a spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in blood. Recent ultrasensitive polymerase chain reaction (PCR) technology now allows absolute quantification of nucleic acids in plasma. We intend to use the droplet-based digital PCR technology to obtain sensitive detection and precise quantification of plasma SARS-CoV-2 viral load (SARS-CoV-2 RNAemia) in hospitalized COVID-19 patients.
Methods
Fifty-eight consecutive COVID-19 patients with pneumonia 8 to 12 days after onset of symptoms and 12 healthy controls were analyzed. Disease severity was categorized as mild to moderate in 17 patients, severe in 16, and critical in 26. Plasma SARS-CoV-2 RNAemia was quantified by droplet digital Crystal Digital PCR next-generation technology (Stilla Technologies, Villejuif, France).
Results
Overall, SARS-CoV-2 RNAemia was detected in 43 (74.1%) patients. Prevalence of positive SARS-CoV-2 RNAemia correlated with disease severity, ranging from 53% in mild-to-moderate patients to 88% in critically ill patients (P = .036). Levels of SARS-CoV-2 RNAemia were associated with severity (P = .035). Among 9 patients who experienced clinical deterioration during follow-up, 8 had positive SARS-CoV-2 RNAemia at baseline, whereas only 1 critical patient with undetectable SARS-CoV-2 RNAemia at the time of analysis died at day 27.
Conclusion
SARS-CoV-2 RNAemia measured by droplet-based digital PCR constitutes a promising prognosis biomarker in COVID-19 patients.
Plasma severe acute respiratory syndrome coronavirus 2 RNAemia quantified by droplet-based digital polymerase chain reaction is correlated with clinical severity of coronavirus disease 2019 (COVID-19) and constitutes a promising prognosis biomarker to monitor in hospitalized COVID-19 patients.
•VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described autoinflammatory syndrome mostly affecting men older than 50 years, caused by somatic mutation in ...the UBA1 gene.•Patients develop both inflammatory and hematologic manifestations, leading to significant morbidity and mortality.•The therapeutic management is currently poorly codified, but is based on two main approaches: targeting immune and inflammatory pathways or targeting the UBA1-mutated hematopoietic population.
VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described autoinflammatory syndrome, mostly affecting men older than 50 years, caused by somatic mutation in the UBA1 gene, a X-linked gene involved in the activation of ubiquitin system. Patients present a broad spectrum of inflammatory manifestations (fever, neutrophilic dermatosis, chondritis, pulmonary infiltrates, ocular inflammation, venous thrombosis) and hematological involvement (macrocytic anemia, thrombocytopenia, vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow) that are responsible for a significant morbidity and mortality. The therapeutic management is currently poorly codified but is based on two main approaches: controlling inflammatory symptoms (by using corticosteroids, JAK inhibitor or tocilizumab) or targeting the UBA1-mutated hematopoietic population (by using azacitidine or allogeneic hematopoietic stem cell transplantation). Supportive care is also important and includes red blood cell or platelet transfusions, erythropoiesis stimulating agents, thromboprophylaxis and anti-infectious prophylaxis. The aim of this review is to provide a current overview of the VEXAS syndrome, particularly focusing on its pathophysiological, diagnostic and therapeutic aspects.
Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Among them, ICIs-induced systemic sclerosis (SSc) is poorly known.
To better characterize this irAE, our ...comprehensive approach combined the description of ICIs-induced scleroderma cases, the systematic review of the literature and the analysis of VigiBase, the WHO pharmacovigilance database.
We identified two cases with underlying limited cutaneous SSc who presented a dramatic increase in the skin thickening following pembrolizumab, associated with scleroderma renal crisis in one case. In the literature, four cases of scleroderma and four cases of morphea have been reported with pembrolizumab or nivolumab. None following ipilimumab, atezolizumab or durvalumab were retrieved. Skin changes appeared or worsened more quickly with pembrolizumab than nivolumab, and had different patterns between both drugs. Patients with generalized skin changes required high-dose prednisone to improve skin thickening. Among the 2527 scleroderma cases identified in VigiBase, 35 were associated with ICIs. Nivolumab and pembrolizumab showed a disproportionality in scleroderma reporting. No disproportionality was found for ipilimumab, atezolizumab or durvalumab.
The risk of scleroderma or fibrosis extension in SSc patients should be considered when initiating anti-PD-1 agents. It suggests the role of PD-1/PD-L1 interaction in the pathophysiology of SSc.
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