α1-Antitrypsin deficiency and the risk of COVID-19: an urgent call to action

Yang, Chengli; Chapman, Kenneth R.; Wong, Aaron; Liu, Mingyao

doi:10.1016/s2213-2600(21)00018-7

Cited by 47 publications

(47 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have reported that CKD and biomarkers indicative of renal impairment predict critical COVID-19, while survivors remain at high risk of CKD [28]. The COV50 urinary signature showed upregulation of a1-antitrypsin degradation products, which is in line with reports that a1-antitrypsin deficiency is a major risk factor for life-threatening COVID-19 [29]. No information in the context of COVID-19 is currently available on CD99, which is involved in cell recruitment, leukocyte trans-endothelial migration, and maintaining the integrity of the endothelial barrier [30,31].…”

Section: Discussionsupporting

confidence: 81%

A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients

Wendt¹,

Thijs²,

Kalbitz³

et al. 2021

EClinicalMedicine

View full text Add to dashboard Cite

Background COVID-19 prediction models based on clinical characteristics, routine biochemistry and imaging, have been developed, but little is known on proteomic markers reflecting the molecular pathophysiology of disease progression. Methods he multicentre (six European study sites) Prospective Validation of a Proteomic Urine Test for Early and Accurate Prognosis of Critical Course Complications in Patients with SARS-CoV-2 Infection Study (Crit-COV-U) is recruiting consecutive patients (≥ 18 years) with PCR-confirmed SARS-CoV-2 infection. A urinary proteomic biomarker (COV50) developed by capillary-electrophoresis-mass spectrometry (CE-MS) technology, comprising 50 sequenced peptides and identifying the parental proteins, was evaluated in 228 patients (derivation cohort) with replication in 99 patients (validation cohort). Death and progression along the World Health Organization (WHO) Clinical Progression Scale were assessed up to 21 days after the initial PCR test. Statistical methods included logistic regression, receiver operating curve (ROC) analysis and comparison of the area under the curve (AUC). Findings in the derivation cohort, 23 patients died, and 48 developed worse WHO scores. The odds ratios (OR) for death per 1 standard deviation (SD) increment in COV50 were 3·52 (95% CI, 2·02–6·13, p <0·0001) unadjusted and 2·73 (1·25–5·95, p = 0·012) adjusted for sex, age, baseline WHO score, body mass index (BMI) and comorbidities. For WHO scale progression, the corresponding OR were 2·63 (1·80–3·85, p< 0·0001) and 3·38 (1·85–6·17, p< 0·0001), respectively. The area under the curve (AUC) for COV50 as a continuously distributed variable was 0·80 (0·72–0·88) for mortality and 0·74 (0·66–0·81) for worsening WHO score. The optimised COV50 thresholds for mortality and worsening WHO score were 0·47 and 0·04 with sensitivity/specificity of 87·0 (74·6%) and 77·1 (63·9%), respectively. On top of covariates, COV50 improved the AUC, albeit borderline for death, from 0·78 to 0·82 ( p = 0·11) and 0·84 ( p = 0·052) for mortality and from 0·68 to 0·78 ( p = 0·0097) and 0·75 ( p = 0·021) for worsening WHO score. The validation cohort findings were confirmatory. Interpretation this first CRIT-COV-U report proves the concept that urinary proteomic profiling generates biomarkers indicating adverse COVID-19 outcomes, even at an early disease stage, including WHO stages 1–3. These findings need to be consolidated in an upcoming final dataset.

show abstract

Section: Discussionsupporting

confidence: 81%

A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients

Wendt¹,

Thijs²,

Kalbitz³

et al. 2021

EClinicalMedicine

View full text Add to dashboard Cite

show abstract

“…It is an inhibitor of papain-like cysteine proteases such as cathepsin [67] , which is required for Spike cleavage during SARS CoV-2 entry [68] . Interestingly SERPINA1 deficiencies or mutations in populations were found to be associated with severe forms of COVID-19 [69] . Taken together, this indicates a potential antiviral role for SERPINs against SARS-CoV-2, which needs further exploration.…”

Section: Discussionmentioning

confidence: 99%

Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples

Biji

Khatun²,

Swaraj³

et al. 2021

EBioMedicine

View full text Add to dashboard Cite

Background While our battle with the COVID-19 pandemic continues, a multitude of Omics data have been generated from patient samples in various studies. Translation of these data into clinical interventions against COVID-19 remains to be accomplished. Exploring host response to COVID-19 in the upper respiratory tract can unveil prognostic markers and therapeutic targets. Methods We conducted a meta-analysis of published transcriptome and proteome profiles of respiratory samples of COVID-19 patients to shortlist high confidence upregulated host factors. Subsequently, mRNA overexpression of selected genes was validated in nasal swabs from a cohort of COVID-19 positive/negative, symptomatic/asymptomatic individuals. Guided by this analysis, we sought to check for potential drug targets. An FDA-approved drug, Auranofin, was tested against SARS-CoV-2 replication in cell culture and Syrian hamster challenge model. Findings The meta-analysis and validation in the COVID-19 cohort revealed S100 family genes (S100A6, S100A8, S100A9, and S100P) as prognostic markers of severe COVID-19. Furthermore, Thioredoxin (TXN) was found to be consistently upregulated. Auranofin, which targets Thioredoxin reductase, was found to mitigate SARS-CoV-2 replication in vitro. Furthermore, oral administration of Auranofin in Syrian hamsters in therapeutic as well as prophylactic regimen reduced viral replication, IL-6 production, and inflammation in the lungs. Interpretation Elevated mRNA level of S100s in the nasal swabs indicate severe COVID-19 disease, and FDA-approved drug Auranofin mitigated SARS-CoV-2 replication in preclinical hamster model. Funding This study was supported by the DBT-IISc partnership program (DBT (IED/4/2020-MED/DBT)), the Infosys Young Investigator award (YI/2019/1106), DBT-BIRAC grant (BT/CS0007/CS/02/20) and the DBT-Wellcome Trust India Alliance Intermediate Fellowship (IA/I/18/1/503613) to ST lab.

show abstract

“…AAT has also been shown to exert anti-SARS-CoV-2 viral effects by inhibiting transmembrane serine protease 2 (TMPRSS2), a cell membrane-bound protease that promotes SARS-CoV-2 entry into host cells, and the disintegrin and metalloproteinase 17 (ADAM17). Therefore, it is conceivable that AAT in CCP exerts protective effects against COVID-19 infection, not only in patients suffering from congenital deficiency [ 22 ]. Plasma-derived AAT concentrates are currently under clinical evaluation in patients with COVID-19.…”

Section: Potential Beneficial Factors In Ccpmentioning

confidence: 99%

COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors

Focosi¹,

Franchini

Pirofski

et al. 2021

Viruses

View full text Add to dashboard Cite

COVID-19 convalescent plasma (CCP) is currently under investigation for both treatment and post-exposure prophylaxis. The active component of CCP mediating improved outcome is commonly reported as specific antibodies, particularly neutralizing antibodies, with clinical efficacy characterized according to the level or antibody affinity. In this review, we highlight the potential role of additional factors in CCP that can be either beneficial (e.g., AT-III, alpha-1 AT, ACE2+ extracellular vesicles) or detrimental (e.g., anti-ADAMTS13, anti-MDA5 or anti-interferon autoantibodies, pro-coagulant extracellular vesicles). Variations in these factors in CCP may contribute to varied outcomes in patients with COVID-19 and undergoing CCP therapy. We advise careful, retrospective investigation of such co-factors in randomized clinical trials that use fresh frozen plasma in control arms. Nevertheless, it might be difficult to establish a causal link between these components and outcome, given that CCP is generally safe and neutralizing antibody effects may predominate.

show abstract

α1-Antitrypsin deficiency and the risk of COVID-19: an urgent call to action

Cited by 47 publications

References 13 publications

A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients

A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients

Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples

COVID-19 Convalescent Plasma Is More than Neutralizing Antibodies: A Narrative Review of Potential Beneficial and Detrimental Co-Factors

Contact Info

Product

Resources

About