Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection.

BACKGROUND: Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. METHODS: Using measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261). RESULTS: We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. CONCLUSIONS: Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Acute kidney injury (AKI) is a sudden, sometimes fatal, episode of kidney failure or damage. It is a known complication of COVID-19, albeit through unclear mechanisms. COVID-19 is also associated with kidney dysfunction in the long term, or chronic kidney disease (CKD). There is a need to better understand which patients with COVID-19 are at risk of AKI or CKD. We measure levels of several thousand proteins in the blood of hospitalized COVID-19 patients. We discover and validate sets of proteins associated with severe AKI and CKD in these patients. The markers identified suggest that kidney injury in COVID-19 patients involves damage to kidney cells that reabsorb fluid from urine and reduced blood flow to the heart, causing damage to heart muscles. Our findings might help clinicians to predict kidney injury in patients with COVID-19, and to understand its mechanisms.

Assessment of Cardiac Adverse Events following COVID-19 Vaccination by Speckle Tracking Echocardiography (preprint)

Background: Cardiac discomfort has been reported periodically in COVID-19 vaccinated individuals. Thus, this study aimed to evaluate the role of myocardial strains in the early assessment of the clinical presentations after COVID-19 vaccination. Methods and Results: Totally, 121 subjects who received at least one dose of vaccine within 6 weeks underwent laboratory tests and echocardiogram. Two-dimensional speckle tracking echocardiography (2D-STE) was implemented to analyze changes in the left ventricular myocardium. After vaccination, 66 individuals (55.4 ± 17.4 years) developed cardiac discomfort, such as chest tightness, palpitations, dyspnea, and chest pain. All had normal serum levels of creatine phosphokinase, creatine kinase myocardial band, troponin, N-terminal pro b-type natriuretic peptide, platelets, and D-dimer. Left ventricular ejection fraction in the symptomatic group (71.41% ± 7.12%) and the control group (72.18% ± 5.11%) (p = 0.492) were normal. Use of 2D-STE presented global longitudinal strain (GLS) and global circumferential strain (GCS) were reduced in symptomatic group (17.86% ± 3.22% and 18.37% ± 5.22%) compared to control group (19.54% ± 2.18% and 20.73% ± 4.09%) (p = 0.001 and p = 0.028). Conclusion: COVID-19 vaccine-related cardiac adverse effects can be assessed early by 2D-STE. The prognostic implications of GLS and GCS enable evaluation of subtle changes in myocardial function after vaccination.

Circulating proteins to predict COVID-19 severity.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care.

Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.

Fluid-structure interaction analysis of airflow, structural mechanics and aerosol dynamics in a four-generation acinar model.

Elucidating the aerosol dynamics in the pulmonary acinar region is imperative for both health risk assessment and inhalation therapy, especially nowadays with the occurrence of the global COVID-19 pandemic. During respiration, the chest's outward elastic recoil and the lungs' inward elastic recoil lead to a change of transmural pressure, which drives the lungs to expand and contract to inhale and expel airflow and aerosol. In contrast to research using predefined wall motion, we developed a four-generation acinar model and applied an oscillatory pressure on the model outface to generate structure deformation and airflow. With such tools at hand, we performed a computational simulation that addressed both the airflow characteristic, structural mechanics, and aerosol dynamics in the human pulmonary acinar region. Our results showed that there is no recirculating flow in the sac. The structural displacement and stress were found to be positively related to the change of model volume and peaked at the end of inspiration. It was noteworthy that the stress distribution on the acinar wall was significantly heterogeneous, and obvious concentrations of stress were found at the junction of the alveoli and the ducts or the junction of the alveoli and alveoli in the sac. Our result demonstrated the effect of breathing cycles and aerosol diameter on deposition fraction and location of aerosols in the size range of 0.1-5 µm. Multiple respiratory cycles were found necessary for adequate deposition or escape of submicron particles while having a negligible influence on the transport of large particles, which were dominated by gravity. Our study can provide new insights into the further investigation of airflow, structural mechanics, and aerosol dynamics in the acinar depth.

Increasing serum iron levels and their role in the risk of infectious diseases: a Mendelian randomization approach.

OBJECTIVES: Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. METHODS: As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). RESULTS: Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P <0.05). CONCLUSION: Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them.

Liver injury in COVID-19: Clinical features, potential mechanisms, risk factors and clinical treatments.

The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to global health for nearly 3 years. In addition to pulmonary complications, liver injury is not uncommon in patients with novel COVID-19. Although the prevalence of liver injury varies widely among COVID-19 patients, its incidence is significantly increased in severe cases. Hence, there is an urgent need to understand liver injury caused by COVID-19. Clinical features of liver injury include detectable liver function abnormalities and liver imaging changes. Liver function tests, computed tomography scans, and ultrasound can help evaluate liver injury. Risk factors for liver injury in patients with COVID-19 include male sex, preexisting liver disease including liver transplantation and chronic liver disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-19-related liver injury is not fully understood. Its pathophysiological basis can generally be explained by systemic inflammatory response, hypoxic damage, ischemia-reperfusion injury, and drug side effects. In this review, we systematically summarize the existing literature on liver injury caused by COVID-19, including clinical features, underlying mechanisms, and potential risk factors. Finally, we discuss clinical management and provide recommendations for the care of patients with liver injury.

The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals.

INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Real-world study of the effectiveness of BBIBP-CorV (Sinopharm) COVID-19 vaccine in the Kingdom of Morocco.

BACKGROUND: The Kingdom of Morocco approved BBIBP-CorV (Sinopharm) COVID-19 vaccine for emergency use on 22 January 2021 in a two-dose, three-to-four-week interval schedule. We conducted a retrospective cohort study to determine real-world BBIBP-CorV vaccine effectiveness (VE) against serious or critical hospitalization of individuals RT-PCR-positive for SARS-CoV-2 during the first five months of BBIBP-CorV use in Morocco. METHODS: The study was conducted among adults 18-99 years old who were tested by RT-PCR for SARS-CoV-2 infection between 1 February and 30 June 2021. RT-PCR results were individually linked with outcomes from the COVID-19 severe or critical hospitalization dataset and with vaccination histories from the national vaccination registration system. Individuals with partial vaccination (< 2 weeks after dose two) or in receipt of any other COVID-19 vaccine were excluded. Unadjusted and adjusted VE estimates against hospitalization for serious or critical illness were made by comparing two-dose vaccinated and unvaccinated individuals in logistic regression models, calculated as (1-odds ratio) * 100%. RESULTS: There were 348,190 individuals able to be matched across the three databases. Among these, 140,892 were fully vaccinated, 206,149 were unvaccinated, and 1,149 received homologous BBIBP-CorV booster doses. Unadjusted, full-series, unboosted BBIBP-CorV VE against hospitalization for serious or critical illness was 90.2% (95%CI: 87.8-92.0%). Full-series, unboosted VE, adjusted for age, sex, and calendar day of RT-PCR test, was 88.5% (95%CI: 85.8-90.7%). Calendar day- and sex-adjusted VE was 96.4% (95%CI: 94.6-97.6%) for individuals < 60 years, and was 53.3% (95%CI: 39.6-63.9%) for individuals 60 years and older. There were no serious or critical illnesses among BBIBP-CorV-boosted individuals. CONCLUSIONS: Effectiveness of Sinopharm's BBIBP-CorV was consistent with phase III clinical trial results. Two doses of BBIBP-CorV was highly protective against COVID-19-associated serious or critical hospitalization in working-age adults under real-world conditions and moderately effective in older adults. Booster dose vaccination was associated with complete protection, regardless of age, although only a small proportion of subjects received booster doses.

A Review: The Manifestations, Mechanisms, and Treatments of Musculoskeletal Pain in Patients With COVID-19.

The outbreak of COVID-19 poses a serious threat to global health. Musculoskeletal (MSK) pain is the most frequent symptom in patients with COVID-19 besides fever and cough. There are limited studies addressing MSK symptoms in patients with COVID-19. This review aims to provide an overview of current studies related to MSK pain in patients with COVID-19, summarize the possible mechanisms of myalgia, and describe the current management options. In addition to acute respiratory manifestations, COVID-19 might also affect neurological systems which include skeletal manifestations and muscular injury. A possible mechanism of MSK pain and myalgia in COVID-19 may be related to the distribution of angiotensin-converting enzyme 2 (ACE-2) and the occurrence of cytokine storms. ACE-2 has been shown to be the receptor of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2). Moreover, studies have shown that inflammatory cytokines could cause myalgia by inducing prostaglandin E2 (PGE2) production. In addition, it was also found that the plasma levels of IL2, IL7, IL10, IL-6, TNFα, and e lymphopenia were higher in patients with COVID-19. In general, the treatment of MSK pain in patients with COVID-19 falls into pharmacological and non-pharmacological interventions. Various treatments of each have its own merits. The role of vaccination is irreplaceable in the efforts to prevent COVID-19 and mitigates its subsequent symptoms.

Visualization of the infection risk assessment of SARS-CoV-2 through aerosol and surface transmission in a negative-pressure ward.

Since December 2019, coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a great challenge to the world's public health system. Nosocomial infections have occurred frequently in medical institutions worldwide during this pandemic. Thus, there is an urgent need to construct an effective surveillance and early warning system for pathogen exposure and infection to prevent nosocomial infections in negative-pressure wards. In this study, visualization and construction of an infection risk assessment of SARS-CoV-2 through aerosol and surface transmission in a negative-pressure ward were performed to describe the distribution regularity and infection risk of SARS-CoV-2, the critical factors of infection, the air changes per hour (ACHs) and the viral variation that affect infection risk. The SARS-CoV-2 distribution data from this model were verified by field test data from the Wuhan Huoshenshan Hospital ICU ward. ACHs have a great impact on the infection risk from airborne exposure, while they have little effect on the infection risk from surface exposure. The variant strains demonstrated significantly increased viral loads and risks of infection. The level of protection for nurses and surgeons should be increased when treating patients infected with variant strains, and new disinfection methods, electrostatic adsorption and other air purification methods should be used in all human environments. The results of this study may provide a theoretical reference and technical support for reducing the occurrence of nosocomial infections.

Identification of transcriptional regulatory network associated with response of host epithelial cells to SARS-CoV-2.

Identification of transcriptional regulatory mechanisms and signaling networks involved in the response of host cells to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable the identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, our goal was to identify a transcriptional regulatory network that is associated with gene expression changes between samples infected by SARS-CoV-2 and those that are infected by other respiratory viruses to narrow the results on those enriched or specific to SARS-CoV-2. We combined a series of recently developed computational tools to identify transcriptional regulatory mechanisms involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus when compared to other viruses. In addition, using network-guided analyses, we identified kinases associated with this network. The results identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory network identified herein reflects a combination of known hits and novel candidate pathways supporting the novel computational pipeline presented herein to quickly narrow down promising avenues of investigation when facing an emerging and novel disease such as COVID-19.

Proactive COVID-19 Infection Prevention Measures in a Hyperbaric Oxygen Therapy Center.

Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China in December 2019 and its subsequent global spread, Taiwan has been combatting this pandemic. COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As SARS-CoV-2 can be transmitted through droplets and aerosols, we cannot ignore the risk of transmission during hyperbaric oxygen therapy (HBOT). Our hyperbaric oxygen therapy center prioritizes preventing the spread of COVID-19 and maintaining operation for the patients during the pandemic. The aim of this article is to share the protocol that we have adopted in our hyperbaric oxygen therapy center to help prevent the spread of COVID-19.