PROGNOSIS - Fondazione MISI

Martin Potts et al.

Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity

Cell, May 2023 ; doi.org/10.1016/j.celrep.2023.112613

Abstract

Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors are non-specific, providing limited mechanistic insight into the peripheral blood mononuclear cell (PBMC) populations that drive the pathogenesis of severe COVID-19. To identify cellular phenotypes associated with disease, we performed a comprehensive, unbiased analysis of total and plasma-membrane PBMC proteomes from 40 unvaccinated individuals with SARS-CoV-2, spanning the whole disease spectrum. Combined with RNA sequencing (RNA-seq) and flow cytometry from the same donors, we define a comprehensive multi-omic profile for each severity level, revealing that immune-cell dysregulation progresses with increasing disease. The cell-surface proteins CEACAMs1, 6, and 8, CD177, CD63, and CD89 are strongly associated with severe COVID-19, corresponding to the emergence of atypical CD3+CD4+CEACAM1/6/8+CD177+CD63+CD89+ and CD16+CEACAM1/6/8+ mononuclear cells. Utilization of these markers may facilitate real-time patient assessment by flow cytometry and identify immune populations that could be targeted to ameliorate immunopathology.

Martin Potts et al.

Proteomic analysis of circulating immune cells identifies cellular phenotypes associated with COVID-19 severity

Cell, May 2023; doi.org/10.1016/j.celrep.2023.112613

Abstract

YukiyoshiKimura et al.

Prognostic utility of the chest computed tomography severity score for the requirement of mechanical ventilation and mortality in hospitalized patients with COVID-19

Cell, May 2023; doi.org/10.1016/j.heliyon.2023.e16020

Abstract

To correlate the chest computed tomography severity score (CT-SS) with the need for mechanical ventilation and mortality in hospitalized patients with COVID-19.

Materials and methods

The chest CT images of 224 inpatients with COVID-19, confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR), were retrospectively reviewed from April 1 to 25, 2020, in a tertiary health care center. We calculated the CT-SS (dividing each lung into 20 segments and assigning scores of 0, 1, and 2 due to opacification involving 0%, <50%, and ≥50% of each region for a global range of 0–40 points, including both lungs), and collected clinical data. The receiver operating characteristic curve and Youden Index analysis was performed to calculate the CT-SS threshold and accuracy for classification for risk of mortality or MV requirement.

Results

136 men and 88 women were recruited, with an age range of 23–91 years and a mean of 50.17 years; 79 met the MV criteria, and 53 were nonsurvivors. The optimal threshold was >27.5 points for mortality (area under ROC curve >0.96), with a sensitivity of 93% and specificity of 87%, and >25.5 points for the need for MV (area under ROC curve >0.94), with a sensitivity of 90% and specificity of 89%. The Kaplan-Meier curves show a significant difference in mortality by the CT-SS threshold (Log Rank p < 0.001).

Conclusions

In our cohort of hospitalized patients with COVID-19, the CT-SS accurately discriminates the need for MV and mortality risk. In conjunction with clinical status and laboratory data, the CT-SS may be a useful imaging tool that could be included in establishing a prognosis for this population.

G. Craig Wood et al.

Prior metabolic surgery reduced COVID-19 severity: Systematic analysis from year one of the COVID-19 pandemic

Cell, April 2023; doi.org/10.1016/j.heliyon.2023.e15824

Abstract

Background

Obesity is a risk factor for COVID-19 severity. Recent studies suggest that prior metabolic surgery (MS) modifies the risk of COVID-19 severity.

Methods

COVID-19 outcomes were compared between patients with MS (n = 287) and a matched cohort of unoperated patients (n = 861). Multiple logistic regression was used to identify predictors of hospitalization. A systematic literature review and pooled analysis was conducted to provide overall evidence of the influence of prior metabolic surgery on COVID-19 outcomes.

Results

COVID-19 patients with MS had less hospitalization (9.8% versus 14.3%, p = 0.049). Age 70+, higher BMI, and low weight regain after MS were associated with more hospitalization after COVID-19. A systematic review of 7 studies confirmed that MS reduced the risk of post-COVID-19 hospitalization (OR = 0.71, 95%CI = [0.61–0.83], p < 0.0001) and death (OR = 0.44, 95%CI = [0.30–0.65], p < 0.0001).

Conclusion

MS favorably modifies the risks of severe COVID-19 infection. Older age and higher BMI are major risk factors for severity of COVID-19 infection.

Jesús F Bermejo-Martin et al.

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

The Lancet, April 2023; doi.org/10.1016/S2666-5247(23)00041-1

Abstract

The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19.

Methods

We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1–2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis.

Interpretation

The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood.

MelyssaYaugel-Novoa et al.

Association of IFNAR1 and IFNAR2 with COVID-19 severity

The Lancet, April 2023; doi.org/10.1016/S2666-5247(23)00095-2

Abstract

Type I interferons propagate and amplify the antiviral response at the start of an infection and are crucial for effective antiviral immunity. Type I interferons bind interferon alpha/beta receptors 1 (IFNAR1) and 2 (IFNAR2), which are ubiquitous, but expressed differentially depending on the cell type.1

Interferon pathways have been identified as involved in COVID-19 and are associated with disease severity.2 Genome-wide association studies, transcriptomic studies, and single-cell studies, have identified IFNAR2 as a risk factor for severe COVID-19.3 However, the correlation between serum amounts of soluble forms of IFNAR in individuals with COVID-19 at early stages of infection and COVID-19 disease severity has not been investigated.

In this Correspondence, we compared serum IFNAR1 and IFNAR 2 amounts (quantified by two commercial sandwich ELISA kits: LS-F17211 and ab264610) in 77 individuals. This study included ten individuals who were PCR-negative for SARS-CoV-2 and 67 who were PCR-positive (ten asymptomatic patients, 20 patients with mild disease, 17 hospitalised patients [not intensive care unit], and 16 patients in the intensive care unit). Written informed consent for participation was obtained from all participants and ethics approval was obtained from Comité Protection des Personnes Ile de France V (NCT04648709). All samples were collected at the time of patient inclusion in the study (days 3–7 after symptom onset).

Although we found no differences in IFNAR1 concentrations between groups separated by disease severity, IFNAR1 amounts seemed to be inversely correlated to COVID-19 severity (appendix p 1). These results are in concordance with findings from other studies that associated autosomal recessive IFNAR1 deficiency with severe COVID-19.4 By contrast, IFNAR2 concentrations were significantly higher in patients with severe COVID-19 (appendix p 1). IFNAR2 is expressed in three isoforms, two of which are soluble but cannot activate signalling after interaction with type I interferon. Therefore, the action of type I interferon might depend on the relative abundances of IFNAR2 isoforms, as suggested by Aliaga-Gaspar and colleagues in 2021.5 The higher amounts of soluble IFNAR2 in serum observed in our study might underlie an impairment of the immune response in patients with severe COVID-19, which decreases sensitivity to interferon beta and therefore antiviral activity. Our results contrast with the genome-wide association studies or transcriptomic studies. However, these studies did not quantify the soluble IFNAR isoforms in the serum of individuals with COVID-19. Our study contributes to a better understanding of the interferon response damage during SARS-CoV-2 infection. Whether the increased serum concentrations of soluble IFNAR2 in patients with COVID-19 are due to splicing mechanisms, as is the case in patients with multiple sclerosis,5 remains unclear and requires further studies. We believe serum IFNAR1 and IFNAR2 concentrations in patients with COVID-19 can be used as predictors of disease severity and response to interferon treatment outcomes.

Sarah H. Elsea et al.

Association of Glucose-6-Phosphate Dehydrogenase Deficiency With Outcomes in US Veterans With COVID-19

JAMA, March 2023; doi:10.1001/jamanetworkopen.2023.5626

Abstract

Importance The underlying biological risk factors for severe outcome due to SAR-CoV-2 infection are not well defined.

Objective To determine the association between glucose-6-phosphate dehydrogenase (G6PD) deficiency and severity of COVID-19.

Design, Setting, and Participants This retrospective cohort study included analysis of 24 700 veterans with G6PD enzyme testing prior to January 1, 2020, obtained through the US Veterans Health Administration national databases. These veterans were cross-referenced with the Veterans Administration COVID-19 Shared Data Resource for SARS-CoV-2 testing from February 15, 2020, to January 1, 2021. The final study population consisted of 4811 veterans who tested positive for SARS-CoV-2. Statistical analysis was performed from June to December 2021.

Exposures G6PD deficiency.

Main Outcomes and Measures COVID-19 severe illness, as defined by the Centers for Disease Control and Prevention: hospitalization, need for mechanical ventilation and/or intensive care unit admission, or in-hospital mortality after a positive SARS-CoV-2 test.

Conclusions and Relevance In this cohort study of COVID-19–positive veterans, Black male veterans less than 65 years of age and White male veterans 65 years of age or older with G6PD deficiency had an increased likelihood of developing severe COVID-19 compared with veterans without G6PD deficiency. These data indicate a need to consider the potential for G6PD deficiency prior to treatment of patients with SARS-CoV-2 infection as part of clinical strategies to mitigate severe outcomes.

Anna M Parker et al.

Association of Upper Respiratory Streptococcus pneumoniae Colonization With Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Adults

CID, November 2022; doi.org/10.1093/cid/ciac907

Abstract

Background

Streptococcus pneumoniae interacts with numerous viral respiratory pathogens in the upper airway. It is unclear whether similar interactions occur with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods

We collected saliva specimens from working-age adults undergoing SARS-CoV-2 molecular testing at outpatient clinics and via mobile community-outreach testing between July and November 2020 in Monterey County, California. After bacterial culture enrichment, we tested for pneumococci by means of quantitative polymerase chain reaction targeting the lytA and piaB genes, and we measured associations with SARS-CoV-2 infection using conditional logistic regression.

Conclusions

Associations of pneumococcal carriage detection and density with SARS-CoV-2 suggest a synergistic relationship in the upper airway. Longitudinal studies are needed to determine interaction mechanisms between pneumococci and SARS-CoV-2.

MártonKolossváry et al.

Identification of pre-infection markers and differential plasma protein expression following SARS-CoV-2 infection in people living with HIV

The Lancet, March 2023; doi.org/10.1016/j.ebiom.2023.104538

Abstract

Mechanisms contributing to COVID-19 severity in people with HIV (PWH) are poorly understood. We evaluated temporal changes in plasma proteins following SARS-CoV-2 infection and identified pre-infection proteomic markers associated with future COVID-19.

Methods

We leveraged data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Antiretroviral therapy (ART)-treated PWH with clinical, antibody-confirmed COVID-19 as of September 2021 were matched on geographic region, age, and sample timing to antibody negative controls. For cases and controls, pre COVID-19 pandemic specimens were obtained prior to January 2020 to assess change over time and relationship to COVID-19 severity, using false-discovery adjusted mixed effects modeling.

Findings

We compared 257 unique plasma proteins in 94 COVID-19 antibody-confirmed clinical cases and 113 matched antibody-negative controls, excluding COVID-19 vaccinated participants (age 50 years, 73% male). 40% of cases were characterized as mild; 60% moderate to severe. Median time from COVID-19 infection to follow-up sampling was 4 months. Temporal patterns of protein changes differed based on COVID-19 disease severity. Among those experiencing moderate to severe disease vs. controls, NOS3 increased whereas ANG, CASP-8, CD5, GZMH, GZMB, ITGB2, and KLRD1 decreased. Higher pre-pandemic levels of granzymes A, B and H (GZMA, GZMB and GZMH) were associated with the future development of moderate-severe COVID-19 and were related to immune function.

Interpretation

We identified temporal changes in proteins closely linked to inflammatory, immune, and fibrotic pathways which may relate to COVID-19-related morbidity among ART-treated PWH. Further we identified key granzyme proteins associated with future COVID-19 in PWH.

Mehmet Tahir Huyut, ZübeyirHuyut

Effect of ferritin, INR, and D-dimer immunological parameters levels as predictors of COVID-19 mortality: A strong prediction with the decision trees

Cell, March 2023; doi.org/10.1016/j.heliyon.2023.e14015

Abstract

Background and objective

A hyperinflammatory environment is thought to be the distinctive characteristic of COVID-19 infection and an important mediator of morbidity. This study aimed to determine the effect of other immunological parameter levels, especially ferritin, as a predictor of COVID-19 mortality via decision-trees analysis.

Material and method

This is a retrospective study evaluating a total of 2568 patients who died (n = 232) and recovered (n = 2336) from COVID-19 in August and December 2021. Immunological laboratory data were compared between two groups that died and recovered from patients with COVID-19. In addition, decision trees from machine learning models were used to evaluate the performance of immunological parameters in the mortality of the COVID-19 disease.

Results

Non-surviving from COVID-19 had 1.75 times higher ferritin, 10.7 times higher CRP, 2.4 times higher D-dimer, 1.14 times higher international-normalized-ratio (INR), 1.1 times higher Fibrinogen, 22.9 times higher procalcitonin, 3.35 times higher troponin, 2.77 mm/h times higher erythrocyte-sedimentation-rate (ESR), 1.13 s times longer prothrombin time (PT) when compared surviving patients. In addition, our interpretable decision tree, which was constructed with only the cut-off values of ferritin, INR, and D-dimer, correctly predicted 99.7% of surviving patients and 92.7% of non-surviving patients.

Conclusions

This study perfectly predicted the mortality of COVID-19 with our interpretable decision tree constructed with INR and D-dimer, especially ferritin. For this reason, we think that it may be important to include ferritin, INR, and D-dimer parameters and their cut-off values in the scoring systems to be planned for COVID-19 mortality.

KuanRong Chan et al.

Early peripheral blood MCEMP1 and HLA-DRA expression predicts COVID-19 prognosis

eBioMedicine, February 2023; doi.org/10.1016/j.ebiom.2023.104472

Abstract

Background

Mass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy.

Interpretation

Elevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19.

A liver drug reduces SARS-CoV-2 entry into cells

https://www.nature.com/articles/d41586-022-04149-7

This is a summary of: Brevini, T. et al. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. https://doi.org/10.1038/s41586-022-05594-0

Abstract

A widely used drug called UDCA reduces SARS-CoV-2 infection in human organoid structures, animals and human organs maintained outside the body. Individuals using UDCA for liver conditions are less likely to develop severe COVID-19 than are people who did not use it. UDCA treatment could help to protect people with suppressed immune systems and offer protectionagainst vaccine-resistant variants.

The problem

Vaccines changed the course of the COVID-19 pandemic by training people’s immune systems to recognize and clear the SARS-CoV-2 virus. However, they are not always effective in individuals with weak immune systems, or against some viral variants1. Moreover, despite international efforts, not everyone has access to vaccination, owing to its cost and disparities in vaccine availability. A huge challenge in managing COVID-19 in this post-vaccine era is preventing SARS-CoV-2 infection in high-risk unvaccinated groups2. Using drugs that are widely accessible could provide a solution.

The solution

To help individuals with weak immunity, such drugs against SARS-CoV-2 should not require a well-functioning immune system. And to prevent the virus from being able to escape treatment by mutating, they should not act on the virus. To meet these requirements, we targeted a receptor protein called angiotensin-converting enzyme 2 (ACE2) that is found on the membrane of human cells and constitutes the main ‘doorway’ that SARS-CoV-2 uses to

enter and infect cells3. To study ACE2’s function and how it affects viral infection, we used human cells to create organoids — 3D tissue structures grown in vitro to resemble and model different organs — in the laboratory4.

The implications

UDCA is widely used, accessible, cost effective, off-patent and easy to manufacture and store — overcoming cost and distribution barriers. It does not target the immune system or the virus itself and could therefore be both effective in people with weak immune systems and protect against viral resistance. It could also be effective in future coronavirus pandemics, because ACE2 is a doorway for many such viruses.

This is one of the first studies to provide a proof of concept for drug testing in donated human organs. This approach could reduce the need for animal experiments and increase the predictive power of preclinical drug testing.

Our results suggest that UDCA could have an important role in the management of COVID-19. However, this study is not a clinical trial, and our findings must be validated and confirmed in large groups of individuals who are studied over time. Importantly, where possible, we propose that UDCA should be used together with vaccination, rather than replacing it. The obvious next step is to conduct large, randomized and controlled trials to assess its effectiveness in the clinic.

Klingler J et al.

Immune profiles to distinguish hospitalized versus ambulatory COVID-19 cases in older patients

Cell, November 2022; doi.org/10.1016/j.isci.2022.105608

Abstract

A fraction of patients with COVID-19 develops severe disease requiring hospitalization, while the majority, including high-risk individuals, experience mild symptoms. Severe disease has been associated with higher levels of antibodies and inflammatory cytokines but often among patients with diverse demographics and comorbidity status.

SARS-CoV-2-specific antibody levels and functions were similar in ambulatory and hospitalized patients. However, a strong correlation between anti-S2 antibody levels and the other antibody parameters, along with higher IL-27 levels, was observed in hospitalized but not ambulatory cases.

Gavriilaki E. , Kokoris S.

COVID-19 sequelae: can long-term effects be predicted?

The Lancet, August 2022, doi.org/10.1016/S1473-3099(22)00529-1

Abstract

The COVID-19 pandemic has had an unprecedented impact on all aspects of human activity worldwide.1 Despite the positive effect that vaccination, anti-viral treatment, and monoclonal antibodies have had, unmet clinical needs still exist such as early prediction of patients who will develop severe COVID-19 or sequelae.

These findings might support the hypothesis of endothelial dysfunction as a primary driver of COVID-19 sequelae. Obesity, dyslipidaemia, and low physical activity are known risk factors for future cardiovascular complications, characterised by endothelial dysfunction. Cardiovascular risk factors can be modified through lifestyle changes and medications. More importantly, novel vascular and biochemical markers have been discovered over the last decade that can better predict cardiovascular risk.

In conclusion, although no accurate prediction models exist for who will develop severe COVID-19 or sequelae, risk factors of vascular damage have emerged as important predictors. Large and high-quality studies are needed utilising multidisciplinary teams not only from different medical specialties but also from computational scientists that could suggest novel predictive models for the development of COVID-19 sequelae.

Gallardo V.J. and Shapiro R.E.

The relationship of headache as a symptom to COVID-19 survival: A systematic review and meta-analysis of survival of 43,169 inpatients with COVID-19

https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14376

Abstract

Objective

To study the relationship between coronavirus disease 2019 (COVID-19) mortality and headache among patients evaluated for COVID-19 in Emergency Departments and hospitals.

Background

COVID-19 has disparate impacts on those who contract it. Headache, a COVID-19 symptom, has been associated with positive disease prognosis. We sought to determine whether headache is associated with relative risk of COVID-19 survival.

Conclusion

Headache among patients with COVID-19 presenting to hospitals may be a marker of host processes which enhance COVID-19 survival. Future studies should further confirm these findings, in order to better understand this relation and to try to address possible limitations related to the inclusion of more severe patients who would be unable to report symptoms (e.g., patients who were intubated).

Tanha H.M. et al

Shared genetic influences between blood analyte levels and risk of severe COVID-19

Cell, November 2022; doi.org/10.1016/j.celrep.2022.111708

Abstract

Genome-wide association studies (GWAS) show that genetic factors contribute to the risk of severe Coronavirus disease 2019 (COVID-19) and blood analyte levels. Here we utilise GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene and single nucleotide polymorphism levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of investigation—suggesting shared biological mechanisms or causal relationships. Six analytes (alanine aminotransferase, alkaline phosphatase, apolipoprotein B, C-reactive protein, triglycerides, and urate) display evidence of pleiotropy with severe COVID-19 at all three levels. Causality analyses indicate that higher triglyceride levels causally increase the risk of severe COVID-19 thereby providing important support for the use of lipid-lowering drugs such as statins and fibrates to prevent severe COVID-19.

Toyoshima Y. et al.

SARS-CoV-2 genomic variations associated with mortality rate of COVID-19

Journal of Human Genetics, july 2020; doi.org/10.1038/s10038-020-0808-9

Abstract

The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly expanded to a global pandemic. However, numbers of infected cases, deaths, and mortality rates related to COVID-19 vary from country to country. Although many studies were conducted, the reasons of these differences have not been clarified. Our findings suggest that SARS-CoV-2 mutations as well as BCG-vaccination status and a host genetic factor, HLA genotypes might affect the susceptibility to SARS-CoV-2 infection or severity of COVID-19.

H. Zeberg& S. Pääbo

The major genetic risk factor for severe COVID-19 isinherited from Neanderthals

Nature, September 2022; doi.org/10.1038/s41586-020-2818-3

Abstract

A recentgeneticassociation study identified a gene cluster on chromosome 3 as a risk locus for respiratoryfailure after infection with severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2). Another study showedthatthis cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. In this study the authorsshow that the risk isconferred by a genomicsegment of around 50 kilobases in size thatisinherited from Neanderthals and iscarried by around 50% of people in south Asia and around 16% of people in Europe.

S. DeWolf S et al.

SARS-CoV-2 in immunocompromised individuals

Immunity, September 2022; doi.org/10.1016/j.immuni.2022.09.006

Abstract

Immunocompromised individuals and particularly those with hematologic malignancies are at increased risk for SARS-CoV-2-associated morbidity and mortality due to immunologic deficits that limit prevention, treatment, and clearance of the virus. Studies focused on these individuals have provided key insights into aspects of innate and adaptive immunity underlying both the antiviral immune response and excess inflammation in the setting of COVID-19. The authors presents what is known about distinct states of immunologic vulnerability to SARS-CoV-2 and how this information can be harnessed to improve prevention and treatment strategies for immunologically high-risk populations.

G. Figueroa-Parra et al.

Risk of severe COVID-19 outcomes associated with rheumatoid arthritis and phenotypic subgroups: a retrospective, comparative, multicentre cohort study

Lancet Rheumatology, September 2022; doi: 10.1016/S2665-9913(22)00227-2

Abstract

Rheumatoid arthritis has been associated with severe COVID-19, but few studies have investigated how phenotypes of rheumatoid arthritis affect these associations. The authors aimed to investigate the associations between rheumatoid arthritis and phenotypes of interstitial lung disease, serostatus, and bone erosions with COVID-19 severity. Patients with rheumatoid arthritis have an increased risk of severe COVID-19 across phenotypic subgroups, especially among patients with interstitial lung disease. These findings suggest that rheumatoid arthritis with interstitial lung disease, or its treatment, might be a substantial contributor to severe COVID-19 outcomes for patients with rheumatoid arthritis.

A.J. Rogers et al.

The association of baseline plasma Sars-Cov-2 nucleocapsid antigen level and outcomes in patients hospitalized with Covid-19 free

Annals Internal Med, August 2022 Aug; doi: 10.7326/M22-0924

Abstract

Background: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.

Objective: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.

Conclusion: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.

F. Yasari et al.

The role of electrolyte imbalances in predicting the severity of COVID-19 in the hospitalized patients: a cross-sectional study

Scientific Reports, August 2022; doi: 10.1038/s41598-022-19264-8

Abstract

Coronavirus disease 2019 (COVID-19) can be fatal in severe cases. Accordingly, predicting the severity and prognosis of the disease is valuable. This study examined the role of electrolyte imbalances in predicting the severity of COVID-19. In this cross-sectional study, 169 hospitalized patients with COVID-19 were included and categorized into three groups based on the severity of the disease (moderate, severe, and critical). Serum levels of electrolytes (calcium [Ca], phosphorus [P], sodium [Na], potassium [k], and magnesium [Mg]), inflammatory markers (D-dimer, C-reactive protein [CRP], ferritin, and lactate dehydrogenase [LDH]), and 25OHVitamin D were measured. The mean age of patients was 53 years, and 54% were male. They had moderate, severe, and critical illnesses in 22%, 47%, and 31%, respectively. CRP, D-dimer, and ferritin increased with the severity of the disease. The lower median values of Mg, Na, 25OHVitamin D, Ca, LDH, and higher median lymphocyte counts were observed in the moderate vs. the severe group (P < 0.05). These parameters have acceptable sensitivity and specificity at the suggested cut-off level to discriminate the moderate and critical cases. Serum parameters introduced in this study are appropriate for differentiating between critical and moderate cases. The electrolyte imbalance can predict critical patients.

P. Bastard et al.

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Science, June 2022; doi: 10.1126/science.abd4585

Abstract

Interindividual clinical variability is vast in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from silent infection to rapid death. Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified— being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms of morbidity and mortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial.

P. Bastardet al.

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Science Immunology, June 2022; doi: 10.1126/sciimmunol.abp8966

Abstract

Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Vergara-Alertet al.

An anti-SARS-CoV-2 metabolite is reduced in diabetes

Nature Metabolism, May 2022; doi.org/10.1038/s42255-022-00569-x

Abstract

A glucose-like metabolite, which is reduced in the serum of diabetic patients, inhibits the entry of SARS-CoV-2 into key cellular targets. The work led by Cheng and colleagues provides a molecular explanation for the increased risk of severe COVID-19 in patients with diabetes.

From the very beginning of the SARS-CoV-2 pandemic, patients with diabetes and other comorbidities were shown to be more prone to COVID-19 severe progression, probably due to complex and multifactorial complications of their metabolic disease. Since then, understanding which risk factors increase the severity of COVID-19 in patients with diabetes has become a priority for improving their clinical management.

G. D’Alterioet al.

Germline rare variants of lectin pathway genes predispose to asymptomatic SARS-CoV-2 infection in elderly individuals

Genetics in Medicine, May 2022 ; doi.org//10.1016/j.gim.2022.04.007

Abstract

Purpose

Emerging evidence suggest that infection-dependent hyperactivation of complement system (CS) may worsen COVID-19 outcome. We investigated the role of predicted high impact rare variants — referred as qualifying variants (QVs) — of CS genes in predisposing asymptomatic COVID-19 in elderly individuals, known to be more susceptible to severe disease.

Methods

Exploiting exome sequencing data and 56 CS genes, we performed a gene-based collapsing test between 164 asymptomatic subjects (aged ≥60 years) and 56,885 European individuals from the Genome Aggregation Database. We replicated this test comparing the same asymptomatic individuals with 147 hospitalized patients with COVID-19.

Results

We found an enrichment of QVs in 3 genes (MASP1, COLEC11, and COLEC10), which belong to the lectin pathway, in the asymptomatic cohort. Analyses of complement activity in serum showed decreased activity of lectin pathway in asymptomatic individuals with QVs. Finally, we found allelic variants associated with asymptomatic COVID-19 phenotype and with a decreased expression of MASP1, COLEC11, and COLEC10 in lung tissue.

Conclusion

This study suggests that genetic rare variants can protect from severe COVID-19 by mitigating the activity of lectin pathway and prothrombin. The genetic data obtained through ES of 786 asymptomatic and 147 hospitalized individuals are publicly available at http://espocovid.ceinge.unina.it/

R. Marfellaet al.

Glycaemic control is associated with SARS-CoV-2 breakthrough infections in accinated patients with type 2 diabetes

Nature Communications, April 2022 ;doi.org/10.1038/s41467-022-30068-2

Abstract

Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p < 0.001). The comparison of patients with poor and good glycaemic control through Cox regression also show an increased risk for patients with poor control (adjusted hazard ratio [HR], 0.261; 95% CI, 0.097-0.700; p = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p < 0.001) and sex (HR = 0.105, CI 0.035-0.317 for females; p < 0.001) are significantly associated with the incidence of breakthrough infections.

Shoaib N et al.

Mol Biol Rep.

Factors associated with cycle threshold values (Ct-values) of SARS-CoV2-rRT-PCR

Mol Biol Rep., https://link.springer.com/content/pdf/10.1007/s11033-022-07360-x.pdf

CONTENUTO E COMMENTO : In questo studio condotto su 6331 individui vengono posti in relazione severità dei sintomi, fattori demografici e storia clinica con i valori di cicli soglia di rRT-PCR (sia per gene Orf1ab, che per N e RdRp). Non è stata riscontrata correlazione fra valore di cicli soglia e età, sesso o storia clinica del paziente. E’ stata riscontrata solo una debole correlazione fra valore di cicli soglia dei geni Orf1ab e N e la presenza di sintomi al momento del test molecolare, ma non è stata riscontrata una correlazione con la severità dei sintomi. Gli autori dello studio concludono che il valore di cicli soglia potrebbe essere poco utile nel predire la severità della COVID-19 e pertanto dovrebbe essere riportato con cautela nei referti.

Mentre alcuni lavori sembrano suggerire come il valore di cicli soglia possa essere di una certa utilità a scopo diagnostico (ad esempio per differenziare una pregressa infezione da una infezione attiva), probabilmente, anche alla luce di questo lavoro, è di scarsa utilità nella definizione prognostica della COVID-19.

Veyrenche N. et al.

SARS-CoV-2 nucleocapsid urine antigen in hospitalized patients with Covid-19

J Infect Dis., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903449/pdf/jiac073.pdf

CONTENUTO E COMMENTO: In questo studio viene valutata la capacità diagnostica di un test per la ricerca dell’antigene nucleocapsidico di SARS-CoV-2 su urine e su sangue e la sua relazione con la severità della malattia. Sono stati testati 82 pazienti ospedalizzati con infezione da SARS-CoV-2 provata tramite test molecolare. E’ stato osservato che nella prima e nella seconda settimana della COVID-19 il test antigenico su urine è risultato positivo rispettivamente nell’81.25% e nel 71.79%, mentre quello su sangue rispettivamente nel 93.75% e nel 94.87%. Elevati livelli di antigene urinario sono stati direttamente correlati all’assenza di anticorpi anti-nucleocapside, ammissione in terapia intensiva, elevati livelli di proteina C reattiva, linfopenia, eosinopenia e elevati livelli di latticodeidrogenasi. Il test su urine si è rivelato più accurato di quello su sangue nel predire la severità della malattia.

I risultati di questo studio rendono questo test per la rilevazione dell’antigene nucleocapsidico urinario estremamente interessante : da un lato infatti potrebbe rappresentare una metodica non invasiva, con buona sensibilità, per la diagnosi dell’infezione, dall’altra, in virtù della sua relazione con la severità della malattia, potrebbe rappresentare un utile elemento per la stratificazione prognostica dei pazienti.

Gretel Sanabria Diaz et al.

Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms

Medrxiv.org, https://www.medrxiv.org/content/10.1101/2022.02.13.22270662v1.full.pdf

CONTENUTO E COMMENTO: Studio prospettico multicentrico condotto su 33 pazienti con lo scopo di valutare le alterazioni corticali cerebrali in pazienti affetti da Sars-CoV2 ricoverati e con sintomi neurologici. Sono state evidenziate alterazioni della corteccia orbitofrontale, cingolata e temporale con associate alterazioni liquorali (aumento delle proteine e del rapporto fra proteine liquorali e sieriche), suggerendo che l'infiammazione innescata dal virus provochi danni neurotossici in alcune aree corticali.

Choteau M et al.

Development of SARS-CoV-2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection

Sci Rep., https://www.nature.com/articles/s41598-022-06038-5.pdf

CONTENUTO E COMMENTO : In questo studio condotto su 187 individui affetti da infezione da SARS-CoV-2 in differenti fasi della malattia (asintomatici, malattia lieve, severa, pazienti deceduti per COVID-19 e soggetti guariti dall’infezione) mira a valutare la risposta anticorpale sviluppata da tali individui nei confronti del virus. E’ stato utilizzato un test ELISA “in-house” per misurare il titolo delle IgG, IgM e IgA dirette contro le regioni RBD e N del virus e per analizzare il potere neutralizzante del siero. Sono stati riscontrati titoli di anticorpi più elevati nei pazienti con malattia severa, inclusi pazienti deceduti per COVID-19, rispetto ai pazienti asintomatici o con malattia lieve. Inoltre, la maggior parte dei pazienti guariti dall’infezione virale sembrano continuare a produrre IgG anti-SARS-CoV-2 per oltre 3 mesi dopo l’infezione.

La risposta immunitaria nei confronti del virus SARS-CoV-2 è sicuramente estremamente complessa: non è ancora chiaro il ruolo della risposta umorale nella prevenzione dell’infezione o nella modulazione della severità della malattia. Tale studio sembrerebbe comunque smentire l’ipotesi secondo cui nelle forme severe e fatali della malattia esisterebbe un deficit della risposta umorale, dal momento che chi ha forme più severe della malattia sembrerebbe avere addirittura dei titoli anticorpali più elevati, ma sono necessari ulteriori studi per dimostrarlo.

The Severe Covid-19 GWAS Group

Genomewide Association Study of Severe Covid-19 with Respiratory Failure

NEJM, https://www.nejm.org/doi/full/10.1056/NEJMoa2020283

CONTENUTO E COMMENTO : Studio genome-wide (GWAS) su 1980 pazienti con COVID-19, in cui si osserva che un cluster di geni del locus 3p21.31 fra cui quelli determinanti il gruppo sanguigno A sono associati a maggiore gravità di malattia.

Mastboim NS et al

An immune-protein signature combining TRAIL, IP-10 and CRP for accurate prediction of severe COVID-19 outcome

MedRXiv, https://www.semanticscholar.org/paper/An-immune-protein-signature-combining-TRAIL%2C-IP-10-Mastboim-Angel/f5d96efc49e00537794f9e729c8b6f683df4d86b

CONTENUTO E COMMENTO : Creazione di uno score predittivo di outcome avverso (ricovero in Rianimazione, ventilazione meccanica o decesso) per pazienti con COVID-19, a partire dai dati di 394 adulti ricoverati in diversi centri in Israele, Germania e Stati Uniti.

Meyer H et al

Computed tomography-defined body composition as prognostic markers for unfavourable outcomes and in-hospital mortality in coronavirus disease 2019

J Cachexia Sarcopenia Muscle, https://doi.org/10.1002/jcsm.12868

CONTENUTO E COMMENTO : Osservazione di una associazione fra ridotta massa muscolare/elevata massa adiposa viscerale, stimate tramite tomografia computerizzata, e outcome dell’infezione da SARS-CoV-2 : la possibilità di prédire quali pazienti avranno un outcome peggiore è molto utile per una allocazione razionale delle risorse.