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1.
Front Immunol ; 13: 844304, 2022.
Article in English | MEDLINE | ID: covidwho-1903005

ABSTRACT

Background: The role of type I interferons (IFNs) in the early phase of COVID-19 remains unclear. Objectives: To evaluate the relationship between IFN-I levels in patients with COVID-19 and clinical presentation, SARS-CoV-2 viral load, and other major pro-inflammatory cytokines. Methods: This prospective observational study recruited patients hospitalized with COVID-19. The levels of interferon-alpha (IFN-α), interferon-beta (IFN-ß), interleukin-6 (IL-6), and C-X-C motif chemokine ligand (CXCL10) within 5 days after symptom onset were measured using an ELISA, in serum from blood collected within 5 days after the onset of symptoms. The SARS-CoV-2 viral load was determined via qPCR using nasal-swab specimens and serum. Results: The study enrolled 50 patients with COVID-19. IFN-α levels were significantly higher in patients who presented with pneumonia or developed hypoxemic respiratory failure (p < 0.001). Furthermore, IFN-α levels were associated with viral load in nasal-swab specimens and RNAemia (p < 0.05). In contrast, there was no significant association between IFN-ß levels and the presence of pneumonia or RNAemia, despite showing a stronger association with nasal-swab viral load (p < 0.001). Correlation analysis showed that the serum levels of IFN-α significantly correlated with those of IFN-ß, IL-6, and CXCL10, while the levels of IFN-ß did not correlate with those of IL-6 or CXCL10. Conclusions: Serum IFN-I levels in the early phase of SARS-CoV-2 infection were higher in patients who developed hypoxemic respiratory failure. The association between IFN-α, IL-6, and CXCL10 may reflect the systemic immune response against SARS-CoV-2 invasion into pulmonary circulation, which might be an early predictor of respiratory failure due to COVID-19.


Subject(s)
COVID-19/blood , Interferon Type I/blood , Respiratory Insufficiency/blood , Adult , COVID-19/complications , COVID-19/virology , Cytokines/blood , Female , Hospitalization , Humans , Inflammation , Male , Middle Aged , Prospective Studies , Respiratory Insufficiency/etiology , Respiratory Insufficiency/virology , SARS-CoV-2/pathogenicity , Viral Load
2.
Virol J ; 18(1): 244, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1559217

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a huge challenge worldwide. Although previous studies have suggested that type I interferon (IFN-I) could inhibit the virus replication, the expression characteristics of IFN-I signaling-related miRNAs (ISR-miRNAs) during acute severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and its relationship with receptor-binding domain (RBD) IgG antibody response at the recovery phase remain unclear. METHODS: Expression profiles of 12 plasma ISR-miRNAs in COVID-19 patients and healthy controls were analyzed using RT-qPCR. The level of RBD-IgG antibody was determined using the competitive ELISA. Spearman correlation was done to measure the associations of plasma ISR-miRNAs with clinical characteristics during acute SARS-CoV-2 infection and RBD-IgG antibody response at the recovery phase. RESULTS: Compared with the healthy controls, COVID-19 patients exhibited higher levels of miR-29b-3p (Z = 3.15, P = 0.002) and miR-1246 (Z = 4.98, P < 0.001). However, the expression of miR-186-5p and miR-15a-5p were significantly decreased. As the results shown, miR-30b-5p was negatively correlated with CD4 + T cell counts (r = - 0.41, P = 0.027) and marginally positively correlated with fasting plasma glucose in COVID-19 patients (r = 0.37, P = 0.052). The competitive ELISA analysis showed the plasma level of miR-497-5p at the acute phase was positively correlated with RBD-IgG antibody response (r = 0.48, P = 0.038). CONCLUSIONS: Our present results suggested that the expression level of ISR-miRNAs was not only associated with acute SARS-CoV-2 infection but also with RBD-IgG antibody response at the recovery phase of COVID-19. Future studies should be performed to explore the biological significance of ISR-miRNAs in SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/immunology , COVID-19/diagnosis , Immunoglobulin G/immunology , Interferon Type I/genetics , MicroRNAs , Virus Replication/genetics , COVID-19/blood , COVID-19 Nucleic Acid Testing , Case-Control Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Immunoglobulin G/blood , Interferon Type I/blood , Male , MicroRNAs/blood , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Pregnancy , SARS-CoV-2
3.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1501524

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Interferon Type I/blood , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/therapy , Comorbidity , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Spike Glycoprotein, Coronavirus/metabolism
4.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1381012

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
5.
Dtsch Med Wochenschr ; 146(13-14): 904-907, 2021 Jul.
Article in German | MEDLINE | ID: covidwho-1307355

ABSTRACT

From an infectious disease perspective, there have been outstanding findings since January 2020 far beyond the knowledge gained about SARS-CoV, which hopefully will help us to manage future pandemics. Positive highlights include the increased public awareness of infectious disease epidemiology, the increase in immunological knowledge, and the successful use of existing vaccine development platforms and technologies. This article presents a personal selection of interesting developments in recent months.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Infectious Disease Medicine , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/prevention & control , Humans , Interferon Type I/blood
6.
Cell Death Differ ; 28(12): 3297-3315, 2021 12.
Article in English | MEDLINE | ID: covidwho-1298835

ABSTRACT

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.


Subject(s)
COVID-19/complications , COVID-19/virology , Lymphopenia/complications , Neoplasms/complications , RNA, Viral/analysis , SARS-CoV-2/genetics , Virus Shedding , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , DNA, Bacterial/blood , Enterobacteriaceae/genetics , Female , Humans , Interferon Type I/blood , Lymphopenia/virology , Male , Micrococcaceae/genetics , Middle Aged , Nasopharynx/virology , Neoplasms/diagnosis , Neoplasms/mortality , Pandemics , Prognosis , Time Factors , Young Adult
7.
Front Immunol ; 12: 657363, 2021.
Article in English | MEDLINE | ID: covidwho-1247860

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, resulting in a range of clinical manifestations and outcomes. Laboratory and immunological alterations have been considered as potential markers of disease severity and clinical evolution. Type I interferons (IFN-I), mainly represented by IFN-α and ß, are a group of cytokines with an important function in antiviral responses and have played a complex role in COVID-19. Some studies have demonstrated that IFN-I levels and interferon response is elevated in mild cases, while other studies have noted this in severe cases. The involvement of IFN-I on the pathogenesis and outcomes of SARS-CoV-2 infection remains unclear. In this study, we summarize the available evidence of the association of plasma protein levels of type I IFN with the severity of COVID-19. Methods: The PRISMA checklist guided the reporting of the data. A systematic search of the MEDLINE (PubMed), EMBASE, and Web of Science databases was performed up to March of 2021, looking for articles that evaluated plasma protein levels of IFN-I in mild, severe, or critical COVID-19 patients. Comparative meta-analyses with random effects were performed to compare the standardized mean differences in plasma protein levels of IFN-I of mild versus severe and mild versus critical patients. Meta-regressions were performed to test the moderating role of age, sex, time that the IFN-I was measured, and limit of detection of the assay used in the difference between the means. Results: There was no significant difference in plasma levels of IFN-α when comparing between mild and severe patients (SMD = -0.236, 95% CI -0.645 to 0.173, p = 0.258, I2 = 82.11), nor when comparing between patients mild and critical (SMD = 0.203, 95% CI -0.363 to 0.770, p = 0.481, I2 = 64.06). However, there was a significant difference between healthy individuals and patients with mild disease (SMD = 0.447, 95% CI 0.085 to 0.810, p = 0.016, I2 = 62.89). Conclusions: Peripheral IFN-α cannot be used as a severity marker as it does not determine the clinical status presented by COVID-19 patients.


Subject(s)
Biomarkers/blood , COVID-19/diagnosis , Interferon Type I/blood , SARS-CoV-2/physiology , Disease Progression , Humans , Severity of Illness Index
8.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1243489

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
9.
Clin Microbiol Rev ; 34(3)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1226710

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/pathology , Interferon Type I/blood , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/blood , COVID-19/therapy , Comorbidity , Humans , Immunity, Innate/immunology , Immunization, Passive/methods , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Spike Glycoprotein, Coronavirus/metabolism
10.
Eur J Immunol ; 51(4): 989-994, 2021 04.
Article in English | MEDLINE | ID: covidwho-1187983

ABSTRACT

Low concentrations of type-I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID-19). However, following the type-I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU-admitted patients with severe COVID-19, and (iii) healthcare workers with mild COVID-19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN-α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r-Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID-19 pandemic to evaluate the IR in 45-min with 2 min hand-on-time at hospitalization and to monitor the IR in future clinical trials.


Subject(s)
COVID-19/blood , Interferon-alpha/blood , Polymerase Chain Reaction/methods , SARS-CoV-2/immunology , Adult , Aged , COVID-19/immunology , Child , Female , Health Personnel , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-alpha/genetics , Male
11.
Cell Host Microbe ; 29(3): 489-502.e8, 2021 03 10.
Article in English | MEDLINE | ID: covidwho-1064930

ABSTRACT

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.


Subject(s)
COVID-19/immunology , COVID-19/virology , Interferon Type I/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Nonstructural Proteins/genetics , A549 Cells , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Base Sequence , COVID-19/blood , Cell Line , Child , Child, Preschool , Chlorocebus aethiops , Female , Gene Deletion , Genomics , HEK293 Cells , Humans , Infant , Interferon Type I/blood , Interferon-beta/blood , Interferon-beta/metabolism , Male , Middle Aged , Molecular Epidemiology , Reverse Genetics , Vero Cells , Viral Nonstructural Proteins/immunology , Young Adult
13.
Front Immunol ; 11: 1636, 2020.
Article in English | MEDLINE | ID: covidwho-646395

ABSTRACT

The current pandemic of coronavirus disease 19 (COVID-19) has affected millions of individuals and caused thousands of deaths worldwide. The pathophysiology of the disease is complex and mostly unknown. Therefore, identifying the molecular mechanisms that promote progression of the disease is critical to overcome this pandemic. To address such issues, recent studies have reported transcriptomic profiles of cells, tissues and fluids from COVID-19 patients that mainly demonstrated activation of humoral immunity, dysregulated type I and III interferon expression, intense innate immune responses and inflammatory signaling. Here, we provide novel perspectives on the pathophysiology of COVID-19 using robust functional approaches to analyze public transcriptome datasets. In addition, we compared the transcriptional signature of COVID-19 patients with individuals infected with SARS-CoV-1 and Influenza A (IAV) viruses. We identified a core transcriptional signature induced by the respiratory viruses in peripheral leukocytes, whereas the absence of significant type I interferon/antiviral responses characterized SARS-CoV-2 infection. We also identified the higher expression of genes involved in metabolic pathways including heme biosynthesis, oxidative phosphorylation and tryptophan metabolism. A BTM-driven meta-analysis of bronchoalveolar lavage fluid (BALF) from COVID-19 patients showed significant enrichment for neutrophils and chemokines, which were also significant in data from lung tissue of one deceased COVID-19 patient. Importantly, our results indicate higher expression of genes related to oxidative phosphorylation both in peripheral mononuclear leukocytes and BALF, suggesting a critical role for mitochondrial activity during SARS-CoV-2 infection. Collectively, these data point for immunopathological features and targets that can be therapeutically exploited to control COVID-19.


Subject(s)
Betacoronavirus/immunology , Chemokines/blood , Coronavirus Infections/immunology , Interferon Type I/blood , Neutrophils/immunology , Pneumonia, Viral/immunology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , COVID-19 , Coronavirus Infections/pathology , Gene Expression Profiling , Humans , Inflammation/virology , Influenza, Human/immunology , Interferon Type I/immunology , Neutrophils/cytology , Oxidative Phosphorylation , Pandemics , Pneumonia, Viral/pathology , SARS-CoV-2 , Transcriptome/genetics
14.
16.
Cytokine Growth Factor Rev ; 53: 33-37, 2020 06.
Article in English | MEDLINE | ID: covidwho-154941

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that four well-recognized features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (i.e. the SARS-CoV-2 receptor); and iv. accelerated biological aging. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.


Subject(s)
Aging/pathology , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Interleukin-6/immunology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Female , Humans , Inflammation/pathology , Interferon Type I/blood , Interferon Type I/immunology , Interleukin-6/antagonists & inhibitors , Male , Pandemics , Peptidyl-Dipeptidase A/biosynthesis , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , Severe Acute Respiratory Syndrome/pathology
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