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1.
Int J Biol Sci ; 18(15): 5591-5606, 2022.
Article in English | MEDLINE | ID: covidwho-2040345

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 sequentially enrolled hospitalized patients with COVID-19-associated pneumonia from Brescia, Italy using the VirScan phage-display method to characterize circulating antibodies binding to 96,179 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in immune antibody repertoires against many known pathogenic and non-pathogenic human viruses. This antiviral antibody response was linked to longitudinal trajectories of disease severity and was further confirmed in additional 125 COVID-19 patients from the same geographical region in Northern Italy. By applying a machine-learning-based strategy, a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival was developed and validated. These results provide a basis for understanding the role of memory B-cell repertoire to viral epitopes in COVID-19-related symptoms and suggest that a unique anti-viral antibody repertoire signature may be useful to define COVID-19 clinical severity.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Virome , Antiviral Agents , Epitopes
2.
JCI Insight ; 7(16)2022 08 22.
Article in English | MEDLINE | ID: covidwho-1950563

ABSTRACT

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes," remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.


Subject(s)
COVID-19 , Extracellular Traps , Actins/metabolism , Adult , COVID-19/complications , Child , Deoxyribonuclease I , Humans , Neutrophils , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
3.
Bastard, Paul, Vazquez, Sara, Liu, Jamin, Laurie, Matthew T.; Wang, Chung Yu, Gervais, Adrian, Le Voyer, Tom, Bizien, Lucy, Zamecnik, Colin, Philippot, Quentin, Rosain, Jérémie, Catherinot, Emilie, Willmore, Andrew, Mitchell, Anthea M.; Bair, Rebecca, Garçon, Pierre, Kenney, Heather, Fekkar, Arnaud, Salagianni, Maria, Poulakou, Garyphallia, Siouti, Eleni, Sahanic, Sabina, Tancevski, Ivan, Weiss, Günter, Nagl, Laurenz, Manry, Jérémy, Duvlis, Sotirija, Arroyo-Sánchez, Daniel, Paz Artal, Estela, Rubio, Luis, Perani, Cristiano, Bezzi, Michela, Sottini, Alessandra, Quaresima, Virginia, Roussel, Lucie, Vinh, Donald C.; Reyes, Luis Felipe, Garzaro, Margaux, Hatipoglu, Nevin, Boutboul, David, Tandjaoui-Lambiotte, Yacine, Borghesi, Alessandro, Aliberti, Anna, Cassaniti, Irene, Venet, Fabienne, Monneret, Guillaume, Halwani, Rabih, Sharif-Askari, Narjes Saheb, Danielson, Jeffrey, Burrel, Sonia, Morbieu, Caroline, Stepanovskyy, Yurii, Bondarenko, Anastasia, Volokha, Alla, Boyarchuk, Oksana, Gagro, Alenka, Neuville, Mathilde, Neven, Bénédicte, Keles, Sevgi, Hernu, Romain, Bal, Antonin, Novelli, Antonio, Novelli, Giuseppe, Saker, Kahina, Ailioaie, Oana, Antolí, Arnau, Jeziorski, Eric, Rocamora-Blanch, Gemma, Teixeira, Carla, Delaunay, Clarisse, Lhuillier, Marine, Le Turnier, Paul, Zhang, Yu, Mahevas, Matthieu, Pan-Hammarström, Qiang, Abolhassani, Hassan, Bompoil, Thierry, Dorgham, Karim, consortium, Covid Hge, French, Covid study group, consortium, Comet, Gorochov, Guy, Laouenan, Cédric, Rodríguez-Gallego, Carlos, Ng, Lisa F. P.; Renia, Laurent, Pujol, Aurora, Belot, Alexandre, Raffi, François, Allende, Luis M.; Martinez-Picado, Javier, Ozcelik, Tayfun, Keles, Sevgi, Imberti, Luisa, Notarangelo, Luigi D.; Troya, Jesus, Solanich, Xavier, Zhang, Shen-Ying, Puel, Anne, Wilson, Michael R.; Trouillet-Assant, Sophie, Abel, Laurent, Jouanguy, Emmanuelle, Ye, Chun Jimmie, Cobat, Aurélie, Thompson, Leslie M.; Andreakos, Evangelos, Zhang, Qian, Anderson, Mark S.; Casanova, Jean-Laurent, DeRisi, Joseph L..
Science immunology ; 2022.
Article in English | EuropePMC | ID: covidwho-1918542

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. Type I IFN auto-Abs are found in 20% of hypoxemic, mRNA vaccinated COVID-19 patients despite SARS-CoV-2 neutralizing antibodies. Description

4.
Nat Med ; 28(5): 1050-1062, 2022 05.
Article in English | MEDLINE | ID: covidwho-1701612

ABSTRACT

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.


Subject(s)
COVID-19 , COVID-19/complications , COVID-19/genetics , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/genetics , T-Lymphocytes
5.
Open forum infectious diseases ; 8(Suppl 1):S77-S77, 2021.
Article in English | EuropePMC | ID: covidwho-1602523

ABSTRACT

Background T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3–7 = 85.1%;Day 8–14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring. Disclosures Thomas M. Snyder, PhD, Adaptive Biotechnologies (Employee, Shareholder) Rachel M. Gittelman, PhD, Adaptive Biotechnologies (Employee, Shareholder) Mark Klinger, PhD, Adaptive Biotechnologies (Employee, Shareholder) Damon H. May, PhD, Adaptive Biotechnologies (Employee, Shareholder) Edward J. Osborne, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ruth Taniguchi, PhD, Adaptive Biotechnologies (Employee, Shareholder) H. Jabran Zahid, PhD, Microsoft Research (Employee, Shareholder) Rebecca Elyanow, PhD, Adaptive Biotechnologies (Employee, Shareholder) Sudeb C. Dalai, MD, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ian M. Kaplan, PhD, Adaptive Biotechnologies (Employee, Shareholder) Jennifer N. Dines, MD, Adaptive Biotechnologies (Employee, Shareholder) Matthew T. Noakes, PhD, Adaptive Biotechnologies (Employee, Shareholder) Ravi Pandya, PhD, Microsoft Research (Employee, Shareholder) Lance Baldo, MD, Adaptive Biotechnologies (Employee, Shareholder, Leadership Interest) James R. Heath, PhD, Merck (Research Grant or Support, Funding (from BARDA) for the ISB INCOV project, but had no role in planning the research or in writing the paper.) Joaquin Martinez-Lopez, MD, PhD, Adaptive Biotechnologies (Consultant) Jonathan M. Carlson, PhD, Microsoft Research (Employee, Shareholder) Harlan S. Robins, PhD, Adaptive Biotechnologies (Board Member, Employee, Shareholder)

7.
Biol Sex Differ ; 12(1): 45, 2021 08 11.
Article in English | MEDLINE | ID: covidwho-1352670

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) severity seems to be influenced by genetic background, sex, age, and presence of specific comorbidities. So far, little attention has been paid to sex-specific variations of demographic, clinical, and laboratory features of COVID-19 patients referred to the same hospital in the two consecutive pandemic waves. METHODS: Demographic, clinical, and laboratory data were collected in 1000 COVID-19 patients (367 females and 633 males), 500 hospitalized in the first wave and 500 in the second one, at the ASST Spedali Civili of Brescia from March to December 2020. Statistical analyses have been employed to compare data obtained in females and males, taking into account their age, and during the first and second COVID-19 waves. RESULTS: The mean age at the time of hospitalization was similar in females and males but was significantly higher for both in the second wave; the time elapsed from symptom onset to hospital admission did not differ between sexes in the two waves, and no correlation was observed between delayed hospital admission and length of hospitalization. The number of multi-symptomatic males was higher than that of females, and patients with a higher number of comorbidities were more frequently admitted to intensive care unit (ICU) and more frequently died. Older males remained in the ICU longer than females and showed a longer disease duration, mainly the first wave. The highest levels of white blood cells, neutrophils, C-reactive protein, and fibrinogen were significantly higher in males and in the first, and along with higher levels of D-dimer, ferritin, lactate dehydrogenase, and procalcitonin which were preferentially documented in patients requiring ICU or died. While the rate of death in ICU was higher in males, the overall death rate did not differ between the sexes; however, the deceased women were older. CONCLUSIONS: These data indicate that once patients were hospitalized, the risk of dying was similar between females and males. Therefore, future studies should aim at understanding the reasons why, for a given number of SARS-CoV-2 infections, fewer females develop the disease requiring hospitalization. HIGHLIGHTS: Although the hospitalized males were significantly more, the similar number of hospitalizations of the > 75-year-old females and males could be due to the fact that in Brescia province, elderly women are about twice as many as men. Although males spent more days in the hospital, had a longer disease duration, developed a critical illness more frequently, and were admitted and died in the ICU more than females, the total rate of deaths among patients was not significantly different between sexes. Overall, the most frequent comorbidities were cardiovascular diseases, which were preferentially seen among patients hospitalized in the second wave; it is possible that the knowledge gained in the first wave concerning the association between certain comorbidities and worse disease evolution has guided the preferential hospitalization of patients with these predominant comorbidities.


Subject(s)
COVID-19/mortality , Hospitalization/statistics & numerical data , Sex Characteristics , Aged , Female , Humans , Italy/epidemiology , Male , Middle Aged , Retrospective Studies
8.
Blood ; 136(Supplement 1):4-4, 2020.
Article in English | PMC | ID: covidwho-1339036

ABSTRACT

Introduction. Covid-19 patients (pts) with hematologic malignancies have a severe prognosis with mortality rates around 40%, particularly when on active treatment (Cattaneo et al, Cancer, in press). However, the long-term prognosis and persistence of specific immune responses among those who survive acute infection are unclear.Aim: Pts with hematological diseases were followed longitudinally after the acute phase of COVID-19 according to protocol NP4156 approved by the local EC. Clinical outcome and specific antibody responses to SARS-CoV-2 were monitored during convalescence, and correlated to the diagnosis and treatment of the underlying hematological disease.Pts and Methods. Pts affected by multiple myeloma (MM), follicular (FL) and diffuse large B-cell (DLC) lymphoma (NHL), chronic lymphoproliferative disorders (CLD), myelodysplastic/chronic myeloproliferative syndromes (MDS/MPN) and surviving the acute phase of virologic-proven COVID-19 were eligible. Immune response parameters were evaluated at +1, +3, +6, +9 and +12 months after nasal swab negativization. Antibodies (Ab) to different conformations of COVID-19 virus proteins, nucleocapsid (N) and spike (S), were measured using a highly sensitive luciferase-immunoprecipitation system (LIPS) assay.Results. Of 51 eligible pts, 41 were tested for SARS-CoV-2 Ab at first timepoint (+1m) (6 pts too early, 2 refusal, 2 lost to follow-up). For 9 of them, Ab levels at +3m were also available. Ab levels of 14 controls without hematologic disorders (Ctrls) also surviving COVID-19 were evaluable at +1m and in 9 of them at +3 months as well. Diagnoses included FL (9) and DLC (6) NHL, CLD (7), MM (10), MDS/MPS (9). The status of hematological disease at the time of COVID-19 diagnosis was as follows: diagnosis (n=4;10%), complete or partial remission (n=16;39%), relapse/refractory (n=6;15%;stable (n=15;36%). Twenty-one pts (51%) were on active treatment, including 6 on chemoimmunotherapy;7 pts had received chemoimmunotherapy previously. Median time from SARS-CoV-2 detection to swab negativity was 30d (range 8-63), and was not influenced by sex, age, hematologic diagnosis, disease status, nor treatment received. Two pts, both affected by DLC secondary to FL, remained swab-positive at day 119+ and 123+.At +1m, both N- and S- seropositivity rate was slightly lower in pts [N+ in 30/41 (73%);S+ in 27/41 (66%)] vs 13/14 for both N+ and S+ in Ctrls (93%) (P=0.16 and 0.08, respectively). Discrepancies between N and S seropositivity were observed in 7 (17%) pts, all with lymphoid disorders. Ab levels were similar in hematologic pts and in Ctrls (N+ 894,707 vs 870,541 LU and S+ 907,591 LU vs 724,120 LU, respectively, P=NS) (Fig.1a). Both seroconversion rates and Ab levels were not influenced by age, sex, status of hematologic disease, ongoing treatment, time to swab negativity, severity of pneumonia and steroid treatment during acute COVID-19. However, a diagnosis of NHL negatively impacted on seroconversion for both N and S. In 15 pts with NHL compared to 26 pts with other hematologic cancers, the N-seropositivity rate was 47% vs 92%, and the S-seropositivity rate was 40% vs 85%y (P=0.002 and 0.0053, respectively). N and S Ab levels were also lower than in other hematologic diseases (515,281 LU vs 1105409 LU, P=.002 and 474,309 LU vs 1,148,303 LU, P=.005 respectively) (Fig.1b). Rituximab (RTX) had been used in 13 of 15 NHL (87%), and treatment was ongoing in 6/13. While N-seroconversion and Ab levels were not influenced, no pts on ongoing RTX had S-seroconversion vs 5/7 pts with past RTX use (P=0.021) and mean antibody levels were 17622 LU vs 668548 LU, respectively (P=0.008).At +3m, no significant variations of both anti-N and anti-S antibody levels had occurred compared to timepoint +1m. Seroconversion status was maintained by 9/9 Ctrls and by 8/8 pts;the only pt with Ab levels below the cut-off at +1m did not show seroconversion at+3m.Conclusions: Overall, hematologic pts surviving COVID-19 have N- and S- antibodies levels and seroconversion rates similar to controls witho t hematologic disorders, although time to swab negativity seems more similar to critically ill pts than in the general population. A diagnosis of NHL negatively impacts on seroconversion and Ab levels, and ongoing RTX seems to have a negative role specifically on anti-S Ab production. Ab response persists at 3 months;the study is ongoing and further data will be available at time of meeting.

9.
Blood ; 136(Supplement 1):47-48, 2020.
Article in English | PMC | ID: covidwho-1339032

ABSTRACT

It has been proposed that patients with hematologic malignancy and autoimmune diseases receiving anti-CD20 monoclonal antibody (mAb) therapy are particularly at risk of severe Coronavirus disease (COVID-19) because the profound and long-lasting B-cell depletion induced by anti-CD20 mAb may impair virus clearance and may also contribute to reactivation of latent viruses, especially hepatitis B and JC viruses.As of July 20, 2020, the total number of COVID-19 cases reported by the Italian authorities reached 245,000. The north of the country was mostly hit, and Milan and Brescia were among the Italian provinces that registered the highest number of COVID-19 cases. Consistent with this, a high number of COVID-19 patients affected with multiple types of hematological disorders (n. 137) and with multiple sclerosis (MS, n. 114) were referred to ASST Spedali Civili di Brescia. Antibodies to SARS-CoV-2 were analyzed in 70 patients with hematological disease, and in few patients with MS. Among these, 10 patients (7 with hematologic disease and 3 with MS) had received treatment with rituximab or ocrelizumab, two anti-CD20 mAbs, within 3 months prior to COVID-19 onset. Clinical indication to CD20-depleting treatment for patients with hematological disorders included Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Non Hodgkin Lymphoma (NHL).Anti-spike protein (anti-S) and anti-nucleocapsid (anti-N) antibodies to SARS-CoV-2 were analyzed during the acute phase of infection and up to 3 months since the onset of symptoms by quantitative measurements of plasma or serum antibodies with luciferase immune precipitation assay systems (LIPS). With this technique, production of anti-S and anti-N antibodies has been demonstrated between day 8 and day 14 after onset of symptoms in immunocompetent individuals, whereas specific antibody production was delayed by few days in immunocompromised patients (Burbelo PD et al, medRxiv. 2020 Apr 24:2020.04.20.20071423).All 10 patients remained seronegative to SARS-CoV-2 for the first 20 days since onset of symptoms. One patient with DLBCL secondary to Follicular NHL had detectable anti-S and anti-N antibodies at day +25, and one patient with MS developed anti-N antibodies by day +23. Two patients, one with DLBCL secondary to Follicular NHL and one with Follicular NHL were still seronegative for both anti-S and anti-N antibodies at 133 and 74 days since onset of symptoms. Two MS patients were seronegative at the last examination, and one other MS patient was anti-S seronegative at day +74.Three of the 10 patients have died;all three were SARS-CoV-2 RT-qPCR+ and seronegative at the time of death.While it has been reported that SARS-CoV-2 is cleared without significant problems by the majority of people with MS or other autoimmune diseases on immunotherapy, these data indicate that treatment with anti-CD20 mAb may significantly alter humoral responses to the virus. Until a vaccine to SARS-CoV-2 is available, the risk-benefit ratio of anti-CD20 mAb therapy in areas with high rates of SARS-CoV-2 infection should be carefully weighed. Moreover, for patients with B-cell malignancies or autoimmune diseases, transient discontinuation of this therapy, or use of alternative therapeutic approaches, should be considered once an efficacious vaccine becomes available.This study was performed according to protocol NP-4000 (Comitato Etico Provinciale), and supported by Regione Lombardia and by the Division of Intramural Research, NIAID.Figure 1

10.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1077815

ABSTRACT

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/metabolism , Gene Expression/immunology , Killer Cells, Natural/metabolism , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19/mortality , Case-Control Studies , Dendritic Cells/cytology , Female , Humans , Killer Cells, Natural/cytology , Longitudinal Studies , Male , Middle Aged , Transcriptome/immunology , Young Adult
11.
JCI Insight ; 6(1)2021 01 11.
Article in English | MEDLINE | ID: covidwho-1027164

ABSTRACT

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , Biomarkers , COVID-19/genetics , COVID-19/therapy , Calgranulin B/genetics , Calgranulin B/immunology , Case-Control Studies , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CXCL9/genetics , Chemokine CXCL9/immunology , Enzyme Inhibitors/therapeutic use , Female , Ferritins/genetics , Ferritins/immunology , Gene Expression Profiling , Humans , Hydroxychloroquine/therapeutic use , Immunologic Factors/therapeutic use , Interferon Type I/genetics , Interferon Type I/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-15/genetics , Interleukin-15/immunology , Interleukin-2/genetics , Interleukin-2/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Lactoferrin/genetics , Lactoferrin/immunology , Lipocalin-2/genetics , Lipocalin-2/immunology , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/immunology , Middle Aged , Multivariate Analysis , NF-kappa B/genetics , NF-kappa B/immunology
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