Acute COVID-19 gene-expression profiles show multiple etiologies of long-term sequelae

Thompson, Ryan; Simons, Nicole W.; Wilkins, Lillian; Cheng, Esther; Del-Valle, Diane Marie; Hoffman, Gabriel E.; Fennessy, Brian; Mouskas, Konstantinos; Francoeur, Nancy; Johnson, Jessica; Lepow, Lauren; Bérichel, Jessica Le; Chang, Christie; Beckmann, Aviva G.; Wang, Ying-Chih; Nie, Kai; Zaki, Nicholas; Tuballes, Kevin; Barcessat, Vanessa; Cedillo, Mario A.; Huckins, Laura; Roussos, Panagiotis; Marron, Thomas U.; Glicksberg, Benjamin S.; Nadkarni, Girish N.; Gonzalez-Kozlova, Edgar; Kim‐Schulze, Seunghee; Sebra, Robert; Mérad, Miriam; Gnjatic, Sacha; Schadt, Eric E.; Charney, Alexander; Beckmann, Noam D.

doi:10.1101/2021.10.04.21264434

Cited by 5 publications

(5 citation statements)

References 51 publications

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“…Notably, these patients did not statistically differ in various metrics of clinical severity in hospital [ e.g. , highest recorded SOFA score and World Health Organization COVID-19 Clinical Progression Score ( 45 )], cell proportions, lab values, treatments received, rates of ICU admission, and hospitalization duration compared to patients without post-COVID symptoms (termed “asymptomatic”) ( Table 1 ), which was consistent with the literature indicating that the presence of these post-COVID symptoms is not associated with disease severity ( 46 ), since many mild and even non-hospitalized patients can also develop persistent symptoms ( 7 , 8 ). In addition, common confounders including age and sex, as well as the time between discharge date and follow-up date, were not statistically different between these two groups.…”

Section: Resultssupporting

confidence: 84%

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

An,

Baghela,

Zhang

et al. 2023

Front. Immunol.

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IntroductionPersistent symptoms after COVID-19 infection (“long COVID”) negatively affects almost half of COVID-19 survivors. Despite its prevalence, its pathophysiology is poorly understood, with multiple host systems likely affected. Here, we followed patients from hospital to discharge and used a systems-biology approach to identify mechanisms of long COVID.MethodsRNA-seq was performed on whole blood collected early in hospital and 4-12 weeks after discharge from 24 adult COVID-19 patients (10 reported post-COVID symptoms after discharge). Differential gene expression analysis, pathway enrichment, and machine learning methods were used to identify underlying mechanisms for post-COVID symptom development.ResultsCompared to patients with post-COVID symptoms, patients without post-COVID symptoms had larger temporal gene expression changes associated with downregulation of inflammatory and coagulation genes over time. Patients could also be separated into three patient endotypes with differing mechanistic trajectories, which was validated in another published patient cohort. The “Resolved” endotype (lowest rate of post-COVID symptoms) had robust inflammatory and hemostatic responses in hospital that resolved after discharge. Conversely, the inflammatory/hemostatic responses of “Suppressive” and “Unresolved” endotypes (higher rates of patients with post-COVID symptoms) were persistently dampened and activated, respectively. These endotypes were accurately defined by specific blood gene expression signatures (6-7 genes) for potential clinical stratification.DiscussionThis study allowed analysis of long COVID whole blood transcriptomics trajectories while accounting for the issue of patient heterogeneity. Two of the three identified and externally validated endotypes (“Unresolved” and “Suppressive”) were associated with higher rates of post-COVID symptoms and either persistently activated or suppressed inflammation and coagulation processes. Gene biomarkers in blood could potentially be used clinically to stratify patients into different endotypes, paving the way for personalized long COVID treatment.

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Section: Resultssupporting

confidence: 84%

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

An,

Baghela,

Zhang

et al. 2023

Front. Immunol.

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“…The prognosis in the acute phase of the disease has been mainly linked to the severity of the respiratory involvement (including the development of acute respiratory distress syndrome (ARDS), the need for admission to intensive care units (ICUs), and mechanical ventilation), the length of hospital stay (LOS), the levels of some inflammatory markers, and previous comorbidities [ 4 – 6 ]. Moreover, studies focusing on transcriptomics have suggested that a small set of regulatory genes might act as strong predictors of patient outcomes [ 7 , 8 ]. Two years into the pandemic, the long-term sequelae of COVID-19 are exacerbating the global health crisis.…”

Section: Introductionmentioning

confidence: 99%

“…Transcriptomic and genomic research could shed light on the reasons why certain individuals present post-COVID-19 sequelae, allowing us to design drugs to prevent it. Thompson et al [ 7 ] have been able to directly link these sequelae to the host response to the virus.…”

Section: Introductionmentioning

confidence: 99%

Persistent COVID-19 symptoms 1 year after hospital discharge: A prospective multicenter study

Aranda

Oriol²,

Feria³

et al. 2022

PLoS ONE

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Objective To determine the health status and exercise capacity of COVID-19 survivors one year after hospital discharge. Methods This multicenter prospective study included COVID-19 survivors 12 months after hospital discharge. Participants were randomly selected from a large cohort of COVID-19 patients who had been hospitalized until 15th April 2020. They were interviewed about persistent symptoms, underwent a physical examination, chest X-ray, and a 6-minute walk test (6MWT). A multivariate analysis was performed to determine the risk factors for persistent dyspnea. Results Of the 150 patients included, 58% were male and the median age was 63 (IQR 54–72) years. About 82% reported ≥1 symptoms and 45% had not recovered their physical health. The multivariate regression analysis revealed that the female sex, chronic obstructive pulmonary disease, and smoking were independent risk factors for persistent dyspnea. Approximately 50% completed less than 80% of the theoretical distance on the 6MWT. Only 14% had an abnormal X-ray, showing mainly interstitial infiltrates. A third of them had been followed up in outpatient clinics and 6% had undergone physical rehabilitation. Conclusion Despite the high rate of survivors of the first wave of the COVID-19 pandemic with persistent symptomatology at 12 months, the follow-up and rehabilitation of these patients has been really poor. Studies focusing on the role of smoking in the persistence of COVID-19 symptoms are lacking.

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“…To date, most biological assessments of PASC have focused on the post-acute phase of infection (4,(6)(7)(8)(9)(19)(20)(21)(22)(23)(24)(25). Only a few studies have assessed the relationship between biomarkers in the acute phase of SARS-CoV-2 infection and the later development of PASC (12,13,26). Such efforts have identified the presence of SARS-CoV-2 RNA in blood at the time of diagnosis (26) and prolonged duration of viral shedding from the upper respiratory tract (12) as correlates of PASC.…”

Section: Discussionmentioning

confidence: 99%

Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection

Peluso

Glidden

et al. 2023

Preprint

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To understand the roles of acute phase viral dynamics and host immune responses in PASC, we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR. Participants self-collected nasal specimens up to 21 times within the first 28 days after symptom onset; Interviewer-administered clinical questionnaires and blood samples were collected at enrollment and days 9, 14, 21, 28, and month 4 and 8 post-symptom. Defining PASC as the presence of any symptom new or worse since infection reported at their 4-month visit, we compared viral markers (quantity and duration of viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-a, IFN-a, IFN-g, MCP, IP-10, and Spike IgG) over the acute period. In comparison to those who fully recovered, those who developed PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA, infectious virus, and N-antigen, longer duration of viral shedding, and lower Spike-specific IgG levels within the first 10 days of the acute phase of illness. No significant differences were identified among a panel of host immune markers, though there was a trend toward higher initial levels of certain markers (e.g., MCP-1, IFN-a, and IFN-g) in those who went on to develop PASC. Early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC. These findings highlight the importance of understanding the early biological markers from acute SARS-CoV-2 infection in the natural history of PASC.

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Acute COVID-19 gene-expression profiles show multiple etiologies of long-term sequelae

Cited by 5 publications

References 51 publications

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Persistent COVID-19 symptoms 1 year after hospital discharge: A prospective multicenter study

Early Biological Markers of Post-Acute Sequelae of SARS-CoV-2 Infection

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