. 2022 Dec 28;12(1):22471.

doi: 10.1038/s41598-022-26965-7.

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

Paul W Blair^{1

2}, Joost Brandsma³, Josh Chenoweth³, Stephanie A Richard^{3

4}, Nusrat J Epsi^{3

4}, Rittal Mehta³, Deborah Striegel³, Emily G Clemens⁵, Sultanah Alharthi^{3

5}, David A Lindholm^{6

7}, Ryan C Maves^{8

9}, Derek T Larson¹⁰, Katrin Mende^{3

4

7}, Rhonda E Colombo^{3

4

11}, Anuradha Ganesan^{3

4

12}, Tahaniyat Lalani^{3

4

13}, Christopher J Colombo¹¹, Allison A Malloy¹⁴, Andrew L Snow¹⁵, Kevin L Schully¹⁶, Charlotte Lanteri⁴, Mark P Simons⁴, John S Dumler⁵, David Tribble⁴, Timothy Burgess⁴, Simon Pollett^{3

4}, Brian K Agan^{3

4}, Danielle V Clark³; EPICC COVID-19 Cohort Study Group

Collaborators, Affiliations

Collaborators

EPICC COVID-19 Cohort Study Group:
J Cowden, M Darling, T Merritt, T Wellington, A Rutt, C Conlon, P Faestel, C Mount, A Smith, R Tant, T Warkentien, C Berjohn, G Utz, C Madar, C Uyehara, K Chung, C English, C Fox, M Grother, P Hickey, E Laing, J Livezey, E Parmelee, J Rozman, M Sanchez, A Scher, T Chao, R Chapleau, A Fries, K Reynolds, D Hostler, J Hostler, K Lago, C Maldonado, T Hunter, R Mody, M Wayman, N Huprikar

Affiliations

¹ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr, Bethesda, MD, 20817, USA. pblair@aceso-sepsis.org.
² Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. pblair@aceso-sepsis.org.
³ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr, Bethesda, MD, 20817, USA.
⁴ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵ Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷ Brooke Army Medical Center, Joint Base San Antonio-Ft Sam Houston, San Antonio, TX, USA.
⁸ Departments of Internal Medicine and Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁹ Naval Medical Center San Diego, San Diego, CA, USA.
¹⁰ Fort Belvoir Community Hospital, Fort Belvoir, VA, USA.
¹¹ Madigan Army Medical Center, Joint Base Lewis-McChord, Tacoma, WA, USA.
¹² Walter Reed National Military Medical Center, Bethesda, MD, USA.
¹³ Naval Medical Center Portsmouth, Portsmouth, VA, USA.
¹⁴ Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁵ Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁶ Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Ft. Detrick, MD, USA.

PMID: 36577783
PMCID: PMC9795438
DOI: 10.1038/s41598-022-26965-7

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

Paul W Blair et al. Sci Rep. 2022.

. 2022 Dec 28;12(1):22471.

doi: 10.1038/s41598-022-26965-7.

Authors

Collaborators

EPICC COVID-19 Cohort Study Group:
J Cowden, M Darling, T Merritt, T Wellington, A Rutt, C Conlon, P Faestel, C Mount, A Smith, R Tant, T Warkentien, C Berjohn, G Utz, C Madar, C Uyehara, K Chung, C English, C Fox, M Grother, P Hickey, E Laing, J Livezey, E Parmelee, J Rozman, M Sanchez, A Scher, T Chao, R Chapleau, A Fries, K Reynolds, D Hostler, J Hostler, K Lago, C Maldonado, T Hunter, R Mody, M Wayman, N Huprikar

Affiliations

¹ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr, Bethesda, MD, 20817, USA. pblair@aceso-sepsis.org.
² Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. pblair@aceso-sepsis.org.
³ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr, Bethesda, MD, 20817, USA.
⁴ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁵ Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷ Brooke Army Medical Center, Joint Base San Antonio-Ft Sam Houston, San Antonio, TX, USA.
⁸ Departments of Internal Medicine and Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁹ Naval Medical Center San Diego, San Diego, CA, USA.
¹⁰ Fort Belvoir Community Hospital, Fort Belvoir, VA, USA.
¹¹ Madigan Army Medical Center, Joint Base Lewis-McChord, Tacoma, WA, USA.
¹² Walter Reed National Military Medical Center, Bethesda, MD, USA.
¹³ Naval Medical Center Portsmouth, Portsmouth, VA, USA.
¹⁴ Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁵ Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
¹⁶ Biological Defense Research Directorate, Naval Medical Research Center-Frederick, Ft. Detrick, MD, USA.

PMID: 36577783
PMCID: PMC9795438
DOI: 10.1038/s41598-022-26965-7

Abstract

The associations between clinical phenotypes of coronavirus disease 2019 (COVID-19) and the host inflammatory response during the transition from peak illness to convalescence are not yet well understood. Blood plasma samples were collected from 129 adult SARS-CoV-2 positive inpatient and outpatient participants between April 2020 and January 2021, in a multi-center prospective cohort study at 8 military hospitals across the United States. Plasma inflammatory protein biomarkers were measured in samples from 15 to 28 days post symptom onset. Topological Data Analysis (TDA) was used to identify patterns of inflammation, and associations with peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated using logistic regression. The study population (n = 129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct inflammatory biomarker clusters were identified and were associated with significant differences in peak disease severity (p < 0.001), age (p < 0.001), BMI (p < 0.001), and CCI (p = 0.001). Host-biomarker profiles stratified a heterogeneous population of COVID-19 patients during the transition from peak illness to convalescence, and these distinct inflammatory patterns were associated with comorbid disease and severe illness due to COVID-19.

PubMed Disclaimer

Conflict of interest statement

S. D. P., M.P.S., T. H. B, and D.R.T. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc (HJF) were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US Government COVID-19 response. Neither is related to the work presented here. All other authors declare no competing interests.

Figures

**Figure 1**
Topological data analysis (TDA) network of protein expression during the middle-phase of COVID-19. Distinct protein expression phenotypes (Clusters 1, 2, and 3) were identified based on density and break points in the network and persistence of the clusters. Each node represents a combination of 12 plasma protein analyte levels and its size increases with the number of participants that are included. Edges (lines between nodes) indicate that patients are represented in more than one node. The network is colored by the average score on the disease severity scale (from outpatients without limitations [green] to death [red]) in each node. Analysis was performed on the EurekaAI Workbench (SymphonyAI, Los Altos, CA, USA).

**Figure 2**
Cluster differences with bar plots (% [n]) of comorbid diseases and severity by cluster. (A) BMI (body mass index) category (range in kg/m²) prevalence by cluster; (B) Charlson Comorbidity Index (CCI) category prevalence by cluster; (C) peak levels of severity by cluster. Total (n) presented in the center of each category.

**Figure 3**
Box plots of markers selected in stepwise regression to identify characteristic biomarkers of each cluster: Ferritin (A), IL1RA (B), RAGE (C), and VEGFA (D) by cluster. Kruskal–Wallis test performed comparing analyte levels between clusters. **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001.

See this image and copyright information in PMC

References

1. Buicu AL, Cernea S, Benedek I, Buicu CF, Benedek T. Systemic inflammation and COVID-19 mortality in patients with major noncommunicable diseases: Chronic coronary syndromes, diabetes and obesity. J. Clin. Med. 2021 doi: 10.3390/jcm10081545. - DOI - PMC - PubMed
1. Cummings MJ, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: A prospective cohort study. Lancet. 2020;395:1763–1770. doi: 10.1016/s0140-6736(20)31189-2. - DOI - PMC - PubMed
1. RECOVERY Collaborative Group Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet. 2021;397:1637–1645. doi: 10.1016/s0140-6736(21)00676-0. - DOI - PMC - PubMed
1. Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: Illness beyond acute infection and public health implications. JAMA. 2020;324:2251–2252. doi: 10.1001/jama.2020.22717. - DOI - PubMed
1. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ. 2020;371:m3862. doi: 10.1136/bmj.m3862. - DOI - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

Collaborators

Affiliations

Distinct blood inflammatory biomarker clusters stratify host phenotypes during the middle phase of COVID-19

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances