# Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients

Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer

Gautier, Cédric Annweiler

► To cite this version:

Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier, et al.. Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS ONE, 2021, 16 (9), pp.e0256931. 10.1371/journal.pone.0256931. hal-04592900

HAL Id: hal-04592900

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Submitted on 29 May 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients

Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer

Gautier, Cédric Annweiler

► To cite this version:

Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier, et al.. Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS ONE, 2021, 16 (9), pp.e0256931. 10.1371/journal.pone.0256931. hal-04592900

HAL Id: hal-04592900

https://nantes-universite.hal.science/hal-04592900v1

Submitted on 29 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
RESEARCH ARTICLE

# Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients

Adeline Villoteau<sup>1,2</sup>, Marine Asfar<sup>1,2</sup>, Marie Otekpo<sup>1,2</sup>, Jocelyne Loison<sup>2</sup>, Jennifer Gautier<sup>2</sup>, Cédric Annweiler<sup>1,2,3,4,5*</sup>, on behalf of the GERIA-COVID study group<sup>¶</sup>

1 School of Medicine, Health Faculty, University of Angers, Angers, France, 2 Department of Geriatric Medicine and Memory Clinic, Research Center on Autonomy and Longevity, University Hospital, Angers, France, 3 UPRES EA 4638, University of Angers, Angers, France, 4 Gérontopôle Autonomie Longévité des Pays de la Loire, Pays de la Loire, France, 5 Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada

¶ Membership of the GERIA-COVID Study Group is listed in the Acknowledgments.

* Cedric.Annweiler@chu-angers.fr

<figure><img src="image_2.png" /></figure>

## Abstract

<figure><img src="image_3.png" /></figure>

### OPEN ACCESS

**Citation:** Villoteau A, Asfar M, Otekpo M, Loison J, Gautier J, Annweiler C, et al. (2021) Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS ONE 16(9): e0256931. https://doi.org/10.1371/journal.pone.0256931

**Editor:** Ehab Farag, Cleveland Clinic, UNITED STATES

**Received:** May 20, 2021

**Accepted:** August 18, 2021

**Published:** September 10, 2021

**Copyright:** © 2021 Villoteau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

**Data Availability Statement:** Patient level data are freely available from the corresponding author or Jean-Marie Chretien, health data protection officer at the University Hospital of Angers, France (JMChretien@chu-angers.fr). There is no personal identification risk within this anonymized raw data, which is available after notification and authorization of the competent authorities including the Ethics Board of the University Hospital of Angers, France (ethique@chu-angers.fr).

## Background

The objective of this cohort study was to determine whether elevated CRP in early COVID-19 was associated with 14-day mortality in geriatric patients.

## Methods

Plasma CRP levels at hospital admission and 14-day all-cause mortality were assessed in geriatric inpatients hospitalized for COVID-19. Potential confounders were age, sex, functional abilities, history of malignancies, hypertension, cardiomyopathy, albuminemia, number of acute health issues, use of antibiotics and respiratory treatments.

## Results

Ninety-five participants (mean±SD 88.0±5.5years; 49.5% women; mean CRP, 76.7±77.5mg/L; mean albuminemia, 32.9±6.0g/L) were included. Sixteen participants who did not survive at day 14 exhibited higher CRP level at baseline than the others (120.3±71.2 versus 67.9±76.1 mg/L, P = 0.002). There was no difference in albuminemia (P = 0.329). Plasma CRP level was directly associated with 14-day mortality (fully adjusted HR = 1.11, P = 0.025). The cut-off for CRP associated with 14-day mortality was set at 35mg/L (sensitivity = 0.88; specificity = 0.56). Those with CRP<35mg/L had longer survival time than the others (log-rank P<0.001).

## Conclusions

Elevated CRP levels were associated with poorer 14-day survival in hospitalized geriatric COVID-19 patients.
RESEARCH ARTICLE

# Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients

Adeline Villoteau<sup>1,2</sup>, Marine Asfar<sup>1,2</sup>, Marie Otekpo<sup>1,2</sup>, Jocelyne Loison<sup>2</sup>, Jennifer Gautier<sup>2</sup>, Cédric Annweiler<sup>1,2,3,4,5*</sup>, on behalf of the GERIA-COVID study group<sup>1</sup>

1 School of Medicine, Health Faculty, University of Angers, Angers, France, 2 Department of Geriatric Medicine and Memory Clinic, Research Center on Autonomy and Longevity, University Hospital, Angers, France, 3 UPRES EA 4638, University of Angers, Angers, France, 4 Gérontopôle Autonomie Longévité des Pays de la Loire, Pays de la Loire, France, 5 Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada

¶ Membership of the GERIA-COVID Study Group is listed in the Acknowledgments.

* Cedric.Annweiler@chu-angers.fr

<figure><img src="image_2.png" /></figure>

## Abstract

<figure><img src="image_3.png" /></figure>

### OPEN ACCESS

**Citation:** Villoteau A, Asfar M, Otekpo M, Loison J, Gautier J, Annweiler C, et al. (2021) Elevated C-reactive protein in early COVID-19 predicts worse survival among hospitalized geriatric patients. PLoS ONE 16(9): e0256931. https://doi.org/10.1371/journal.pone.0256931

**Editor:** Ehab Farag, Cleveland Clinic, UNITED STATES

**Received:** May 20, 2021

**Accepted:** August 18, 2021

**Published:** September 10, 2021

**Copyright:** © 2021 Villoteau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

**Data Availability Statement:** Patient level data are freely available from the corresponding author or Jean-Marie Chretien, health data protection officer at the University Hospital of Angers, France (JMChretien@chu-angers.fr). There is no personal identification risk within this anonymized raw data, which is available after notification and authorization of the competent authorities including the Ethics Board of the University Hospital of Angers, France (ethique@chu-angers.fr).

## Background

The objective of this cohort study was to determine whether elevated CRP in early COVID-19 was associated with 14-day mortality in geriatric patients.

## Methods

Plasma CRP levels at hospital admission and 14-day all-cause mortality were assessed in geriatric inpatients hospitalized for COVID-19. Potential confounders were age, sex, functional abilities, history of malignancies, hypertension, cardiomyopathy, albuminemia, number of acute health issues, use of antibiotics and respiratory treatments.

## Results

Ninety-five participants (mean±SD 88.0±5.5years; 49.5% women; mean CRP, 76.7±77.5mg/L; mean albuminemia, 32.9±6.0g/L) were included. Sixteen participants who did not survive at day 14 exhibited higher CRP level at baseline than the others (120.3±71.2 versus 67.9±76.1 mg/L, P = 0.002). There was no difference in albuminemia (P = 0.329). Plasma CRP level was directly associated with 14-day mortality (fully adjusted HR = 1.11, P = 0.025). The cut-off for CRP associated with 14-day mortality was set at 35mg/L (sensitivity = 0.88; specificity = 0.56). Those with CRP<35mg/L had longer survival time than the others (log-rank P<0.001).

## Conclusions

Elevated CRP levels were associated with poorer 14-day survival in hospitalized geriatric COVID-19 patients.
**Funding:** The author(s) received no specific funding for this work.

**Competing interests:** The authors have declared that no competing interests exist.

## Introduction

The discovery of SARS-CoV-2 in Wuhan, China, at the end of 2019 and the subsequent global COVID-19 pandemic poses an unprecedented challenge for modern society. The pandemic results, particularly among older adults with comorbidities, in a high mortality rate mainly due to a poorly controlled inflammatory cascade reaction called cytokine storm and subsequent acute respiratory distress syndrome (ARDS) [1-3].

How SARS-CoV-2 causes such a cytokine storm mostly in older adults is not fully eluci-dated [4]. Aging is associated with chronic low-grade inflammation (aka inflammaging) char-acterized by higher local and systemic pro-inflammatory cytokine levels associated with a predominantly atypical ARDS [5-7]. C-reactive protein (CRP), an acute phase glycoprotein produced by the liver in response to interleukin 6 (IL-6), is a useful marker of inflammaging commonly used in clinical practice [8], as well as a sign of serious bacterial infection, trauma and various chronic diseases widely met in older adults such as malignancies for example. Although CRP potently predicts adverse outcome in these diseases, experimental data suggest that CRP may instead play a protective role in alveolitis and previous clinical evidence reported that elevated levels of CRP were associated with decreased mortality among patients with acute lung injury [9, 10]. There was also some evidence that decreased albumin levels, another strong prognostic indicator of inflammation, may be of greater value than CRP in predicting and monitoring the severity and course of ARDS in critically patients with or at risk for the syn-drome after new onset fever [11, 12]. Therefore, it remains unclear whether the elevation of CRP in the early stages of COVID-19 could serve as a prognostic marker in patients with COVID-19, especially in the group of older adults. The aim of the present longitudinal cohort study was to determine whether elevated CRP levels measured in the early stages of COVID-19 were associated, independently from the albumin levels, with higher 14-day mortality in geriatric patients hospitalized for COVID-19.

## Materials and methods

The GERIA-COVID study is a longitudinal observational study conducted in the geriatric acute care unit dedicated to COVID-19 patients in the University Hospital of Angers, France, during the first wave of the COVID-19 pandemic (ClinicalTrials.gov NCT04560608). Data of the GERIA-COVID study were retrospectively collected from patients' records. The detailed procedure has been previously described elsewhere [13].

### Study population

The inclusion criteria were the following: i) patients aged 75 years and over admitted into the geriatric acute care unit of the University Hospital of Angers, France, during the first wave of the pandemic (between March and June 2020); ii) no objection from the patients and/or their relatives for using anonymized clinical and biological data for research purpose; iii) diagnosis of COVID-19 with RT-PCR and/or chest CT-scan; iv) data available on the plasma CRP and albumin levels at hospital admission; v) data available on the vital status 14 days after the diag-nosis of COVID-19.

### Plasma level of C-reactive protein

All patients had a blood test on the day of admission into hospital, along with the diagnostic tests for COVID-19. Plasma CRP levels were measured in mg/L locally at the laboratory of the University Hospital of Angers, France, with latex-enhanced immunoturbidimetry assay (ADVIA Chemistry System, Bayer Healthcare AG, Leverkusen, Germany). Elevated plasma
**Funding:** The author(s) received no specific funding for this work.

**Competing interests:** The authors have declared that no competing interests exist.

## Introduction

The discovery of SARS-CoV-2 in Wuhan, China, at the end of 2019 and the subsequent global COVID-19 pandemic poses an unprecedented challenge for modern society. The pandemic results, particularly among older adults with comorbidities, in a high mortality rate mainly due to a poorly controlled inflammatory cascade reaction called cytokine storm and subsequent acute respiratory distress syndrome (ARDS) [1-3].

How SARS-CoV-2 causes such a cytokine storm mostly in older adults is not fully eluci-dated [4]. Aging is associated with chronic low-grade inflammation (aka inflammaging) char-acterized by higher local and systemic pro-inflammatory cytokine levels associated with a predominantly atypical ARDS [5-7]. C-reactive protein (CRP), an acute phase glycoprotein produced by the liver in response to interleukin 6 (IL-6), is a useful marker of inflammaging commonly used in clinical practice [8], as well as a sign of serious bacterial infection, trauma and various chronic diseases widely met in older adults such as malignancies for example. Although CRP potently predicts adverse outcome in these diseases, experimental data suggest that CRP may instead play a protective role in alveolitis and previous clinical evidence reported that elevated levels of CRP were associated with decreased mortality among patients with acute lung injury [9, 10]. There was also some evidence that decreased albumin levels, another strong prognostic indicator of inflammation, may be of greater value than CRP in predicting and monitoring the severity and course of ARDS in critically patients with or at risk for the syn-drome after new onset fever [11, 12]. Therefore, it remains unclear whether the elevation of CRP in the early stages of COVID-19 could serve as a prognostic marker in patients with COVID-19, especially in the group of older adults. The aim of the present longitudinal cohort study was to determine whether elevated CRP levels measured in the early stages of COVID-19 were associated, independently from the albumin levels, with higher 14-day mortality in geriatric patients hospitalized for COVID-19.

## Materials and methods

The GERIA-COVID study is a longitudinal observational study conducted in the geriatric acute care unit dedicated to COVID-19 patients in the University Hospital of Angers, France, during the first wave of the COVID-19 pandemic (ClinicalTrials.gov NCT04560608). Data of the GERIA-COVID study were retrospectively collected from patients' records. The detailed procedure has been previously described elsewhere [13].

### Study population

The inclusion criteria were the following: i) patients aged 75 years and over admitted into the geriatric acute care unit of the University Hospital of Angers, France, during the first wave of the pandemic (between March and June 2020); ii) no objection from the patients and/or their relatives for using anonymized clinical and biological data for research purpose; iii) diagnosis of COVID-19 with RT-PCR and/or chest CT-scan; iv) data available on the plasma CRP and albumin levels at hospital admission; v) data available on the vital status 14 days after the diag-nosis of COVID-19.

### Plasma level of C-reactive protein

All patients had a blood test on the day of admission into hospital, along with the diagnostic tests for COVID-19. Plasma CRP levels were measured in mg/L locally at the laboratory of the University Hospital of Angers, France, with latex-enhanced immunoturbidimetry assay (ADVIA Chemistry System, Bayer Healthcare AG, Leverkusen, Germany). Elevated plasma
CRP levels were defined using a threshold value calculated from a sensitivity-specificity analy-
sis to best fit the studied group.

Overall mortality

The main outcome was all-cause mortality at day 14. Follow-up started from the day of
COVID-19 diagnosis for each patient and continued for 14 days or until death when applica-
ble. This follow-up was long enough to cover the critical period of the 7 to 10 days of COVID-
19 during which the cytokine storm may occur with its severe clinical consequences such as
the often-fatal ARDS.

Covariables

Potential confounders were age, female sex, functional abilities, history of malignancies, his-
tory of hypertension, history of cardiomyopathy, albuminemia, lymphopenia, number of acute
health issues at hospital admission, use of antibiotics and use of pharmacological treatments
for respiratory disorders.

Functional abilities prior to COVID-19 were measured from 1 to 6 (best) with the Iso-
Resources Groups (GIR) [14]. Plasma lymphocytes (in G/L) and albumin concentration (in g/
L) were measured on admission with standard techniques locally at the University Hospital of
Angers, France. Lymphopenia was defined as lymphocytes ≤1G/L. Acute health issues were
defined as diseases with sudden onset and rapid progression, whatever their nature or site
[15]. History of hematological and solid malignancies, of hypertension and of cardiomyopathy
were noted from the medical register, and by interviewing patients, their relatives and family
physicians. The use of antibiotics (i.e., quinolones, beta-lactams, sulfonamides, macrolides, lin-
cosamides, aminoglycosides, among others) and/or pharmacological treatments for respira-
tory disorders (i.e., beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among
others) were noted from prescriptions during hospitalization.

Statistical analysis

The participants' characteristics were summarized using means and standard deviations (SD) or frequencies and percentages, as appropriate. As the number of observations was higher than 40, comparisons were not affected by the shape of the error distribution and no transformation was applied [16]. Firstly, comparisons between participants separated according to the vital status 14 days after the diagnosis of COVID-19 were performed using Chi-square test (or Fisher exact test) or Student t test (or Mann-Whitney Wilcoxon test according to the normality assessment), as appropriate. Secondly, a multiple Cox regression was used to examine the associations of 14-day mortality (dependent variable) with plasma CRP level and covariables (independent variables). The model produces a survival function that provides the probability of death at a given time for the characteristics supplied for the independent variables. Thirdly, the cut-off value for plasma CRP associated with 14-day survival was determined by a sensitivity analysis. Finally, the elapsed time to death was studied by survival curves computed according to Kaplan-Meier method and compared by log-rank test. P-values<0.05 were considered significant. All statistics were performed using SAS® version 9.4 software (Sas Institute Inc) and R (R core Team, 2018).

Ethics

The study was conducted in accordance with the ethical standards set forth in the Helsinki
Declaration (1983). All data were fully anonymized in this retrospective study of medical
CRP levels were defined using a threshold value calculated from a sensitivity-specificity analysis to best fit the studied group.

## Overall mortality

The main outcome was all-cause mortality at day 14. Follow-up started from the day of COVID-19 diagnosis for each patient and continued for 14 days or until death when applicable. This follow-up was long enough to cover the critical period of the 7 to 10 days of COVID-19 during which the cytokine storm may occur with its severe clinical consequences such as the often-fatal ARDS.

## Covariables

Potential confounders were age, female sex, functional abilities, history of malignancies, history of hypertension, history of cardiomyopathy, albuminemia, lymphopenia, number of acute health issues at hospital admission, use of antibiotics and use of pharmacological treatments for respiratory disorders.

Functional abilities prior to COVID-19 were measured from 1 to 6 (best) with the Iso-Resources Groups (GIR) [14]. Plasma lymphocytes (in G/L) and albumin concentration (in g/L) were measured on admission with standard techniques locally at the University Hospital of Angers, France. Lymphopenia was defined as lymphocytes $\le 1$G/L. Acute health issues were defined as diseases with sudden onset and rapid progression, whatever their nature or site [15]. History of hematological and solid malignancies, of hypertension and of cardiomyopathy were noted from the medical register, and by interviewing patients, their relatives and family physicians. The use of antibiotics (i.e., quinolones, beta-lactams, sulfonamides, macrolides, lin-cosamides, aminoglycosides, among others) and/or pharmacological treatments for respiratory disorders (i.e., beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among others) were noted from prescriptions during hospitalization.

## Statistical analysis

The participants' characteristics were summarized using means and standard deviations (SD) or frequencies and percentages, as appropriate. As the number of observations was higher than 40, comparisons were not affected by the shape of the error distribution and no transformation was applied [16]. Firstly, comparisons between participants separated according to the vital status 14 days after the diagnosis of COVID-19 were performed using Chi-square test (or Fisher exact test) or Student t test (or Mann-Whitney Wilcoxon test according to the normality assessment), as appropriate. Secondly, a multiple Cox regression was used to examine the associations of 14-day mortality (dependent variable) with plasma CRP level and covariables (independent variables). The model produces a survival function that provides the probability of death at a given time for the characteristics supplied for the independent variables. Thirdly, the cut-off value for plasma CRP associated with 14-day survival was determined by a sensitivity analysis. Finally, the elapsed time to death was studied by survival curves computed according to Kaplan-Meier method and compared by log-rank test. P-values<0.05 were considered significant. All statistics were performed using SAS® version 9.4 software (Sas Institute Inc) and R (R core Team, 2018).

## Ethics

The study was conducted in accordance with the ethical standards set forth in the Helsinki Declaration (1983). All data were fully anonymized in this retrospective study of medical
records. The Ethics Board of the University Hospital of Angers, France, approved the study and waived the requirement for informed consent (2020/100). No participant or relatives objected to the use of anonymized clinical and biological data for research purposes. The study protocol was also declared to the National Commission for Information Technology and civil Liberties (CNIL; ar20-0087v0).

## Results

Ninety-seven patients were consecutively diagnosed in the unit with COVID-19 during the study period and were recruited in the GERIA-COVID cohort study. Among them, two participants had missing values of plasma CRP and albumin levels. The vital status of all participants was known at day 14. Ninety-five participants were finally included in the present analysis (mean±SD, 88.0±5.5 years; 49.5% women; mean CRP level, 76.7±77.5 mg/L; mean albumin concentration, 32.9±6.0 g/L).

Table 1 indicates the characteristics of the participants who survived at day 14 (n = 79) or those who did not (n = 16). The two groups were similar at baseline, except for the proportion of participants with a history of malignancies (Table 1). The plasma CRP level was higher in those who did not survive at day 14 (respectively, 120.3±71.2 versus 67.9±76.1 mg/L, P = 0.002). There was no difference in albumin level (P = 0.329).

Table 2 shows a direct association between plasma CRP level at baseline and 14-day mortality. The hazard ratio (HR) for mortality was 1.06 [95% confidence interval (CI): 1.01;1.12] (P = 0.012) in the unadjusted model, and 1.11 [95%CI: 1.02;1.21] (P = 0.014) after adjustment for all potential confounders. The history of malignancies was also associated with greater mortality risk (HR = 7.65, P = 0.001) in the adjusted model.

<table><caption>Table 1. Characteristics and comparison of COVID-19 geriatric patients separated into two groups according to 14-day mortality (n = 95).</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Total cohort (n = 95)</th><th colspan="2">14-day mortality</th><th rowspan="2">P-value*</th></tr><tr><th>No (n = 79)</th><th>Yes (n = 16)</th></tr></thead><tbody><tr><td><strong>Demographical data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (years), mean±SD</td><td>88.0±5.5</td><td>87.8±5.6</td><td>89.2±4.8</td><td>0.353</td></tr><tr><td>Female sex</td><td>47 (49.5)</td><td>39 (49.4)</td><td>8 (50.0)</td><td>0.963</td></tr><tr><td>GIR score (/6), mean±SD</td><td>3.5±1.5</td><td>3.7±1.4</td><td>2.9±1.7</td><td>0.051</td></tr><tr><td><strong>Comorbidities</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Hematological and solid malignancies</td><td>32 (33.7)</td><td>22 (26.6)</td><td>11 (68.8)</td><td><strong>0.001</strong></td></tr><tr><td>Hypertension</td><td>60 (63.2)</td><td>49 (62.0)</td><td>11 (68.8)</td><td>0.611</td></tr><tr><td>Cardiomyopathy</td><td>50 (52.6)</td><td>40 (50.6)</td><td>10 (62.5)</td><td>0.386</td></tr><tr><td><strong>Hospitalization</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Plasma CRP (mg/L), mean±SD</td><td>76.7±77.5</td><td>67.9±76.1</td><td>120.3±71.2</td><td><strong>0.002</strong></td></tr><tr><td>Plasma albumin (g/L), mean±SD</td><td>32.9±6.0</td><td>33.2±6.1</td><td>31.6±5.7</td><td>0.329</td></tr><tr><td>Lymphopenia</td><td>42 (4.2)</td><td>34 (43.0)</td><td>8 (50.0)</td><td>0.609</td></tr><tr><td>Number of acute health issues at hospital admission, mean±SD</td><td>2.9±1.6</td><td>2.8±1.6</td><td>3.3±1.5</td><td>0.317</td></tr><tr><td>Use of antibiotics<sup>‡</sup></td><td>64 (67.4)</td><td>51 (64.6)</td><td>13 (81.3)</td><td>0.194</td></tr><tr><td>Use of pharmacological treatments for respiratory disorders<sup>||</sup></td><td>11 (11.6)</td><td>8 (10.1)</td><td>3 (18.8)</td><td>0.389</td></tr></tbody></table>

Data presented as n (%) where applicable; COVID-19: Coronavirus Disease 2019; CRP: C-reactive protein; GIR: Iso Resource Groups

*: between-group comparisons based on Chi-square test (or Fisher exact test) or Student t test (or Mann-Whitney Wilcoxon test according to the normality assessment), as appropriate

‡: quinolones, beta-lactams, sulfonamides, macrolides, lincosamides, aminoglycosides, among others

||: beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among others.

https://doi.org/10.1371/journal.pone.0256931.t001
records. The Ethics Board of the University Hospital of Angers, France, approved the study and waived the requirement for informed consent (2020/100). No participant or relatives objected to the use of anonymized clinical and biological data for research purposes. The study protocol was also declared to the National Commission for Information Technology and civil Liberties (CNIL; ar20-0087v0).

## Results

Ninety-seven patients were consecutively diagnosed in the unit with COVID-19 during the study period and were recruited in the GERIA-COVID cohort study. Among them, two participants had missing values of plasma CRP and albumin levels. The vital status of all participants was known at day 14. Ninety-five participants were finally included in the present analysis (mean±SD, 88.0±5.5 years; 49.5% women; mean CRP level, 76.7±77.5 mg/L; mean albumin concentration, 32.9±6.0 g/L).

Table 1 indicates the characteristics of the participants who survived at day 14 (n = 79) or those who did not (n = 16). The two groups were similar at baseline, except for the proportion of participants with a history of malignancies (Table 1). The plasma CRP level was higher in those who did not survive at day 14 (respectively, 120.3±71.2 versus 67.9±76.1 mg/L, P = 0.002). There was no difference in albumin level (P = 0.329).

Table 2 shows a direct association between plasma CRP level at baseline and 14-day mortality. The hazard ratio (HR) for mortality was 1.06 [95% confidence interval (CI): 1.01;1.12] (P = 0.012) in the unadjusted model, and 1.11 [95%CI: 1.02;1.21] (P = 0.014) after adjustment for all potential confounders. The history of malignancies was also associated with greater mortality risk (HR = 7.65, P = 0.001) in the adjusted model.

<table><caption>Table 1. Characteristics and comparison of COVID-19 geriatric patients separated into two groups according to 14-day mortality (n = 95).</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Total cohort (n = 95)</th><th colspan="2">14-day mortality</th><th rowspan="2">P-value*</th></tr><tr><th>No (n = 79)</th><th>Yes (n = 16)</th></tr></thead><tbody><tr><td><strong>Demographical data</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (years), mean±SD</td><td>88.0±5.5</td><td>87.8±5.6</td><td>89.2±4.8</td><td>0.353</td></tr><tr><td>Female sex</td><td>47 (49.5)</td><td>39 (49.4)</td><td>8 (50.0)</td><td>0.963</td></tr><tr><td>GIR score (/6), mean±SD</td><td>3.5±1.5</td><td>3.7±1.4</td><td>2.9±1.7</td><td>0.051</td></tr><tr><td><strong>Comorbidities</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Hematological and solid malignancies</td><td>32 (33.7)</td><td>22 (26.6)</td><td>11 (68.8)</td><td><strong>0.001</strong></td></tr><tr><td>Hypertension</td><td>60 (63.2)</td><td>49 (62.0)</td><td>11 (68.8)</td><td>0.611</td></tr><tr><td>Cardiomyopathy</td><td>50 (52.6)</td><td>40 (50.6)</td><td>10 (62.5)</td><td>0.386</td></tr><tr><td><strong>Hospitalization</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Plasma CRP (mg/L), mean±SD</td><td>76.7±77.5</td><td>67.9±76.1</td><td>120.3±71.2</td><td><strong>0.002</strong></td></tr><tr><td>Plasma albumin (g/L), mean±SD</td><td>32.9±6.0</td><td>33.2±6.1</td><td>31.6±5.7</td><td>0.329</td></tr><tr><td>Lymphopenia</td><td>42 (4.2)</td><td>34 (43.0)</td><td>8 (50.0)</td><td>0.609</td></tr><tr><td>Number of acute health issues at hospital admission, mean±SD</td><td>2.9±1.6</td><td>2.8±1.6</td><td>3.3±1.5</td><td>0.317</td></tr><tr><td>Use of antibiotics<sup>‡</sup></td><td>64 (67.4)</td><td>51 (64.6)</td><td>13 (81.3)</td><td>0.194</td></tr><tr><td>Use of pharmacological treatments for respiratory disorders<sup>||</sup></td><td>11 (11.6)</td><td>8 (10.1)</td><td>3 (18.8)</td><td>0.389</td></tr></tbody></table>

Data presented as n (%) where applicable; COVID-19: Coronavirus Disease 2019; CRP: C-reactive protein; GIR: Iso Resource Groups

*: between-group comparisons based on Chi-square test (or Fisher exact test) or Student t test (or Mann-Whitney Wilcoxon test according to the normality assessment), as appropriate

‡: quinolones, beta-lactams, sulfonamides, macrolides, lincosamides, aminoglycosides, among others

||: beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among others.
<table><caption>Table 2. Multiple Cox proportional-hazards model showing the hazard ratio for 14-day mortality (dependent variable) according to baseline plasma CRP (independent variable), adjusted for participants' characteristics (n = 95).</caption><thead><tr><th rowspan="3"></th><th colspan="4">14-day mortality</th></tr><tr><th colspan="2">Unadjusted model</th><th colspan="2">Fully-adjusted model</th></tr><tr><th>HR [95% CI]</th><th>P-value</th><th>HR [95% CI]</th><th>P-value</th></tr></thead><tbody><tr><td>Plasma CRP level (for 10mg/L)</td><td>1.06 [1.01; 1.12]</td><td><strong>0.012</strong></td><td>1.11 [1.02; 1.21]</td><td><strong>0.014</strong></td></tr><tr><td>Age</td><td>1.05 [0.95; 1.15]</td><td>0.354</td><td>1.01 [0.89; 1.15]</td><td>0.859</td></tr><tr><td>Female sex</td><td>1.00 [0.38; 2.67]</td><td>0.995</td><td>1.58 [0.42; 5.94]</td><td>0.500</td></tr><tr><td>GIR score</td><td>0.71 [0.50; 1.02]</td><td>0.061</td><td>0.80 [0.51; 1.27]</td><td>0.342</td></tr><tr><td>Hematological and solid malignancies</td><td>4.84 [1.68; 13.95]</td><td><strong>0.004</strong></td><td>7.65 [2.27; 25.76]</td><td><strong>0.001</strong></td></tr><tr><td>Hypertension</td><td>1.30 [0.45; 3.75]</td><td>0.622</td><td>1.94 [0.54; 7.02]</td><td>0.310</td></tr><tr><td>Cardiomyopathy</td><td>1.52 [0.55; 4.18]</td><td>0.419</td><td>1.16 [0.34; 3.93]</td><td>0.809</td></tr><tr><td>Plasma albumin concentration</td><td>0.96 [0.88; 1.04]</td><td>0.301</td><td>1.07 [0.95; 1.21]</td><td>0.240</td></tr><tr><td>Lymphopenia</td><td>1.26 [0.47; 3.37]</td><td>0.640</td><td>1.01 [0.27; 3.79]</td><td>0.989</td></tr><tr><td>Number of acute health issues at hospital admission</td><td>1.17 [0.86; 1.60]</td><td>0.273</td><td>1.11 [0.71; 1.72]</td><td>0.648</td></tr><tr><td>Use of antibiotics<sup>†</sup></td><td>2.16 [0.62; 7.58]</td><td>0.230</td><td>2.67 [0.54; 12.23]</td><td>0.237</td></tr><tr><td>Use of pharmacological treatments for respiratory disorders<sup>‡</sup></td><td>1.94 [0.55; 6.81]</td><td>0.301</td><td>2.44 [0.46; 12.89]</td><td>0.295</td></tr></tbody></table>

CI: confidence interval; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; GIR: Iso Resource Groups; HR: hazard ratio

†: quinolones, beta-lactams, sulfonamides, macrolides, lincosamides, aminoglycosides, among others

‡: beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among others.

https://doi.org/10.1371/journal.pone.0256931.t002

The cut-off value for plasma CRP associated with mortality was set at 35 mg/L, as determined by the sensitivity analysis (sensitivity = 0.88; specificity = 0.56). Kaplan-Meier distributions showed in Fig 1 that COVID-19 participants with CRP<35 mg/L had longer survival time than the others (log-rank P = 0.0016).

Discussion

The main result of this cohort study is that, irrespective of all measured potential confounders including albuminemia, the elevated CRP levels in early COVID-19 were associated with

<figure><img src="image_4.png" /><figcaption>Fig 1. Kaplan-Meier estimates of the cumulative probability of COVID-19 participants' survival according to plasma CRP (n = 95). Group 1: plasma CRP < 35 mg/L; Group 2: plasma CRP ≥ 35 mg/L.</figcaption></figure>

https://doi.org/10.1371/journal.pone.0256931.g001
<table><caption>Table 2. Multiple Cox proportional-hazards model showing the hazard ratio for 14-day mortality (dependent variable) according to baseline plasma CRP (independent variable), adjusted for participants' characteristics (n = 95).</caption><thead><tr><th rowspan="3"></th><th colspan="4">14-day mortality</th></tr><tr><th colspan="2">Unadjusted model</th><th colspan="2">Fully-adjusted model</th></tr><tr><th>HR [95% CI]</th><th>P-value</th><th>HR [95% CI]</th><th>P-value</th></tr></thead><tbody><tr><td>Plasma CRP level (for 10mg/L)</td><td>1.06 [1.01; 1.12]</td><td><strong>0.012</strong></td><td>1.11 [1.02; 1.21]</td><td><strong>0.014</strong></td></tr><tr><td>Age</td><td>1.05 [0.95; 1.15]</td><td>0.354</td><td>1.01 [0.89; 1.15]</td><td>0.859</td></tr><tr><td>Female sex</td><td>1.00 [0.38; 2.67]</td><td>0.995</td><td>1.58 [0.42; 5.94]</td><td>0.500</td></tr><tr><td>GIR score</td><td>0.71 [0.50; 1.02]</td><td>0.061</td><td>0.80 [0.51; 1.27]</td><td>0.342</td></tr><tr><td>Hematological and solid malignancies</td><td>4.84 [1.68; 13.95]</td><td><strong>0.004</strong></td><td>7.65 [2.27; 25.76]</td><td><strong>0.001</strong></td></tr><tr><td>Hypertension</td><td>1.30 [0.45; 3.75]</td><td>0.622</td><td>1.94 [0.54; 7.02]</td><td>0.310</td></tr><tr><td>Cardiomyopathy</td><td>1.52 [0.55; 4.18]</td><td>0.419</td><td>1.16 [0.34; 3.93]</td><td>0.809</td></tr><tr><td>Plasma albumin concentration</td><td>0.96 [0.88; 1.04]</td><td>0.301</td><td>1.07 [0.95; 1.21]</td><td>0.240</td></tr><tr><td>Lymphopenia</td><td>1.26 [0.47; 3.37]</td><td>0.640</td><td>1.01 [0.27; 3.79]</td><td>0.989</td></tr><tr><td>Number of acute health issues at hospital admission</td><td>1.17 [0.86; 1.60]</td><td>0.273</td><td>1.11 [0.71; 1.72]</td><td>0.648</td></tr><tr><td>Use of antibiotics<sup>†</sup></td><td>2.16 [0.62; 7.58]</td><td>0.230</td><td>2.67 [0.54; 12.23]</td><td>0.237</td></tr><tr><td>Use of pharmacological treatments for respiratory disorders<sup>‡</sup></td><td>1.94 [0.55; 6.81]</td><td>0.301</td><td>2.44 [0.46; 12.89]</td><td>0.295</td></tr></tbody></table>

CI: confidence interval; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; GIR: Iso Resource Groups; HR: hazard ratio

†: quinolones, beta-lactams, sulfonamides, macrolides, lincosamides, aminoglycosides, among others

‡: beta2-adrenergic agonists, inhaled corticosteroids, antihistamines, among others.

https://doi.org/10.1371/journal.pone.0256931.t002

The cut-off value for plasma CRP associated with mortality was set at 35 mg/L, as determined by the sensitivity analysis (sensitivity = 0.88; specificity = 0.56). Kaplan-Meier distributions showed in Fig 1 that COVID-19 participants with CRP<35 mg/L had longer survival time than the others (log-rank P = 0.0016).

Discussion

The main result of this cohort study is that, irrespective of all measured potential confounders including albuminemia, the elevated CRP levels in early COVID-19 were associated with

<figure><img src="image_4.png" /><figcaption>Fig 1. Kaplan-Meier estimates of the cumulative probability of COVID-19 participants' survival according to plasma CRP (n = 95). Group 1: plasma CRP < 35 mg/L; Group 2: plasma CRP ≥ 35 mg/L.</figcaption></figure>

https://doi.org/10.1371/journal.pone.0256931.g001
higher 14-day mortality among geriatric patients with COVID-19. This novel finding encourages the understanding of CRP as a possible prognostic marker in COVID-19 even in older adults. Further studies are needed to determine whether drugs aimed at normalizing CRP levels may improve COVID-19 survival.

The association between CRP levels and COVID-19 prognosis has been the subject of some previous studies [17]. Bannaga et al. reported in 321 adults with COVID-19 that increased CRP and decreased albumin levels on admission to intensive care units were associated with greater mortality after adjustment for advancing age [18]. Similarly, higher levels and a higher velocity of increase of CRP levels were observed in non-survivors compared to survivors among 577 middle-aged adults hospitalized for COVID-19 [19]. Consistently, the CRP level was also found as one of the variables most predictive of respiratory failure and of the need for mechanical ventilation in 89 adults hospitalized for COVID-19 [20]. Compared to our analysis, these previous studies did not focus on older adults specifically. Our study therefore provides novel information by confirming that the elevation of CRP above 35 g/L predicts fatal outcomes in COVID-19 also in older adults despite the inflammaging that usually characterizes this population. Confirming such link in COVID-19 is even more important since this result is contrary to what was previously reported in non-COVID-19 ARDS, in which the increase in CRP is thought to be protective instead [10].

How CRP is associated with decreased survival in older adults with COVID-19 is not yet fully understood. First, CRP in the early stage of COVID-19 has been reported to be positively correlated with lung lesions [21, 22] and may thus be a biomarker of the disease severity [23, 24]. Second, since the synthesis of CRP by hepatic cells is linked to IL-6, the levels of CRP might reflect the IL-6 secretion due to the activation by SARS-CoV-2 of monocytes, macrophages, and dendritic cells. The clinical importance is linked to the fact that IL-6 is involved in the cytokine storm, which subsequently involves the secretion of VEGF and a decrease in the expression of E-cadherin contributing to greater vascular permeability, arterial hypotension, organ failures and ARDS, with the risk of fatal outcome [25]. Third, the inflammatory state illustrated by the elevation of CRP could induce a prothrombin state with consequent increased risks of arterial events such as stroke [26] or venous thromboembolic events [27] such as pulmonary embolism [28]. Fourth, elevated CRP may also be associated with higher mortality risk by inducing hypercatabolism consuming respiratory muscle proteins with subsequent less opportunity for compensatory responses in respiratory distress. Fifth, the level of CRP may be the marker of the pre-COVID-19 health status of older individuals and illustrates both the burden of chronic diseases -which are mostly risk factors for severe COVID-19- and the inflammaging. Inflammaging is the chronic activation of innate immune system while advancing in age, which results in a low-grade, chronic, controlled inflammation in older adults [29, 30]. Inflammaging is represented by increased number of natural killer cells and increased production of pro-inflammatory cytokines, especially IL-6 and CRP [31]. This chronic inflamed state has detrimental effect on health, contributes to biological aging, and may explain the frequency of severe and fatal forms of COVID-19 in the elderly population.

The finding that higher CRP levels are associated with higher mortality risk in older patients with COVID-19 has interesting potential clinical and research implications. To the best of our knowledge, there are no clear reference on what a 'pathological' CRP value is in the early stage of COVID-19 among older adults. Such estimates of a cut-off value around 35 mg/L may help to justify, plan, evaluate, and compare the efficacy of interventions aimed at improving COVID-19 survival based on the monitoring and/or correction of inflammation in older adults with COVID-19.

Some limitations should be acknowledged. First, the present study was single-centered and participants restricted to geriatric patients hospitalized for COVID-19 who might be not
higher 14-day mortality among geriatric patients with COVID-19. This novel finding encourages the understanding of CRP as a possible prognostic marker in COVID-19 even in older adults. Further studies are needed to determine whether drugs aimed at normalizing CRP levels may improve COVID-19 survival.

The association between CRP levels and COVID-19 prognosis has been the subject of some previous studies [17]. Bannaga et al. reported in 321 adults with COVID-19 that increased CRP and decreased albumin levels on admission to intensive care units were associated with greater mortality after adjustment for advancing age [18]. Similarly, higher levels and a higher velocity of increase of CRP levels were observed in non-survivors compared to survivors among 577 middle-aged adults hospitalized for COVID-19 [19]. Consistently, the CRP level was also found as one of the variables most predictive of respiratory failure and of the need for mechanical ventilation in 89 adults hospitalized for COVID-19 [20]. Compared to our analysis, these previous studies did not focus on older adults specifically. Our study therefore provides novel information by confirming that the elevation of CRP above 35 g/L predicts fatal outcomes in COVID-19 also in older adults despite the inflamming that usually characterizes this population. Confirming such link in COVID-19 is even more important since this result is contrary to what was previously reported in non-COVID-19 ARDS, in which the increase in CRP is thought to be protective instead [10].

How CRP is associated with decreased survival in older adults with COVID-19 is not yet fully understood. First, CRP in the early stage of COVID-19 has been reported to be positively correlated with lung lesions [21, 22] and may thus be a biomarker of the disease severity [23, 24]. Second, since the synthesis of CRP by hepatic cells is linked to IL-6, the levels of CRP might reflect the IL-6 secretion due to the activation by SARS-CoV-2 of monocytes, macrophages, and dendritic cells. The clinical importance is linked to the fact that IL-6 is involved in the cytokine storm, which subsequently involves the secretion of VEGF and a decrease in the expression of E-cadherin contributing to greater vascular permeability, arterial hypotension, organ failures and ARDS, with the risk of fatal outcome [25]. Third, the inflammatory state illustrated by the elevation of CRP could induce a prothrombin state with consequent increased risks of arterial events such as stroke [26] or venous thromboembolic events [27] such as pulmonary embolism [28]. Fourth, elevated CRP may also be associated with higher mortality risk by inducing hypercatabolism consuming respiratory muscle proteins with subsequent less opportunity for compensatory responses in respiratory distress. Fifth, the level of CRP may be the marker of the pre-COVID-19 health status of older individuals and illustrates both the burden of chronic diseases -which are mostly risk factors for severe COVID-19- and the inflamming. Inflamming is the chronic activation of innate immune system while advancing in age, which results in a low-grade, chronic, controlled inflammation in older adults [29, 30]. Inflamming is represented by increased number of natural killer cells and increased production of pro-inflammatory cytokines, especially IL-6 and CRP [31]. This chronic inflamed state has detrimental effect on health, contributes to biological aging, and may explain the frequency of severe and fatal forms of COVID-19 in the elderly population.

The finding that higher CRP levels are associated with higher mortality risk in older patients with COVID-19 has interesting potential clinical and research implications. To the best of our knowledge, there are no clear reference on what a 'pathological' CRP value is in the early stage of COVID-19 among older adults. Such estimates of a cut-off value around 35 mg/L may help to justify, plan, evaluate, and compare the efficacy of interventions aimed at improving COVID-19 survival based on the monitoring and/or correction of inflammation in older adults with COVID-19.

Some limitations should be acknowledged. First, the present study was single-centered and participants restricted to geriatric patients hospitalized for COVID-19 who might be not
representative of the general population of older adults. Second, although we were able to con-
trol for important characteristics that could modify the association, residual potential con-
founders might still be present such as the IL-6 levels. Third, the observational design of our
study was less robust than an interventional study and precluded any causal inference. Fourth,
the diagnostic strategy for COVID-19 was heterogeneous, sometimes relying only on a chest
CT-scan as was recommended during the first wave of the pandemic [32], although more
recent studies showed that the assessment of radiological signs is highly dependent on the
experience of the radiologist and not objective [33].

Conclusions

In conclusion we found that, irrespective of potential confounders including albuminemia,
elevated CRP levels measured in the early stages of COVID-19 were associated with lower
14-day survival among hospitalized geriatric patients. Biomarkers' clinical usefulness is defined
as their capability to influence clinicians to diagnose the disease, predict prognosis, and guide
treatment. Here, the elevation of CRP above 35 mg/L is certainly not credible as a diagnostic
marker of COVID-19 but may be considered as a useful prognostic marker for severe forms of
COVID-19, even in older adults. In the context of the emergence of immune-escape SARS--
CoV-2 variants, continued efforts should be made to continue exploring the value of drugs
aimed at normalizing the inflammatory state, such as corticosteroids or immunosuppressants,
to improve the ability of the host to resist infection and to prevent the fatal consequences of
the cytokine storm.

Acknowledgments

The authors wish to thank the GERIA-COVID study group. GERIA-COVID study group: Cédric Annweiler, MD, PhD,¹ Marine Asfar, MD, MS,¹ Mélinda Beaudenon, MS,¹ Jean Barré, MD,¹ Antoine Brangier, MD, MS,¹ Mathieu Corvaisier, PharmD, MS,¹ Guillaume Duval, MD, MS,¹ Jennifer Gautier, MS,¹ Mialy Guenet, MS,¹ Jocelyne Loison, MD,¹ Frédéric Noublanche, MS,¹ Marie Otekpo, MD, BS,¹ Hélène Rivière, MD,¹ Guillaume Sacco, MD, PhD,¹ Romain Simon, MS¹. Affiliations: 1: Department of Geriatric Medicine, University Hospital, Angers, France. The lead author for the GERIA-COVID study group is Cedric Annweiler, MD, PhD, Cedric.Annweiler@chu-angers.fr

The authors have listed everyone who contributed significantly to the work in the Acknowledg-
edgments section. Permission has been obtained from all persons named in the Acknowledg-
ments section. There was no compensation for this contribution.

**Author Contributions**

**Conceptualization:** Cédric Annweiler.

**Data curation:** Jennifer Gautier.

**Formal analysis:** Adeline Villoteau, Jennifer Gautier, Cédric Annweiler.

**Investigation:** Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Cédric Annweiler.

**Methodology:** Cédric Annweiler.

**Project administration:** Cédric Annweiler.

**Resources:** Cédric Annweiler.

**Supervision:** Cédric Annweiler.
representative of the general population of older adults. Second, although we were able to con-
trol for important characteristics that could modify the association, residual potential con-
founders might still be present such as the IL-6 levels. Third, the observational design of our
study was less robust than an interventional study and precluded any causal inference. Fourth,
the diagnostic strategy for COVID-19 was heterogeneous, sometimes relying only on a chest
CT-scan as was recommended during the first wave of the pandemic [32], although more
recent studies showed that the assessment of radiological signs is highly dependent on the
experience of the radiologist and not objective [33].

Conclusions

In conclusion we found that, irrespective of potential confounders including albuminemia,
elevated CRP levels measured in the early stages of COVID-19 were associated with lower
14-day survival among hospitalized geriatric patients. Biomarkers' clinical usefulness is defined
as their capability to influence clinicians to diagnose the disease, predict prognosis, and guide
treatment. Here, the elevation of CRP above 35 mg/L is certainly not credible as a diagnostic
marker of COVID-19 but may be considered as a useful prognostic marker for severe forms of
COVID-19, even in older adults. In the context of the emergence of immune-escape SARS--
CoV-2 variants, continued efforts should be made to continue exploring the value of drugs
aimed at normalizing the inflammatory state, such as corticosteroids or immunosuppressants,
to improve the ability of the host to resist infection and to prevent the fatal consequences of
the cytokine storm.

Acknowledgments

The authors wish to thank the GERIA-COVID study group. GERIA-COVID study group: Cédric Annweiler, MD, PhD,¹ Marine Asfar, MD, MS,¹ Mélinda Beaudenon, MS,¹ Jean Barré, MD,¹ Antoine Brangier, MD, MS,¹ Mathieu Corvaisier, PharmD, MS,¹ Guillaume Duval, MD, MS,¹ Jennifer Gautier, MS,¹ Mialy Guenet, MS,¹ Jocelyne Loison, MD,¹ Frédéric Noubleche, MS,¹ Marie Otekpo, MD, BS,¹ Hélène Rivière, MD,¹ Guillaume Sacco, MD, PhD,¹ Romain Simon, MS¹. Affiliations: 1: Department of Geriatric Medicine, University Hospital, Angers, France. The lead author for the GERIA-COVID study group is Cedric Annweiler, MD, PhD, Cedric.Annweiler@chu-angers.fr

The authors have listed everyone who contributed significantly to the work in the Acknowledg-
edgments section. Permission has been obtained from all persons named in the Acknowledg-
ments section. There was no compensation for this contribution.

**Author Contributions**

**Conceptualization:** Cédric Annweiler.

**Data curation:** Jennifer Gautier.

**Formal analysis:** Adeline Villoteau, Jennifer Gautier, Cédric Annweiler.

**Investigation:** Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Cédric Annweiler.

**Methodology:** Cédric Annweiler.

**Project administration:** Cédric Annweiler.

**Resources:** Cédric Annweiler.

**Supervision:** Cédric Annweiler.
**Validation:** Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier, Cédric Annweiler.

**Writing – original draft:** Adeline Villoteau, Cédric Annweiler.

**Writing – review & editing:** Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier.

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11. Hoeboer SH, Straaten HMO, Groeneveld AJ. Albumin rather than C-reactive protein may be valuable in predicting and monitoring the severity and course of acute respiratory distress syndrome in critically ill patients with or at risk for the syndrome after new onset fever. BMC Pulm Med. 2015; 15: 22. https://doi.org/10.1186/s12890-015-0004-4 PMID: 25887940

12. Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, Christman BW, Dupont WD, et al. Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med. 2000; 28: 3137–3145. https://doi.org/10.1097/00003246-200009000-00001 PMID: 11008971

13. Annweiler G, Corvaisier M, Gautier J, Dubée V, Legrand E, Sacco G, et al. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients. 2020 Nov 2; 12(11):3377. https://doi.org/10.3390/nu12113377 PMID: 33147894

14. Vetel JM, Leroux R, Ducoudray JM. AGGIR. Practical use. Geriatric Autonomy Group Resources Needs. Soins Gerontol. 1998;(13): 23–27. PMID: 9735854

15. Sutra del Galy A, Bertrand M, Bigot F, Abraham P, Thomlinson R, Paccalin M, et al. Vitamin D Insufficiency and Acute Care in Geriatric Inpatients. J Am Geriatr Soc. 2009; 57: 1721–1723. https://doi.org/10.1111/j.1532-5415.2009.02408.x PMID: 19895442

16. Rochon J, Gondan M, Kieser M. To test or not to test: Preliminary assessment of normality when comparing two independent samples. BMC Med Res Methodol. 2012; 12: 81. https://doi.org/10.1186/1471-2288-12-81 PMID: 22712852
**Validation:** Adeline Villoteau, Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier, Cédric Annweiler.

**Writing – original draft:** Adeline Villoteau, Cédric Annweiler.

**Writing – review & editing:** Marine Asfar, Marie Otekpo, Jocelyne Loison, Jennifer Gautier.

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12. Mangialardi RJ, Martin GS, Bernard GR, Wheeler AP, Christman BW, Dupont WD, et al. Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med. 2000; 28: 3137–3145. https://doi.org/10.1097/00003246-200009000-00001 PMID: 11008971

13. Annweiler G, Corvaisier M, Gautier J, Dubée V, Legrand E, Sacco G, et al. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients. 2020 Nov 2; 12(11):3377. https://doi.org/10.3390/nu12113377 PMID: 33147894

14. Vetel JM, Leroux R, Ducoudray JM. AGGIR. Practical use. Geriatric Autonomy Group Resources Needs. Soins Gerontol. 1998;(13): 23–27. PMID: 9735854

15. Sutra del Galy A, Bertrand M, Bigot F, Abraham P, Thomlinson R, Paccalin M, et al. Vitamin D Insufficiency and Acute Care in Geriatric Inpatients. J Am Geriatr Soc. 2009; 57: 1721–1723. https://doi.org/10.1111/j.1532-5415.2009.02408.x PMID: 19895442

16. Rochon J, Gondan M, Kieser M. To test or not to test: Preliminary assessment of normality when comparing two independent samples. BMC Med Res Methodol. 2012; 12: 81. https://doi.org/10.1186/1471-2288-12-81 PMID: 22712852
17. Danwang C, Entomb F T, Neck J R, Wound D, Robert A, Nubian J.J. A meta-analysis of potential bio-markers associated with severity of coronavirus disease 2019 (COVID-19). Biomark Res. 2020; 8: 37. https://doi.org/10.1186/s40364-020-00217-0 PMID: 32879731

18. Bannaga AS, Tabuso M, Farrugia A, Chandrapalan S, Somal K, Lim VK, et al. C-reactive protein and albumin association with mortality of hospitalised SARS-CoV-2 patients: A tertiary hospital experience. Clin Med. 2020; 20: 463–467. https://doi.org/10.7861/clinmed.2020-0424 PMID: 32934038

19. Valerio L, Ferrazzi P, Sacco C, Ruf W, Kucher N, Konstantinides SV, et al. Course of D-Dimer and C-Reactive Protein Levels in Survivors and Nonsurvivors with COVID-19 Pneumonia: A Retrospective Analysis of 577 Patients. Thromb Haemost. 2021; 121: 98–101. https://doi.org/10.1055/s-0040-1721317 PMID: 33212544

20. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020; 146: 128–136.e4. https://doi.org/10.1016/j.jaci.2020.05.008 PMID: 32425269

21. Wang L. C-reactive protein levels in the early stage of COVID-19. Med Mal Infect. 2020; 50: 332–334. https://doi.org/10.1016/j.medmal.2020.03.007 PMID: 32243911

22. Tan C, Huang Y, Shi F, Tan K, Ma Q, Chen Y, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020; 92: 856–862. https://doi.org/10.1002/jmv.25871 PMID: 32281668

23. Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, et al. Prognostic Value of C-Reactive Protein in Patients With Coronavirus 2019. Clin Infect Dis. 2020; 71: 2174–2179. https://doi.org/10.1093/cid/ciaa641 PMID: 32445579

24. Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2020; 127: 104370. https://doi.org/10.1016/j.jcv.2020.104370 PMID: 32344321

25. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020; 368: 473–474. https://doi.org/10.1126/science.abb8925 PMID: 32303591

26. Tsivgoulis G, Katsanos AH, Ornello R, Sacco S. Ischemic Stroke Epidemiology During the COVID-19 Pandemic: Navigating Uncharted Waters With Changing Tides. Stroke. 2020; 51: 1924–1926. https://doi.org/10.1161/STROKEAHA.120.030791 PMID: 32496937

27. Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Off J Int Acad Clin Appl Thromb. 2020; 26: 1076029620938149.

28. Alzoughool F, Alanagreh L, Abumweis S, Atoum M. Cerebrovascular comorbidity, high blood levels of C-reactive protein and D-dimer are associated with disease outcomes in COVID-19 patients. Clin Hemorheol Microcirc. 2021; 77: 311–322. https://doi.org/10.3233/CH-201002 PMID: 33185593

29. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908: 244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x PMID: 10911963

30. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014; 69 Suppl 1: S4–9.

31. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 2005; 579: 2035–2039. https://doi.org/10.1016/j.febslet.2005.02.055 PMID: 15811314

32. ACR Recommendations for the use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection (March 11, 2020). Available at: https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection.

33. Li L, Wang L, Zeng F, Peng G, Ke Z, Liu H, et al. Development and multicenter validation of a CT-based radiomics signature for predicting severe COVID-19 pneumonia. Eur Radiol. 2021: 1–12 https://doi.org/10.1007/s00330-020-07108-w PMID: 32767103
17. Danwang C, Entomb F T, Neck J R, Wound D, Robert A, Nubian J.J. A meta-analysis of potential bio-markers associated with severity of coronavirus disease 2019 (COVID-19). Biomark Res. 2020; 8: 37. https://doi.org/10.1186/s40364-020-00217-0 PMID: 32879731

18. Bannaga AS, Tabuso M, Farrugia A, Chandrapalan S, Somal K, Lim VK, et al. C-reactive protein and albumin association with mortality of hospitalised SARS-CoV-2 patients: A tertiary hospital experience. Clin Med. 2020; 20: 463–467. https://doi.org/10.7861/clinmed.2020-0424 PMID: 32934038

19. Valerio L, Ferrazzi P, Sacco C, Ruf W, Kucher N, Konstantinides SV, et al. Course of D-Dimer and C-Reactive Protein Levels in Survivors and Nonsurvivors with COVID-19 Pneumonia: A Retrospective Analysis of 577 Patients. Thromb Haemost. 2021; 121: 98–101. https://doi.org/10.1055/s-0040-1721317 PMID: 33212544

20. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020; 146: 128–136.e4. https://doi.org/10.1016/j.jaci.2020.05.008 PMID: 32425269

21. Wang L. C-reactive protein levels in the early stage of COVID-19. Med Mal Infect. 2020; 50: 332–334. https://doi.org/10.1016/j.medmal.2020.03.007 PMID: 32243911

22. Tan C, Huang Y, Shi F, Tan K, Ma Q, Chen Y, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020; 92: 856–862. https://doi.org/10.1002/jmv.25871 PMID: 32281668

23. Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, et al. Prognostic Value of C-Reactive Protein in Patients With Coronavirus 2019. Clin Infect Dis. 2020; 71: 2174–2179. https://doi.org/10.1093/cid/ciaa641 PMID: 32445579

24. Liu F, Li L, Xu M, Wu J, Luo D, Zhu Y, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2020; 127: 104370. https://doi.org/10.1016/j.jcv.2020.104370 PMID: 32344321

25. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science. 2020; 368: 473–474. https://doi.org/10.1126/science.abb8925 PMID: 32303591

26. Tsivgoulis G, Katsanos AH, Ornello R, Sacco S. Ischemic Stroke Epidemiology During the COVID-19 Pandemic: Navigating Uncharted Waters With Changing Tides. Stroke. 2020; 51: 1924–1926. https://doi.org/10.1161/STROKEAHA.120.030791 PMID: 32496937

27. Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Off J Int Acad Clin Appl Thromb. 2020; 26: 1076029620938149.

28. Alzoughool F, Alanagreh L, Abumweis S, Atoum M. Cerebrovascular comorbidity, high blood levels of C-reactive protein and D-dimer are associated with disease outcomes in COVID-19 patients. Clin Hemorheol Microcirc. 2021; 77: 311–322. https://doi.org/10.3233/CH-201002 PMID: 33185593

29. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908: 244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x PMID: 10911963

30. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014; 69 Suppl 1: S4–9.

31. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett. 2005; 579: 2035–2039. https://doi.org/10.1016/j.febslet.2005.02.055 PMID: 15811314

32. ACR Recommendations for the use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection (March 11, 2020). Available at: https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recommendations-for-Chest-Radiography-and-CT-for-Suspected-COVID19-Infection.

33. Li L, Wang L, Zeng F, Peng G, Ke Z, Liu H, et al. Development and multicenter validation of a CT-based radiomics signature for predicting severe COVID-19 pneumonia. Eur Radiol. 2021: 1–12 https://doi.org/10.1007/s00330-020-07108-w PMID: 32767103