Home C-reactive protein levels associated with COVID-19 outcomes in the United States
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C-reactive protein levels associated with COVID-19 outcomes in the United States

  • Jacob Lentner EMAIL logo , Taylor Adams , Valene Knutson , Sarah Zeien , Hassan Abbas , Ryan Moosavi , Chris Manuel , Thomas Wallace , Adam Harmon , Richard Waters , Samuel Ledford , Rajakrishnan Vijayakrishnan , Nikhil Jagan , Nezar Falluji , Michael DelCore , Curt Bay and Sunny Jhamnani
Published/Copyright: September 30, 2021
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Journal of Osteopathic Medicine
From the journal Journal of Osteopathic Medicine Volume 121 Issue 12

Abstract

Context

COVID-19 caused a worldwide pandemic, and there are still many uncertainties about the disease. C-reactive protein (CRP) levels could be utilized as a prognosticator for disease severity in COVID-19 patients.

Objectives

This study aims to determine whether CRP levels are correlated with COVID-19 patient outcomes and length of stay (LoS).

Methods

A retrospective cohort study was conducted utilizing data obtained between March and May 2020. Data were collected by abstracting past medical records through electronic medical records at 10 hospitals within CommonSpirit Health. Patients were included if they had a positive COVID-19 test from a nasopharyngeal swab sample, and if they were admitted and then discharged alive or had in-hospital mortality and were ≥18 years. A total of 541 patients had CRP levels measured and were included in this report. Patient outcome and LoS were the endpoints measured.

Results

The 541 patients had their CRP levels measured, as well as the demographic and clinical data required for analysis. While controlling for body mass index (BMI), number of comorbidities, and age, the first CRP was significantly predictive of mortality (p<0.001). The odds ratio for first CRP indicates that for each one-unit increase in CRP, the odds of death increased by 0.007. For LoS, the first CRP was a significant predictor (p<0.001), along with age (p=0.002). The number of comorbidities also predicted LoS (p=0.007), but BMI did not. The coefficient for the first CRP indicates that, for each one-unit increase in CRP, LoS increased 0.003 days.

Conclusions

The results indicate that there is a positive correlation between the CRP levels of COVID-19 patients and their respective outcomes with regard to death and LoS.

Keywords: C-reactive protein; COVID-19; mortality; outcomes

C-reactive protein (CRP) is an acute-phase reactant that is produced by the liver in response to inflammation. It is commonly secreted under the influence of cytokines such as interleukin-6 and tumor necrosis factor-alpha. More specifically, a study including over 50,000 participants noted a significant association between elevated serum or plasma concentrations of CRP and ischemic vascular disease. The study demonstrated that the risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter [1].

Although an elevated CRP is not common in most viral infections, a study conducted in China with 1,099 COVID-19 patients demonstrated that 60.7% had CRP levels ≥10 mg/L [2]. Another study including 76 COVID-19 patients demonstrated that the hospital length of stay (LoS) averaged 20 days in patients with CRP levels ≥20.4 mg/L and 18 days in patients with CRP levels <20.4 mg/L [3]. Furthermore, a study of 27 COVID-19 patients found that CRP levels >20.4 mg/L were 83.0% sensitive and 91.0% specific when predicting severe COVID-19 infection [4]. A study of 1834 COVID-19 patients from Italy and the United Kingdom found that CRP levels ≥40.0 mg/L were associated with 31.9% mortality compared with 15.0% mortality in patients with CRP levels <40.0 mg/L [5]. None of these studies were conducted in the United States, so further investigation into the relationship between CRP and COVID-19 in the U.S. population is warranted. The aim of this study is to determine if the first CRP levels on hospital admission or the highest CRP are associated with mortality, length of hospital stay, and disposition in patients hospitalized with COVID-19.

Methods

This study was approved by the Dignity East Valley IRB (IRB number: EVR-20-510-114-66-17). It did not involve intervention of human patients; therefore, a clinical registry number was not indicated. Informed consent was deemed unnecessary and was waived per the IRB.

Study design

Data were abstracted retrospectively from the medical records of 10 hospitals within CommonSpirit Health (Chandler Regional Medical Center; Mercy Gilbert Medical Center; CHI Health Creighton University Medical Center; CHI Health St. Francis; CHI Memorial Hospital, Chattanooga; CHI St. Joseph Hospital, Lexington; CHI St. Vincent, Little Rock; Sequoia Hospital; St. Joseph’s Hospital and Medical Center, Phoenix; and St. Joseph’s Medical Center, Stockton), the second largest healthcare system in the United States. Patients were included if they: (1) had a confirmed positive COVID-19 test utilizing the polymerase chain reaction method from a nasopharyngeal swab sample; (2) were admitted and then discharged alive or died in the hospital between March 1, 2020 and May 31, 2020; and (3) were ≥18 years.

We evaluated the association of CRP level with: (1) mortality; (2) hospital LoS; and (3) patient disposition to home, long-term rehab facility, or hospice.

Data collection

Data were abstracted from electronic medical records, including admission history and physical notes, discharge summaries, and laboratory records during the patients’ hospital stay.

Statistical analysis

Summary statistics are provided as means (standard deviations), counts (percentages), and medians (interquartile ranges). Standard errors and 95.0% confidence intervals are also reported, where appropriate. A generalized estimating equations approach was utilized to address clustering by hospital, and robust confidence intervals were calculated because a few patients were admitted more than one time. A binary logistic distribution link was utilized for mortality, a gamma distribution link for LoS because data were skewed, and a multinomial link for disposition. Spearman’s rho (rs) was utilized to estimate the correlation between first and highest CRP levels. An alpha of 0.05 was utilized as the criterion for statistical significance. SPSS version 27 (IBM Corp., Armonk, NY) was utilized for analyses.

Constructing models to predict LoS is complicated in the presence of significant mortality. The hospital stay may be terminated by death or by discharge alive. Patients who are not very sick will have a relatively short LoS, and this stay will increase as a function of how sick the patients are. However, the sickest patients may have a short LoS, terminating in death. In order to evaluate the potential impact of CRP on LoS, we conducted LoS analyses utilizing only the patients who were discharged alive.

Results

Dataset

Data from 865 patients were abstracted, and 541 had their CRP levels measured, as along with the demographic and clinical data required for analysis. Table 1 provides summary descriptive statistics for the analysis dataset, subdivided by patients who survived (n=445) and those who died (n=96). Aside from CRP levels, only age differed significantly across groups (p<0.001).

Table 1:

Demographic and clinical summary statistics.

Variable Survived (n=445) Died (n=96)
Age, years 56.8 ± 16.8 69.0 ± 13.1
Sex
Male 233 (82.3) 50 (17.7)
Female 212 (82.2) 46 (17.8)
Race
White 303 (83.0) 62 (17.0)
Black 41 (78.8) 11 (21.2)
American Indian/Alaska Native 32 (72.7) 12 (27.3)
Asian 18 (94.7) 1 (5.3)
Other/unknown 51 (83.6) 10 (16.4)
Ethnicity
Hispanic/Latino 150 (84.7) 27 (15.3)
Not Hispanic/Latino 281 (82.4) 60 (17.6)
Unknown 14 (60.9) 9 (39.1)
Body mass index, kg/m2 32.17 (8.57) 31.03 (8.69)
No. of comorbidities 2.0 ± 1.93 2.77 ± 2.04
First CRP 78.70 ± 85.56 132.63 ± 112.10
First CRP, median (IQR) 42.45 (11.90, 129.21) 127.01 (25.83, 210.22)
Highest CRP 101.63 ± 131.83 194.07 ± 144.22
Highest CRP, median (IQR) 57.70 (16.25, 155.25) 184.11 (43.03, 291.83)

  1. The symbol ± is utilized for mean ± standard deviation. Parentheses are utilized for count (percentage) unless otherwise noted; IQR, interquartile range.

For analyses predicting mortality, LoS, and disposition, the first and highest levels of CRP were of primary interest. In all analyses, age, BMI, and the number of comorbidities were entered as covariates. Sex, race, and ethnicity were tested as covariates, but they altered the solutions only slightly, and none were significantly predictive of the outcomes (i.e., did not alter the confidence intervals or parameter coefficients), so they were removed. The first and highest CRP levels were correlated, rs=0.92 (p<0.001), indicating they were substantially redundant for purposes of prediction. The results of the analyses utilizing these two variables differed only very slightly, so only the results utilizing first CRP are presented.

Mortality

Results for the analysis predicting patient mortality are provided in Table 2. While controlling for BMI, the number of comorbidities, and age, the first CRP was significantly predictive of mortality (p<0.001). Age also predicted mortality (p<0.001), but neither BMI nor the number of comorbidities were significant. The odds ratio for the first CRP indicates that for each one-unit increase in CRP, the odds of death increased by 0.007. For context, each 50-unit increase resulted in odds increasing by almost 42% (OR=1.42, 95% CI: 1.25–1.60), and for each 100-unit increase in CRP, the odds of death increased two-fold (OR=2.01, 95% CI: 1.57–2.56), while controlling for BMI, the number of comorbidities, and age.

Table 2:

Prediction of mortality by BMI, the number of comorbidities, age, and the first CRP.

Parameter Beta SE 95% CI Chi-Sq p-Value OR 95% CI
BMI 0.019 0.017 −0.014, 0.052 1.274 0.259 1.019 0.986, 1.054
Comorbidities 0.087 0.063 −0.036, 0.210 1.913 0.167 1.091 0.964, 1.234
Age 0.055 0.009 0.038, 0.072 38.303 <0.001a 1.057 1.038, 1.075
First CRP 0.007 0.001 0.005, 0.009 30.855 <0.001a 1.007 1.005, 1.009

  1. BMI, body mass index; Chi-Sq, Wald chi-square; CI, confidence interval; CRP, C-reactive protein; OR, odds ratio; SE, standard error. aDenotes statistical significance.

Length of stay (LoS)

Parameter estimates for LoS are provided in Table 3. The first CRP was a significant predictor (p<0.001), along with age (p=0.002). The number of comorbidities also predicted LoS (p=0.007), but BMI did not. The coefficient for the first CRP indicates that for each one-unit increase in CRP, LoS increased 0.003 days; for each 50-unit increase, LoS increased by 0.16 days (95% CI: 0.10–0.21), and for each 100-unit increase in CRP, the LoS increased an average of 0.31 days, (95% CI: 0.20–0.42), while controlling for BMI, the number of comorbidities, and age.

Table 3:

Prediction of LoS by BMI, number of comorbidities, age, and first CRP.

Parameter Beta SE 95% CI Chi-Sq p-Value
BMI 0.002 0.005 −0.007, 0.012 0.258 0.611
Comorbidities 0.073 0.027 0.020, 0.127 7.313 0.007a
Age 0.009 0.003 0.003, 0.015 9.535 0.002a
First CRP 0.003 0.001 0.002, 0.004 31.493 <0.001a

  1. BMI, body mass index; Chi-Sq, Wald chi-square; CI, confidence interval; CRP, C-reactive protein; LoS, length of stay; SE, standard error. aDenotes statistical significance.

Disposition

As shown in Table 4, disposition could be predicted by the number of comorbidities (p=0.002) and age (p<0.001); however, the first CRP did not appear to play a role.

Table 4:

Prediction of disposition by BMI, number of comorbidities, age, and first CRP.

Parameter Beta SE 95% CI Chi-Sq p-Value
BMI 0.001 0.014 −0.027, 0.029 0.004 0.949
Comorbidities −0.172 0.057 −0.283, −0.061 9.279 0.002a
Age −0.039 0.008 −0.054, −0.024 25.489 <0.001a
First CRP 0.000 0.001 −0.003, 0.002 0.094 0.759

  1. BMI, body mass index; Chi-Sq, Wald chi-square; CI, confidence interval; CRP, C-reactive protein; SE, standard error. aDenotes statistical significance.

Discussion

In this study, we found that CRP levels are predictive of mortality, independent of factors such as age, BMI, and comorbidities. The higher the patient’s CRP level, the greater the chance the patient died. We also found a similar association between CRP levels and the length of stay in the hospital from admission to discharge. However, there was no significant association between CRP levels and disposition.

Although age was also a significant predictor of patient mortality, it does not discount the fact that CRP levels demonstrated a positive correlation with death. Similarly, the CRP level was not the only parameter that was statistically significant when evaluating LoS, but further research would need to be conducted to determine which parameter, if any, played the most significant role in prolonging LoS.

In COVID-19, the pathophysiology is underpinned by pulmonary and systemic inflammatory changes, as demonstrated by a study of 191 COVID-19 patients in which 75.0% demonstrated bilateral pulmonary infiltration, 71.0% had ground glass opacities, and 67.0% had a lactate dehydrogenase level >245 U/L [6]. CRP is an inflammatory marker, and the results of this study would suggest that the higher the CRP level in patients, the greater the severity of their disease, and the worse the patient outcomes.

Because higher CRP levels suggest greater systemic inflammation, future studies may be conducted to determine the effects of corticosteroids and/or other anti-inflammatory medications on patient outcomes [7]. However, the data analyzed in this study primarily focused on CRP as a predictor of COVID-19 outcomes, not treatment of the infection. Additionally, the sample of patients from the raw data who received dexamethasone was not large enough to determine its significance.

The previous studies referenced in the introduction [2], [3], [4], [5] demonstrated a positive correlation with CRP levels, LoS, and disease severity/mortality, respectively. This study further supports these findings; however, the levels of CRP measured in this study were higher than those that were found in the previous studies. For example, the average CRP level of patients that died in the United Kingdom study was 115 mg/L5 compared to 159.9 mg/L in this study. At this time, the possible etiology of this discrepancy is unknown to the authors, and further research may be warranted.

This study is necessary because it adds to this knowledge base by assessing each of these variables in one data set. The previous studies also were conducted with COVID-19 patients in China, the United Kingdom, and Italy, whereas this study had patients who were residents of the United States.

The tenet of osteopathic medicine that this study best demonstrates is “self-regulation.” Earlier in the introduction, it was mentioned that CRP is an inflammatory marker. The body releases inflammatory products when it is attempting to fight off an infection, such as COVID-19. The results obtained in this study suggest that higher CRP levels are correlated with worse disease. This suggests that the body is attempting to self-regulate by producing more inflammatory products to eliminate the infection and heal itself.

Some limitations of this study include that this is a retrospective study and therefore is subject to confounding. Additionally, over two-thirds of the patients were white, thus this may not be a fair representation of all races.

Conclusions

The results indicate that there is in fact a positive correlation between the CRP levels of COVID-19 patients and their respective outcomes with regard to death and LoS. CRP could potentially be used as a prognostic indicator in COVID-19 patients as more is discovered about the virus. Clinically, significantly elevated CRP levels may be an indication for more aggressive treatment of COVID-19, yet further research would have to be conducted regarding different treatment methods and their effectiveness on reducing CRP levels and how the treatment correlates to COVID-19 patient outcomes.

Corresponding author: Jacob Lentner, OMS III, A.T. Still University – Kirksville College of Medicine, Kirksville, MO, USA; and 577 E. Baseline Road, Apt. 2011, Tempe, AZ 85283-1692, USA, E-mail:

  1. Research funding: None reported.

  2. Author contributions: T.A., V.K., S.Z., H.A., R.M., C.M., T.W., A.H., R.W., S.L., R.V., N.J., N.F., M.D., and C.B. provided substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; J.L. drafted the article or revised it critically for important intellectual content; S.J. gave final approval of the version of the article to be published; and all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  3. Competing interests: None reported.

  4. Ethical approval: This study was reviewed and approved by the Dignity East Valley IRB (IRB# EVR-20-510-114-66-17).

References

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Received: 2021-04-05
Revised: 2021-08-18
Accepted: 2021-08-20
Published Online: 2021-09-30

© 2021 Jacob Lentner et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/jom-2021-0103
Keywords for this article
C-reactive protein; COVID-19; mortality; outcomes
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Cardiopulmonary Medicine
  3. Brief Report
  4. C-reactive protein levels associated with COVID-19 outcomes in the United States
  5. General
  6. Clinical Practice
  7. Utilizing the Four Tenets of Osteopathic Medicine as an intersectional framework for approaching sexual orientation and gender identity disclosure as a provider
  8. Medical Education
  9. Original Article
  10. Mini-medical school programs decrease perceived barriers of pursuing medical careers among underrepresented minority high school students
  11. Neuromusculoskeletal Medicine (OMT)
  12. Review Article
  13. Efficacy of osteopathic manipulative treatment in patients with Parkinson’s disease: a narrative review
  14. Public Health and Primary Care
  15. Clinical Practice
  16. Masqueraders: how to identify atypical diabetes in primary care
  17. Original Article
  18. A pilot of a modified diabetes prevention program in Quito, Ecuador
  19. Clinical Image
  20. Disseminated peritoneal coccidioidomycosis
  21. Letters to the Editor
  22. Embracing industry sponsored research to expand osteopathic medical student research experiences
  23. Red reflex variations in black patients
  24. Abstracts
  25. 2021 AOA Research Abstracts and Poster Competition
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