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EDIZIONI FS Publishers
397
Systematic Review in Infectious Diseases
Copeptin as a marker of COVID-19 severity: A
systematic review and meta-analysis
Michal MATUSZEWSKI
1
, Aleksandra GASECKA
2
, Jakub M ZIMODRO
3
, Zofia
ZADOROZNA
4
, Michal PRUC
5
, Magdalena BORKOWSKA
6
, Alla NAVOLOKINA
7
,
Gabriella NUCERA
8
, Murat YILDIRIM
9
, Behdin NOWROUZI-KIA
10
, Francesco
CHIRICO
11#
, Lukasz SZARPAK
12#*
Affiliations:
1
Department of Anaesthesiology and Intensive Therapy at the Central Clinical Hospital of the Ministry of Interior and
Administration, 02-507 Warsaw, Poland. E-mail: matuszewski.mike@gmail.com. ORCID: 0000-0002-3467-1377.
2
1st Chair and Department of Cardiology, Medical University of Warsaw, Poland.
E-mail: gaseckaa@gmail.com. ORCID:
0000-0001-5083-7587.
3
1st Chair and Department of Cardiology, Medical University of Warsaw, Poland.
E-mail: zimodro.jakub@gmail.com.
ORCID: 0000-0002-2405-8982.
4
Students Research Club, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland. E-mail:
zosia.zadorozna33@gmail.com. ORCID: 0000-0002-8653-7284.
5
Research Unit, Polish Society of Disaster Medicine, Warsaw, Poland E-mail: m.pruc@ptmk.org. ORCID: 0000-0002-
2140-9732.
6
Maria Sklodowska-Curie Bialystok Oncology Center, Bialystok, Poland; E-mail: mborkowska@onkologia.bialystok.pl.
ORCID: 0000-0002-2390-8375.
7
European School of Medicine, International European University, Kyiv, Ukraine; E-mail: allanavolokina@ieu.edu.ua.
ORCID: 0000-0003-1711-6002.
8
ASST Fatebenefratelli Sacco, Fatebenefratelli Hospital, University of Milan, Milan, Italy. E-mail:
gabriellanucera@gmail.com. ORCID: 0000- 0003-1425-0046.
9
Department of Psychology, Agri Ibrahim Cecen University, Turkey. E-mail: muratyildirim@agri.edu.tr. ORCID: 0000-
0003-1089-1380.
10
Department of Occupational Science and Occupational Therapy, Temerty Faculty of Medicine, University of Toronto,
Toronto, Ontario, Canada. E-mail: behdin.nowrouzi.kia@utoronto.ca. ORCID: 0000-0002-5586-4282.
11
Post-Graduate School of Occupational Health, Università Cattolica del Sacro Cuore, Rome, Italy. Health Service
Department, Italian State Police, Ministry of the Interior, Milan, Italy. E-mail: francesco.chirico@unicatt.it.
ORCID:0000-0002-8737-4368.
12
Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland. Maria Sklodowska-
Curie Bialystok Oncology Center, Bialystok, Poland. Henry JN Taub Department of Emergency Medicine, Baylor College
of Medicine Houston, Houston, TX, United States. E-mail: lukasz.szarpak@gmail.com. ORCID: 0000-0002-0973-5455.
#Last co-authorship
*Corresponding Author:
Associate Professor, Lukasz Szarpak, 10 Zelaznej Bramy Square, 00-136 Warsaw, Poland. E-mail:
lukasz.szarpak@gmail.com.
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
398
Abstract
Introduction: Infection with SARS-CoV-2 is particularly hazardous in patients with cardiovascular
pathology, diabetes or chronic lung disease. Arginine vasopressin (AVP), an antidiuretic hormone
secreted in response to hemodynamic and osmotic disturbances plays a crucial role in maintenance
of cardiovascular homeostasis. Copeptin has shown promising results regarding its utility in
prediction of morbidity and mortality of COVID-19. Therefore, we conducted a meta-analysis to
evaluate the role of copeptin in risk stratification in COVID-19.
Methods: This study was designed as a systematic review and meta-analysis. We systematically
searched the following databases: Scopus, Web of Science, PubMed, EMBASE, Cochrane Library
through September 10th, 2022. Methodological quality was assessed using the Cochrane risk-of-bias
tool.
Results: Pooled analysis of four trials showed that mean copeptin plasma concentrations were higher
in patients with severe course of COVID-19 than in patients with non-severe course of the disease
(26.64 ± 13.59 vs. 16.75 ± 6.13, respectively; MD=9.39; 95%CI: 1.38 to 17.40; I2=99%; p=0.02).
Furthermore, higher copeptin concentrations in COVID-19 patients who died than in those who
survived (13.25 ± 3.23 vs. 44.65 ± 26.92, respectively; MD=-31.40; 95%CI: -42.93 to -19.87; p<0.001).
Discussion: Results from the present meta-analysis revealed that increased copeptin plasma
concentrations found in COVID-19 patients are associated with the severity of the disease. Copeptin
may assist in early identification of COVID-19 progression and possibly in prediction of adverse
outcomes, thus its use in risk stratification could be beneficial.
Take-home message: Copeptin may assist in early identification of COVID-19 progression and
possibly in prediction of adverse outcomes, thus its use in risk stratification could be beneficial.
Keywords: Copeptin; COVID-19; meta-analysis; SARS-CoV-2; severity.
Cite this paper as: Matuszewki M, Gasecka A, Zimodro J, Zadorozna Z, Pruc M, Borkowska M,
Navolokina A, Nucera G, Yildirim M, Nowrouzi-Kia B, Chirico F, Szarpak L. Copeptin as a marker
of COVID-19 severity: A systematic review and meta-analysis. J Health Soc Sci. 2022;7(4):397-409.
Doi: 10.19204/2022/CPPT5.
Received: 03 November 2022 Accepted: 25 November 2022 Published: 15 December 2022
INTRODUCTION
First infections with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) were
reported in Wuhan, China, in December 2019 [1]. Abrupt spread of the pathogen and systematic
emergence of its new variants led to global pandemic of the COVID-19 disease [2
–
6]. With 600 million
cases and over 6 million deaths reported by the end of October 2022 [
7
], COVID-19 has become an
enormous challenge for the public health all over the world [8
–
13].
SARS-CoV-2 causes wide range of illness, from asymptomatic infection to severe pneumonia
with acute respiratory distress syndrome (ARDS) and eventually death. COVID-19 is primarily a
pulmonary disease. However, it can lead to multiorgan involvement, e.g., cardiovascular [14
–
16] or
renal [15,17] disorders. Critically ill patients often require admission to the intensive care unit (ICU)
[
18
]. As they are prone to developing major complications, an appropriate follow-up care must be
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
399
provided. Especially during the pandemic, such cases may overload the health care system. Hence,
patients at high risk of severe course of COVID-19 should be early identified.
Infection with SARS-CoV-2 is particularly hazardous in patients with cardiovascular pathology,
diabetes or chronic lung disease [19
–
23]. Risk factors also include older age, current smoking status,
obesity, cancer and some other chronic medical conditions. Furthermore, socio-demographic features
shall be considered in predictions [2]. Besides clinical characteristics, numerous studies aimed to
detect applicable biomarkers [24
–
28]. Correlations between COVID-19 and markers of inflammation
and hemostasis have been reported [29
–
31]. As a robust assay for risk stratification remains unknown,
novel biomarkers have been investigated [32].
Arginine vasopressin (AVP), an antidiuretic hormone secreted in response to hemodynamic and
osmotic disturbances [33,34] plays a crucial role in maintenance of cardiovascular homeostasis.
Disturbances in its secretion are likely to occur in COVID-19. Assessment of AVP plasma
concentration may be challenging though. Thus, copeptin, simply measured C-terminal fragment of
pro-AVP, serves as surrogate biomarker for AVP [35,36]. Multiple trials revealed that evaluation of
copeptin levels may be beneficial in pulmonary [37,38] or cardiovascular diseases and in critical
conditions [39,40]. Copeptin has shown promising results regarding its utility in prediction of
morbidity and mortality of COVID-19
[24,29,41]. Therefore, we conducted a meta-analysis to evaluate
the role of copeptin in risk stratification in COVID-19.
METHODS
This meta-analysis was conducted in accordance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRIMSA) statement [42] and the guidelines described in the
Cochrane Handbook [43]. Due to the character of the study, ethical approval or patient consent was
not required.
Search strategy and study selection
The Scopus, Web of Science, PubMed, EMBASE, Cochrane Library databases were searched
independently by two authors (M.M. and M.P.) to identify papers published in English between
January 1st, 2020, and September 10th, 2022, that reported copeptin plasma concentrations in COVID-
19 patients. Databases were explored using the following keywords: “copeptin” AND “covid-19” OR
“corona virus disease 2019” OR “novel coronavirus” OR “SARS-CoV-2”. Search strategies were
modified for each database using free text terms and controlled vocabularies.
Inclusion and exclusion criteria
Eligibility criteria for included studies were as follows:
1) Types of studies: randomized controlled trials or observational studies (in English language).
2) Types of participants: adult patients with COVID-19.
3) Types of prognostic factor: copeptin levels.
Case reports, conference papers, editorials, review articles and studies where no comparison was
conducted were excluded from the review process as well as studies not reported in English.
Data extraction
Two authors (M.M. and M.P.) extracted the data using a standardized data collection sheet, which
was checked for accuracy by a third author (A.G.). The following data was extracted from the
included studies: study characteristics (first author name, year publication, country, study design,
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
400
inclusion and exclusion criteria, primary outcome(s), findings), study groups (no of participants,
male sex, age) for severe and non-severe COVID-19 patients or survive vs. dead COVID-19 patients.
Risk of bias assessment
Two authors (M.M. and M.P.) independently assessed the quality of the included studies according
to he Newcastle-Ottawa scale [44]. Any disagreements were resolved by discussion with third author
(A.G.).
Statistical analysis
All statistical analyses were performed using Review Manager 5.4 (Cochrane Collaboration, Oxford,
UK). A P-value less than 0.05 was considered statistically significant. For dichotomous data, odds
ratios (OR) with 95% confidence intervals (CI) were analyzed. For continuous data, mean difference
(MD) with 95% CI was analyzed. In case when data were reported as median with interquartile range,
we estimated means and standard deviations using the formula described by Hozo [45].
Heterogeneity was quantified with Cochran’s Q test and I-squared (I
2
) statistic in all the measured
outcomes. The I
2
value of 25%, 50%, and 75% as cut-off points represented low, moderate, and high
degrees of heterogeneity respectively [46]. If significant heterogeneity was present (P ≤ 0.1 and I
2
≥
50%), the random-effects model (Mantel-Haenszel) was used to combine MD and 95%CI, otherwise,
otherwise the fixed effects model was employed. A funnel plot was not performed because of the
limited number of studies (n < 10).
RESULTS
Study characteristics
The flow chart of the literature search and the study selection process is pictured in Figure 1. A total
of 911 articles were identified through database search. After excluding duplicates and studies that
did not meet inclusion criteria, a total of 4 studies comprising 579 patients and published between
August 2021 and March 2022 were included [29,47
–
49]. Of the total population, 54.6% were males.
Copeptin may assist in early identification of COVID-19 progression and possibly in prediction of
adverse outcomes, thus its use in risk stratification could be beneficial.
Meta-analysis outcome
As shown in Table 1, pooled analysis of four trials showed that mean copeptin plasma concentrations
were higher in patients with severe course of COVID-19 than in patients with non-severe course of
the disease (26.64 ± 13.59 vs. 16.75 ± 6.13, respectively; MD=9.39; 95%CI: 1.38 to 17.40; I
2
=99%; p=0.02).
Furthermore, one trial found higher copeptin concentrations in COVID-19 patients who died than in
those who survived (13.25 ± 3.23 vs. 44.65 ± 26.92, respectively; MD=-31.40; 95%CI: -42.93 to -19.87;
p<0.001).
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
401
Figure 1. Flowchart detailing selection and screening of the studies included in this review.
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
402
Table 1. Baseline characteristics of included trials.
Study and year Country Study group No. of
patients
Age (ys)
Sex, male
Copeptine
,
Pmol/L
NOS score
Hammad et al, 2022
[47] Egypt Severe
Non-severe
80
80
62.5 ± 2.21
44.7 ± 2.92
40 (50.0%)
39 (48.7%)
30.1 ± 1.96
13.7 ± 0.61 9
In et al, 2021 [48] Turkey Severe
Non-severe
55
35
58.8 ± 16.8
44.5 ± 14.9
35 (63.6%)
18 (51.4%)
26.3 ± 10.3
14.4 ± 4.9 8
Indirli et al, 2022 [49] Italy Survive
Dead
95
21
NS
NS
NS
NS
13.25 ± 3.23
44.65 ± 26.92 7
Kaufmann et al,
2022 [29] Austria Severe (ICU)
Non-severe
55
158
72.0 ± 16.25
63.5 ± 16.46
37 (67.3%)
82 (51.9%)
38.3 ± 15.4
20.7 ± 5.6 8
Legend: NS: no specified.
DISCUSSION
In our meta-analysis of four studies, we found copeptin concentrations to positively correlate
with COVID-19 severity. Additionally, higher copeptin levels were prognostic for subsequent
mortality among COVID-19 patients.
Activation of the vasopressin system preserves homeostasis, thus helps adapt to stressful
conditions, e.g., infections [50]. AVP is a nonapeptide produced in the supraoptic and paraventricular
nuclei of the hypothalamus [51,52]. Initially synthesized pre-pro-AVP is subsequently cleaved into
pro-AVP. Eventually, pro-AVP is split into equimolar amounts of AVP, copeptin and neurophysin-
II. The latter is engaged in transport of AVP to its storage in the neurohypophysis, whereas copeptin,
a 39-aminoacid glycoprotein, may assist in formation of pro-AVP [39].
AVP is released from the neurohypophysis due to hyperosmolality, hypovolemia, hypotonia,
hypoxia or acidosis, as well as in response to stressors, e.g., pain or injury [48]. AVP not only has a
key role in maintenance of water-electrolyte balance and regulation of circulation, but also controls
the respiratory system via V1aRs receptors. AVP may act as an inhibitor or activator of ventilation.
The former effect is seen in the area postrema, the latter in the carotid bodies, whereas both are
observed in the brainstem. Contrary to the systemic circulation, AVP exerts a vasodilatory effect on
pulmonary arteries. Overall, as a circulating hormone, AVP suppresses ventilation, thus prevents
excessive increase in breathing rate under pathological conditions [50].
Infection with SARS-CoV-2 leads to hemodynamic disturbances due to widespread
inflammation with cytokine storm or direct injury [24,53]. Cytokines, especially elevated interleukin
6 levels, promote AVP secretion [47]. Furthermore, SARS-CoV-2 enters a host cell through interaction
between its spike glycoprotein and a cellular receptor - angiotensin-converting enzyme 2. As a result,
renin-angiotensin system is disturbed and concentration of angiotensin II increases [54], what further
activates AVP release. Moreover, lung injury present in COVID-19 causes hypoxic pulmonary
vasoconstriction, which subsequently leads to increase in AVP levels [55]. Nevertheless, as AVP has
a short half-life, is primarily bound to platelets and requires specialist assays, its availability as a
biomarker is limited. Therefore, copeptin with greater stability, longer half-life and less demanding
analysis, is applied as surrogate biomarker [39].
Increased copeptin levels have been reported in various pulmonary disorders. In patients with
chronic obstructive pulmonary disease copeptin predicted exacerbation and all-cause mortality
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
403
[56,57]. Elevated copeptin concentrations were observed in conditions characterized by abnormal
respiratory pattern, e.g., sleep apnea [58]. High prevalence of pituitary hormone alterations was seen
in critically ill patients admitted to the ICU. Interestingly, among this population, higher copeptin
levels were found in patients with ARDS than in those with subarachnoid hemorrhage or traumatic
brain injury. High copeptin concentrations predicted unfavorable outcome in the latter condition [59].
Copeptin was shown to be applicable in diagnosis of ARDS or acute lung injury, whereas it was a
stronger prognostic marker for short-term mortality than established N-terminal pro-B-type-
natriuretic peptide. Furthermore, increased copeptin levels were present in patients admitted to the
ICU or emergency department with acute, severe dyspnea or sepsis [60].
Rise in copeptin concentrations was also observed in infections of the lower respiratory tract
[56]. In community-acquired pneumonia (CAP) copeptin was described as independent predictor of
mortality, superior to traditionally used biomarkers [37,38]. Copeptin levels were reported to
positively correlate with the severity of CAP and to be the highest in non-survivors [36]. Another
study confirmed that increased copeptin concentrations reflected the severity of pneumonia in
children and predicted further complications [61].
Elevated copeptin levels were consecutively reported in COVID-19. Whether copeptin could
help distinguish COVID-19 from other pulmonary infections is uncertain. One study described
higher copeptin concentrations in COVID-19 in comparison to CAP [33]. Conversely, in another trial,
copeptin levels in COVID-19 and acute or sever bronchitis or pneumonia were comparable [62].
Nevertheless, association between copeptin levels and disease severity was reported in several
studies. More pronounced elevation in copeptin concentrations were seen in severe than in non-
severe COVID-19 cases [47]. Higher copeptin levels at admission were also observed in COVID-19
patients with in-hospital or short-term mortality. Importantly, its ability to identify non-survivors
persisted after statistical adjustment for comorbidities, that worsen the prognosis and contribute to
raised copeptin levels, e.g., heart failure. Therefore, copeptin was described as an independent
predictor of COVID-19 severity. Moreover, one study found positive correlation between copeptin
and length of hospital stay. An association with occurrence of sepsis and acute kidney injury was
reported, suggesting that copeptin may not only predict mortality, but also certain complications [49].
Connections between copeptin and markers of inflammation, as well as other laboratory
findings, has been investigated in COVID-19 [25,28,63,64]. Copeptin positively correlated with C-
reactive protein, ferritin and D-dimers [47]. After comparison, predictive value of copeptin was
superior to that of mentioned, traditional biomarkers. Conversely, negative correlation was found
with leukocyte, neutrophil and platelet count [33]. Unfortunately, no association was reported with
clinical parameters, e.g., oxygen saturation, need for ventilation or radiological findings on chest
imaging studies.
As SARS-CoV-2 often causes additional cardiac injury, particular attention was drawn to cardiac
biomarkers, emphasizing their role in prediction of morbidity and mortality in COVID-19 patients
[65,66]. High sensitivity cardiac troponin I (hs-cTnI) was reported to predict adverse outcomes within
28 days from index admission. Importantly, the highest prognostic sensitivity was reached once hs-
cTnI was combined with copeptin. Furthermore, individuals with increased hs-cTNI, but normal
copeptin levels, were identified as low-risk patients [29]. Moreover, natriuretic peptides were shown
to raise due to development or exacerbation of heart failure in course of COVID-19 [24]. Value of its
J Health Soc Sci 2022, 7, 4, 397-409. Doi: 10.19204/2022/CPPT5
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combination with copeptin in COVID-19 remains uncertain though. Conversely, measurement of
copeptin together with mid-regional pro-adrenomedullin was reported to increase diagnostic
accuracy of both markers [49]. Although currently available data is inconsistent, multimarker
approach seems to be a promising strategy.
Some limitations of our meta-analysis are to be acknowledged. Firstly, a small number of studies
was included, as limited evidence is available on the discussed topic. Consequently, our results did
not reach statistical significance. Furthermore, laboratory techniques applied in measurements of
copeptin levels, as well as clinical criteria for identification of COVID-19 severity and established
copeptin cut-off concentrations differed per study. For this reason, considerable heterogeneity was
observed between included trials. Therefore, further studies should be conducted to entirely assess
copeptin performance.
CONCLUSION
Results from the present meta-analysis revealed that increased copeptin plasma concentrations
found in COVID-19 patients are associated with the severity of the disease. Copeptin may assist in
early identification of COVID-19 progression and possibly in prediction of adverse outcomes, thus
its use in risk stratification could be beneficial.
Author Contributions: Conceptualization: MM, LS; methodology: MM, FC, LS; software: MP, LS; validation:
MM, AN, MY, BNK, GN; formal analysis: LS, MM; investigation: MM, MB, MP, ZZ, AN, GN; resources: MM,
MB, LS; data curation: MM, JZ, FC, MP, LS; writing—original draft preparation: MM, JZ, FC, MP, LS;
writing—review and editing, all authors; visualization: MM, LS; supervision: LS; project administration: MM.
All authors have read and agreed to the published version of the manuscript.
Funding: None
Acknowledgments: None
Conflicts of Interest: None
Data Availability Statement: Some or all data and models that support the findings of this study are available
from the corresponding author upon reasonable request.
Publisher’s Note: Edizioni FS stays neutral with regard to jurisdictional claims in published maps and
institutional affiliation.
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