PROSPERO

International prospective register of systematic reviews

Complete blood count parameters and risks of mortality and cardiovascular events among
patients with coronavirus disease 2019 (COVID-19) infections: a systematic review and
meta-analysis
Teeranan Angkananard, Soontaree Agaslerg, Worawut Roongsangmanoon, Arthit Wongsoasup, Nattapun
Rattanajaruskul

Citation
Teeranan Angkananard, Soontaree Agaslerg, Worawut Roongsangmanoon, Arthit Wongsoasup,
Nattapun Rattanajaruskul. Complete blood count parameters and risks of mortality and
cardiovascular events among patients with coronavirus disease 2019 (COVID-19) infections: a
systematic review and meta-analysis. PROSPERO 2020 CRD42020177461 Available from:
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020177461

Review question
To determine whether complete blood count parameters could be used to predict cardiovascular events, and
overall mortality in patients infected by coronavirus disease 2019 (COVID-19).

Searches
PubMed, Scopus and EMBASE will be searched for relevant studies published since January 1, 2020 to April
15, 2020, without limits.

Studies published in English will be included.

Types of study to be included

Inclusion criteria:

1. Any types of peer-reviewed studies (cohort, case-control, case reports and case series) that have reported
on patients with confirmed COVID-19 infections by real-time PCR (WHO criteria);

2. Studies published in English;

3. Studies in adult patients aged ?18 years;

4. Studies looking at CBC, WBC, neutrophil, monocyte, lymphocyte or platelet data;

5. Studies involving at least one of the following outcomes which was evaluated during acute setting and/or
follow up: composite or individual CV event of CV death, development of a new episode or a recurrence of
ACS (acute coronary syndrome, MI or UA), development or worsening of heart failure (HF), occurring cardiac
arrhythmia (ventricular arrhythmia and/or atrial fibrillation) or any types of stroke or myocarditis, and/or all-
cause mortality (ACM);

6. Studies which have provided sufficient data for pooling, i.e., numbers of subjects, mean and standard
deviation of continuous outcomes, and/or numbers of patients per group for dichotomous outcomes.

Exclusion criteria:

1. Studies in which there is no sufficient data for pooling;

2. Studies for which there is no response after contacting the authors three times to request further

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information/clarification;

3. Studies for which the full article(s) cannot be retrieved.

Condition or domain being studied

Coronavirus disease 2019 (COVID-19) is an emerging and global pandemic which is caused by the severe
acute respiratory syndrome coronavirus-2 (SARSCoV-2).

Infection by this virus is caused by the binding of the viral surface spike protein to the human angiotensin-
converting enzyme 2 (ACE2) receptor, which is expressed principally in the lung, and also in the heart, and
there is increasing evidence for an association between COVID-19 infection and high cardiovascular (CV)
morbidity and mortality. Moreover, ACE2 is also expressed in the intestinal epithelium, the vascular
endothelium, and in the kidneys, leading to the the multi-organ dysfunction and high mortality rates
associated with the disease. Thus, knowing the predictive factors for CV events and all-cause mortality is
crucial for intensive care and treatment with proper anti-viral regimens.

From previous studies, complete blood count (CBC) data and parameters such as the neutrophil lymphocyte
ratio (NLR) have recently emerged as inflammatory biomarkers, and inexpensive predictors of risk and
outcome for diverse CV diseases, and mortality. The magnitude of the impact of CBC parameters on CV
events and overall mortality of COVID-19 patients are, however, still unknown.

Participants/population

Adult patients aged ?18 years infected with COVID-19.

Intervention(s), exposure(s)
Complete blood count parameters, including WBC (white blood cell), neutrophil, monocyte, lymphocyte, or
platelet data, measured using the methods used in the original studies.

Comparator(s)/control
None.

Main outcome(s)
Composite or individual events of ACM and/or CVEs, which are CV death, the development of a new
episode or a recurrence of ACS (MI or UA), the receiving or repeating of coronary revascularization, the
development or worsening of HF, the occurrence of cardiac arrhythmia (ventricular arrhythmia and/or atrial
fibrillation), any types of stroke and myocarditis.

Definition of outcomes:

All-cause mortality includes any death recorded between baseline, and the end of follow-up.

Cardiovascular death includes death resulting from an acute MI, myocarditis, sudden cardiac death, death
due to HF, death due to stroke, death due to CV procedures, death due to CV hemorrhage, and death due to
other CV causes.

Transient ischemic attack is defined as a transient episode of focal neurological dysfunction caused by brain,
spinal cord, or retinal ischemia, without acute infarction.

Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal
cord, or retinal vascular injury as a result of hemorrhage or infarction.
* Measures of effect
For data for pooling, contingency data of CBC parameters categories and outcomes will be extracted from
individual studies.

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For studies which do not provide contingency data, but which have reported relative risk (e.g., odds ratio, risk
ratio, hazard ratio) along with confidence intervals (CIs) from either univariate or multivariate analysis
instead, these summary statistics will be extracted.

For studies comparing mean CBC parameters values between outcome groups, mean and standard
deviation will be extracted.

Additional outcome(s)
None.
* Measures of effect
Not applicable.

Data extraction (selection and coding)

The studies retrieved during the searches will be screened for relevance, and those identified as being
potentially eligible for inclusion will be fully assessed against the inclusion/exclusion criteria, and selected, or
rejected, as appropriate.
All relevant data will then be extracted from the studies chosen for inclusion by two reviewers independently,
using a data extraction form.
Any discrepancies will be resolved through discussion with a third author.

The following general data and characteristics of the studies will be extracted: the first author’s last name,
the publication year, the location where the study was performed, the type of the study, the follow-up period,
percentages of loss to follow-up, the gender and mean age of the patient samples, and the types of patients
and outcomes (type of CVEs and/or ACM).

Risk of bias (quality) assessment

The selected studies will be critically appraised by two independent authors using a standardized approach.

In the case of discrepancies, authors will try to reach an agreement, but if necessary, a third author will
resolve any ongoing differences in opinion.

The review authors will not be blinded to the study authors, institutions, or publication journals, due to
feasibility issues.
We will assess the risk of bias of each study using the QUIPS tool, which will be modified for this review. We
will consider and illustrate six domains for the modified QUIPS tool: study participation (5 items), study
attrition (4 items), risk/prognostic factor measurement (5 items), outcome measurement (4 items), study
confounding factors (5 items), and statistical analysis and reporting (2 items). Each item will be graded as 1,
if a criterion has been fulfilled; 0, if a there is doubt over whether a criterion has been fulfilled; and -1, if a
criterion has not been fulfilled. A total score will then be calculated, with a higher total score reflecting a lower
risk of bias, or higher quality in the studies.

Strategy for data synthesis

For continuous data for CBC parameters, mean difference between outcome groups (i.e., CVEs/ACM versus
no events for prognostic studies) will be calculated and pooled across the studies using unstandardized
mean difference.

For categorical data (i.e., NLR (neutrophil lymphocyte ratio) or PLR (platelets lymphocyte ratio)), each
individual study may categorize NLR or PLR into low, low-intermediate, intermediate and high groups, using
different cut-offs. Because we are working on aggregate data, we will re-categorize them into two groups:
low versus high. For studies with four categories, two lower and two higher categories will be defined,
corresponding to the low and high groups, respectively, and if studies have three categories, the low and
intermediate categories will be combined. A risk ratio (RR) will be then estimated for each study.

Before the pooling of the data in all cases, an assessment of the level of heterogeneity in effect size will be
undertaken, in order to ensure that the correct statistical model is chosen for use (fixed- or random-effects).

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The Cochran’s Q statistic will be applied, and heterogeneity quantified using the I² statistic. If heterogeneity
is detected (p-value < 0.10 or I² ? 25%), the random-effects model (DerSimonian and Laird approach) will be
used for pooling effect sizes, whilst if significant heterogeneity is not found to be present, the fixed-effect
model (inverse-variance method) will be used instead.

Heterogeneity will be examined using tests and graphs, by constructing a forest plot or meta-view of all
selected studies.

Sources of heterogeneity will then be explored in terms of possible variation factors (covariables), as
described in Field #29 (Analysis of subgroups or subsets) below.

Mean difference and RRs will be then pooled using the random-effects model (DerSimonian and Laird
approach) if heterogeneity is present, otherwise the fixed-effect model (i.e., inverse variance method) will be
used.

All analyses will be performed using Stata software, version 15.1.

A two-sided test with p-value < 0.05 will be considered to be statistically significant, except for the test of
heterogeneity, for which a p-value < 0.1 will be applied.

Analysis of subgroups or subsets

Heterogeneity will be examined using tests and graphs, by constructing a forest plot or meta-view of all
selected studies.

Sources of heterogeneity will be explored in terms of possible variation factors. These variation factors, or
covariables, which can cause heterogeneity (e.g. clinical presentation, region, race, NLR or PLR cut-off, age,
gender, BMI, diabetes, hypertension, hyperlipidemia, chronic kidney disease, smoking history, ACEI/ARB,
cancer) will be fitted into a meta-regression one by one, if the data is available.

Subgroup analyses will also be conducted according to the covariables which have significant regression
coefficients, or for which ?² is decreased >50%.

Contact details for further information

Teeranan Angkananard
theeranana89@gmail.com

Organisational affiliation of the review

Srinakharinwirot Medical University

Review team members and their organisational affiliations

Assistant/Associate Professor Teeranan Angkananard. Srinakharinwirot Medical University
Dr Soontaree Agaslerg. Ratchaphiphat Hospital, Bangkok
Assistant/Associate Professor Worawut Roongsangmanoon. Srinakharinwirot Medical University
Dr Arthit Wongsoasup. Srinakharinwirot Medical University
Dr Nattapun Rattanajaruskul. Srinakharinwirot Medical University

Type and method of review

Epidemiologic, Meta-analysis, Prognostic, Systematic review

Anticipated or actual start date

15 April 2020

Anticipated completion date

31 October 2020

Funding sources/sponsors
None

Conflicts of interest

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Language
English

Country
Thailand

Stage of review
Review Ongoing

Subject index terms status

Subject indexing assigned by CRD

Subject index terms

Blood Cell Count; Blood Cells; Cardiovascular Diseases; Coronavirus; Coronavirus Infections; Disease
Progression; Heart Failure; Humans; Mortality; Prognosis; Public Health; Risk; Risk Factors; Stroke

Date of registration in PROSPERO

08 April 2020

Date of first submission

31 March 2020

Stage of review at time of this submission

The review has not started

Stage Started Completed

Preliminary searches No No

Piloting of the study selection process No No

Formal screening of search results against eligibility criteria No No

Data extraction No No

Risk of bias (quality) assessment No No

Data analysis No No

The record owner confirms that the information they have supplied for this submission is accurate and
complete and they understand that deliberate provision of inaccurate information or omission of data may be
construed as scientific misconduct.

The record owner confirms that they will update the status of the review when it is completed and will add
publication details in due course.

Versions
08 April 2020

PROSPERO
This information has been provided by the named contact for this review. CRD has accepted this information in good
faith and registered the review in PROSPERO. The registrant confirms that the information supplied for this submission
is accurate and complete. CRD bears no responsibility or liability for the content of this registration record, any
associated files or external websites.

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