MAIN ARTICLE
Introduction
In December 2019, a severe viral pneumonia case series of 41 people, the
causative agent of which could not be revealed, was reported in the city
of Wuhan, in the Hubei Province of China.1 Subsequent
whole-genome sequencing and phylogeny analysis showed that SARS-CoV-2
belonged to the betacoronavirus 2b lineage, which belongs to the same
group as the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), a
highly virulent pathogen in humans.2,3 On January 30,
2020, the SARS-CoV-2 infection (COVID-19) was declared a global public
health emergency and a pandemic on March 11 by the World Health
Organization (WHO).4,5
The disease is transmitted by inhalation or contact with infected
droplets and the incubation period varies between 2-14 days. Symptoms
are usually fever, cough, sore throat, shortness of breath. In most
asymptomatic cases, the signs of the disease are mild. However, the
disease may progress to pneumonia, acute respiratory distress syndrome
and multi-organ dysfunction in some patients (usually the elderly and
those with comorbidities). According to recent reports, the death rate
from COVID-19 is 5.6-20.3%, while the mortality rate in severe patients
can reach 30-60%.6
COVID-19 is mainly diagnosed by reverse transcription-polymerase chain
reaction (RT-PCR) to detect SARS CoV-2 nucleic acid in a nasopharyngeal
swab (NS) sample. However, due to inappropriate clinical sampling, low
patient viral load, and differences in detection rates of different
RT-PCR kits, the sensitivity of RT-PCR for COVID-19 infection is
approximately 71%.7 In addition, direct chest
radiographs (x-ray) are less sensitive than thoracic CT, especially in
the early stage of COVID-19.8 According to current
reports, CT can detect the disease before the development of clinical
symptoms.9,10 Therefore, thorax CT is vital in
preclinical screening and is highly recommended as a first-line strategy
for investigating possible cases of COVID-19.11 In
addition, the combination of routine laboratory biomarkers (CRP, LDH,
and ferritin ±D- dimer) can be used for the diagnosis of COVID-19 with
an accepted sensitivity and specificity before making a definitive
diagnosis by RT-PCR.12 However, different results have
been reported between CRP levels and the severity of thorax CT
involvement, clinical outcomes and disease prognosis in patients
diagnosed with COVID-19.13–15
This study demonstrates that the increase in CRP levels in correlation
with CT-SS in patients with COVID-19 presenting to the emergency
department successfully predicted adverse clinical outcomes
Materials and Methods
Patients
Patients who met the inclusion criteria from among those who came to the
emergency room with the suspicion of COVID-19 between 01.04.2020 and
31.12.2020 were included in the study. The medical records of the
patients included in the study were analyzed through the hospital data
processing database. Patients aged 18 years and older who applied to the
emergency department of our hospital, for whom the COVID-19 diagnosis
code (U07.3) was entered according to the ICD-10 classification, were
included in the study. Patients younger than 18 years of age, for whom
the COVID-19 diagnosis code was not entered, and patients with the
COVID-19 diagnosis code but did not have RT-PCR and Thorax CT
examination were excluded from the study.
Ethical Committee Approval
This study was reviewed and approved by the XXXX University Medical
Ethics Committee (approval number: XXX). Written and verbal consent
forms were obtained from all participants in the study.
Diagnosis of COVID-19 Pneumonia
A confirmed case of COVID-19 was identified based on the Coronavirus
Pandemic Outbreak Method Guide published by the National Health
Commission of the Turkish Ministry of Health Science Board. According to
this guideline, positive sputum in a nasopharyngeal swab (NS) or
endotracheal aspirates (RT-PCR) is accepted as the gold standard in the
diagnosis of COVID-19. Disease onset date, clinical classification, RNA
test results during hospitalization, and personal demographic
information were obtained from clinical records.
Cases with SARS-CoV-2 detected by molecular methods, among the cases
suitable for a possible COVID-19 case definition, were included in the
study. Patients over 18 years of age and with a hospital stay of 48
hours or more were included in the study. On the contrary, patients who
were found to have another infection focus within the first 48 hours
were excluded from the study.
Real-Time RT-PCR
rRT-PCR analysis was performed on materials obtained by NS from patients
admitted to the emergency department. A 1-step real-time RT-PCR assay
(Bio-Speedy, Turkey) targeting the nucleocapsid gene and open reading
frame 1 ab gene was performed with 5 µL of total nucleic acid according
to the manufacturer’s instructions (2B010271500RD, COVID-19
/Flu-RT-qPCR, Bioeksen Ar-GE).
Thorax CT protocol
CT imaging was performed in the supine position with the arms raised and
at the end of inspiration (Toshiba Alexion/Advance, Toshiba Medical
Systems Corporation Nashua, Japan). Patients were instructed to hold
their breath if clinically possible. Two radiologists experienced in
thoracic CT radiology respectively reviewed the thin-section CT images
and a decision reached by consensus. Readers identified predominant
appearances in CT images such as ground-glass density, crazy-paving
pattern, consolidation, and other findings. Both radiologists were
unaware of the PCR test results as these were only available after 12-24
hours.
Thorax CT image analysis
Two experienced radiologists with 11 and 15 years of clinical experience
in thoracic CT radiology respectively, reviewed the thin-slice CT images
and reached a consensus. They classified the dominant patterns on CT
scans as ground-glass opacification (GGO, hazy areas of increasing
attenuation that do not block underlying vessels), cobblestone
appearance (GGO with interlobular and intralobular septal thickening)
and consolidation (homogeneous opacification of the parenchyma). Some
other minor findings such as air bronchogram, cavitation,
bronchiectasis, pleural effusion, pericardial effusion, pneumothorax and
mediastinal lymphadenopathy (>1 cm in short axis diameter)
were also recorded in the scans. A pulmonary nodule was defined as a
well- or ill-defined round opacity less than 3.0 cm in
diameter.16 Pleural effusions were recorded. In the
current study, a semi-quantitative CT severity scoring suggested by the
RSNA17, taking into account the severity of
radiological involvement, was calculated separately for 6 lung zones as
follows: 1, <0-25% involvement; 2, 25–50% involvement; 3,
50-75% involvement; 4, 75-100% involvement. The overall CT score was
calculated as the sum of the individual zonal scores, and the maximum
score was 24.
Statistical Analysis
The SPSS 26.0 (IBM Corporation, Armonk, New York, United States) program
was used to analyze the variables. The suitability of the data for
normal distribution was evaluated with the Kolmogorov-Smirnov test and
the Shapiro-Wilk Francia test. The Mann-Whitney U test was used together
with the Monte Carlo results to compare two independent groups with each
other according to the quantitative data. The Kruskal-Wallis H Test was
used with the Monte Carlo simulation technique to compare more than two
groups with each other according to the quantitative data, while the
Dunn’s Test was used for Post Hoc analyses. The Spearman’s rho test was
used to examine the correlations of the variables with each other.
Sensitivity, specificity and diagnostic accuracy likelihood odds were
analyzed and expressed by ROC (Receiver Operating Curve) curve analysis
for the relationship between the classification separated by the cut-off
value calculated according to the CRP of the groups and the actual
classification. Odds ratio values were calculated with 95% confidence
intervals according to these cut-off values. While quantitative
variables were expressed as mean (standard deviation) and Median
(Minimum / Maximum) and Median (Percentile 25 / Percentile 75) in the
tables, categorical variables were shown as n (%). Variables were
analyzed at a 95% confidence level and a p-value less than 0.05 was
considered significant.
Results
Demographics
A total of 974 COVID-19 patients, 572 men (58.7%) and 402 women
(41.3%), with a mean age of 59.64±17.34 years, were included in the
study. At least one comorbidity was current in 564 (58.6%) of the
patients. The distribution of the most common comorbidities was found to
be HT (21.2%), T2DM (15%), CVD (13.4%) and COPD (10.8%), in order of
frequency, similar to that in the literature. The distribution of other
comorbidities is summarized in Table 1.
Symptoms
The most common complaints of patients presenting to the emergency
department were found to be shortness of breath (29.1%), cough
(21.7%), fatigue (11.5%) and fever (11.4%). However, 111 (5.3%)
patients were found to be asymptomatic (contact). Other application
complaints are summarized in Table 2 .
Laboratory Results
Laboratory tests performed during the patients’ admission to the
emergency department are summarized in Table 1 . The median CRP
value was 56.2 (0.26-460) mg/dL, the median ferritin value was 324.65
(61-3130) mg/dL, and the median D-dimer level was 226 (12-43453) mg/dL.
The mean leucocyte level measured at the time of admission of the
patients was 7.86±6.05 cells/mm3, the lymphocyte count was 1.29±0.1
h/mm3 and the mean neutrophil count was 5.88±3.83 h/mm3. The median NLR
value was 4.09 (0.25-71.85) (Table 1) .
Radiological Results
Thorax CT findings obtained during the patients’ admission to the
emergency department are summarized in Table 1. Thorax CT findings
consistent with typical COVID-19 were detected in 677 patients. While 90
patients had partially significant involvement, 40 patients had
involvement consistent with atypical pneumonic infiltrates, 167 patients
had negative CT findings for COVID-19 pneumonia despite rt-PCR test
positivity. While no signs of involvement were observed on thorax CT in
203 patients (21%), there were findings consistent with mild lung
involvement in 403 patients (41.8%), moderate in 212 patients (22%),
and severe lung involvement in 145 patients (15%) (Details inTable 1 ).
COVID-19 Treatment
Antiviral treatment (Favipiravir) was initiated in all patients because
of rt-PCR positivity. In addition, 595 (33.4%) of the patients were
given additional antibiotic therapy, while 85 (4.8%) were also given
convalescent immune plasma therapy (Table 4 ).
Clinical Outcome
The median hospital stay of the patients was 8 (1-95) days, while the
mean thorax CT-SS was 7.59±4.2. It was determined that 307 (31.5%)
patients were treated without complications. While the need for
intensive care developed in 56 patients (36.9%), the need for
additional respiratory support (NIMV or MV) developed in 290 patients
(29.9%) during admission or follow-up. A total of 318 (32.7%) patients
were diagnosed with severe COVID-19 and mortality developed in 217
(22.3%) patients (Table 1 ).
Different complications were observed in 298 (30.6%) patients during
the follow-up period after the diagnosis of COVID-19. There was impaired
liver function in 153 patients (15.3%), acute kidney injury in 71
patients (6.06%), acute coronary syndrome in 15 patients (1.54%),
atrial fibrillations (AF) in 13 patients (1.13%), pneumothorax in 10
patients (1.03%), and diabetic ketoacidosis developed in 10 patients
(1.03%). However, while thrombocytopenia and mucosal bleeding, fluid
electrolyte imbalance, stroke and acute abdomen were determined in order
of frequency, they were at lower rates (Table 3 andTable 4 ).
Relationship between CRP and clinical findings
CRP values measured at admission were higher in males than females
(73.55 vs 35.4) (p<0.001). It was determined that patients
with comorbidities had higher CRP values (70.65 vs. 41.85 mg/dL). The
CRP values of the patients, who needed intensive care and needed
respiratory support, were also found to be significantly higher at
admission (95.1 mg/dL vs. 31.05 mg/dL) (p<0.001)(Table 2) .
While a positive correlation was determined between CRP and patients’
ages, the length of hospital stay (r=0.118), lung density level
(r=0.445), leucocyte count (r=0.367), neutrophil count (r=0.474),
D-dimer (r=0.408), and ferritin levels (r=0.539), there was a negative
correlation with lymphocyte levels (r=0.367). The CRP values of the
patients who developed any complications during the treatment of
COVID-19 were higher (79.9 mg/dL vs. 41.85 mg/dL) (p<0.001)
(Table 2 ).
In the analysis performed to predict the severity of clinical findings
and the need for respiratory support, it was determined that a CRP value
>32.6 mg/dL increased the need for additional respiratory
support by 5.05 times. In addition, when the cut-off value of
CRP>65.95 was taken, it was determined that there was a
3.81-fold increase in the risk of death. If the CRP value was
>125 mg/dL, mortality increased significantly
(Table 5 ).
Relationship between Thorax CT and CRP
It was determined that the increase in the severity of involvement in
thorax CT was positively correlated with CRP (p<0.001).
Patients with typical COVID-19 thorax CT findings had higher CRP levels
compared to those in other patients. If the CRP value was
>124.5, there was a 7.35 times higher thorax CT density
score. In addition, it was determined that there was a 9.09-fold
increase in the incidence of negative imaging findings in terms of
COVID-19 in cases where the CRP value was <12.5 mg/dL. The
cut-off value for detecting COVID-19 lung involvement with negative
imaging findings was determined to be 12.35 mg/dL (Table 5 ).
Discussion
The symptoms of symptomatic COVID-19 range widely from mild fever
(>37.5°C) and cough to acute respiratory distress syndrome
(ARDS) and death, and the disease follows an unpredictable course. This
variability has led to the need for rational use of biomarkers of
disease severity and imaging modalities to manage patients appropriately
and prevent fatal complications. Based on this, the planned study shows
that the increase in CRP levels in patients with a diagnosis of COVID-19
admitted to the emergency department successfully predicts adverse
clinical outcomes in correlation with CT-SS.
Many studies have shown that serious illness and death occur in patients
with certain risk factors, including advanced age and underlying medical
comorbidities. In a case series study of 5,700 patients with COVID-19
infection in New York, the most common comorbidities in hospitalized
patients were hypertension (56.6%), obesity (41.7%), and diabetes
(33.8%).18 In addition, a retrospective cohort study
of 124 patients with SARS-CoV-2 infection found obesity to be an
important risk factor with respect to the need for intubation.
Typical symptoms of COVID-19 are fever, dry cough and fatigue, and in
more severe cases, shortness of breath. Less common symptoms include
increased sputum, headache, hemoptysis, diarrhea, anorexia, sore throat,
chest pain, chills, and nausea and vomiting.1 In most
people, symptoms appear after an incubation period of 1-14 days (usually
about 5 days), and dyspnea and pneumonia develop within an average of 8
days from disease onset. In addition, smell and taste disorders stand
out as important symptoms.19 In the current study, the
most common complaints in patients presenting to the emergency
department were dyspnea (29.1%), cough (21.7%), malaise (11.5%), and
fever (11.4%). In the patient-based evaluation, it was observed that
the patients had multiple complaints at the time of their admission and
their first complaints were included in the study. However, the fact
that 111 (5.3%) patients were asymptomatic (contact) is also seen as an
important finding.
CRP is a nonspecific acute phase protein produced by hepatocytes and is
elevated in acute infection or inflammation.20 High
CRP levels have been observed in COVID-19 patients and are used as an
important adjunctive test in triage, diagnosis and predicting
prognosis.20,21 Elshazli et
al 22 while examining various hematological and
immunological markers, emphasized that CRP is a valid biomarker of death
from COVID-19. It is also thought that the association of higher CRP
with worse outcomes may depend on the severity of the disease, which is
consistent with the ’cytokine storm’ theory of COVID-19, in which the
innate immune system is activated by increasing TNF-alpha, IL-6 and IL-1
levels. Studies addressing the clinical utility of CRP have mostly
reported a positive association between disease severity and baseline
values.
Ali et al. 23 emphasized that for each unit
increase in CRP level, there is a 5% greater risk that the course of
COVID-19 infection in patients will be severe and emphasized that the
CRP level can predict a worsening of the disease in non-serious cases.
In addition, CRP levels were found to be 10 times higher in patients who
died from COVID-19 than those who survived.23,24However, it should be noted that in the review conducted by Ali et
al., only studies dealing with the positive relationship between CRP
level and disease severity were included. In contrast, other studies
have documented no significant differences in CRP levels between mild,
severe, and critically ill patients, and sample sizes have been
relatively small.25,26
In some studies, it has been shown that there are more frequent changes
in some laboratory parameters in COVID-19 patients (such as lymphocyte
count, CRP, LDH, D-dimer and fibrinogen).27,28Lymphopenia, CRP, LDH, D-dimer and fibrinogen elevation can be used as
an auxiliary diagnostic tool in suspected patients with high clinical
and thorax CT scanning features, despite a double negative RT-PCR
test.29 In addition, systemic inflammation as measured
by CRP is strongly associated with VTE, AKI, critical illness and
mortality in COVID-19. Evaluating the associations between CRP
concentrations and respiratory failure requiring mechanical ventilation,
patients with a recent CRP >5 mg/dL had an approximately
five-fold greater reported risk for acute respiratory distress syndrome
(ARDS).30,31 In light of the studies mentioned above,
it is clear that high CRP, ESR, IL-6, procalcitonin and serum ferritin
levels are associated with worse outcomes and increased mortality in
COVID-19 patients. CRP-based approaches to risk stratification and
treatment should be tested.32
In the current study, CRP levels were high in severe and fatal COVID-19
patients. Patients with severe COVID-19 had significantly higher CRP
levels compared to those in patients with non-serious disease [57.9
(20.9–103.2) mg/dL vs 33.2 (8.2–59.7) mg/dL].33 In
this study, it was determined that the CRP values of the patients, who
developed any complications during the treatment of COVID-19, were
higher (79.9 mg/dL vs. 41.85 mg/dL) (p<0.001).
A CRP level of >4 mg/dL has been shown to be beneficial in
the triage of PCR (+) cases presenting with respiratory symptoms/fever
[Odds Ratio (OR) 4.75; 95%, CI 3,28-6,88].34 In
most of these studies, CRP with a dual threshold value was used.
Recommended values for estimating in-patient mortality ranged from
>10 mg/dL to >76mg/dL. In addition to a dual
threshold, CRP was also studied in a trichotomized model with two
thresholds at >40mg/dL and
>100mg/dL.35 In the current study, in the
analysis performed to predict the need for respiratory support according
to the severity of clinical findings, it was determined that a CRP value
of >32.6 mg/dL increased the need for additional
respiratory support by 5.05 times. In addition, it was determined that
when the CRP value was >65.95, there was a 3.81-fold
increase in the risk of death, and if the CRP value was
>125 mg/dl, the mortality rate increased significantly.
Recently, with the increase in clinical data, the relationship between
liver injury and clinical outcomes of COVID-19 has been further
investigated. Ponziani et al .36 found that the
baseline level of liver enzyme abnormality was associated with an
increased risk of intensive care unit admission (OR: 2.19; 1.24-3.89],
p=0.007). However, further studies have shown that liver enzyme
abnormality is an independent predictor of poor prognosis for COVID-19
patients. Yip et al. 37 found that COVID-19
patients who developed adverse clinical outcomes (including ICU
admission, use of invasive mechanical ventilation, and/or death) had a
significantly higher incidence of elevated ALT/AST and acute liver
injury compared to those who did not (ALT/AST elevation: 70.9% vs.
19.1%, p<0.001, acute liver injury: 14.5% vs. 0.9%,
p<0.001). Similarly, Piano et al .38showed that liver enzyme abnormality is an independent predictor of ICU
admission or death. Therefore, according to the available evidence, it
is necessary to regularly monitor the liver functions of patients with
COVID-19. In the current study, the highest incidence rate recorded
(15.3%) was that in relation to impaired liver function. Although this
condition is often related to the treatments used for the patients, it
may also develop secondarily to viral load and hypoxemia.
While the median hospital stay of the patients in this study was 8
(1-95) days, the mean of thorax CT-SS was 7.59±4.2. While 307 of the
patients recovered without any complications, 349 patients had mild to
moderate COVID-19. While the need for intensive care developed in 356
(36.9%) patients, the need for additional respiratory support developed
in 290 patients at admission or during follow-up. A total of 318
patients were diagnosed with severe COVID 19 and mortality developed in
217 (22.2%) patients. In the current study, the significantly higher
mortality rate compared to that in the literature was thought to be
related to a number of factors, including the fact that our hospital is
a tertiary center (as a result of its location within the region), the
admission of complicated cases, the evaluation of patients with multiple
comorbidities and prolonged stay at hospital after symptom onset.
In a large series of 1,014 patients, Ai et
al. 39 found that thorax CT had a 97% sensitivity for
the diagnosis of COVID-19, while the mean time interval between initial
negative and positive RT-PCR was defined as approximately 5 days.
Therefore, CT can play a crucial role in the early detection and
treatment of COVID-19 pneumonia, at least for patients who have been
symptomatic for more than three days.40 Indeed, 56%
of patients screened within the first 2 days of symptom onset have
normal CT findings. Given the important role of thoracic CT, it is
important for radiologists to be familiar with the typical CT features
associated with this new infection, as well as the imaging criteria for
an alternative diagnosis. In our center, where the patients included in
the current study were evaluated and the density of the pandemic was
quite high, we showed a liberal approach to CT imaging of the thorax in
patients with suspected COVID-19 and used the imaging option as early as
possible regardless of symptom onset. Therefore, in this study, the time
between symptom onset and hospital admission and CT imaging after PCR
positivity was detected was very short. This seems to have resulted in
negative results with regard to thoracic CT and an increase in the
frequency of thorax CT applications even in asymptomatic cases.
In the current study, we aimed to determine the benefit of CRP levels
and thorax CT-SS results in determining the clinical outcome and
prognosis based on this information. It was determined that patients
with typical COVID-19 thorax CT findings had higher CRP levels compared
to those of other patients, and thorax CT-SS was positively correlated
with CRP (p<0.001). In addition, it was determined that a
cut-off value of CRP>124.5 mg/dL increased the risk of
severe involvement of thorax CT-SS 7.35 times, and negative imaging
findings in terms of COVID-19 were detected more frequently in cases
where the CRP value was <12.5 mg/dL, and the CRP cut-off value
should be >12.35 mg/dL to detect COVID-19-related lung
involvement in any severe condition. This study demonstrates that the
thorax CT severity score constitutes a useful tool for the initial
assessment of COVID-19 patients, as it positively correlates with
markers of disease severity and offers promising efficacy in predicting
critical illness and intensive care unit admissions.
Limitations
There are some inevitable limitations in relation to our study, which
was conducted using a retrospective file-scanning-based method. Some of
these deficiencies are the contact status of the patients, information
about the incubation period, and the inability to access medical
treatment and examination histories before presentation at the emergency
department. In addition, some clinical features were not recorded
regularly in some patients in this study, except fever and length of
hospital stay. Therefore, only the basic clinical features at
presentation, the dynamic change of clinical features, and the
relationship between clinical features and CT findings could be
analyzed. However, in the current study, the evaluation of a high number
of PCR (+) patients with laboratory tests, CT images and clinical
outcome characteristics is a strength.
Conclusion
As a result, as CRP levels and CT-SS increase, the risk in relation to
the patient’s need for intensive care increases. This information will
help guide the management of patients and determine appropriate
treatment. CRP levels measured at emergency room admission of COVID-19
patients are correlated with the severity of lung involvement and are an
important predictor of clinical outcomes.