Correlation of C-Reactive Protein (CRP) Levels with D-Dimer Levels in COVID-19 Patients

Coronavirus disease 2019 is caused by SARS-CoV-2 infection. COVID-19 causes increased levels of proinflammatory cytokines, so CRP and d-dimer levels in COVID-19 patients tend to increase. This study aimed to analyze the correlation between C-Reactive Protein (CRP) levels and D-dimer levels in COVID-19 patients. This research method is analytic observational by using cross-sectional secondary data. The population of this study were all COVID-19 inpatients at Budhi Asih Hospital, East Jakarta, with a sample of 338 patients and were taken by random sampling. The results of this study found that female and male COVID-19 patients had the same risk of being infected with female patients as much as 52,7% and male patients amounting to 47,3%. Most COVID-19 patients occurred at the age of ≥60 years, namely 32,2%. All patients, which is 100% patients had high CRP levels, with a mean of 76,06 mg/L. As for D-dimer levels, 47,9% of patients had normal D-dimer levels and 52,1% had high D-dimer levels with an average of 721,48 ng/mL. The results of the Spearman's correlation test obtained a p value = 0,000, so it can be seen that there is a correlation between C-Reactive Protein (CRP) levels and D-dimer levels in COVID-19 patients with a correlation strength of 0,300 (medium). An increase in CRP levels followed by an increase in D-dimer levels but evaluation of other laboratory examination parameters also needs to be considered.


INTRODUCTION
The SARS-CoV-2 virus spreads through respiratory droplets with an incubation period of 1-14 days (Wilson et al., 2020).When the virus enters the cell, the viral antigen will be presented to the Antigen Presentation Cell (APC) which then T cells and B cells will mediate the immune and cellular system response.The humoral immune system will produce IgM and IgG, but viruses can evade the immune system by inducing double membrane vesicles that do not have pattern recognition receptors (PRRs) and replicating in these vesicles (Levani, Prastya and Mawaddatunnadila, 2021).Proinflammatory mediators such as interleukin 6 (IL-6) and IL-1β also increase and produce CRP in response (McFadyen et al., 2018).Evaluation of C-reactive protein (CRP) levels is routinely used to assess inflammatory markers, the levels of which will then increase in most COVID-19 patients, and can indicate the severity of the disease (Luo et al., 2020).CRP was chosen to evaluate inflammation because it is cheap and easy to perform with very specific results (Zadeh et al., 2018) and has superior diagnostic value compared to procalcitonin (Pourbagheri-sigaroodi, 2020), and can differentiate well between severe and nonsevere pneumonia in COVID-19 (Vita and Syambani, 2020).
As a result of the increase in pro- In research by Yu et al (2020), it was found that increasing D-dimer levels was related to inflammatory markers, namely CRP.
Research by Valerio et al (2021) shows that increased levels of D-dimer and CRP occur in COVID patients with a high level of severity so that these parameters can help monitor disease activity (Valerio et al., 2021).In research conducted in Indonesia  The characteristics of COVID-19 patients can be seen in Table 1 and it is known that the characteristics based on gender consist of 178 people (52.7%) female and 160 male patients (47.3%).This is in line with data from the DKI Jakarta Health Service ( 2022    angiotensin II regulation will increase and induce plasminogen activator inhibitor-1 (PAI-1) which is a suppressor of fibrinolysis and may also explain the fibrin deposits seen in the lung alveoli (Manzoor et al., 2021) .

RESULTS AND DISCUSSION
Due to the high fibrinolytic capacity of the lungs, vigorous fibrinolysis occurs which causes the production of D-dimer in the bloodstream (Samprathi and Jayashree, 2021).The results of the data normality test using the Kolmogorov-Smirnov test showed that CRP levels and D-dimer levels had a p-value = 0.000 (p<0.05).It can be concluded that both data have a non-normal distribution, so the Spearman test is used for correlation test.
Coronavirus disease 2019 or better known as COVID-19 is a disease caused by infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is a new type of virus discovered from βcoronavirus.The first case of COVID-19 was reported in December 2019 in the city of Wuhan, Hubei Province, China, which then spread to various countries and became a pandemic ((Wilson et al., 2020).COVID-19 has spread to 223 countries with a total of 1,745,880 cases as of 31 December 2021 (World Health Organization, 2021) and on the same day the Indonesian government reported 4,262,720 confirmed cases of COVID-19 with 144,094 of them declared dead (COVID-19 Handling Task Force, 2021).DKI Jakarta Province as the capital city of Indonesia had 865,297 positive COVID-19 cases as of December 31 2021, making DKI Jakarta one of the provinces with the highest number of COVID-19 cases in Indonesia and particularly East Jakarta the region as the most COVID-19 cases with cases reaching 213,389 ((Dinas Kesehatan DKI Jakarta, 2022a).Referral hospitals for COVID-19 patients in the East Jakarta area, one of which is RSUD Budhi Asih (Dinas Kesehatan DKI Jakarta, 2022b).
Each patient can show different symptoms, with the most common symptoms that can be experienced are fever, cough, fatigue, and loss of the ability to taste and smell.Apart from that, patients can also experience less common symptoms such as sore throat, headache, pain, diarrhea, skin rashes and eye irritation (WHO, 2022).Patients with higher degrees of disease can show severe clinical manifestations such as severe pneumonia, C.E.Choirunisa, R.M.Widhyasih, R Fajrunni'mah.Correlation of C-Reactive Protein (CRP) Levels with D-Dimer Levels in COVID-19 Patients 128 sepsis, septic shock, acute respiratory distress syndrome (ARDS), and multiple organ dysfunction syndrome (MODS) (Wilson et al., 2020).With symptoms that have been recognized, examination parameters are needed that can have good diagnostic accuracy in confirming COVID-19.The gold standard for COVID-19 diagnostics is Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) which is a type of Nucleic Acid Amplification Test (NAAT) method (Indonesian Ministry of Health, 2021).In addition, supporting examinations are required such as physical examination, routine hematology and chemistry tests, computed tomography (CT), and serology for COVID-19 immunoglobulin (Carpenter et al., 2020).Laboratory supporting examinations are needed because the virus can damage the vital organs of the heart, liver and kidneys and the main examinations used are complete blood count, coagulation and fibrinolysis tests, and parameters for inflammation examination (Pourbagherisigaroodi, 2020).The SARS-CoV-2 virus attacks the human respiratory tract, especially the cells lining the alveoli.The virus has a glycoprotein in the enveloped spike (Protein S) which then binds to the ACE 2 receptor on the plasma membrane of human cells to infect.The virus will replicate the required genetic material and proteins and form new virions on the cell surface (Levani, Prastya and Mawaddatunnadila, 2021).
inflammatory mediators that occur, it will cause lung organ damage with the formation of fibrotic tissue(Levani, Prastya and Mawaddatunnadila, 2021).The tissue is broken down into soluble fragments (Ddimers) formed from enhanced fibrin synthesis activating plasminogen and plasmin(Grobler et al., 2020).D-dimer examination, which is a fibrin degradation product, was used because it has proven useful in clinical decision rules for pulmonary embolism(Yu et al.,

by
Wardika and Sikersa (2021), it was also found that CRP and D-dimer levels showed a significant relationship with the severity of infection and mortality.However, there has been no research on the correlation between CRP levels and D-dimer levels in COVID-19 patients conducted at Budhi Asih Regional Hospital with data from the first examination after the patient was confirmed positive for SARS-CoV-2 and was treated at the hospital.Based on the description above, the author wants to analyze the correlation between C-Reactive Protein (CRP) levels and D-dimer levels in COVID-19 patients.METHOD This research has received permission from the research ethics commission of the Budhi Asih Jakarta Regional General Hospital with ethics letter number No. 50/KEP-ETIK/III/2022 dated March 18 2022.This research is observational analytic with a cross sectional design.This research, which was conducted at the Budhi Asih Regional General Hospital in January -June 2022, used all data on 1319 COVID-19 inpatients in 2021 at the Budhi C.E.Choirunisa, R.M.Widhyasih, R Fajrunni'mah.Correlation of C-Reactive Protein (CRP) Levels with D-Dimer Levels in COVID-19 Patients 130 DOI: 10.32668/jitek.v11i1.1317Asih Regional General Hospital as the population and 338 patients were selected as samples by random sampling.The samples used were patients who had odd medical record numbers.The research procedure begins with submitting a letter of application for an ethical review and research permit to the Poltekkes institution, Ministry of Health, Jakarta III, then the application letter along with the other requirements were handed over to the Budhi Asih Regional Hospital.After the ethics letter and permission letter for data collection have been processed, the medical record data containing CRP and D-dimer data is sorted, with the examination result data is recorded, recapitulated, and is presented in the form of tables and narratives.Data were analyzed univariately to describe the results of examination of CRP and Ddimer levels in COVID-19 patients at Budhi Asih Regional Hospital in the form of mean, median, standard deviation, minimum value, and maximum value.Bivariate analysis using statistical software for Windows were also carried out using Kolmogorf-Smirnov for data normality distribution and continued with Spearman test because the data is not normally distributed.
) which shows that almost equal proportions of confirmed cases of COVID-19 are 51.04% female and 48.96% male.In Satria, Kuncioho and Chalidyanto's (2020) research, results were also obtained with balanced proportions, namely from 253 data, 50.2% of whom were women.A fairly balanced proportion can also be seen in the research of Maryati et al. (2022), namely 55.9% of COVID-19 experienced by men with a total of 501 data.This research also shows that COVID-19 most often occurs in people aged ≥60 years, namely 109 patients (32.2%), followed by with ages 50-59 years, namely 88 patients (26%).This is in line with research conducted by Nanda Nur Illah (2021) which states that the risk of being infected with a virus will increase when a person reaches the age of 40 because a person's immunity tends to decrease so that their susceptibility to pathogens becomes higher.Apart from that, those aged 45-60 years have a high level of productivity and mobility (Nanda Nur Illah, 2021).These results are also reinforced by research conducted by Biswas et al. (2021) which explains that someone over 50 years of age has a higher risk of exposure to the virus and death than those under age, which is related to higher ACE2 gene expression in older patients (Biswas et al., 2021).

(
2020) which shows that there is a positive relationship between CRP levels and the severity of COVID-19 and the duration of hospitalization, and research by Zhang et al. (2020) explains that the most common laboratory findings for COVID-19 patients is an increase in CRP levels (Zhang et al., 2020).Meanwhile, in the D-dimer level variable, 162 patients (47.9%) had normal levels and the other 176 patients (52.1%) experienced an increase with a mean of 721.48 ng/mL with a level range of 100-2000 ng/mL.This is in line with research conducted by Shi et al. (2020) which shows that coagulopathy that occurs in patients shows increased levels of D-dimer as well as research by Zhou et al. (2020) which states that there are COVID-19 patients with increased levels of D-dimer and some have not increased.After attachment of the SARS-CoV-2 virus then ACE2 dysregulation will occur and then

Table 2 .
Descriptive analysis of CRP and D-dimer examination results in patientsCOVID-19 at Budhi Asih Regional Hospital in 2021

Table 4
Data Normality Test

Table 5
Correlation of CRP Levels with D-dimer Levels