INTRODUCTION:

Coronavirus disease (COVID-19) is a viral respiratory disease caused by the novel Coronavirus 19 (nCov-19) caused by a pneumonic pandemic in the world. Clinical manifestations of COVID-19 infection range from asymptomatic, to more severe diseases such as bronchitis, pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure, and even death.¹ COVID-19 infection, in those with comorbidities, has a more rapid progression and more severe clinical manifestations. Much worse results for COVID-19 have been associated with cardiovascular comorbidities conditions. Patients with type 2 diabetes are also more likely to experience an increase in the severity of COVID-19.¹

Certain comorbidities are associated with strong ACE-2 receptor expression and higher proprotein convertase release which will increase the amount of virus that enters the host cell.² The diagnostic test for COVID-19 is quantitative (real-time) reverse transcription polymerase chain reaction (PCR) analysis of nasopharyngeal/oropharyngeal swab viral RNA. Positive results indicated that SARS-CoV-2 RNA was detected with a cycle threshold value (Ct) of less than 38 amplification cycles. The Ct value is inversely proportional to the amount of target nucleic acid in the sample. So a lower Ct value indicates a higher viral load andindirectly describes the level of viral replication activity which ultimately affects patient infectivity.^3,4

More active systemic inflammation in moderate/severe cases may contribute to the development of secondary sequelae, including renal failure or acute liver injury, supporting the concept of an inflammatory state secondary to COVID-19 and associated with a higher risk of death.⁵ The Ct value has the direct effect of viral load high levels and may be an important trigger for an unregulated immune response ultimately leading to higher mortality.⁶

However, the Ct value is influenced by many factors, such as the time of illness since its onset symptoms, technician competence, tool calibration, reagents used, and analytical skills interpretation technician. In many cases, the low Ct value correlates with a high viral load and is a predictor of disease severity in the second week.⁷ In conjunction with hyperactivity of inflammatory mediators occurs, causing a cytokine storm and worsening clinical conditions.⁷

The hypothesis of this study is that patients who have comorbidities of asthma, hypertension, and diabetes mellitus, will have a greater degree of severity, as seen from the clinical picture, and laboratory parameters compared to patients without comorbidities.

There is a link between comorbidities, peripheral blood biomarkers, inflammatory markers, and increased clinical severity in COVID-19 patients. For example, CRP, IL-6, IL-8, and TNFα levels were significantly higher in deceased patients, suggesting a greater degree of systemic inflammation perpetuated by the “cytokine storm” supported by significant increases in IL-6, IL-8, and TNFα. These findings reflect a more active systemic inflammation in severe cases which may contribute to the development of secondary sequelae, including renal failure or acute liver injury, and associated increased risk of death.⁵

MATERIAL AND METHODS:

Study Design and Subjects:

This research was an analytic observational study usinga retrospective study method. The population of this study was patients diagnosed with COVID-19 at the RSKI UniversitasAirlangga (UNAIR) Surabaya in the 5-month study period (June-November 2021). It used a total sampling of all inpatients diagnosed by clinicians with COVID-19 based on clinical symptoms and laboratory results in the form of a positive antigen swab as well as other supporting examinations. Obtained samples with complete data totaling 561 samples. Inclusion Criteria: Patients diagnosed with suspected COVID-19, SARS CoV 2, by a pulmonary or internal medicine clinician in the inpatient ward of the Rumah Sakit Khusus Infeksi, Universitas Airlangga Surabaya, without comorbidities and who have comorbidities of Diabetes Mellitus, hypertension and asthma.

Statistical Analysis:

The data normality test was carried out using the Kolmogorov-Smirnov method. Furthermore, statistical analysis. Statistical tests were conducted to see the correlation between CT values and inflammatory markers in patients with and without comorbidities.

RESULT:

A total of 561 samples were obtained, as many as 276 (49.2%) patients with comorbidities and 285(50.80%) patients without comorbidities. For those with comorbidities, as many as 143(25%) patients with hypertension, 11(2%) patients with asthma and 122 (22%) patients experienced diabetes mellitus (Figure 1).

Figure 1: Percentage of patients sampled with and without comorbidities.

The results of the Mann-Whitney test showed the significance of the Ct value was p=0.221 (p>0.05). There was no significant difference in the CT value in the group with and without comorbid hypertension (p = 0.221). The significance of the Procalcitonin (PCt) value was p =0.001 (p<0.05). There is a significant difference in the PCt value in the group with and without comorbid hypertension. The significance of the CRP value was 0.001(p<0.05). There was a significant difference in CRP values in the group with and without comorbid hypertension. There was no significant difference in the CT Value, CRP, and Procalcitonin protein (PCT) in the comorbid and non-asthmatic comorbid groups because all of the significance values were 0.221(>0.05).

The significance value for the CT value is 0.084 (p >0.05). There was no difference in the CT value in the group with and without comorbid DM. The CT value in the group with comorbid DM is 21.55 compared to those without comorbid DM, which is 18,687. The significance of the procalcitonin value was 0.000 (p< 0.05). There was a significant difference in procalcitonin in the group with and without comorbid DM. Where the procalcitonin value was higher in those with comorbid DM with a mean rank value of 222.54ng/ml compared to those without comorbid DM of 170.39ng/mL.The significance of the CRP value was 0.000(p<0.05), there was a significant difference in CRP in the group with and without comorbid DM. Where the CRP value is higher for those with comorbid DM with a mean rank value of 294.39mg/dl compared to those without comorbid DM of 187.96 mg/dl.

Table 1: Results will be easier to read with table illustrations.

Group	Ct Value (Mean ± SD)	CRP (Mean ± SD)	Procalcitonin (Mean±SD)
Hypertension	20.3	265	21.6
Non-hypertension	18.7	193	16.9
	P value = 0.211	P value = 0.000	P value = 0.000

Asthma	17.73	267.78	20,394
Non-Asthma	19.23	211.81	18,298
	P value : 0.672	P value : 0.556	P value : 0.176
Diabetic	21.05	294.39	22,254
Non-Diabetic	18.6	187.96	17,039
	P value: 0.084	P value: 0.000	P value = 0.000

DISCUSSION:

In this study, patients with comorbid hypertension had the highest number, followed by comorbid diabetes mellitus in second place and asthma being the least number. This is in line with the results of research by Wei Pan (2020) from Wuhan University which found that the most comorbid groups infected with COVID-19 came from groups with a history of hypertension.⁸

In this study, there was no significant CT value between the groups with and without comorbid hypertension. However, the values of inflammatory markers, procalcitonin and C C-reactive protein, were significantly different in both groups with and without comorbid hypertension. CT values in this study showed unusual results, where low CT values were found in groups without comorbid hypertension, while high CT values were found in groups with comorbid hypertension. There is a need for further analysis on this matter.

SARS-CoV-2 at the beginning of infection will bind to alveolar epithelial cells and then the virus triggers the innate immune system and adaptive immune system, causing the release of large amounts of cytokines.⁹This is consistent with the results of this study, that in the group with comorbid hypertension, the immune response to infection will affect high levels of pro-inflammatory cytokines such as CRP and procalcitonin.

The results of this study are in line with the results of Pan et al's study in 2020 which explained that hypertensive patients with a history of ACE-2 inhibitor treatment had higher levels of C-reactive protein and CD4⁺ cell levels. It was explained that this was because patients with hypertension had worse immune dysfunction and increased inflammatory cytokines at the time of infection.⁸

In vitro, findings that inhaled corticosteroids alone or in combination with bronchodilators can suppress coronavirus replication and decrease cytokine production.¹⁰ However, in our study, there were no data on the use of corticosteroids in any patients with comorbid asthma. It was also mentioned that in asthma there was a decrease in the expression of ACE2 in the lower airways of asthmatics, both in the form of protein and gene expression. The results on the value of C reactive protein, procalcitonin levels, and CT values in patients with comorbid asthma also did not show significant differences with patients without comorbid asthma. This is related to the causes mentioned above.^10,11

In this study, there was no significant difference in the CT value in the group with and without comorbid DM.^12-14 Where the CT value in the group with comorbid DM is greater than that in the group without comorbid DM. It should be to the above theory, that the CT value in the group with comorbid DM is lower than that without comorbidities, but this was not proven in this study.^15-17 It is possible that the patients with comorbid DM in this study were in a state of regulated glucose levels.

Patients with diabetes mellitus who are infected with SARS CoV2 will have more severe clinical symptoms than healthy people.¹⁸Infection will increase metabolism and cause tissue hypoxia induce interstitial lung tissue damage and cause acute respiratory distress. Dysregulation of glucose homeostasis will exacerbate the inflammatory response and disturbances in the function of the immune system, thus increasing oxidative stress and increasing cytokine productionas well as causing endothelial dysfunction which causes an increased risk of thromboembolism and organ damage.¹⁹ All of these factors contribute to the risk of increasing the severity of COVID-19 infection in patients with co-morbid diabetes mellitus.

Other research states that patients with comorbid diabetes have an increased risk of being admitted to the ICU compared to those without comorbidities. This is related to increased expression of ACE-2 receptors in the airways, dysregulation of the immune response, increased rates of lung inflammation, and low insulin levels in patients with diabetes. Meanwhile, patients with hypertension who use ACE inhibitor drugs, Angiotensin Receptor Blockers, cause upregulation of ACE 2 receptors and cause higher susceptibility to COVID-19 infection.²

A meta-analysis study in China stated that patients with comorbid hypertension and diabetes have a risk of severe lung injuries, Acute Respiratory Distress Syndrome, cytokine storms, and increased mortality rates.^24,26

Meanwhile, the values of procalcitonin and CRP showed significant differences in the group of patients with COVID with comorbidities.^22-24The procalcitonin value was higher in patients with comorbid DM.^25,26 Likewise, the value of C reactive protein in this study was higher in patients who had comorbid DM.²⁷ The two inflammatory parameter values in this study, it based on the theory that states that pro-inflammatory cytokines are more elevated in patients with diabetes mellitus when COVID-19 infection occurs.²⁸

CONCLUSION:

Patients with comorbid hypertension and diabetes mellitus can experience more severe COVID-19 infections, while asthmatic comorbid patients infected with COVID-19 relatively do not experience more severe infections than those without comorbidities.

ACKNOWLEDGMENTS:

Thank you to the Rumah Sakit Khusus Infeksi, Airlangga University Hospital, Surabaya, Indonesia.

CONFLICT OF INTEREST:

The authors confirm that this article's content has no conflicts.

DISCLOSURE:

There are no conflicts of interest in this research.

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Received on 06.07.2023 Modified on 02.10.2023

Research J. Pharm. and Tech 2024; 17(7):3389-3393.

DOI: 10.52711/0974-360X.2024.00529