ARDS is the leading cause of death in COVID-19 patients due to cytokine storms and uncontrolled systemic inflammatory response. 1,2 Neutrophils are involved in the pathogenesis of ALI / ARDS, while IL-8 (Interleukin-8) has been identified as the main chemotaxis factor for neutrophils in the lung fluid of patients with ALI / ARDS. 3 Neutrophil-to-Lymphocyte Ratio (NLR) has been identified as an independent risk factor in COVID-19 patients. NLR can be identified at earlier stage to determine the severity of COVID-19. Patients ≥ 50 years and an NLR of ≥ 3.13 indicate severe disease, and they should be admitted to the intensive care room if possible. 4Lately, SARS-CoV-2 has also been shown to also infect the gastrointestinal tract based on biopsy results on epithelial cells of the stomach, duodenum, and rectum.5
According to our systematic review on Tocilizumab which was more preferred in overcoming the severe hyperinflammation, there has been no sufficient treatment in order to manage the hyperinflammation in COVID-19 patients with moderate illness.6 Hence, various treatment modalities are still being developed to reduce the hyperinflammation process in moderate illness caused by COVID-19.
Rebamipide is a mucosal protective agent used for the treatment of gastritis and gastric ulcers. It has recently been reported that Rebamipide also acts as an anti-inflammatory agent in acute and chronic inflammation and has an inhibitory effect on proinflammatory cytokines7. Rebamipide is reported to inhibit the infiltration of inflammatory cells, free radical formation, and the production of IL-8 so that it provides a strong anti-inflammatory effect.8,9,10,11 In this study, Rebamipide will be added to standard therapy in COVID-19 patients with ARDS and compared to those who didn’t receive it to determine whether the administration of Rebamipide therapy can help improve the patient's condition, by seeing its effect on neutrophils and lymphocytes and the improvement of Neutrophil-Lymphoctes Ratio (NLR).
This is an observational analytical study with a retrospective cohort design, involving confirmed 180 COVID-19 patients who were admitted to the Airlangga University Hospital, Surabaya in April-September 2020, men or women aged ≥ 18 years, received standard therapy modalities, with no enteral absorption disorders and met the ARDS criteria. The medical records were grouped into data on patients who received additional Rebamipid 100 mg every 8 hours via the enteral route in addition to the standard therapy modality, as well as data on patients who did not receive Rebamipid. Other data obtained were the neutrophil count, lymphocyte count, and Neutrophil-Lymphocyte Ratio. Data analysis was performed after 2 serial evaluations of complete blood counts at day 3 and 6 after baseline blood tests.
Comparison of median neutrophil, lymphocyte, and NLR values in the Rebamipid and non-Rebamipide groups showed higher neutrophil values, lower lymphocytes, and higher NLRs in the Rebamipide group. However, from the analysis using the Wilcoxon test in evaluating laboratory improvements, in the form of a decrease in neutrophils, an increase in lymphocytes, and an improvement in NLR, the group given Rebamipid tended to improve the values of these three parameters both on the third and sixth day in COVID-19 patients who had ARDS. Statistically, the improvement was significant in moderate and severe ARDS cases in the Rebamipid group. Meanwhile, in the group not given Rebamipide, the improvement in neutrophil, lymphocyte, and NLR values showed results that were mostly not statistically significant.
Table 1. Neutrophill, lymphocyte and Neutrophill-Lymphocyte ratio monitoring between Rebamipide group and non Rebamipide group in ARDS COVID-19 patient.
ARDS
|
Rebamipide
|
Lab (median)
|
Day0
|
Day3
|
Day6
|
Lab Improvement
|
Day 0-3
|
pValue
|
Day 3-6
|
pValue
|
Mild (n=7)
|
Yes (n=3)
|
Neu
|
88,8
|
87,3
|
90,2
|
Neu decrease (%)
|
33,33
|
>0,05
|
33,33
|
>0,05
|
Lymph
|
6,3
|
7
|
2,7
|
Lymph increase (%)
|
33,33
|
>0,05
|
66,67
|
>0,05
|
NLR
|
14
|
12
|
24,3
|
NLR improvement (%)
|
33,33
|
>0,05
|
66,67
|
>0,05
|
No (n=4)
|
Neu
|
71,25
|
68,2
|
76,3
|
Neu decrease (%)
|
25
|
0,273
|
0
|
0,197
|
Lymph
|
16,75
|
16,75
|
11,5
|
Lymph increase (%)
|
25
|
0,18
|
50
|
0,655
|
NLR
|
4,5
|
5
|
6,82
|
NLR improvement (%)
|
25
|
0,144
|
0
|
0,18
|
Moderate (n=58)
|
Yes (n=22)
|
Neu
|
85,9
|
88
|
85,45
|
Neu decrease (%)
|
27,27
|
0,019
|
50
|
0,245
|
Lymph
|
9,15
|
7,15
|
9,55
|
Lymph increase (%)
|
13,64
|
0,003
|
57,14
|
0,079
|
NLR
|
9
|
12,7
|
8,91
|
NLR improvement (%)
|
13,64
|
0,004
|
64,29
|
0,03
|
No (n=36)
|
Neu
|
78,8
|
81,5
|
76,4
|
Neu decrease (%)
|
36,11
|
0,611
|
65
|
0,048
|
Lymph
|
13,5
|
12,7
|
12,2
|
Lymph increase (%)
|
44,44
|
0,326
|
65
|
0,048
|
NLR
|
6
|
6,9
|
6,26
|
NLR improvement (%)
|
27,78
|
0,075
|
60
|
0,031
|
Severe (n=115)
|
Yes (n=54)
|
Neu
|
87,3
|
89,1
|
89,6
|
Neu decrease (%)
|
39,62
|
0,15
|
27,5
|
0,116
|
Lymph
|
6,3
|
4,8
|
3,9
|
Lymph increase (%)
|
28,30
|
0,003
|
35
|
0,152
|
NLR
|
14
|
18
|
23
|
NLR improvement (%)
|
33,96
|
0,026
|
35
|
0,046
|
No (n=61)
|
Neu
|
85
|
85,6
|
87,2
|
Neu decrease (%)
|
40,98361
|
0,328
|
44,44
|
0,285
|
Lymph
|
8,8
|
7,5
|
6,5
|
Lymph increase (%)
|
32,78689
|
0,052
|
50
|
0,577
|
NLR
|
9,3
|
12
|
14
|
NLR improvement (%)
|
29,5082
|
0,001
|
50
|
0,677
|
Neu = Neutrophill; Lymph : Lymphocyte; NLR : Neutrophill-Lymphocyte Ratio
Rebamipide administration to patients with ARDS likely gives favorable results. This is concluded from the decrease in the number of neutrophil, increase in the number of lymphocytes and a significant improvement in the NLR value on the 3rd and the 6th day after Rebamipid administration. This treatment is likely to be an adequate adjunctive therapy in the management of COVID-19. The results of this study can be used as a reference for further research.