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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 4  |  Page : 495-501

Comparative, observational study of the use of artesunate injections along with standard-of-care treatment versus only standard-of-care treatment in moderate and severe acute respiratory distress syndrome cases of COVID-19-positive infections


1 Department of General Medicine, MGM Hospitals and Research Centre, Navi Mumbai, Maharashtra, India
2 Department of Orthopaedics, MGM Hospitals and Research Centre, Navi Mumbai, Maharashtra, India
3 Department of Medicine, MGM Hospitals and Research Centre, Navi Mumbai, Maharashtra, India

Date of Submission26-Sep-2022
Date of Acceptance19-Oct-2022
Date of Web Publication29-Dec-2022

Correspondence Address:
Dr. Babita A Ghodke
Department of General Medicine, MGM Hospitals and Research Centre, CBD-Belapur, Navi Mumbai 400614, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_173_22

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  Abstract 

Introduction: COVID-19 is a type of coronavirus disease belonging to the family Coronaviridae. In late December 2019, this virus emerged from Wuhan, Hubei province, China, and resulted in an outbreak in China and expanded globally. In India, the mortality rate today was 521,691 till the date-time of writing this article. Several therapeutic agents have been evaluated for the treatment of COVID-19. Materials and Methods: This was a hospital-based comparative, observational study of the use of artesunate injections with standard-of-care (SOC) treatment (group A) versus only SOC (group B) treatment in moderate-to-severe cases of COVID-19 acute respiratory distress syndrome (ARDS) patients, on a total of 130 patients (comparative group of 65 patients each). The study was done on hospitalized COVID-19-positive moderate and severe cases of ARDS from October 2020 to June 2021 at MGM Hospital and Research Centre, CBD Belapur, Navi Mumbai, Maharashtra, India. Results: One hundred and thirty patients were divided into two groups of 65 each; group A was compared with group B; group A received SOC with artesunate injections and group B received only SOC treatment. The mean age of patients in group A was 57.3 ± 12.5 years (standard deviation [SD]: 54.2–60.3) and in group B was 55.8 ± 12.5 years (SD: 52.8–58.9). Diabetes mellitus was the most comorbid condition. The inflammatory markers, respiratory rate, and SpO2 improved in group A as compared to group B. The proportion of patients progressing to noninvasive and invasive ventilation was more in group B as compared to group A (P < 0.05). About 93.8% of patients (61 patients) recovered in group A compared with 72.3% of patients (47 patients) who recovered in group B. The overall death in group A was 6.2% (four patients) and 27.7% (18 patients) in group B (P < 0.05), indicating the proportion of dead patients is significantly more where only SOC treatment was given. Conclusions: Artesunate injection administration accelerated recovery in our patients with moderate and severe COVID-19 disease by controlling hyperimmune response. The clinical improvement was seen by decreased levels of inflammatory markers, reduced respiratory rate, and improved oxygen saturation and showed significant survival in group A compared with group B. Artesunate injections were given 2 mg/kg body weight diluted in 1 mL 5% sodium bicarbonate solution as a bolus followed by 1 mg/kg body weight after 6 h and 2 mg/kg body weight with 1 mL sodium bicarbonate solution for next 2 days at an interval of 24 h. Patients tolerated the injections well and recovery improved, so artesunate can be considered a therapeutic option in moderate and severe cases of COVID-19 ARDS.

Keywords: Acute respiratory distress syndrome, artemisinin, artesunate, COVID-19, standard-of-care treatment


How to cite this article:
Ghodke BA, Ghodke A, Mali K, Thorat P. Comparative, observational study of the use of artesunate injections along with standard-of-care treatment versus only standard-of-care treatment in moderate and severe acute respiratory distress syndrome cases of COVID-19-positive infections. MGM J Med Sci 2022;9:495-501

How to cite this URL:
Ghodke BA, Ghodke A, Mali K, Thorat P. Comparative, observational study of the use of artesunate injections along with standard-of-care treatment versus only standard-of-care treatment in moderate and severe acute respiratory distress syndrome cases of COVID-19-positive infections. MGM J Med Sci [serial online] 2022 [cited 2023 Jan 27];9:495-501. Available from: http://www.mgmjms.com/text.asp?2022/9/4/495/365976




  Introduction Top


In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease (COVID-19), emerged in Wuhan, China.[1] The declared data to the World Health Organization (WHO) indicated that the spread of COVID-19 in Africa had lower confirmed cases than expected.[2] The hypothesis that may explain this later emergence in Africa could be the use of antimalarial drugs.[3] Our study aimed to evaluate the antiviral activity of artesunate alone at concentrations consistent with those observed in human plasma when artesunate was administered intravenously for COVID-19 infection.

SARS-CoV-2 of this COVID-19 deadly disease relies on the nonstructural protein (Nsp1) for the multiplication within the host cells and disarms the host immune defense by various mechanisms.[4]

Artesunate has a synergistic effect with antiviral drugs decreasing viral replication and decreasing tumor necrosis factor α (TNF α) and interleukin 6 (IL-6) levels, which are keys in COVID-19-induced cytokines storms and acute respiratory distress syndrome (ARDS).[5] In an era of the uncertainty of the prognosis of disease, the severe shortage of resources for treatment, and large financial constraints, artesunate has a synergistic effect along with antiviral drugs.

When proven effective therapies are lacking, we aimed to describe our real-life experience using artesunate for COVID-19 cases of moderate and severe ARDS compared with the combination of standard-of-care (SOC) treatment versus only SOC treatment. The COVID-19 epidemic was more dangerous than previous coronavirus outbreaks, with greater morbidity and death.[4] Despite all the measures, infections by SARS-CoV-2 were a challenge for healthcare systems worldwide.[6]


  Materials and methods Top


Study type

It is a hospital-based observational single-center study of a total of 130 patients with two groups of 65 patients. One group of moderate and severe cases of COVID-19-positive patients with ARDS (group A) received SOC treatment with artesunate injections, and the other group (group B) received SOC treatment only. The inclusion criteria were adults >18–91 years, with no gender specification; patients willing to give written informed consent; confirmed by recombinant technology polymerase chain reaction (RT-PCR), rapid antigen testing (RAT), high resolution computed tomography (HRCT) positive for COVID-19; patients with moderate and severe respiratory distress and respiratory rate (RR) >24 breaths/min to <48 breaths/min, SpO2 (oxygen saturation) < 94% to as low as 19%; patients presenting with respiratory failure and requiring noninvasive and invasive mechanical ventilation; and PaO2/FiO2 ≤ 200 mm of Hg and ≤ 100 mm of Hg (1 mmHg = 0.133 kpa). Exclusion criteria were patients less than 18 years of age and those who refused to take the drug or to participate, and pregnant or breastfeeding patients; and patients with mild COVID-19 disease. A study was conducted from October 2020 to July 2021 at MGM Hospital and Research Centre, CBD Belapur, Navi Mumbai.

Artesunate injection of 2 mg/kg body weight diluted with 1 mL 5% sodium bicarbonate solution was given as a bolus followed by 1 mg/kg body weight after 6 h and 2 mg/kg body weight diluted with 1 mL sodium bicarbonate for the next 2 days intravenously at an interval of 24 h for group A.

Primary outcome measure was the length of stay in the hospital.

Secondary outcome measures

  1. The number of intensive care unit (ICU) admission (time frame: 14 days) and reduction of morbidity and mortality


  2. Resolution of symptoms (time frame: 6–10 days, finding the time that the symptoms disappear)


  3. Changes in SpO2, RR, and inflammatory markers, pre- and postartesunate injections.


Statistical methods

All the data obtained were analyzed using Microsoft Excel SPSS version 21.0. Categorical variables were expressed in numbers and percentages. Continuous variables were presented as mean ± standard deviation (SD). The statistical analysis was carried out to test the significance of the difference between pre- and postchanges in the study parameter. As data satisfy the condition of normality, paired t-test and 95% confidence intervals were used to test the pre- and postsignificance.


  Results Top


During the period from October 2020 to July 2021, this comparative observational study of 65 patients in groups divided as group A where artesunate was added to the SOC treatment, and compared with group B where only SOC treatment was given in moderate and severe cases of COVID-19-positive ARDS cases in our medicine department in a tertiary care hospital at MGM Hospital CBD Belapur and Research Centre, Navi Mumbai.

The mean age in group A was 57.3 ± 12.5 years (range: 54.2–60.3 years) and in group B was 55.8 ± 12.5 years (range: 52.8–58.9 years) [Table 1]. Group A had 30 female patients (46.2%), and group B had 16 female patients (24.6%) [Table 1]. We had 52.30% patients (34/65) in group A and 44.6% patients (29/65) in group B with diabetes mellitus, and 27.69% patients (18/65) in group A and 29.02% patients (19/65) in group B with hypertension. The other comorbidities were seen in both the groups [Table 2].
Table 1: Basic demographic details

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Table 2: Basic demographic details

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We had initially applied the Kolmogorov–Smirnov test of normality and descriptive statistics, which showed the comparative and descriptive statistics of clinical and laboratory parameters among both groups A and B, but as data were not distributed normally in some cases, we used a nonparametric test (Mann–Whitney U test) to compare the significance of the difference between artesunate plus SOC in group A and SOC only in group B along with parametric t-test. The P value of the t-test (parametric test) and Mann–Whitney U test (nonparametric test) is greater than 0.05, indicating that there is no significance of the difference between the average in group A and group B. The results of within-group comparisons were as follows: the RR, hemoglobin (Hb), neutrophilic lymphocytic ratio (NLR), serum ferritin (SF), C-reactive protein (CRP), D-dimer assays, and serum lactate dehydrogenase (LDH) levels decreased significantly in group A (P < 0.05) at postintervention as compared to preintervention; on the other hand, SpO2 (oxygen saturation in %) and white blood cell (WBC) count (per cubic mm) increased significantly at postintervention as compared to preintervention (P < 0.05) in group A. The RR, Hb, CRP (international units [IU]), WBC, and serum LDH levels decreased significantly postintervention in group B as compared to preintervention (P < 0.05); on the other hand, WBC count increased significantly postintervention as compared to preintervention in group B (P < 0.05).

Between the groups, before interventions, the NLR, SF in IU, D-dimer assay, and LDH in IU were significantly different between groups A and B (P < 0.05). Postintervention, RR, SpO2 (%), WBC count (cubic millimeters), SF (IU), D-dimer assay (IU), and LDH (IU) were significantly different between groups A and B (P < 0.05). The data presented are in mean ± SD and 95% confidence interval [Table 3].
Table 3: Comparison of clinical and laboratory parameters within groups and between the groups

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The average stay of the patients of group A in the COVID general ward mean stay was 8.92 days (SD: 2.32), and in group B, the mean stay was 9.14 days (SD: 2.93) [Table 4]. In the high dependency unit, the stay in group A was a mean of 6 days (SD: 3) and in group B was a mean of 6 days (SD: 2). In ICU, the stay in group A was 7 days (SD: 4) and in group B was 7 days (SD: 4). The P value of the t-test (parametric) and Mann–Whitney U test (nonparametric) is greater than that of 0.05, which indicates that there is no significance of the difference between an average stay in groups A and B as shown in [Table 5] and [Table 6].
Table 4: Patient stay

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Table 5: Average stay

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Table 6: t-test and Mann–Whitney U test result

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The percentage of patients with moderate ARDS in group A is 66.2% and 63.1% in group B and that with severe ARDS is 33.8% in group A and 36.9% in group B as shown in [Table 7] and [Table 8]. The P value of the Mann–Whitney U test is greater than that of 0.05, indicating there is no significance of the difference between PaO2 and FiO2 when compared for the case of groups A and B.
Table 7: PaO2/FiO2 ratio

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Table 8: Mann–Whitney U test results

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The proportion of patients on noninvasive ventilation is 24.6% in group B compared with 9.2% in group A, and the proportion of patients in group B on invasive ventilation is 18.5% more than in group A, which had 3.1%, i.e., P value of chi-square is less than 0.05 indicating that the proportion of patients with noninvasive and invasive ventilation is more where only SOC was used, i.e., group B [Table 9].
Table 9: Ventilation

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The P value of chi-square is less than that of 0.05, indicating that the proportion of those in the COVID general ward is significantly less in group B, i.e., those on the SOC treatment. The P value of chi-square greater than that of 0.05 indicates that the proportion of those admitted to high dependency unit (HDU) and ICU is almost the same.

The overall outcome of the patients in group A (artesunate plus SOC) was 93.8% (i.e., 61 patients) who survived and 6.2% (i.e., four patients) who died, and in group B, 72.3% (i.e., 47 patients) who survived and 27.7% (i.e., 18 patients) who died. The P value of chi-square is less than that of 0.05%, indicating that the proportion of death is significantly more in cases where only SOC treatment is given [Table 10].
Table 10: Overall outcome

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  Discussion Top


In the face of the current global pandemic, new drug development is impractical. Repurposing an existing drug with a known safety profile is an effective alternative in managing COVID-19 complications. Artesunate is the only effective derivative of artemisinin that can be made into water-soluble preparations. It has antiviral properties with multiple pleotropic effects, and it can be a perfect potential agent for the treatment of symptomatic COVID-19 infection and related inflammation state.[5]

Artesunate has anti-inflammatory, immunomodulatory, antioxidant, and anticytokine multiorgan protective effects that may be useful in the later stages of inflammation to reduce morbidity and mortality.[5] Artemisinin derivatives have synergistic effects with other antiviral drugs; it decreases viral replication and decreases TNF α and IL-6 levels, which are the key mediators in causing cytokine storms. It has an endocytosis inhibition mechanism and a nuclear factor kappa B (NF κB) signal pathway.[5]

There is no global approved protocol for the treatment of critically ill patients, which leads to a very low survival rate and prolonged stay in the ICU. The results showed that the addition of artesunate to the SOC treatment in group A compared to group B can significantly improve the outcome of clinical symptoms with COVID-19 pneumonia and promote the absorption of lung lesions.

The mean age of patients in group A (SOC + artesunate) was 57.3 ± 12.5 years (SD: 54.2–60.3) and in group B (SOC alone) was 55.8 ± 12.5 years (SD: 52.8–58.9). The female gender outnumbered 46.2% (30) in group A and the male gender outnumbered group B by 75.4% (49). In a similar study by Li et al.,[7] the average age of patients in the artesunate piperazine group was 42.7 ± 11.8 years and 45.8 ± 16.3 years in the control group, which is less comparable to our group. Lin et al.[8] study was less comparable in terms of gender in both groups as compared to our study.

The comorbidities of diabetes mellitus in group A were 52.30% (34/65) and 44.6% (29/65) in group B in our study, which was less comparable to Lin et al.’s study. Almost similar % of hypertensives, 27.69% (18/65) in group A and 23.07% (13/65) in group B were seen in our study.

The results of within-group comparisons were as follows: the RR, Hb, NLR, SF, CRP, D-dimer assays, and serum LDH levels decreased significantly in group A (P < 0.05) at postintervention as compared to preintervention; on the other hand, SpO2 (oxygen saturation in %) and WBC count (per cubic mm) increased significantly at postintervention as compared to preintervention (P < 0.05) in group A. The RR, Hb, CRP (IU) WBC, and serum LDH levels decreased significantly postintervention in group B as compared to preintervention (P < 0.05); on the other hand, WBC count increased significantly postintervention as compared to preintervention in group B (P < 0.05).

Between the groups, before interventions, the NLR, SF in me.U, D-dimer assay, and LDH in IU were significantly different between groups A and B (P < 0.05). Postintervention, RR, SpO2 (%), WBC count (cu mm), SF (IU), D-dimer assay (IU), and LDH (IU) were significantly different between groups A and B (P < 0.05). The data presented are in mean ± SD and 95% confidence interval.

In a study conducted by Lin et al. which was similar to our study where parameters such as WBC count in groups A and B, WBC count showed a mean ± SD of 0.555 over values showed a significant improvement between groups A and B. The N:L ratio in group A was significant (P < 0.001), whereas it was non-significant in group B.

The LDH value was 171.43 ± 41.71 in group A and 179.94 ± 40.66 in group B with a mean SD of 0.55 in the Lin et al. study while the LDH value in Group A in our study post-Artesunate was 0.001 which was significant in GroupB. Since there are not many studies to compare the laboratory parameters. In group A, postartesunate treatment, the RR improved and SpO2 improved (P value < 0.001), whereas in group B, only the RR improved (P value < 0.001), and SpO2 improvement was not significant with SOC-only treatment. All the parameters such as Hb in groups A and B were significant; WBC in groups A and B was significant; and CRP was significant in groups A and B, but the rest of the parameters such as NLR, SF, D-dimer assay, and LDH showed a significant improvement in group A compared with group B (postartesunate treatment), which suggests that artesunate may help reduce the inflammatory markers. We did not see CT imaging values improvement. Posttreatment, we focused on the clinical and laboratory parameters. The average high resolution computed tomography (HRCT) score on 95% confidence interval (CI) pre-to-artesunate treatment was 13.8–15.6 in group A and the 95% CI value in group B pre-to-artesunate treatment was 12.1 ± 14.4.

The length of the stay in the hospital was 13.3 ± 4.8 days in case A and 21.3 ± 9.1 days for the control group (Lin et al.’s study). The average stay of our patients in COVID general ward (CGW) in group A was 8.92 ± 2.32 (mean ± SD) and in group B was 9.14 ± 2.93; in HDU, 6 ± 3 in group A and 6 ± 2 in group B; and in ICU, 7 ± 4 in group A and 7 ± 4 in group B, which was nonsignificant in both the groups but was significantly reduced in our study as compared to Lin et al.’s study.

Faster progression to non-invasive ventilation and invasive ventilation in group B in our study (P < 0.05) are more significant than in group A because injection artesunate was not received in group B in addition to SOC. Patients with moderate and severe ARDS were seen in both groups; there was no significant difference in PaO2 and FiO2 ratios.

The overall outcome in group A where recovery was 93.8% and death was 6.2% (four patients) as compared to group B where recovery was 72.3% and death was 27.7% (18 patients) is significant. The chi-square test and P value of 10,724 and 0.001, respectively are signs indicating that the proportion of death is significantly more in cases where only SOC treatment is given. This study is comparable to Lin et al. study where patients recovered in the intervention group more than in the control group.


  Conclusion Top


Although this study showed that artesunate has a good effect on patients with new COVID-19 pneumonia, its antiviral mechanisms are diverse and its targets for different diseases are different. The mechanism of action of artesunate still needs to be further explored. intravenous artesunate was given to all the patients in the intervention group of 65 patients and compared to the control group. Artesunate helped by controlling immune hyperactivation. The clinical improvement was demonstrated by the reduction of inflammatory markers, and the weaning of oxygen. Artesunate injections were well tolerated by the patients when administered in the early phase of the inflammatory cascade and are an efficient therapeutic option for moderate and severe cases of COVID-19 ARDS.

Limitations

This is a single-center, observational comparative study done in a tertiary healthcare center, and artesunate needs to be still explored.

Acknowledgements

We are grateful for the support of Dr. Sameer S. Kadam, Dr. Sudhirchandra N. Kadam, Dr. Virendra J. Mahadik (Hospital Director, MGM Hospital and Research Centre, CBD Belapur, Navi Mumbai), and Ms. Jayalaxmi Shinde (medical writer), and I thank the unprecedented support of the General and Emergency Department of Medicine, Residents, Duty Medical Officers, the Casualty Medical Officers, the administration, the paramedical staff, the other department working in COVID, the healthcare providers of the hospital, and gratitude toward the patients who participated in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Ethical consideration

The ethical approval has been provided by the Healing Hands Independent Ethics Committee, Healing Hand Clinic, Pune 411001, Maharashtra, India; protocol ID: TARDS/HEC/06/2020 dated 20 July 2020 for performing the present research work.



 
  References Top

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Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in china. Nature 2020;579:265-9.  Back to cited text no. 1
    
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Kobia F, Gitaka J COVID-19: Are Africa’s diagnostic challenges blunting response effectiveness? AAS Open Res 2020;3:4.  Back to cited text no. 2
    
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Izoulet M Countries which primarily use antimalarial drugs as COVID-19 treatment see slower dynamic of daily deaths. Available from: http://dx.doi.org/10.2139/ssrn.3575899. [Last accessed on Sep 15, 2022].  Back to cited text no. 3
    
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Gurung AB, Ali MA, Lee J, Farah MA, Al-Anazi KM, Al-Hemaid F Artesunate induces substantial topological alterations in the SARS-CoV-2 Nsp1 protein structure. J King Saud Univ Sci2022:101810. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722475/.  Back to cited text no. 4
    
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Pradhan B, Nanda BC, Pradhan G Artesunate: An artemisinin derivative having antiviral properties with multiple pleotropic effects is a perfect potential agent for the treatment of symptomatic COVID-19 infection and related hyper inflammation states. J Med Sci Clin Res 2020;8:215-25.  Back to cited text no. 5
    
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Coghi P, Yang LJ, Ng JPL, Haynes RK, Memo M, Gianoncelli A, et al. A drug repurposing approach for antimalarials interfering with SARS-CoV-2 spike protein receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2). Pharmaceuticals (Basel) 2021;14:954.  Back to cited text no. 6
    
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Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, et al. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomized and controlled trial. Int J Antimicrob Agents 2021;57:106216.  Back to cited text no. 7
    
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Lin Y, Wu F, Xie Z, Song X, Zhu Q, Wei J, et al. [Clinical study of artesunate in the treatment of coronavirus disease 2019]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2020;32:417-20.  Back to cited text no. 8
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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