Highlights
-
•
Severe COVID-19 is associated with increased plasma concentrations of IL-6.
-
•
Tocilizumab, an interleukin-6 inhibitor, might alleviate the cytokine storm.
-
•
Tocilizumab treated group has better clinical outcome, laboratory results, and swab conversion.
-
•
The benefit from tocilizumab is more significant in severe COVID-19 patients.
-
•
Therefore, tocilizumab might be one of the promising therapies for severe COVID-19.
Keywords: ARDS, COVID-19, IL-6, Cytokine storm, Tocilizumab
Abbreviations: IL-6, interleukin 6; WBC, white blood cell; NLR, neutrophil-lymphocyte-ratio; CRP, C-reactive protein; SpO2, oxygen saturation; ICU, intensive care unit; MODS, multiple organ dysfunction syndrome; LDH, lactate dehydrogenase; RT-PCR, reverse transcription polymerase chain reaction; BMI, body mass index; RDW, red cell distribution width; ESR, erythrocyte sedimentation rate; BUN, blood urea nitrogen
Abstract
COVID-19 is a public health emergency of international concern with millions confirmed cases globally including in Indonesia with more than two hundred thousand confirmed cases to date COVID-19. (1) COVID-19 has wide clinical manifestation ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitates mechanical ventilation and support in an ICU, to MODS. (2) Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease. (3)–(5) Severe COVID-19 is associated with increased plasma concentrations of IL-6, resulting in cytokine storm. (6) Tocilizumab, an interleukin-6 inhibitor, might alleviates the cytokine storm, prevents significant lungs and organs damage, thus improving clinical outcomes. (7) Therefore, tocilizumab, might be one of the promising therapies for severe COVID-19. (8) However there were limited studies regarding the efficacy in COVID-19 patients, especially with control group. We would like to report our experience in using tocilizumab as treatment in severe COVID-19 patients in Indonesia, which is the first in Indonesia to the best of our knowledge.
1. Introduction
COVID-19 is a public health emergency of international concern with millions of confirmed cases globally, including in Indonesia, with more than five hundred thousand confirmed cases to date [1]. COVID-19 has wide clinical manifestations, ranging from asymptomatic acute respiratory illness and respiratory failure that necessitates mechanical ventilation and support in an ICU to MODS [2]. Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease [3], [4], [5]. Severe COVID-19 is associated with increased plasma concentrations of interleukin 6 (IL-6), resulting in cytokine storms [6]. Tocilizumab, an IL-6 inhibitor, might alleviate cytokine storms and prevent significant lung and organ damage, thus improving clinical outcomes [7]. Therefore, tocilizumab might be a promising therapy for severe COVID-19 [8]. However, there were limited studies regarding the efficacy in COVID-19 patients, especially with control groups. Most of the studies regarding tocilizumab’s effects were conducted in Europe and the US, with China as the only country in Asia. This study was conducted in Indonesia, which is the fourth most populous country in the world and the third in Asia, with a population of 255.46 million people. Therefore, this population helps describe the characteristics of patients with COVID-19 in Southeast Asia and Asia. We would like to report our experience of using tocilizumab as a treatment in severe COVID-19 patients in Indonesia; to the best of our knowledge, this is the first such report in Indonesia.
2. Methods
This retrospective cohort study was approved by the Siloam Hospital ethical committee with ethical clearance number 391/SHLV-HA/VI/2020. We included 30 patients in Siloam Hospital Kelapa Dua with severe to critical manifestations according to WHO severity classifications. Day one (D1) in the study was used to describe the first day of tocilizumab administration in the case group and the first day of hospital admission in the control group. The aim of this study was to comprehend the characteristic differences between tocilizumab-treated and control groups before and after treatment.
3. Results
We reported the clinical characteristics and outcomes of 30 severe COVID-19 patients, including 14 who received tocilizumab therapy and 16 patients who did not. The characteristics of the subjects are described in Table 1, Table 2 . Our study showed that in comparison to the control group, after 5 days of tocilizumab treatment, patients had lower body temperatures and respiratory rates. More patients experienced negative swab conversion and had lower WBC and segment neutrophil counts with higher lymphocyte counts, resulting in a lower NLR. Random blood glucose and CRP levels were lower, and D-dimer levels were slightly higher [9], [10]. However, our study showed that patients treated with tocilizumab had lower SpO2 than in previous studies [9], [10]. In addition, male sex was also associated with higher mortality [11]. BMI and an increased number of comorbidities were associated with higher mortality in both treatment groups [3]. The respiratory rate on D5 appeared to be higher in nonsurvivors than in survivors in both treatment groups [12]. Swab conversion to a negative outcome and on day 5 appeared to be higher in survivors than in nonsurvivors in both treatment groups. Higher WBC count, segment neutrophils, NLR, random blood glucose, CRP, D-dimer, and BUN on day 5 were associated with higher mortality in both treatment groups [12], [13], [14], [15], [16], [17]. Lower lymphocyte count, absolute lymphocyte count, platelet count, and SpO2 on day 5 were associated with higher mortality in both treatment groups [18], [16], [19], [20].
Table 1.
Baseline Characteristics of overall, tocilizumab treated group, and control group.
| Overall (n = 30) | Tocilizumab (n = 14) | No Tocilizumab (n = 16) | P-value | |
|---|---|---|---|---|
| Baseline Characteristics | ||||
| Age | 58.0 ± 10.945 | 58.71 ± 10.09 | 57.38 ± 11.93 | 0.744 |
| Gender | 0.657 | |||
| Male | 24 (80%) | 12 (75%) | 12 (86%) | |
| Female | 6 (20%) | 4 (25%) | 2 (14%) | |
| Weight (kg) | 71.7 ± 11.27 | 70.92 ± 9.36 | 72.31 ± 12.99 | 0.744 |
| Height (cm) | 170(160–180) | 170 (160–178) | 170 (160–180) | 0.481 |
| Body mass index (BMI) (Mean ± SD) | 25.13 ± 0.62 | 24.69 ± 2.72 | 25.51 ± 3.93 | 0.522 |
| Swab | ||||
| Positive | 30 (100%) | 14 (100%) | 16 (100%) | |
| Negative | 0 (0%) | 0 (0%) | 0 (0%) | |
| Comorbid Conditions | ||||
| Hypertension | 12 (40%) | 6 (42.9%) | 6 (37.5%) | 0.765 |
| Dyslipidemia | 1 (3.3%) | 1 (7.1%) | 0 (0.0%) | 0.467 |
| Diabetes Mellitus | 9 (30%) | 4 (28.6%) | 5 (31.3%) | 1.000 |
| Coronary Artery Disease | 3 (10% | 2 (14.3%) | 1 (6.3%) | 0.586 |
| Valve Disease | 1 (3.3%) | 1 (7.1%) | 0 (0.0%) | 0.467 |
| Arrhythmia | 1 (3.3%) | 0 (0.00%) | 1 (6.3%) | 1.000 |
| Hyperthyroid | 1 (3.3%) | 0 (0.00%) | 1 (6.3%) | 1.000 |
| Stroke | 1 (3.3%) | 0 (0.00%) | 1 (6.3%) | 1.000 |
| Autoimmune Disease | 1 (3.3%) | 1 (7.1%) | 0 (0.0%) | 0.467 |
| Number of Comoribidities | ||||
| No Comorbidity | 12(40%) | 6 (42.9%) | 6 (37.5%) | 0.747 |
| Single Comorbidity | 9 (30%) | 3 (21.4%) | 6 (37.5%) | |
| Two Comorbidities | 6 (20%) | 3 (21.4%) | 3 (18.8%) | |
| Three Comorbidities | 2 (10%) | 2 (14.3%) | 1 (6.3%) | |
| Presenting symptoms | ||||
| Fever | 22 (73.3%) | 10 (71.4%) | 12 (75%) | 1.000 |
| Shortness of Breath | 19 (63.3%) | 7 (50%) | 12 (75%) | 0.299 |
| Cough | 19 (63.3%) | 9 (64.2%) | 10 (62.5%) | 1.000 |
| Rhinorrhea | 1 (3.3%) | 1 (7.1%) | 0 (0.0%) | 0.467 |
| Sore Throat | 4 (13.3%) | 0 (0%) | 4 (25%) | 0.103 |
| Anosmia | 2 (6.7%) | 2 (14.3%) | 0 (0.0%) | 0.209 |
| Dysgeusia | 2 (6.7%) | 2 (14.3%) | 0 (0.0%) | 0.209 |
| Gastrointestinal | 6 (20%) | 4 (28.6%) | 2 (12.5%) | 0.378 |
| Other | 9 (30%) | 6 (42.9%) | 3 (18.8%) | 0.236 |
| Vital Signs | ||||
| Temperature D1 | 337.3 ± 0.63 | 37.31 ± 0.61 | 37.29 ± 0.67 | 0.931 |
| Respiratory Rate D1 | 24 (18–42) | 24 (20–36) | 25.5 (18–42) | 0.202 |
| Baseline Laboratory Values on D1 | ||||
| WBC (10^3/ul) | 7.41 (2.52–20.5) | 7.41 (4.29–20.5) | 7.44 (2.52–19.36) | 0.934 |
| Band Neutrophil (%) | 4 (0–75) | 4 (2–6) | 4 (0–75) | 0.812 |
| Segment Neutrophil (%) | 77 (8–88) | 76.50 (50–88) | 77.5 (8.4–88) | 0.917 |
| Lymphocyte (%) | 10.15 (0.3–38.0) | 11.5 (4.9–38) | 8.5 (0.3–36) | 0.308 |
| Neutrophil Lymphocyte Ratio (NLR) | 6.67 (0.42–304.00) | 6.67 (1.39–17.94) | 6.05 (0.42–304) | 0.983 |
| Absolute Lymphocyte Count (10^9/L) | 981.49 ± 526.39 | 1122.63 ± 563.73 | 857.99 ± 474.79 | 0.174 |
| Platelet Count (10^3/ul) | 201.5 (85.0–443.0) | 213 (153–441) | 190 (85–443) | 0.418 |
| RDW (%) | 12.85 (11.1–23.9) | 12.65 (11.6–13.2) | 13.0 (11.1–23.9) | 0.103 |
| Random Blood Glucose (mg/dl) | 145 (82.0–395.0) | 145 (104–256) | 165 (82–395) | 0.635 |
| Erythrocyte Sedimentation Rate (seconds) | 30.5 (3.0–107.0) | 23.5 (14–107) | 41 (3–92) | 0.626 |
| C-Reactive Protein (CRP) (mg/L) | 121.8 ± 86.32 | 114.54 ± 75.15 | 128.03 ± 97.26 | 0.700 |
| D-dimer (ug/mL) | 2.11 (0.27–35.2) | 0.90 (0.27–35.2) | 2.16 (1.52–35.2) | 0.209 |
| SGOT (U/L) | 48.00 (18.00–236.00) | 53.5 (21–236) | 44.5 (18–71) | 0.204 |
| SGPT (U/L) | 45.00 (15.00–236.00) | 47.5 (18–236) | 33 (15–110) | 0.231 |
| Lactate Dehydrogenase (U/L) | 706.87 ± 312.98 | 667.83 ± 398.06 | 732.89 ± 265.48 | 0.709 |
| BUN | 13.12 ± 2.96 (n = 21) | 13.49 ± 3.21 (n = 8) | 12.89 ± 2.91 (n = 13) | 0.661 |
| Creatinine (mg/dL) | 0.85 ± 0.16 (n = 24) | 0.87 ± 0.19 (n = 10) | 0.83 ± 0.13 (n = 14) | 0.639 |
| O2 Saturation (%) | 95.7 (65.7–98.5) | 94.25 (65.7–96.2) | 96.4 (84.5–98.5) | 0.088 |
| PO2 (mmHg) | 71.60 ± 18.86 | 65.41 ± 16.91 | 75.31 ± 19.53 | 0.220 |
| Chest Radiological Abnormality | ||||
| Consolidation and Ground Glass Opacities (GGO) | 30 (100%) | 14 (100%) | 16 (100%) | |
| Bilateral Involvement | 30 (100%) | 14 (100%) | 16 (100%) | |
Table 2.
Characteristics of the survivor and non-survivor in tocilizumab treated group and control group on the fifth day of observation (D5).
| Tocilizumab (n-14) |
No Tocilizumab (n-16) |
|||
|---|---|---|---|---|
| Survive (n = 10) | Death (n = 4) | Survive (n = 10) | Death (n = 6) | |
| Age (Mean ± SD) | 58.90 ± 9.972 | 58.25 ± 11.96 | 59.30 ± 11.53 | 54.17 ± 12.95 |
| Gender | ||||
| Male | 9 (75%) | 3 (25%) | 6 (50%) | 6 (50%) |
| Female | 1 (50%) | 1 (50%) | 4 (100%) | 0 (0%) |
| BMI (Mean ± SD) | 24.36 ± 3.01 | 25.54 ± 1.93 | 25.03 ± 3.55 | 26.30 ± 4.75 |
| Number of Comoribidities | ||||
| No Comorbidity | 4 (40%) | 2 (50%) | 3 (30%) | 3 (50%) |
| Single Comorbidity | 2 (20%) | 1 (25%) | 5 (50%) | 1 (16.7%) |
| Two Comorbidities | 3 (30%) | 0 (0%) | 1 (10%) | 1 (33%) |
| Three Comorbidities | 1 (10%) | 1 (25%) | 1 (10%) | 0 (0%) |
| Temperature Day 5 | 36.50 (36.00–38.00) | 36.85 ± 0.45 | 36.67 ± S0.38 | 36.90 (36.5–38.9) |
| Respiratory Rate Day 5 Tocilizumab Treatment | 20 (16–25) | 25.25 ± 6.60 | 20.80 ± 2.30 | 32.17 ± 8.50 |
| Swab D5 | ||||
| Positive | 4 (10%) | 2 (50%) | 9 (90%) | 6 (100%) |
| Negative | 6 (60%) | 2 (50%) | 1 (10%) | 0 (0%) |
| Swab Outcome | ||||
| Positive | 0 (0%) | 3 (75%) | 1 (10%) | 3 (50%) |
| Negative | 10 (100%) | 1 (25%) | 9 (90%) | 3 (50%) |
| Laboratory Results Day 5 | ||||
| White Blood Cell (10^3/ul) | 4.94 (3.64–22.65) | 11.85 ± 3.37 | 8.47 ± 4.47 | 20.21 (10.03–64.54) |
| Band Neutrophil (%) | 3.00 (2.00–6.00) | 4.25 ± 1.26 | 4.10 ± 1.37 | 4.00 (4.00–6.00) |
| Segment Neutrophil (%) | 54.00 ± 17.99 | 81.00 ± 6.16 | 68.00 ± 13.49 | 87.50 (15.00–91.00) |
| Lymphocyte (%) | 26.78 ± 14.53 | 10.00 ± 2.83 | 15.80 ± 10.28 | 4.50 (2.00–81.00) |
| Neutrophil Lymphocyte Ratio (NLR) | 1.68 (0.38–16.60) | 8.89 ± 3.75 | 6.69 ± 7.26 | 21.94 ± 16.17 |
| Absolute Lymphocyte Count (10^9/L) | 1440.46 ± 334.64 | 981.20 (870.60–1794.00) | 1071.89 ± 574.48 | 662.40 (489.60–52277.40) |
| Platelet Count (10^3/ul) | 338.11 ± 58.30 | 249.00 ± 96.75 | 342.90 ± 96.60 | 204.00 ± 48.66 |
| Red Cell Distribution Width (RDW) (%) | 13.49 ± 0.97 | 13.95 ± 1.24 | 14.20 ± 3.44 | 13.25 (12.10–17.00) |
| Random Blood Glucose (mg/dl) | 101.50 (0.86–117.00) | 155.33 ± 86.12 | 117.00 ± 25.46 | 162.00 ± 32.91 |
| Erythrocyte Sedimentation Rate (seconds) | 13.89 ± 10.42 | 32.25 ± 29.97 | 44.50 ± 29.76 | 31.00 ± 30.09 |
| C-Reactive Protein (CRP) (mg/L) | 2.10 (0–17) | 47.65 ± 48.95 | 13.05 ± 11.68 | 271.00 (120–422 |
| D-dimer (ug/mL) | 4.54 ± 2.71 | 34.84 (16.01–35.20) | 3.53 (1.80–35.00) | 32.35 (6.83–36.50) |
| SGOT (U/L) | 50.20 ± 26.71 | 76.75 ± 28.39 | 53.75 ± 37.62 | 41.00 ± 12.08 |
| SGPT (U/L) | 69.00 ± 36.83 | 61.50 ± 28.86 | 37.25 ± 28.11 | 34.50 ± 24.71 |
| Blood Urea Nitrogen (BUN) | 33.44 (21.70–45.17) | 44.11 ± 13.83 | 15.73 ± 7.64 | 22.70 (14.40–156.20) |
| Creatinine (mg/dL) | 0.82 ± 0.12 | 1.15 ± 0.91 | 0.82 ± 0.27 | 0.80 (0.60–11.44) |
| O2 Saturation (%) | 96.93 ± 1.72 | 95.67 ± 1.53 | 98.96 ± 0.22 | 96.00 (80.2–99.30) |
4. Discussion
A previously published meta-analysis showed that COVID-19 patients treated with tocilizumab had reduced mortality, less need for mechanical ventilation, improved respiratory function, rapid defervescence, and successful discharge compared with the control group, especially when the subgroup analysis was restricted to studies that only included patients with severe COVID‐19 based on the clinical picture and laboratory parameters [21], [22], [23]. Our study is consistent with these studies, and the samples were restricted to severe COVID-19 patients. This is important, as healthcare providers need to identify severe COVID-19 patients to obtain the maximum benefit from tocilizumab. However, an ongoing randomized controlled COVACTA trial failed to show improved clinical status and mortality, although tocilizumab-treated patients spent roughly a week less in the hospital than the control group. This might be caused by different patients having different durations and severities of illness and previous treatments when they were treated with tocilizumab and assessed on the same day [24]. This might cause the study to miss clinically relevant differences between patient groups; therefore, it is important to stratify patients by clinical signs of hyperinflammation, divide them into subpopulations with different illness characteristics, and set the optimal timing to start tocilizumab treatment. To date, there is no clear optimal time to start this drug; however, previous studies recommended starting tocilizumab treatment during the severe phase of the disease, i.e., the beginning of inflammation, at the first signs of decreasing O2 saturation [25], when the patient has a high risk of mechanical ventilation and death [26] and an increased requirement for oxygen support, with progression of thoracic CT and elevation of inflammation markers, including IL-6, CRP, ferritin, and D-dimer, and decreased % lymphocytes [27]. The limitations of this study include its retrospective nature and the lack of determination of serum IL-6 levels before and after tocilizumab therapy.
5. Conclusions
Our study showed that the tocilizumab-treated group had better clinical outcomes, laboratory results, and swab conversion to negative than the control group. Further study with measurement of IL-6 is recommended.
Declarations
Ethics approval and consent to participate: This study was approved by the Siloam Hospital ethical committee with ethical clearance number 391/SHLV-HA/VI/2020.
Consent for publication
Not applicable.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Funding
None.
CRediT authorship contribution statement
Allen Widysanto: Data curation, Investigation, Project administration, Resources, Supervision, Writing - review & editing. Andree Kurniawan: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing - review & editing. Nata Pratama Hardjo Lugito: Data curation, Formal analysis, Investigation, Methodology, Project Administration, Supervision, Writing - review & editing. Mira Yuniarti: Data curation, Formal analysis, Investigation, Resources, Supervision, Validation, Writing - review & editing. Catherine Gunawan: Data curation, Formal analysis, Resources, Software, Visualization, Writing - original draft. Angela: Data curation, Formal analysis, Resources, Software, Visualization, Writing - original draft. Jessica Wiryanto: Data curation, Formal analysis, Resources, Software, Visualization, Writing - original draft. Levinna: Data curation, Formal analysis, Resources, Software, Visualization, Writing - original draft. Tasya Meidy Pradhana: Data curation, Formal analysis, Resources, Software, Visualization, Writing - original draft.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Not applicable.
References
- 1.Sun J., He W.T., Wang L., Lai A., Ji X., Zhai X. COVID-19: epidemiology, evolution, and cross-disciplinary perspectives. Trends Mol. Med. 2020;26(5):483–495. doi: 10.1016/j.molmed.2020.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Cascella M., Rajnik M., Cuomo A., Dulebohn S.C., Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19) StatPearls. 2020 [PubMed] [Google Scholar]
- 3.Zhang F., Xiong Y., Wei Y., Hu Y., Wang F., Li G. Obesity predisposes to the risk of higher mortality in young COVID-19 patients. J. Med. Virol. 2020;92(11):2536–2542. doi: 10.1002/jmv.26039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hariyanto T.I., Kurniawan A. Dyslipidemia is associated with severe coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndr. 2020 doi: 10.1016/j.dsx.2020.07.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hariyanto T.I., Kurniawan A. Thyroid disease is associated with severe coronavirus disease 2019 (COVID-19) infection. Diabetes Metab. Syndr. 2020;14(5):1429–1430. doi: 10.1016/j.dsx.2020.07.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Alattar R., Ibrahim T.B.H., Shaar S.H., Abdalla S., Shukri K., Daghfal J.N. Tocilizumab for the treatment of severe coronavirus disease 2019. J. Med. Virol. 2020 doi: 10.1002/jmv.25964. [Online ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Xu X., Han M., Li T., Sun W., Wang D., Fu B. Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl. Acad. Sci. USA. 2020;117(20):10970–10975. doi: 10.1073/pnas.2005615117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Morena V., Milazzo L., Oreni L., Bestetti G., Fossali T., Bassoli C. Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy. Eur. J. Intern. Med. 2020;76:36–42. doi: 10.1016/j.ejim.2020.05.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Somers E.C., Eschenauer G.A., Troost J.P., Golob J.L., Gandhi T.N., Wang L. Tocilizumab for treatment of mechanically ventilated patients with COVID-1. Clin. Infect Dis. 2020 doi: 10.1093/cid/ciaa954. [Online ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hariyanto T.I., Kurniawan A. Tocilizumab administration is associated with reduction in biomarkers of coronavirus disease 2019 (COVID-19) infection. J. Med. Virol. 2020 doi: 10.1002/jmv.26698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Jin J.M., Bai P., He W., Wu F., Liu X.F., Han D.M. Gender differences in patients with COVID-19: focus on severity and mortality. Front. Public Heal. 2020;8:152. doi: 10.3389/fpubh.2020.00152. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Du R.H., Liang L.R., Yang C.Q., Wang W., Cao T.Z., Li M. Predictors of mortality for patients with COVID-19 pneumonia caused by SARSCoV- 2: a prospective cohort study. Eur. Respir. J. 2020;55(5):2000524. doi: 10.1183/13993003.00524-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Liu Y., Du X., Chen J., Jin Y., Peng L., Wang H.H.X. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J. Infect. 2020;81(1):e6–e12. doi: 10.1016/j.jinf.2020.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sardu C., D’Onofrio N., Balestrieri M.L., Barbieri M., Rizzo M.R., Messina V. Outcomes in patients with hyperglycemia affected by COVID-19: can we do more on glycemic control? Diabetes Care. 2020;43(7):1408–1415. doi: 10.2337/dc20-0723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Terpos E., Ntanasis-Stathopoulos I., Elalamy I., Kastritis E., Sergentanis T.N., Politou M. Hematological findings and complications of COVID-19. Am. J. Hematol. 2020;95(7):834–847. doi: 10.1002/ajh.25829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Lippi G., Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin. Chem. Lab. Med. 2020;58(7):1131–1134. doi: 10.1515/cclm-2020-0198. [DOI] [PubMed] [Google Scholar]
- 17.Cheng Y., Luo R., Wang K., Zhang M., Wang Z., Dong L. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829–838. doi: 10.1016/j.kint.2020.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tan L., Wang Q., Zhang D., Ding J., Huang Q., Tang Y.Q. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Trans. Target. Ther. 2020;5(1):33. doi: 10.1038/s41392-020-0148-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Yang X., Yang Q., Wang Y., Wu Y., Xu J., Yu Y. Thrombocytopenia and its association with mortality in patients with COVID-19. J. Thromb. Haemost. 2020;18(6):1469–1472. doi: 10.1111/jth.14848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Xie J., Covassin N., Fan Z., Singh P., Gao W., Li G. Association between hypoxemia and mortality in patients with COVID-19. Mayo Clin. Proc. 2020;95(6):1138–1147. doi: 10.1016/j.mayocp.2020.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Aziz M., Haghbin H., Abu Sitta E., Nawras Y., Fatima R., Sharma S. Efficacy of tocilizumab in COVID-19: A systematic review and meta-analysis. J. Med. Virol. 2020 doi: 10.1002/jmv.26509. [Online ahead of print] [DOI] [PubMed] [Google Scholar]
- 22.Malgie J., Schoones J.W., Pijls B.G. Decreased mortality in coronavirus disease 2019 patients treated with tocilizumab: a rapid systematic review and meta-analysis of observational studies. Clin. Infect Dis. 2020 doi: 10.1093/cid/ciaa1445. [Online ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sanders J.M., Monogue M.L., Jodlowski T.Z., Cutrell J.B. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA – J. Am. Med. Assoc. 2020;323(18):1824–1836. doi: 10.1001/jama.2020.6019. [DOI] [PubMed] [Google Scholar]
- 24.Furlow B. COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. LancetRheumatol. 2020;2(10):E592. doi: 10.1016/S2665-9913(20)30313-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Samaee H., Mohsenzadegan M., Ala S., Maroufi S.S., Moradimajd P. Tocilizumab for treatment patients with COVID-19: Recommended medication for novel disease. Int. Immunopharmacol. 2020;89 doi: 10.1016/j.intimp.2020.107018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Guaraldi G., Meschiari M., Cozzi-Lepri A., Milic J., Tonelli R., Menozzi M. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. LancetRheumatol. 2020;2(8):E474–E484. doi: 10.1016/S2665-9913(20)30173-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Keske Ş., Tekin S., Sait B., İrkören P., Kapmaz M., Çimen C. Appropriate use of tocilizumab in COVID-19 infection. Int. J. Infect. Dis. 2020;99:338–343. doi: 10.1016/j.ijid.2020.07.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.