Startseite Additional baricitinib loading dose improves clinical outcome in COVID-19
Artikel Open Access

Additional baricitinib loading dose improves clinical outcome in COVID-19

  • Md Jahidul Hasan ORCID logo EMAIL logo , Raihan Rabbani ORCID logo , Ahmad Mursel Anam ORCID logo und Shihan Mahmud Redwanul Huq ORCID logo
Veröffentlicht/Copyright: 5. Dezember 2020

Abstract

Pneumonia associated with coronavirus disease 2019 (COVID-19) has been accounted for high mortality rate in severe COVID-19 worldwide, and additional serious scarcity of standard and effective anti-inflammatory drug in COVID-19 pneumonia management is a big challenge. Baricitinib, a Janus kinase (JAK) inhibitor, is a promising drug in COVID-19 pneumonia. This study aims to compare the clinical outcome of moderate-to-severe COVID-19 pneumonia treated with baricitinib with or without a loading dose. This prospective case-control study enrolled 37 adult patients where 17 patients (control) received baricitinib at 4 mg oral daily dose and 20 patients (case) received an additional single 8 mg oral loading dose. The median day to gain blood oxygen saturation level ≥95% (in room air) and return in normal breathing function were lower in case group than the control group. The requirement of intensive care unit and mechanical ventilation support was higher in the control group than in the case group [29.4% (N = 17)/10% (N = 20), P < 0.05; 11.8% (N = 17)/5% (N = 20), P > 0.05), respectively]. Thus, an additional loading dose of baricitinib revealed better clinical outcome of patients with COVID-19 pneumonia.

1 Introduction

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first introduces to the world as an outbreak in Wuhan, China, in December 2019, was declared as a “global pandemic” by World Health Organization (WHO) on March 11, 2020 [1]. As of July 11, 2020, a total of 12,322,395 confirmed COVID-19 cases and 5,56,335 related deaths have been reported worldwide [2]. Acute respiratory distress syndrome (ARDS) due to hyperinflammation in the lungs and ultimately, respiratory failure from COVID-19 pneumonia has been reported as the prime cause of COVID-19-associated mortality [3,4] ranging from 1% to more than 7% [5]. Cytokine storm due to the overproduction of proinflammatory cytokines, including interleukin (IL)-6, IL-7, IL-8, etc. in critically ill patients with COVID-19 is a critical phase of the disease that may lead to acute respiratory failure or multiple organ dysfunction [6,7]. Therefore, early detection of the COVID-19 infection and prompt management to suppress the cytokine storm is equally important in patients with COVID-19 [8].

IL-6 plays a pivotal role in exacerbating the cytokine storm as a part of host’s innate immune response mechanism that is mostly activated by IL-1 beta, tumor necrosis factor (TNF-alfa), Toll-like receptors (TLRs), prostaglandins, adipokines, and other cytokines [9]. High levels of IL-6 and IL-8 were detected in patients with severe SARS-CoV-1 infection, where high-magnitude of innate inflammatory response in correspondence to SARS-CoV-1 invasion in the host’s respiratory tract was extensively induced by IL-6 [10]. Similarly, high plasma level of IL-6 along with other proinflammatory cytokines, such as IL-2, IL-7, IL-8, IL-10, macrophage inflammatory protein (MIP1A), monocyte chemoattractant protein (MCP1), and TNF-alfa have been found in critically ill patients with COVID-19 and these cytokines significantly contribute in the severity of the disease [5,6,8].

Receptor-mediated endocytosis is a process through which most viruses penetrate the host cells. AP2-associated protein kinase 1 (AAK1) is a regulator of this endocytosis and inactivation of this enzyme interrupts the entry of the virus into the host cells [11]. Baricitinib, a janus kinase (JAK) inhibitor, is an approved drug for rheumatoid arthritis (RA). In effect, baricitinib specifically prevents the expression of proinflammatory cytokines, including IL-6 by inhibiting JAK. Interestingly, among the six highly potent inhibitors of AAK1, baricitinib is one of them which works by binding with the cyclin G-associated kinase that disrupts endocytosis, competently leading to a reduction in viral load [11,12]. Nowadays, baricitinib at a 4 mg once daily oral dose has been highlighted as a promising investigational anti-inflammatory (IL-6 inhibitor) drug therapy in patients with COVID-19 pneumonia [4,11,12,14]. The pharmacokinetics, pharmacodynamics, and safety data of baricitinib at a 4 mg daily dose in COVID-19 are still under investigation and to date, no standard dosing of baricitinib in COVID-19 has yet been established worldwide [11,12,13,14,15]. The objective of this study was to compare the clinical outcomes of patients with moderate-to-severe COVID-19 pneumonia treated with baricitinib at a 4 mg once daily oral dose with or without a high oral loading dose.

2 Materials and methods

2.1 Study design and data collection

This prospective case-control study was conducted in the “COVID-19 Unit” of Square Hospital Ltd, Dhaka, Bangladesh, on 37 adults (≥18 years) with moderate to severe COVID-19 symptoms admitted to this hospital from May 15 to June 13, 2020. All confirmed COVID-19 patients in this study were admitted to “COVID-19 unit” through a two-step triage system in the emergency department of the hospital. COVID-19 infection was confirmed in all patients by a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay (instrument/device: Rotor Gene-Q/Cobas z480, and QIAGEN kits for real-time PCR, QIAGEN GmbH, Germany) of two specimens (nasal and oral swabs) in all patients collected by four trained phlebotomists following the hospital’s standard protocol of COVID-19 sample collection. All the patients were Bangladeshi citizens and older than 18 years. A combined dose of dexamethasone (corticosteroid) (10–20 mg/day, intravenously) and baricitinib was started on day 1 of admission for down-regulating the inflammatory processes in the lungs. Seventeen (N) patients in “no loading dose (LND) group” (control) received baricitinib 4 mg daily orally for 2 weeks, whereas 20 (N) patients in “loading dose (LD) group” (case) received baricitinib 8 mg single dose orally as a loading dose on day 1 and then 4 mg daily orally from days 2 to 14. The dose of baricitinib was taken on an empty stomach. Simple random sampling method was used in this study. The local brand “Baritor 2” (baricitinib 2 mg tablet) of Square Pharmaceuticals Ltd, Bangladesh, was used in this study. Data of this study were collected from online patient-wise data archive of this hospital and directly from patient-prescriptions on daily basis by participating doctors in COVID-19 unit. Adverse events were routinely monitored and reported by two clinical pharmacists.

The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Declaration of Helsinki, and has been approved by the Research Ethics Committee, Square Hospitals Ltd, Dhaka, Bangladesh (no. 2004SH-OR024) on April 11, 2020. Written consent was taken from all participants in this study.

2.2 Inclusion criteria

Sample inclusion criteria were as follows:

  1. presence of SARS-CoV 2 in the nasal/oral swabs

  2. no previous history of COVID-19 infection

  3. having at least 3 of the following symptoms: fever, cough, tiredness, sore throat, anosmia, respiratory distress, and myalgia

  4. evidence of pneumonia in radiological diagnosis

2.3 Exclusion criteria

Sample exclusion criteria were as follows:

  1. more than 10 days from onset of symptoms

  2. patient with pregnancy

  3. any history of trauma or surgical procedure within the last 3 months of admission

  4. any history of acute/chronic autoimmune disease

  5. evidence of bacterial or fungal coinfection

2.4 Definition of moderate and severe COVID-19 pneumonia

Radiological evidence of bilateral pneumonia with clinical signs (fever, cough, difficulty breathing, tachypnea), no sign of severe stage of pneumonia, SpO2 (peripheral capillary blood oxygen saturation level) ≥90% on room air (RA), and ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) 100–300 mmHg represents moderate COVID-19 pneumonia; radiological evidence of severe pneumonia with clinical signs (fever, cough, difficulty breathing, tachypnea) with at least one of the following signs: respiratory rate >30 breaths/min, severe respiratory distress, and SpO2 < 90% on room air represents severe COVID-19 pneumonia [16]. SpO2 ≥ 95% was considered as the targeted SpO2 in patients in this study. The severity of the disease and the progression of the symptoms of COVID-19 were measured on daily basis by assessing the physical condition of the patients and the laboratory investigations, including hematological tests, tests for liver and kidney functions, inflammation and infection markers, and arterial blood gas test.

2.5 Data analysis

Data were analyzed with SPSS version 22.0 statistical software (SPSS, Chicago, IL, USA). Descriptive statistics were presented through median value and interquartile range (IQR). Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using Mann–Whitney U test. P values ≤ 0.05 were considered statistically significant.

3 Results

The number of male patients in both the groups was higher than the number of female patients with a median age of 52 (IQR: 50.5–62) and 59 (IQR: 49.8–69) in NLD and LD groups, respectively (P = 0.414). Fever [100 (IQR: 100–101.5)/100.5 (IQR: 100–101.75)], dry cough (100%, n = 17/100%, n = 20), generalized weakness (100%, n = 17/100%, n = 20), and sore throat (52.9%, n = 9/60%, n = 12) were significantly common in patients of NLD and LD groups (N = 17/20), respectively. Diabetes, hypertension, cardiovascular disease, bronchial asthma, chronic kidney disease, chronic obstructive pulmonary disease, obesity, malignancy, and Parkinson's disease were found as preexisting chronic diseases in patients with COVID-19 of NLD and LD groups (Table 1). Clinical characteristics, including blood-oxygen saturation profile, respiratory and cardiac functions, hematological components, and infection markers of all the patients in the two groups (NLD and LD) are given in Table 1 and compared, statistically.

Table 1

Baseline demographic, symptoms of COVID-19, comorbidity, and laboratory findings in patients treated with or without a loading dose of baricitinib

Characteristics NLD group (control) (N = 17) LD group (case) (N = 20) P value
Male/female, n (%) 13/4 (76/24) 16/4 (80/20) 0.617
Age (year), median (IQR) 52 (50.5–62) 59 (49.8–69) 0.414
Days from onset of symptoms-to-hospitalization, median (IQR) 7 (4.5–7.5) 6.5 (5–7) 0.185
Fever (°F), median (IQR) 101 (100–101.5) 100.5 (100–101.75) 0.012
Dry cough, n (%) 17 (100) 20 (100) 0.001
Shortness of breath, n (%) 14 (82.4) 16 (80) 0.855
Weakness, n (%) 17 (100) 20 (100) 0.001
Diarrhea, n (%) 3 (17.6) 5 (25) 0.289
Anosmia, n (%) 11 (64.7) 14 (70) 0.516
Sore throat, n (%) 9 (52.9) 12 (60) 0.043
Diabetes, n (%) 14 (82.4) 17 (85) 0.675
Hypertension, n (%) 13 (76.5) 12 (60) 0.043
CVD, n (%) 6 (35.3) 4 (20) 0.052
Bronchial asthma, n (%) 4 (23.5) 6 (30) 0.389
CKD, n (%) 2 (11.8) 3 (15) 0.577
COPD, n (%) 2 (11.8) 3 (15) 0.577
Obesity, n (%) 2 (11.8) 2 (10) 0.740
Malignancy, n (%) 1 (5.9) 3 (15) 0.075
PD, n (%) 0 (0) 2 (10) 0.005
SpO2 (%), median (IQR) 89 (87.5–90) 89.5 (88–90) 0.718
Respiratory rate, (breaths/min), median (IQR) 22 (20.5–24) 23 (21–24) 0.825
PaO2/FiO2 (mmHg), median (IQR) 240 (195.5–263.5) 245 (193.8–262.3) 0.010
Heart rate (beat/min), median (IQR) 98 (85.5–105.5) 94.5 (84.5–113) 0.174
CRP (mg/L), median (IQR) 43.5 (30–220) 77.1 (40.9–211.5) 0.946
Procalcitonin (ng/mL), median (IQR) 0.12 (0.06–0.49) 0.18 (0.07–0.86) 0.062
WBC (K/µL), median (IQR) 6.3 (4.7–10) 8 (6.3–14.3) 0.021
Neutrophils (%), median (IQR) 87.6 (79.4–92.1) 82.5 (76.8–88.1) 0.657
Lymphocytes (%), median (IQR) 13.9 (11.9–15.8) 12.2 (8.2–14.5) 0.006
Platelet (K/µL), median (IQR) 186 (128–255) 175 (133.3–245.3) 0.605
d-Dimer (mg/L FEU), median (IQR) 2.7 (1.7–7.6) 2 (1.5–3.2) 0.018
Serum ferritin (ng/mL), median (IQR) 434 (293.5–543.5) 470 (361.3–604.8) 0.227
LDH ((U/L), median (IQR) 272 (216–404.5) 334 (295–390.5) 0.009
Creatinine (mg/dL), median (IQR) 0.9 (0.8–1) 0.9 (0.7–1.1) 0.210
ALT (U/L), median (IQR) 34 (29–57) 44 (35–54) 0.13
AST (U/L), median (IQR) 35 (25.5–49) 40 (29.5–58.8) 0.349
MEWS, median (IQR) 3 (2–3) 3 (2–3) 0.476

IQR = interquartile range; n = number; % = percentage; °F = grade Fahrenheit; CVD = cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; PD = Parkinson’s disease; SpO2 = peripheral capillary oxygen saturation; min = minute; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; mmHg = millimetre of mercury; CRP = C-reactive protein; mg = milligram; L = liter; FEU = fibrinogen equivalent units; ng = nanogram; WBC = white blood cells; K/µL = thousand cells per micro liter; LDH = lactate dehydrogenase; U/L = units per liter; dL = deciliter; ALT = alanine aminotransferase; AST = aspartate aminotransferase; MEWS = Modified Early Warning Score.

All patients in both the groups tolerated baricitinib therapy well with no mild-to-serious adverse events (AEs) during the study period. No bacterial or fungal or any other opportunistic infections, hepatic or hematological toxicity were observed in the groups.

The median day to reach the targeted SpO2 (≥95% in RA) was less in the LD group (case) [3 (IQR: 2–8)] than that in the NLD group (control) [4 (IQR: 4–5)] (P = 0.180), and the median day to return in normal breathing function was significantly less in the LD group [5 (IQR: 4–5)] than that in the NLD group [8 (IQR: 7–10)]. ICU support was required higher in the NLD group with more requirement of mechanical ventilation support than that in the LD group [29.4% (N = 17)/10% (N = 20), P < 0.05; 11.8% (N = 17)/5% (N = 20), P = 0.141, respectively] (Table 2). The median day of hospitalization was lower in the LD group [12 (IQR: 10–14)] than that in the NLD group [15 (IQR: 9–18.5)] and this was statistically significant. The 30-day all-cause mortality rate was similar in NLD and LD groups [5.9%, n = 1 (N = 17)/5%, n = 1 (N = 20), respectively].

Table 2

Clinical outcomes in patients with COVID-19 treated with baricitinib with or without a loading dose

Parameters NLD group (control) (N = 17) LD group (case) (N = 20) P value
Days required to increase SpO2 ≥ 95% in RA, median (IQR) 4 (4–5) 3 (2–8) 0.180
Days required to stop the need of supplement oxygen, median (IQR) 8 (7–10) 5 (4–5) 0.001
Patients required ICU support, n (%) 5 (29.4) 2 (10) 0.005
Patients intubated on ventilator, n (%) 2 (11.8) 1 (5) 0.141
Length of hospital stay (day), median (IQR) 15 (9–18.5) 12 (10–14) 0.028
30-day mortality, n (%) 1 (5.9) 1 (5) 0.906

NLD = no loading dose; LD = loading dose; SpO2 = peripheral capillary oxygen saturation; RA = rheumatoid arthritis; IQR = interquartile range; ICU = intensive care unit; n = number; % = percentage.

4 Discussion

This study found that a single 8 mg oral loading dose of baricitinib added to its daily 4 mg maintenance dose for up to 2 weeks exhibited better clinical outcomes in patients with moderate-to-severe COVID-19 than 4 mg daily oral dose regimen without having a loading dose. The targeted SpO2 (≥95%) was gained earlier in patients who received an early 8 mg of loading dose of baricitinib than the patients treated without a loading dose of baricitinib. Similarly, the requirement of supplement oxygen support was significantly reduced earlier in patients treated with an extra 8 mg of loading dose of baricitinib that the patients received only 4 mg daily maintenance dose.

A recent study showed that around 80% of patients with COVID-19 develop acute lung inflammation due to massive cytokine storm [3,5,6,7] resulting in hypoxemia, impaired hypoxic pulmonary vasoconstriction, and high altitude pulmonary edema leading to ARDS [3,8,17], which may result in death in 2–7% of patients with COVID-19 pneumonia [18]. Janus kinases, a tyrosine kinase, play its major anti-inflammatory role in the cytokine signaling pathways by constitutively binding to cytokine receptors. To potentiate a cytokine storm, proinflammatory cytokines need to transmit more signals through signaling pathways. In-role, more than 40 different types of cytokines transmit signals through JAKs, including JAK1, JAK2, JAK3, and tyrosine kinase-2 (TyK2) [13,18]. Baricitinib has an oral bioavailability of approximately 79%, plasma protein binding ability up to 50%, mean half-life of approximately 12.5 h (in RA), and shows serum drug level of approximately 100–300 nM following a 4 mg oral dose [13,19]. The low molecular weight baricitinib concentration-dependently inhibits JAK1 and JAK2 with high target specificity [13].

In addition, baricitinib suppresses the production of Type-I interferons (IFNs) from plasmacytoid dendritic cells (pDCs), inhibits the synthesis of interleukin (IL)-6 from B cells [20], and possesses strong anti-viral property by inhibiting endocytosis [21]. Therefore, down-regulation of signal transmission of proinflammatory cytokines through JAKs, and suppression of other intrinsic inflammatory pathways makes baricitinib a suitable anti-inflammatory drug therapy in the treatment of COVID-19 pneumonia. The additional strong anti-viral property of baricitinib along with its selective anti-inflammatory ability has attributed its superiority to other oral investigational anti-inflammatory drugs in the treatment of COVID-19 pneumonia.

The plasma drug concentration of baricitinib at 2–4 mg daily oral dose is sufficient to exhibit its anti-inflammatory role (JAKs inhibition) in RA [11,12], but, a standard dose of baricitinib to achieve its optimum therapeutic outcome in COVID-19 pneumonia is still under investigation. In a recent study with a small sample size showed an improved clinical outcome of patients with COVID-19 with baricitinib at 4 mg per day of oral dose for 2 weeks [14]. In this study, a 2-fold higher (2 × 4 mg) single loading dose of baricitinib followed by 4 mg daily dose showed better therapeutic response in the management of moderate-to-severe COVID-19 pneumonia, and a superior clinical outcome was attributed in patients (case group) within 2 weeks of therapy with reduced hospitalization time and mortality rate. The major limitation of this study was small study sample size, short duration of the study, no proven justification of using 8 mg loading dose of baricitinib, and unavailability of serum cytokines monitoring facility in the study setup.

5 Conclusion

Severe pneumonia associated with COVID-19 is a major cause of mortality in COVID-19 infection. No anti-inflammatory drug, including baricitinib for the treatment of COVID-19 pneumonia has yet been recommended. In this study, 2-week-long 4 mg once daily oral maintenance therapy of baricitinib following a single 8 mg loading dose in moderate-to-severe COVID-19 pneumonia showed faster return to normal respiratory function with reduced requirement of ICU and ventilator support, length of hospital stay, and mortality rate than a loading dose less than 4 mg once daily oral dose of baricitinib.


tel: +88-01-91-101-1167
tel: +88 01754544689
tel: +88 01911010841
tel: +88 01713401761

Acknowledgments

The authors of this study are very grateful to the authority of the Square hospital for their ethical permission for this study and also grateful to the participated patients for their consent for this study.

  1. Competing interests: Authors state no conflict of interest.

  2. Funding source: No external funding source for this study.

  3. Author's contribution: The authors confirm that the Principal Investigator for this paper is Raihan Rabbani, MD, Consultant, Internal Medicine and ICU, Square Hospitals Ltd., Dhaka, Bangladesh, and that he had direct clinical responsibility for patients.

  4. Data sharing: The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

[1] World Health Organization. Coronavirus disease (COVID-19) pandemic; 2020 [cited 2020 July10]. Available from https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/novel-coronavirus-2019-ncov.Suche in Google Scholar

[2] World Health Organization. Coronavirus disease (COVID-2019) situation reports-173. Geneva: WHO; 2020 [cited 2020 July11]. Available from https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200711-covid-19-sitrep-173.pdf?sfvrsn=949920b4_2.Suche in Google Scholar

[3] Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–48. 10.1007/s00134-020-05991-x.Suche in Google Scholar

[4] Atal S, Fatima Z. IL-6 inhibitors in the treatment of serious COVID-19: A promising therapy? Pharm Med. 2020;34(4):223–31. 10.1007/s40290-020-00342-z.Suche in Google Scholar

[5] Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA Netw. 2020;323(18):1775–6.10.1001/jama.2020.4683Suche in Google Scholar

[6] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 2020;395(10223):507–13. 10.1016/S0140-6736(20)30211-7.Suche in Google Scholar

[7] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. 10.1016/S0140-6736(20)30183-5.Suche in Google Scholar

[8] Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 2020;92(7):814–8. 10.1002/jmv.25801.Suche in Google Scholar

[9] Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–57. 10.1038/ni.3153.Suche in Google Scholar

[10] Wang WK, Chen SY, Liu IJ, Kao CL, Chen HL, Chiang BL, et al. Temporal relationship of viral load, ribavirin, interleukin (IL)-6, IL-8, and clinical progression in patients with severe acute respiratory syndrome. Clin Infect Dis. 2004;39(7):1071–5. 10.1086/423808.Suche in Google Scholar

[11] Richardson P, Griffin I, Tucker C, Smith D, Oechsle O, Phelan A, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30–1. 10.1016/S0140-6736(20)30304-4.Suche in Google Scholar

[12] Cingolani A, Tummolo AM, Montemurro G, Gremese E, Larosa L, Cipriani MC, et al. Baricitinib as rescue therapy in a patient with COVID-19 with no complete response to sarilumab. Infection. 2020;48(5):767–71. 10.1007/s15010-020-01476-7.Suche in Google Scholar PubMed PubMed Central

[13] Kubo S, Nakayamada S, Sakata K, Kitanaga Y, Ma X, Lee S, et al. Janus kinase inhibitor baricitinib modulates human innate and adaptive immune system. Front Immunol. 2018;9:1510. 10.3389/fimmu.2018.01510.Suche in Google Scholar PubMed PubMed Central

[14] Cantini F, Niccoli L, Matarrese D, Nicastri E, Stobbione P, Goletti D. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J Infect. 2020;81(2):318–56.10.1016/j.jinf.2020.04.017Suche in Google Scholar PubMed PubMed Central

[15] Bronte V, Ugel S, Tinazzi E, Vella A, De Sanctis F, Canè E, et al. Baricitinib restrains the immune dysregulation in patients with severe COVID-19. J Clin Invest. 2020:141772.10.1101/2020.06.26.20135319Suche in Google Scholar

[16] World Health Organization. 2020 [cited 2020 July 17]. Available from clinical management of COVID-19. Interim guidance: https://www.who.int/publications/i/item/clinical-management-of-covid-19.Suche in Google Scholar

[17] Archer SL, Sharp WW, Weir EK. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema. Circulation. 2020;142(2):101–4. 10.1161/CIRCULATIONAHA.120.047915.Suche in Google Scholar PubMed PubMed Central

[18] Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32. 10.1038/nbt1358, PMID: 18183025.Suche in Google Scholar PubMed

[19] Kim H, Brooks KM, Tang CC, Wakim P, Blake M, Brooks SR, et al. Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI Patients. Clin Pharmacol Ther. 2018;104(2):364–73. 10.1002/cpt.936.Suche in Google Scholar PubMed PubMed Central

[20] McInnes IB, Byers NL, Higgs RE, Lee J, Macias WL, Na S, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183. 10.1186/s13075-019-1964-1.Suche in Google Scholar PubMed PubMed Central

[21] Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R, et al. The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19. J Autoimmun. 2020;111:102468. 10.1016/j.jaut.2020.102468.Suche in Google Scholar PubMed PubMed Central

Received: 2020-08-07
Revised: 2020-10-02
Accepted: 2020-10-06
Published Online: 2020-12-05

© 2021 Md Jahidul Hasan et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Research Articles
  2. Identification of ZG16B as a prognostic biomarker in breast cancer
  3. Behçet’s disease with latent Mycobacterium tuberculosis infection
  4. Erratum
  5. Erratum to “Suffering from Cerebral Small Vessel Disease with and without Metabolic Syndrome”
  6. Research Articles
  7. GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway
  8. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  9. Additional baricitinib loading dose improves clinical outcome in COVID-19
  10. The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats
  11. SLC12A8 plays a key role in bladder cancer progression and EMT
  12. LncRNA ATXN8OS enhances tamoxifen resistance in breast cancer
  13. Case Report
  14. Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy
  15. Spleno-adrenal fusion mimicking an adrenal metastasis of a renal cell carcinoma: A case report and embryological background
  16. Research Articles
  17. TRIM25 contributes to the malignancy of acute myeloid leukemia and is negatively regulated by microRNA-137
  18. CircRNA circ_0004370 promotes cell proliferation, migration, and invasion and inhibits cell apoptosis of esophageal cancer via miR-1301-3p/COL1A1 axis
  19. LncRNA XIST regulates atherosclerosis progression in ox-LDL-induced HUVECs
  20. Potential role of IFN-γ and IL-5 in sepsis prediction of preterm neonates
  21. Rapid Communication
  22. COVID-19 vaccine: Call for employees in international transportation industries and international travelers as the first priority in global distribution
  23. Case Report
  24. Rare squamous cell carcinoma of the kidney with concurrent xanthogranulomatous pyelonephritis: A case report and review of the literature
  25. An infertile female delivered a baby after removal of primary renal carcinoid tumor
  26. Research Articles
  27. Hypertension, BMI, and cardiovascular and cerebrovascular diseases
  28. Case Report
  29. Coexistence of bilateral macular edema and pale optic disc in the patient with Cohen syndrome
  30. Research Articles
  31. Correlation between kinematic sagittal parameters of the cervical lordosis or head posture and disc degeneration in patients with posterior neck pain
  32. Review Articles
  33. Hepatoid adenocarcinoma of the lung: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database
  34. Research Articles
  35. Thermography in the diagnosis of carpal tunnel syndrome
  36. Pemetrexed-based first-line chemotherapy had particularly prominent objective response rate for advanced NSCLC: A network meta-analysis
  37. Comparison of single and double autologous stem cell transplantation in multiple myeloma patients
  38. The influence of smoking in minimally invasive spinal fusion surgery
  39. Impact of body mass index on left atrial dimension in HOCM patients
  40. Expression and clinical significance of CMTM1 in hepatocellular carcinoma
  41. miR-142-5p promotes cervical cancer progression by targeting LMX1A through Wnt/β-catenin pathway
  42. Comparison of multiple flatfoot indicators in 5–8-year-old children
  43. Early MRI imaging and follow-up study in cerebral amyloid angiopathy
  44. Intestinal fatty acid-binding protein as a biomarker for the diagnosis of strangulated intestinal obstruction: A meta-analysis
  45. miR-128-3p inhibits apoptosis and inflammation in LPS-induced sepsis by targeting TGFBR2
  46. Dynamic perfusion CT – A promising tool to diagnose pancreatic ductal adenocarcinoma
  47. Biomechanical evaluation of self-cinching stitch techniques in rotator cuff repair: The single-loop and double-loop knot stitches
  48. Review Articles
  49. The ambiguous role of mannose-binding lectin (MBL) in human immunity
  50. Case Report
  51. Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report
  52. Fertility problems in males carrying an inversion of chromosome 10
  53. Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature
  54. Metastatic renal Ewing’s sarcoma in adult woman: Case report and review of the literature
  55. Burkitt-like lymphoma with 11q aberration in a patient with AIDS and a patient without AIDS: Two cases reports and literature review
  56. Skull hemophilia pseudotumor: A case report
  57. Judicious use of low-dosage corticosteroids for non-severe COVID-19: A case report
  58. Adult-onset citrullinaemia type II with liver cirrhosis: A rare cause of hyperammonaemia
  59. Clinicopathologic features of Good’s syndrome: Two cases and literature review
  60. Fatal immune-related hepatitis with intrahepatic cholestasis and pneumonia associated with camrelizumab: A case report and literature review
  61. Research Articles
  62. Effects of hydroxyethyl starch and gelatin on the risk of acute kidney injury following orthotopic liver transplantation: A multicenter retrospective comparative clinical study
  63. Significance of nucleic acid positive anal swab in COVID-19 patients
  64. circAPLP2 promotes colorectal cancer progression by upregulating HELLS by targeting miR-335-5p
  65. Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients
  66. Risk factors of left atrial appendage thrombus in patients with non-valvular atrial fibrillation
  67. Clinical features of hypertensive patients with COVID-19 compared with a normotensive group: Single-center experience in China
  68. Surgical myocardial revascularization outcomes in Kawasaki disease: systematic review and meta-analysis
  69. Decreased chromobox homologue 7 expression is associated with epithelial–mesenchymal transition and poor prognosis in cervical cancer
  70. FGF16 regulated by miR-520b enhances the cell proliferation of lung cancer
  71. Platelet-rich fibrin: Basics of biological actions and protocol modifications
  72. Accurate diagnosis of prostate cancer using logistic regression
  73. miR-377 inhibition enhances the survival of trophoblast cells via upregulation of FNDC5 in gestational diabetes mellitus
  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
  77. A four-lncRNA signature for predicting prognosis of recurrence patients with gastric cancer
  78. Knockdown of circ_0003204 alleviates oxidative low-density lipoprotein-induced human umbilical vein endothelial cells injury: Circulating RNAs could explain atherosclerosis disease progression
  79. Propofol postpones colorectal cancer development through circ_0026344/miR-645/Akt/mTOR signal pathway
  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
  81. COVID-19 severity in relation to sociodemographics and vitamin D use
  82. Clinical analysis of 11 cases of nocardiosis
  83. Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
  84. Four long noncoding RNAs act as biomarkers in lung adenocarcinoma
  85. Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens
  86. Relation between IL-8 level and obstructive sleep apnea syndrome
  87. circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level
  88. Nomogram prediction model for renal anaemia in IgA nephropathy patients
  89. Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis
  90. NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma
  91. A nomogram for predicting metabolic steatohepatitis: The combination of NAMPT, RALGDS, GADD45B, FOSL2, RTP3, and RASD1
  92. Clinical and prognostic features of MMP-2 and VEGF in AEG patients
  93. The value of miR-510 in the prognosis and development of colon cancer
  94. Functional implications of PABPC1 in the development of ovarian cancer
  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
  97. Prediction of improvement after anterior cruciate ligament reconstruction
  98. Effluent Osteopontin levels reflect the peritoneal solute transport rate
  99. circ_0038467 promotes PM2.5-induced bronchial epithelial cell dysfunction
  100. Significance of miR-141 and miR-340 in cervical squamous cell carcinoma
  101. Association between hair cortisol concentration and metabolic syndrome
  102. Microvessel density as a prognostic indicator of prostate cancer: A systematic review and meta-analysis
  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
Heruntergeladen am 9.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2021-0010/html
Button zum nach oben scrollen