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DOI: 10.1016/j.medcli.2020.07.002
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Disponible online el 17 de Septiembre de 2020
Anti-IL-6 receptor antibody treatment for severe COVID-19 and the potential implication of IL-6 gene polymorphisms in novel coronavirus pneumonia
Tratamiento con anticuerpos anti-receptor de IL-6 para COVID-19 grave y la posible implicación de polimorfismos del gen IL-6 en la nueva neumonía por coronavirus
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Zulvikar Syambani Ulhaqa,1,
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, Gita Vita Sorayab,1
a Department of Biochemistry, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim Islamic State University of Malang, Batu, East Java 65151, Indonesia
b Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi 90245, Indonesia
Recibido 28 mayo 2020. Aceptado 03 julio 2020
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Table 1. Systematic review of case report and case-series evaluating anti-IL-6R treatment in severe COVID-19.
Table 2. Characteristic of retrospective case-control and prospective cohort studies included in the analysis of anti-IL-6R treatment in severe COVID-19.
Table 3. The characteristics of included studies on IL-6 gene polymorphism and pneumonia.
Table 4. Meta-analysis results of IL-6 gene polymorphism and pneumonia.
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Despite the rapid global increase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there is currently no effective treatment for patients who have developed severe coronavirus disease 2019 (COVID-19). These severe COVID-19 cases are marked with excess cytokine production and a higher mortality rate. Our previous analysis confirmed that an elevated level of interleukin-6 (IL-6) and C-reactive protein (CRP) are strongly associated with COVID-19 progression.1,2 Thus, it is reasonable to suggest that the inhibition of IL-6 signaling cascade may effectively treat patients with severe SARS-CoV-2 infection. Another potential consideration regarding disease progression is the role of IL-6 gene polymorphisms. The two most extensively studied IL-6 gene promoter polymorphisms, −174G/C (rs1800795) and −572C/G (rs1800797), have been shown to affect both the transcription and secretion level of IL-6.3 Although the role of such polymorphisms have not been studied among COVID-19 patients specifically, it has been demonstrated in other infectious pneumonias.

In this article, we present a systematic review and meta-analysis on the efficacy of anti-IL-6 receptor (anti-IL-6R) antibody in neutralizing IL-6 by evaluating the reduction of the C-reactive protein (CRP) inflammatory marker, clinical outcomes, and the adverse events among severe COVID-19-infected patients. Additionally, a meta-analysis was also performed to estimate the association between IL-6 gene polymorphism with predisposition as well as disease severity of pneumonia.

All meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.4 Records were identified through electronic databases dated up to May 2020 with search terms such as “COVID-19” “SARS-CoV-2”, “IL-6”, “anti-IL-6R”, “Tocilizumab (TCZ), polymorphism”, and “pneumonia” (See Supplementary material). No language restrictions were applied. For TCZ treatment, studies with case-control design evaluating clinical outcomes (i.e., mortality rate, ICU admission, the requirement of mechanical ventilation, and the number of discharged patients) and its adverse events were included. Whereas, for IL-6 gene polymorphisms, studies were included on the basis of the following criteria: (1) aims to evaluate the association between IL-6 gene polymorphisms with predisposition to pneumonia; (2) conducted with a case-control design; and (3) evaluates IL-6 gene polymorphisms in pneumonia patients with or without severe condition (i.e., extra pulmonary bacterial dissemination, sepsis, and multiple organ dysfunction syndrome (MODS)).

Meta-analysis for each gene polymorphism was performed for two or more studies. Genotypic frequency of IL-6 gene polymorphism was tested for deviation from the Hardy–Weinberg equilibrium (HWE) in the control subjects. The associations between IL-6 gene polymorphism with predisposition to pneumonia or severity of pneumonia were calculated by pooled odds ratio (OR) and 95% confidence interval (CI). The Z test was used to evaluate the significance of the pooled effect size. Study heterogeneity was evaluated using Q test and I2 statistic. A significant Q-statistic (p<0.10) indicated heterogeneity across studies, with substantial heterogeneity indicated by an I2 value over 50%. The fixed-effect model (FEM) was used in the absence of heterogeneity, whilst the random-effect model (REM) was implemented if heterogeneity was present. A funnel plot and Begg's test were used to investigate the publication bias if the pooled effect size consisted of 10 or more studies. The value of 0.05 was indicative of the statistical significance. The Newcastle–Ottawa scale (NOS) was used to assess the study quality, in which a score7 is considered a good study.5–10

Nine case reports/case-series were included for the analysis on anti-IL-6R antibody treatment (summarized in Table 1) with a total sample of n=66 patients. A large proportion of the samples (89%) were male, with ages ranging from 42 to 73 years old.10–18 All patients developed severe COVID-19, marked by acute respiratory distress syndrome (ARDS) during admission, and more than half of studies reported the use of mechanical ventilators. Hypertension was the most common co-morbidity observed in patients with SARS-CoV-2 infection, followed by diabetes mellitus (DM), cerebrovascular disease, cardiovascular disease (CVD), and chronic kidney disease (CKD). Eight of the studies administered TCZ treatment,11–18 while one utilized Siltuximab.19 One to three times injection of anti-IL-6R antibody was mainly given during the onset of ARDS,11,13–15,18 while the rest were administered several days after the admission/ARDS onset12,15,18,19 or depending on the level of IL-6 or CRP.17 Several additional treatments were given in the studies, including antivirals, antibiotics, corticosteroids, anti-malaria (hydroxychloroquine/HCQ), and vasopressors.

Table 1.

Systematic review of case report and case-series evaluating anti-IL-6R treatment in severe COVID-19.

Characteristics  Michot et al.  Zhang et al.  De Luna et al.  Cellina et al.  Di Giambenedetto et al.  Radbel et al.  Gritti et al.  Xu et al.  Luo et al. 
Location  France  China  France  Italy  Italy  USA  Italy  China  China 
Study type  Case report  Case report  Case report  Case report  Case report  Case report  Retrospective case-series  Retrospective case-series  Retrospective case-series 
Number of cases  21  21  15 
Age [years]  42  60  45  64  56.33 [mean]  54.5 [mean]  64 [median]  56.8 [mean]  73 [median] 
Males, %  100  100  100  100  100  50  85.7  85.7  80 
Major clinical feature  ARDS  ARDS  ARDS  ARDS  ARDS  ARDS  ARDS  ARDS  ARDS 
Onset of ARDS  7-days after admission/2-days after SARS-CoV-2 was confirmed  15-days after admission/12-days after SARS-CoV-2 was confirmed  1 day after admission  5-days after admission  8-days after admission (patient 1)At admission (patient 2)2-Days after admission (patient 3)  2-days after admission  NR  NR  6-days after the onset of fever 
Mechanical ventilation  No  NR  No  Yes  Yes  Yes  Yes  NR  Yes (15%) 
Co-morbidities  Renal cell carcinoma  Multiple myeloma  SCD  NR  Hypertension  DM, rheumatoid arthritis, aplastic anemia  Hypertension, CVD, CKD, DM malignancies, cerebrovascular disease  Hypertension, DM, CHD, COPD, CKD, Brain infarction, Bronchiectasis, Auricular fibrillation  Hypertension, DM, stroke 
Anti-IL-6R  TCZ  TCZ  TCZ  TCZ  TCZ  TCZ  Siltuximab  TCZ  TCZ 
Time to start Anti-IL-6R treatment  At the onset of ARDS  24-days after admission/9-days after the onset of ARDS  At the onset of ARDS  At the onset of ARDS  At the onset of ARDS (patient 1 and 3)4-Days after admission (patient 2)  2-days after diagnosed with ARDS/at the onset of septic shock (patient 1)At the onset of ARDS and septic shock (patient 2)  3-Days after admission [median]  NR  Depending on the level of IL-6 or CRP 
Dose  8mg/kg IV(2 times, 8h interval)  8mg/kg IV(1 time)  8mg/kg IV(1 time)  8mg/kg IV(2 times, 12h interval)  8mg/kg IV(2 or 3 times, 12h interval for the second dose or 24/36h for the third dose)  400mg IV(1 time, patient 1)560mg IV and 700mg IV(2 times, 2 days interval, patient 2)  11mg/kg IV(1 time)  400mg IV(1 time)  80–600mg IV(≥2 times) 
Co-treatment  Ceftriaxone, Piperacilline tazobactam, Lopinavir/Ritonavir  MoxifloxacinUmifenovir  Amoxicillin-clavulanic acidHCQ  NR  Lopinavir/RitonavirHCQ  HCQ, azithromycin,NE (vasopressor), steroids  NR  Lopinavir, Methyl-prednisolone  Methyl-prednisolone 
Evaluation time (for CRP level)  Day-4 post- treatment  Day-7/14 post- treatment  NR  Day-1 post-treatment  Day-2/3/10 post- treatment  Day-1/2/3 post-treatment  Day-5 post- treatment  Day-1/3/5 post-treatment  Day-1/2/3/4/5/6/7 post-treatment 
% Reduction of CRP from baseline (before treatment)  85.33  10/77.9  NR  71.42  77.29/95.72/98  -10.16/12.46/66.23  ∼78.63  49.20/85.86/96.37  64.89/73.93/86.65/92.83/82.42/58.75/88.64 
IL-6 level  NR  82.88% reduction after 10-days of TCZ treatment  NR  NR  NR  –  NR  IL-6 level tended to spike and then decreased following TCZ treatment  NR 
Chest CT  Improvement after 4-days TCZ treatment  Improvement after 12-days TCZ treatment  NR  Improvement after 7-days TCZ treatment  Improvement after 2 or 3-days TCZ treatment  NR  NR  NR  Improvement after TCZ treatment 
Clinical outcome  Generally improved (afebrile and decreased oxygen consumption  Gradually recovered after TCZ treatment  Generally improved after 1-day TCZ treatment  Generally improved (released from mechanical ventilation)  Generally improved (afebrile and improvement of PaO2-to-FiO2 ratio)  Died (both patients progressed to secondary hemophagocytic lymphohistiocytosis (sHLH).  33% of patients were clinically improved (released from mechanical ventilation)  Generally improved  Generally improved (afebrile and improvement of the peripheral oxygen saturation) 

ARDS, acute respiratory distress syndrome; CVD, cardiovascular disease; CKD, chronic kidney disease; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DM, diabetes mellitus; HCQ, hydroxychloroquine; IV, intravenous; NR, not reported; SCD, sickle cell disease. TCZ, Tocilizumab.

The analysis revealed that despite some variability in the levels of CRP post-treatment with anti-IL-6R antibody, peak CRP reduction was observable at 3 to 4-days after the administration (Fig. 1). Additionally, anti-IL-6R antibody treatment also resulted in the suppression of IL-6 levels12,16 and remarkable reduction of COVID-19 severity characterized by the improvement of chest CT and its symptoms. However, as reported by Radbel et al.,18 adverse secondary hemophagocytic lymphohistiocytosis (sHLH) occurred despite the lowered CRP levels, indicating the potential risk of side effects with this treatment. Thus, further studies evaluating efficacy and safety of anti-IL-6R antibody in treating COVID-19-infected patients is indispensable.

Fig. 1.

Pooled reduction of C-Reactive Protein following administration of anti-IL-6R antibody in severe pneumonia. Figure shows mean ± standard error of the mean. n=2–4 studies per group.

(0,09MB).

Five case-control studies evaluating TCZ treatment in severe COVID-19 were initially included20–24; followed by the exclusion of one study in which the control group displayed milder clinical presentation24 (Table 2). No statistical significance was observed between the pooled mortality rates of the TCZ and standard treatment (STD) groups, which may be due to the heterogeneity between studies. However, it can be noted that relative to STD treatment, TCZ treatment was marginally associated with lower mortality rate (HR=0.39, 95%CI 0.01–0.77, p=0.09, Fig. 2A; OR=0.30, 95%CI 0.08–1.10, p=0.07, Fig. 2B). In a study conducted by Sciascia et al.,25 TCZ treatment was shown to increase the likelihood of survival among severe COVID-19 patients (Table 2).

Table 2.

Characteristic of retrospective case-control and prospective cohort studies included in the analysis of anti-IL-6R treatment in severe COVID-19.

Author  Location  No. of TCZ/STD treated patients  TCZ eligibility criteria  Therapy  Outcome at days  Survival rate (HR, 95% CI)  MortalityRequired IMVICU admissionDischargeAdverse effect*
              TCZ  STD  TCZ  STD  TCZ  STD  TCZ  STD  TCZ  STD 
Campochiaro et al.  Italy  32/33  2x Positive RT-PCR of SARS-CoV-2 on nasopharyngeal swab; hyper-inflammation (CRP, ≥100mg/L or r ferritin900ng/mL); severe respiratory involvement (chest X-ray/CT, SaO292%, PaO2:FiO2300mmHg)  STD: HCQ, lopinavir/ritonavir, ceftriaxone, azithromycin, anti-coagulation prophylaxisTCZ: STD+TCZ 400mg IV (1 time, 24h interval for the second dose)  28  HR for death 0.44, 95% CI 0.167–1.184, p=0.122  5/32  11/33  0/32  1/33  –  –  20/32  16/33  4/32a5/32b  4/336/33 
Capra et al.  Italy  62/23  Confirmed SARS-CoV-2, and one of the following criteria: RR30 breaths/min, SpO293%, PaO2/FiO2300mmHg, severe respiratory involvement by chest X-ray  STD: HCQ, lopinavir, ritonavirTCZ: STD+TCZ 400mg IV or 324mg SC (1 time)  35  HR for death 0.035, 95% CI 0.004–0.347, p=0.004  2/62  11/23  –  –  –  –  23/62  8/23  –  – 
Colaneri et al.  Italy  21/91  Confirmed SARS-CoV-2, CRP>5mg/dl, PCT<0.5ng/mL, PaO2:FiO2<300; ALT<500U/L  STD: HCQ, azithromycin, prophylactic dose of low weight heparin, and methylprednisoloneTCZ: STD+TCZ 400mg IV  –  5/21  19/91  –  –  3/21  12/91  –  –  0/21b  0/91 
Klopfensteina et al.  France  20/25  Confirmed SARS-CoV-2; failure of standard treatment, oxygen therapy5l/min, >25% of lung damages on chest computed tomography (CT) scan, and ≥ 2 parameters of inflammation (high level of ferritin, CRP, D-dimers, lymphopenia, and LDH)  STD: HCQ, lopinavir-ritonavir, antibiotics, corticosteroidsTCZ: STD+TCZ (1 or 2 doses)  11  –  5/20  12/25  0/20  8/25  0/20  11/25  11/20  11/25  –  – 
Quartuccio et al.  Italy  42/69  Confirmed SARS-CoV-2; level of CRP and IL-6  STD: antivirals, antimalarials, glucocorticoids, antibiotics, LMWHTCZ: STD+TCZ 8mg/kg IV single infusion  12  –  4/42  0/69**  –  –  –  –  –  –  –  – 
Author  Location  No. of patients  TCZ eligibility criteria  Therapy  Outcome (HR, 95% CI)
          Adverse effect  Clinical improvement  Survival rate 
Morena et al.  Italy  51  Confirmed SARS-CoV-2, age ≥ 18 years, RR ≥ 30min–1, SpO2<93%, PaO2/FiO2 < 250mmHg, IL-6 plasma level > 40pg/mL.  TCZ 400mg IV or 8mg/kg (1 time, 12h interval for the second dose)  Increased AST/ALT (29%), Bacteremia (27%)  HR 67% (95% CI 56–68)Clinical improvement based on severity or discharge, 30 days follow up  Mortality rate 27%, 30 days follow up 
Sciascia et al.  Italy  56  Confirmed SARS-CoV-2, SpO2<93%, PaO2/FiO2<300mmHg, CRP or D-dimer>10× normal values, LDH>2× the upper limits, ferritin>1000ng/mL  TCZ 8mg/kg IV or 324mg SC (1 or 2 doses)  No adverse effect was reported  –  TCZ increased survival rate, HR 2.2 (95% CI 1.3–6.7), p<0.05, Survival rate according to D-dimer levels, 14 days follow up 

TCZ, Tocilizumab; STD, Standard treatment; *adverse effects including secondary infectiona or severe hepatic injury/increase ALT/ASTb; **milder clinical presentation; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; CT, computerized tomography; FiO2, fraction of inspired oxygen (FiO2); HCQ, hydroxychloroquine; ICU, intensive care unit; IV, intravenous; IMV, invasive mechanical ventilation; LDH lactate dehydrogenase; PaO2, partial pressure of oxygen; PCT, procalcitonin; RT-PCR, reverse transcription polymerase chain reaction; SC, subcutaneous, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 2.

(A) Forest plot of studies reporting hazard ratio (HR) that investigates the mortality rate between Tocilizumab (TCZ) group and standard treatment (STD) group. (B–E) Forest plot of pooled studies evaluating mortality rate, invasive mechanical ventilation (IMV) requirement, ICU admissions, and the number of discharged patients between Tocilizumab (TCZ) group and standard treatment (STD) group, respectively.

(0,62MB).

This analysis also showed that invasive mechanical ventilation (IMV) was required less in the TCZ group (OR=0.10, 95%CI 0.01–0.77, p=0.03, Fig. 2C). No statistical difference was observed in terms of ICU admissions, the number of discharged patients, and the adverse effects of treatment (bacteremia and an elevated level of AST/ALT) between the two groups (Fig. 2D, E, Supplemental Fig. 1, respectively). Interestingly, however, Morena et al.26 demonstrated that 67% of patients administered with TCZ showed an improvement in their clinical severity class. Thus, the administration of TCZ seems beneficial in lowering the mortality rate and increased favorable clinical outcomes in patients with severe SARS-CoV-2 infection. However, additional data are still required to understand the effect of TCZ in treating patients with severe and critically ill COVID-19.

For the analysis on IL-6 gene polymorphisms and pneumonia, 24 articles were found using the aforementioned search strategy. Irrelevant articles were subsequently excluded, leaving a total of 11 eligible studies. The total sample included for analysis were 3958 cases and 3671 controls; 717 cases and 579 controls for IL-6 –174G/C and –572C/G polymorphisms, respectively27–30 (Supp. Refs. 1–7). To assess the association between IL-6 –174G/C with pneumonia severity, 671 severe and 2910 non-severe cases were examined29 (Supp. Ref. 3,6]) The characteristics of the included studies are shown in Table 2. All but four of the studies30 (Supp. Ref. 2,3,5) did not comply with the HWE (p<0.05). Overall, a lack of association between IL-6 −174G/C and −572C/G polymorphisms with pneumonia predisposition was observed in all genetic models (Table 3). Additionally, results remained insignificant following subgroup analysis based on ethnicity and age (data not shown).

Table 3.

The characteristics of included studies on IL-6 gene polymorphism and pneumonia.

First author, Year  Age group  Country  Ethnicity  Sample size (cases/controls)  Genotype (wtwt/wtmt/mtmt)p value for HWE  NOS score 
          Cases  Controls     
−174G/C [rs1800795]
Endeman, 2011  Adult  The Netherlands  Caucasian  200/311  83/92/25  113/150/48  0.878 
Mao, 2016  Adult  China  Asian  162/200  68/46/48  97/66/37  0.000 
Martinez-Ocana, 2013  Adult  Mexico  Caucasian  65/46  53/12/0  39/7/0  0.576 
Martın-Loeches, 2012  Adult  Spain  Caucasian  953/1246  581/516/130  438/413/102  0.752 
Salnikova, 2013 [a]  Adult  Russia  Caucasian  334/141  37/80/22  103/150/69  0.299 
Salnikova, 2013 [b]  Adult  Russia  Caucasian  216/105  32/56/12  83/81/42  0.009 
Schaaf, 2005  Adult  Germany  Caucasian  100/50  29/51/20  17/25/8  0.812 
Sole-Violan, 2010  Adult  Spain  Caucasian  1413/1162  533/485/120  590/502/123  0.288 
Zhao, 2017  Pediatric  China  Asian  415/300  391/24/0  296/4/0  0.907 
Zidan, 2014  Pediatric  Egypt  African  100/110  32/55/13  22/60/28  0.323 
−572C/G [rs1800797]
Chou, 2016  Adult  Taiwan  Asian  279/156  184/62/33  106/32/18  0.000 
Su, 2019  Pediatric  China  Asian  438/423  206/193/39  351/58/14  0.000 
First Author, Year  Age group  Country  Ethnicity  Sample Size (Severe/Non-severe)  Genotype (GG/GC/CC)p value for HWE  NOS score 
          Severe  Non-severe     
−174G/C [rs1800795]
Mao, 2016  Adult  China  Asian  188/200  56/37/95  68/46/48  0.000 
Schaaf, 2005  Adult  Germany  Caucasian  25/75  3/15/7  26/36/13  0.929 
Sole-Violan, 2010 [a]  Adult  Spain  Caucasian  159/817  73/68/18  392/341/84  0.441 
Sole-Violan, 2010 [b]  Adult  Spain  Caucasian  162/817  68/76/18  392/341/84  0.441 
Sole-Violan, 2010 [c]  Adult  Spain  Caucasian  137/1001  59/62/16  474/423/104  0.504 

Bold values indicate the results were deviated from HWE (Hardy–Weinberg equilibrium); mt, mutant type; wt, wild type.

Interestingly however, we found that IL-6 −174G/C polymorphism was significantly associated with the severity of pneumonia (C vs. G, OR: 1.33, 95%CI 1.04–1.69, p=0.019, Fig. 3A; particularly in the Caucasian population, OR: 1.15, 95%CI 1.00–1.33, p=0.049; CC+GC vs. GG; OR: 1.20, 95%CI 1.07–1.53, p=0.006, Fig. 3B; CC vs. GG; OR: 1.55, 95%CI 1.18–2.03, p=0.001, Fig. 3C, Table 3). In line with our results, Feng et al. [Supp. Ref. 8] observed that carriers of the IL-6 −174G/C had a 2.42-fold higher risk for pneumonia-induced septic shock, thereby implying a higher tendency of severe pneumonia in patients harboring the IL-6 −174C. Indeed, the CC genotype has been correlated with significantly higher IL-6 levels [Supp. Ref. 3,9]. Moreover, it has been shown that the haplotype spanning from −1363 to +4835 from the transcription start site of IL-6 conferred susceptibility to acute lung injury (ALI) [Supp. Ref. 10] (Table 4).

Fig. 3.

Association between IL-6 −174G/C polymorphism with the severity of pneumonia. (A) C vs. G; (B) CC+GC vs. GG; (C) CC vs. GG.

(0,45MB).
Table 4.

Meta-analysis results of IL-6 gene polymorphism and pneumonia.

Genetic model  Group  No. of studies  Test of associationTest of heterogeneityp Egger's test 
      OR  95% CI  p  Model  p (Q test)  I2 (%)   
A. Case - Control
−174G/C [rs1800795]
C vs. G  Overall  10  1.02  [0.88; 1.18]  0.776  Random  0.006  60.71  0.477 
  Overall*  1.02  [0.94; 1.10]  0.591  Fixed  0.260  21.23  0.502 
CC vs. GC+GG  Overall  0.92  [0.69; 1.18]  0.462  Random  0.015  59.41  0.443 
  Overall*  0.97  [0.75; 1.24]  0.833  Random  0.051  51.99  0.694 
CC+GC vs. GG  Overall  10  1.08  [0.90; 1.30]  0.394  Random  0.025  52.56  0.304 
  Overall*  1.04  [0.94; 1.15]  0.432  Fixed  0.400  3.84  0.211 
CC vs. GG  Overall  0.94  [0.72; 1.24]  0.690  Random  0.033  53.86  0.514 
  Overall*  1.03  [0.87; 1.21]  0.711  Fixed  0.226  26.52  0.949 
GC vs. GG  Overall  10  1.10  [0.91; 1.33]  0.312  Random  0.028  51.82  0.229 
  Overall*  1.04  [0.93; 1.16]  0.447  Fixed  0.243  23.34  0.252 
−572C/G [rs1800797]
G vs. C  Overall  2.06  [0.57; 7.45]  0.268  Random  0.000  97.25  NA 
GG vs. CG+CC  Overall  1.70  [0.62; 4.65]  0.293  Random  0.022  80.90  NA 
GG+CG vs. CC  Overall  2.46  [0.50; 11.97]  0.262  Random  0.000  97.26  NA 
GG vs. CC  Overall  2.23  [0.51; 9.75]  0.284  Random  0.000  90.90  NA 
CG vs. CC  Overall  2.54  [0.51; 12.49]  0.251  Random  0.000  96.50  NA 
B. Severe - Non-severe
174G/C [rs1800795]
C vs. G  Overall  1.33  [1.04; 1.69]  0.019  Random  0.015  67.44  0.320 
  Caucasian  1.15  [1.00; 1.33]  0.049  Fixed  0.409  0.043 
CC vs. GC+GG  Overall  1.42  [0.98; 2.06]  0.058  Random  0.088  50.60  0.743 
  Caucasian  1.16  [0.85; 1.57]  0.331  Fixed  0.842  0.002 
CC+GC vs. GG  Overall  1.20  [1.07; 1.53]  0.006  Fixed  0.240  27.16  0.059 
  Caucasian  1.21  [0.99; 1.47]  0.054  Fixed  0.308  16.64  0.061 
CC vs. GG  Overall  1.55  [1.18; 2.03]  0.001  Fixed  0.121  45.15  0.561 
  Caucasian  1.28  [0.92; 1.77]  0.131  Fixed  0.392  0.004 
GC vs. GG  Overall  1.17  [0.96; 1.43]  0.103  Fixed  0.460  0.229 
  Caucasian  1.20  [0.98; 1.48]  0.076  Fixed  0.371  4.21  0.086 

Bold values indicate statistically significant differences between severe and non-severe cases. Asterisk (*) indicates that studies deviated from HWE (Hardy–Weinberg equilibrium) were excluded.

Tocilizumab, Sarilumab, or Siltuximab are humanized recombinant monoclonal antibodies that inhibit IL-6 signal transduction of IL-6 by binding with the soluble and membrane IL-6R, sIL-6R and mIL-6R, respectively. So far, anti-IL-6R antibody is mainly used to treat rheumatoid arthritis patients with favorable safety profile.11 Since these agents are immunosuppressive, their administrations are normally contraindicated in patients with active infection, thrombocytopenia, and an elevated liver function, which is also observed in COVID-19-infected patients2 (Supp. Ref. 11). Interestingly, however, pooled results collected from nine studies indicated that anti-IL-6R antibody treatment could effectively treat severe COVID-19-infected patients, marked by suppression of CRP and improvement of clinical symptoms. This may be due to transcriptional induction of the CRP gene was inhibited by TCZ, which then further suppressed inflammatory responses during SARS-CoV-2 infection. Although IL-6 gene polymorphism results may not directly correlate with novel coronavirus pneumonia (NCP), this analysis demonstrated that IL-6 −174C allele carrier status is associated with higher level of IL-6 production and more severe forms of pneumonia in general. This analysis strengthens the notion that IL-6 plays a pivotal role in novel coronavirus pneumonia (NCP) progression.

At present, 32 clinical trials have been registered (clinicaltrials.gov) to evaluate the efficacy and safety of anti-IL-6R antibodies. Despite the limited number of participants so far, suppression of IL-6 signaling cascade shows a promising therapy in the ARDS induced by SARS-CoV-2 infection.

Conflict of interest

None to declare.

Appendix A
Supplementary data

The following are the supplementary data to this article:

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