Tocilizumab-A beacon of hope in the management of severe COVID-19?

interquartile range

number of patients

percentage of patients

reference

severe acute respiratory syndrome coronavirus 2

tocilizumab

To the Editor,

We read with interest the article entitled “Early use of tocilizumab in the prevention of adult respiratory failure in SARS‐CoV‐2 infections and the utilization of interleukin‐6 levels in the management” by Antony et al. A major pathological hallmark underlying Coronavirus disease 2019 (COVID‐19) is the activation of a cytokine release syndrome (CRS). As interleukin‐6 (IL‐6) seems to be the main chemokine driving the CRS in COVID‐19, investigating the role of tocilizumab (TCZ), an IL‐6 receptor antagonist, has attracted much attention. The authors have suggested that early use of TCZ may reduce the requirement for mechanical ventilation (MV) and the associated increased morbidity and mortality. However, we feel it is important to highlight the study's deficiencies that influence the interpretation of the results.

A total of 80 out of 112 COVID‐19 patients were included, which constitutes a relatively small sample size and limits study power. Although partially explained by the short timeframe of the study, the lack of a reported power calculation hampers determination of the significance of the results. A combined primary endpoint could have also been used to minimize the impact of the limited sample size. The sample selection process was also poorly described with very little mention of recruitment procedures.

The authors explain that the purpose of the 72‐h methylprednisolone therapy was to prolong the suppression of CRS in combination with TCZ. Recent data on corticosteroid efficacy in COVID‐19 is encouraging; however, there was no explanation of the steroid choice or treatment duration. Moreover, even though the authors acknowledged the potential cointervention bias with the addition of methylprednisolone, the title of the study does not acknowledge this, potentially misleading readers. Although described as a limitation by the authors, the lack of a “standard care” control group further limits interpretation of the relevance of TCZ's perceived efficacy.

Descriptions of TCZ dosage lacked overall clarity. The authors mention the use of an “optional” second dose 12 h after the first, which did not exceed 800 mg. However, this was seemingly not considered when analysing the results, with no indication of how many patients received a second dose. Additional doses of TCZ may have influenced patient outcomes and is, therefore, an important confounder not acknowledged. This was similarly seen in a study by Klopfenstein et al, which stated that participants received “one or two doses” of TCZ but did not specify which did better.

IL‐6 levels were measured with the authors claiming that IL‐6 may be a good prognostic indicator for the management of the CRS. However, they also showed a statistically significant increase in IL‐6 levels post‐TCZ, when comparing days 0–6. They suggested that this could be explained by the “ongoing cytokine storm” but this was not discussed further. Moreover, the stated limitation of lack of long‐term follow up does not allow readers to determine the long‐term effects of TCZ on IL‐6 in COVID‐19.

Data displayed in Table 1 on the characteristics of patients included in the study is unclear and inconsistent. For example, the authors state that there were 80 SARS‐CoV‐2‐positive patients (n = 80) included in the study, although when stating the gender, data show only 79 patients (45 males, 56.96%; 34 females, 43.04%). This inconsistency is replicated when giving data on other patient characteristics. The authors mention that data were taken from electronic health records and perhaps there were incomplete data. This could have been discussed, to avoid confusion.

Table 1

General sociodemographic characteristics, medical history, and clinical presentations of SARS‐CoV‐2 patients treated with TCZ

Characteristics	Frequency (n = 80)	Percentage (%)	Characteristics	Frequency (n = 80)	Percentage (%)
Age			Fever
<30R	37	46.84	Yes	53	73.61
30‐64	39	49.37	No	19	26.39
≥65	37	46.84	Cough
Median values (IQR)	63 (51, 72)		Yes	49	68.06
Sex			No	23	31.94
Male	45	56.96	Shortness of breath
Female	34	43.04	Yes	62	86.11
Race/ethnicity			No	10	13.89
Hispanic	44	57.14	Other symptoms
White/Hispanic	25	32.47	Yes	42	58.33
White/non‐Hispanic	3	3.90	No	30	41.67
White/none listed	2	2.60	Total number of symptoms
White	1	1.30	≤2	20	27.78
Black/non‐Hispanic	1	1.30	3 or more	52	72.22
Caucasian	1	1.30	Median values (IQR)	3 (2‐5)
Diabetes			Bacterial coinfection
Yes	37	51.39	Yes	12	15.00
No	35	48.61	No	68	85.00
Hypertension			Multiorgan damage
Yes	47	65.28	Yes	10	12.50
No	25	34.72	No	70	87.50
Hyperlipidaemia			Travel history
Yes	18	25.00	Yes	11	15.71
No	54	75.00	No	59	84.29
Other comorbidities			Contact history
Yes	31	43.05	Yes	34	48.57
No	41	56.94	No	36	51.43
Total number of comorbidities
≤2	46	63.89
3 or more	26	36.11
Median values (IQR)	2 (1–3)

Abbreviations: IQR, interquartile range; n, number of patients; %, percentage of patients; R, reference; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TCZ, tocilizumab.

Despite recent literature on TCZ as a treatment option in COVID‐19 being encouraging, there is still limited data on efficacy. A recent Lancet study by Kewan et al demonstrated that TCZ resulted in shorter median time (8 vs. 13 days) to clinical improvement and shorter duration of invasive MV (7 vs 10 days) in TCZ versus no TCZ cohorts, respectively. Furthermore, RECOVERY, the largest trial to‐date evaluating the efficacy of interventions for COVID‐19 involves a second randomisation for patients who deteriorate to either TCZ or control. The recent inclusion of TCZ is based on evidence suggesting its potential role in the management of severe COVID‐19. Given the theorised role of IL‐6 in COVID‐19, future studies investigating other IL‐6 antagonists such as Sarilumab would be welcome, given its higher affinity for the IL‐6 receptor compared with TCZ. Overall, TCZ is a promising therapeutic candidate for severe COVID‐19. However, there is currently insufficient evidence supporting its routine use with a desperate need for larger, high‐quality studies before firm conclusions are made about clinical safety and efficacy.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.