Tocilizumab in COVID-19: a study of adverse drug events reported in the WHO database.

BACKGROUND: Elevated inflammatory cytokines in Coronavirus disease 2019 (COVID-19) affect the lungs leading to pneumonitis with a poor prognosis. Tocilizumab, a type of humanized monoclonal antibody antagonizing interleukin-6 receptors, is currently utilized to treat COVID-19. The present study reviews tocilizumab adverse drug events (ADEs) reported in the World Health Organization (WHO) pharmacovigilance database. RESEARCH DESIGN AND METHODS: All suspected ADEs associated with tocilizumab between April to August 2020 were analyzed based on COVID-19 patients' demographic and clinical variables, and severity of involvement of organ system.
RESULTS: A total of 1005 ADEs were reported among 513 recipients. The majority of the ADEs (46.26%) were reported from 18-64 years, were males and reported spontaneously. Around 80%, 20%, and 64% were serious, fatal, and administered intravenously, respectively. 'Injury, Poisoning, and Procedural Complications' remain as highest (35%) among categorized ADEs. Neutropenia, hypofibrinogenemia were common hematological ADEs. The above 64 years was found to have significantly lower odds than of below 45 years. In comparison, those in the European Region have substantially higher odds compared to the Region of Americas.
CONCLUSION: Neutropenia, superinfections, reactivation of latent infections, hepatitis, and cardiac abnormalities were common ADEs observed that necessitate proper monitoring and reporting.

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS ‐CoV‐2) is the pathogen responsible for the current pandemic of coronavirus disease 2019 (COVID ‐19) [1]. The initial case was identified in December 2019 from Wuhan, China, as several new pneumonia cases, and on 11 March 2020, it was declared a global pandemic by the World Health Organization (WHO) [2]. As of 20 October 2020, WHO has reported that the United States of America is the worst hit, followed by South-East Asia. Globally 40,114,293 people have been infected with COVID-19; the disease has already claimed 1,114,692 lives [3]. A severe form of COVID‐19 affects the lungs primarily and is associated with a hyperinflammatory condition, which damages the lungs and leads to pneumonitis and Accute Respiratory Distress Syndrome (ARDS) [4]. Based on the evidence, it is proposed that acute lung injury due to cytokine storm is the pathological basis for lung damage. As reported that in severe cases, the level of interleukins (IL) including IL-2, IL-6, IL-7, IL-10, Macrophage inflammatory protein 1A (MIP-1α/CCL3), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and Interferon gamma-induced protein were raised and lead to a worse prognosis [5-8]. A higher expression of the IL-6 is present in the CD4+ T-cells and monocytes from patients with COVID-19 infection, which points toward the central act of IL-6 in inciting the inflammatory cytokine storm, which potentially damages the lungs and worsens the prognosis of the patient [8-10]. Therefore, IL-6 can be considered a prognostic marker and a crucial target for therapeutic interventions like immunological therapies for SARS-CoV-2 infections. IL-6 can also be used to check the inflammatory lung damage and other multiorgan damage in COVID-19 patients. Henceforth controlling IL-6 should decrease the severity and improve the prognosis in these patients. In support of the fact, IL-6 inhibitors are being used in patients with COVID-19 and have reduced the severity and improved outcomes [11].

Tocilizumab

Tocilizumab, a type of humanized monoclonal antibody (MAb) that belongs to a class of IL- inhibitors with Anatomical Therapeutic Chemical (ATC) classification code: L04AC07 [12]. It is a MAb that attaches to both soluble and membrane-bound IL-6 receptors (sIL-6 R and mIL-6 R), leading to the blockade of inflammatory signaling pathways associated with IL-6 [13,14]. Tocilizumab was first approved in Japan to manage Multicentric Castleman’s Disease in 2007 [15]. It was initially approved for treating Rheumatoid Arthritis by the Food and Drug Administration (FDA) in 2010 [14]. Later on, it was also approved for varied immunological diseases like Systemic Juvenile Idiopathic Arthritis, Giant Cell Arteritis, Polyarticular Juvenile Idiopathic Arthritis, and lately was approved for managing severe cytokine release syndrome (CRS) due to chimeric antigen receptor T cell therapy [13,14]. The recommended dosage of tocilizumab for various immunological disorders ranges from 4–12 mg per kg and is administered as an intravenous infusion [14].

Tocilizumab and COVID-19: efficacy and safety

The primary idea of using Tocilizumab in patients of COVID-19 was to curb the inflammatory process and improve the disease outcome. Evidence shows that tocilizumab has effectively improved the prognosis in COVID-19 patients by reducing the inflammatory markers, the severity of the disease, enhancing lung changes, and reducing mechanical ventilation risk [16-24]. On the contrary, some studies have reported no effect of tocilizumab on these patients [25-28]. There is limited data available regarding tocilizumab’s safety in COVID-19 patients; hence, chronic use and robust multicentric randomized controlled trials are essential to establish the drug’s safety and efficacy and assess and quantify the adverse drug events (ADEs) specific in COVID-19 patients. Its safety analysis in completed trials among COVID-19 patients has shown ADEs like raised liver transaminases, hypertriglyceridemia, increased median QTc interval, severe neutropenia, activation of latent infections [16,18,20,21,23,25,27,29-31]. Tocilizumab is still under investigation and has not been approved for the treatment of COVID-19 patients by FDA but has permitted its emergency use in COVID-19 patients. It is currently being used on an emergency basis by prescribers worldwide to treat COVID-19 patients [14,30]. The ADEs encountered during the therapy have been reported in the global database VigiBase® maintained by WHO [32]. The current study was undertaken to review ADEs’ status associated with tocilizumab in managing patients with COVID-19 recorded in the WHO pharmacovigilance database.

Methods and materials

The present study was conducted using VigiBase, a global database containing individual case safety reports (ICSRs) of various interventions. This extensive database is maintained by WHO and includes over 20 million reports of suspected adverse effects reported by the WHO Program for International Drug Monitoring member countries since 1968 [32]. VigiBase is an archive of all the alleged ADEs from 130 countries worldwide, reported by respective national pharmacovigilance centers. The reports in the VigiBase are appropriately structured and arranged with details of sociodemographic profile (age, sex, continent, and country), drugs (date of initiation of therapy, last date of treatment, route of administration, and indications), suspected ADEs with their onset date, degree of seriousness, causality, outcome and administrative data which is a type of report and the source of the report. VigiBase allows effortless and pliable extraction and analysis of the data documented over time [33]. In this database, the medicines are coded accordingly as per the WHO Drug Dictionary Enhanced (WHO DDE), and it also encompasses the Anatomical Therapeutic Chemical (ATC) classification [34]. The ADEs were coded using WHO Adverse Reaction Terminology and the Medical Dictionary for Regulatory Authorities (MedDRA) [35,36]. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) developed MedDRA, which contains distinct standardized medical terminologies to ensure and promote the sharing of regulatory information for medicinal products humans across the countries [35,37]. The hierarchy in MedDRA has five levels and are arranged in order of very specific to very general levels, which are as follows: LTTs (Lowest Level Terms), PTs (Preferred Terms), HLTs (High-Level Terms), HLGTs (High-Level Group Terms), and SOCs (System Organ Classes) . This study uses the PT and SOC information. Preferred Terms are definite terminologies for a symptom, manifestation, diagnosis of a disorder, clinical use, investigation, medical or surgical procedure, and medical social or family history characteristic. Whereas the SOCs are the categorization based on their causality (e.g. infections and infestations), site of manifestation (e.g. gastrointestinal disorders), and indication (e.g. surgical and medical procedures) [37]. Additionally, the SOC also categorizes the issues regarding products and social circumstances [37]. The analysis of all the suspected ADEs from April-2 to August-11, 2020, related to tocilizumab was reported while treating COVID-19 patients. All ADEs published in the VigiBase refer to a single individual who might have had one or multiple ADEs concomitantly. Due to this, the count of ADEs reported could be higher when equated with patients’ numbers. The ADEs were classified according to the MedDRA, grouped at the SOC and individual PT levels. The methodology is summarized (Figure 1).

Figure 1.

Schematic diagram of Adverse Drug Events selection from VigiBase data used to filter the records

Statistical analysis

The data were entered in Microsoft Excel and were reported in frequency and percentages. Descriptive statistics were used for analysis. STATA 15.1, StataCorp, Texas, USA, was used to analyze the data using simple, followed by multiple logistic regression to find the factors associated with the patients’ outcome reported with ADESs in this study. The significance level was set at 0.05, where the odds ratio (OR) was reported with its 95% confidence interval (CI). The multiple logistic regression model’s fitness was checked using the sensitivity, specificity, and correctly classified outcome. The Pearson and Hosmer-Lemeshow chi-square goodness-of-fit tests confirmed the excellent fit of the model tested. Missing values rendered the adequate sample size reduced to 261 from the original 513 patients included in the initial data analysis.

Ethical approval

This study was based on the WHO’s database and did not involve direct interaction with human participants; hence ethical approval was not required.

Results

There were a total of 1005 adverse drug events reported from 513 individuals. On analyzing the data based on number of reported ADEs, the majority of these ADEs were reported from the age group 18–64 years (46.26%). There were only a few ADEs reported from the age group < 18 years. More than half of the ADEs were reported from the males. Reporting was more from Europe and the Americas as compared to Asia, Africa, and Oceania. Only 12% of the ADEs were reported from the clinical trials, rest were spontaneous reporting. 80% of these ADEs were serious and 20% were fatal. The intravenous route was used for administration of the tocilizumab in around 64% of ADEs. To manage these ADEs, the drug was withdrawn in 17% of ADEs, and Rechallenge was done in 27% of the events. (Table 1)

Table 1.

Characteristics of Adverse Events (1005 AEs reported from 513 Individuals) reported for Tocilizumab in WHO database (N = Number of adverse events)

Parameter		Number of adverse events (%)
Age (N = 1005)	< 18 Years	5 (0.49)
	18–64 Years	465 (46.26)
	≥ 65 Years	320 (31.84)
	Not reported	215 (21.39)
Gender (N = 1005)	Female	220 (21.89)
	Male	572 (56.91)
	Not reported	213 (21.19)
Report Type (N = 1005)	Report from study	122 (12.13)
	Spontaneous	872 (86.76)
	Other	11 (1.09)
Seriousness of Adverse Event(N = 1005)	Serious	803 (79.90)
	Non-Serious	202 (20.09)
Route of Administration (N = 1005)	Intravenous	642 (63.88)
	Subcutaneous	36 (3.58)
	Unknown	289 (28.75)
	Not reported	38 (3.78)

*Number of adverse events reported are more than number of patients.

The distribution of 1005 reported ADEs within the WHO regions is illustrated in Figure 2. Among the various outcomes of 1005 reported ADEs, the majority were unknown (N = 419) followed by fatality (N = 207), recovered or resolved (N = 125), not reported (N = 106), recovering or resolving (N = 91), not recovered or not resolved (N = 56) and recovered or resolved with sequelae (N = 1) (Figure 3). To manage these ADEs, the drug was withdrawn in 17% of ADEs (Figure 4), and following the dechallenge, the reaction was decreased by 20.2% (Figure 5). Rechallenge was attempted in 27% of the events, and most were not reported (Figure 6). Following the rechallenge, the effect was unknown in 26.5% of the events (Figure 7).

Figure 2.

Distribution of Adverse Drug events with Tocilizumab use in COVID-19 across continents

Figure 3.

Adverse Drug Event Outcomes of Tocilizumab use in COVID-19

Figure 4.

Summary of Dechallenge Action taken on encountering Adverse Drug Events with Tocilizumab use in COVID-19. (N = Number of adverse events with tocilizumab)

Figure 5.

Summary of Dechallenge outcomes of Adverse Drug Events with Tocilizumab use in COVID-19. (N = Number of adverse events with tocilizumab)

Figure 6.

Summary of Rechallenge Action taken with Tocilizumab in COVID-19 patients. (N = Number of adverse events with tocilizumab)

Figure 7.

Summary of Rechallenge outcomes with Tocilizumab in COVID-19 patients. (N = Number of adverse events with tocilizumab)

On further examining the demographic characteristics data based on number of patients, with 27.9% of unreported age, most of the ADEs were reported in the 45 to 64 years old age group (32.6%). With 26.5% unreported sex, more than half of the ADEs were reported in males (53.2%). Most of the cases were reported from Europe (51.1%) and the Americas (32.0%). Only 11.7% of ADEs were reported from formal clinical trials, while the rest were spontaneous reporting except for 0.8% from other sources. Among the reports, 71.5% of ADEs were serious ADEs. The intravenous route was used for administration of the tocilizumab was 56.8% of the ADEs. The information above is detailed out in Table 2.

Table 2.

Socio-demographic Characteristics of Patients with Reported Adverse Drug Events suspected due to Tocilizumab in the WHO database (n = Number of patients)

Parameter		Number of patients	Percentage
Age (n = 513)	2–44 years old	54	10.5
	45–64 years old	167	32.6
	≥ 65 Years	149	29.0
	Not reported	143	27.9
Sex (n = 513)	Female	104	20.3
	Male	273	53.2
	Not reported	136	26.5
Continents (n = 513)	Americas	164	32.0
	Europe	262	51.1
	Others	87	17.0
Report Type (n = 513)	Report from the study	60	11.7
	Spontaneous	449	87.5
	Other	4	0.8
The seriousness of Adverse Event (n = 513)	Serious	367	71.5
	Non-Serious	146	28.5
Route of Administration (n = 513)	Intravenous	291	56.8
	Subcutaneous	18	3.5
	Unknown	204	39.8

Examining broad categories, the highest number of ADEs were reported from the ‘Injury, Poisoning and Procedural Complications’ (35%), followed by ‘General Disorders and Administration Site Condition’ (17.61%), ‘Investigations’ (8.6%), and ‘Infections and Infestations’ (7.8%). In the broad category ‘Blood and Lymphatic System Disorders,’ the most frequently reported ADEs were neutropenia (1.5%), hypercoagulable state/hypofibrinogenemia (0.80%), and anemia (0.50%). Cardiac arrest (0.90%) and dysrhythmia, including atrial fibrillation and flutter, were common ADEs reported from the broad category ‘Cardiac Disorders.’ Intestinal perforations (1.2%) and ulcers were commonly reported ADEs from the ‘Gastrointestinal Disorders’ category. Simultaneously, deterioration of the condition/unexpected therapeutic response was common ADEs from the broad category ‘General disorders and administrative site conditions.’ More than 50% of ADEs reported from the wide variety ‘Hepatobiliary Disorders’ were hepatitis, and four ADEs were reported as hypersensitivity from the general category ‘Immune System Disorders.’ Fungal infections and pneumonia were very commonly reported from the category ‘Infections and Infestations.’ An increase in the liver enzymes was predominant in the broad category ‘Investigations.’ There were six acute kidney injury events, four end-stage renal disease events, and four renal failure events in the general category ‘Renal and urinary disorders.’ Amongst the ‘Respiratory, thoracic and mediastinal disorders,’ the most frequent ADEs were pulmonary embolism and respiratory failure . The ADEs distribution of tocilizumab use in patients with COVID-19 is summarized (Figure 8). The detailed adverse events are presented in supplementary Table 1.

Figure 8.

System-wide Distribution of Adverse drug events attributed to Tocilizumab use in COVID-19

To assess the factors associated with the outcome (recovered compared to fatal and not recovered as the reference group) in patients with reported ADEs suspected to be caused by tocilizumab used in the treatment of COVID-19 in the WHO database in this study, the simple logistic regression was used, followed by the multiple logistic regression to control for the confounding effects during analysis. The results are reported in Table 3, where the simple logistic regression shows that the sex, age groups, and regions are not significantly associated with the outcome (p > 0.05). However, the results of the multiple logistic regression show that the oldest age group (more than 64 years old) has less odds or chance to recover from ADEs (OR = 0.363, 95% CI = 0.153, 0.862, p = 0.022) compared to the youngest age group (less than 45 years old). It was also observed from the multiple logistic regression that those from the European Region were more likely to recover compared to those from the Regions of America with the OR of 3.716 (95% CI = 2.018, 6.845, p < 0.001).

Table 3.

Factors Associated with the Outcome (Recovered vs. Fatal/Not Recovered*) Among Patients with Reported Adverse Drug Events Suspected to be Caused by Tocilizumab Used in the Treatment of COVID-19 in the World Health Organization (WHO) Database (n = 261)

Variables	Simple Logistic Regression		Multiple Logistic Regression
	Odds ratio (95% CIb)	p-value	Odds ratio (95% CIb)	p-value
Sex:
Male*	0	1.000	0	1.000
Female	1.096 (0.653, 1.839)	0.729	1.217 (0.652, 2.268)	0.538
Age Group (years):
< 45*	0	1.000	0	1.000
45–64	0.879 (0.436, 1.773)	0.718	0.642 (0.277, 1.485)	0.300
> 64	0.617 (0.304, 1.255)	0.183	0.363 (0.153, 0.862)	0.022
WHO Region:
Americas*	0	1.000	0	1.000
Europe	1.440 (0.922. 2.248)	0.109	3.716 (2.018, 6.844)	< 0.001
Other regions	0.991 (0.561, 1.753)	0.976	0.964 (0.397, 2.493)	0.887

aControlled for the confounding effect. b Confidence interval. * The reference group.

In a multiple logistic regression model, the seriousness of ADEs (‘yes’ or ‘no’) was significantly associated with the age group. The odds of having serious ADEs were more than twice higher in patients aged 65 years and above instead of those aged 44 years and below [OR = 2.09, 95% CI (1.09, 4.00), p = 0.026]. There was a marginally significant association between the seriousness of ADEs and the WHO region. Patients from the European region had 39% lower odds of having serious ADEs than those from the Americas [OR = 0.61, 95% CI (0.37, 1.00), p = 0.049]. No significant association was found between the seriousness of ADEs and sex (Table 4).

Table 4.

Predictors of Serious Adverse Drug Events suspected to be caused by Tocilizumab used in treating COVID-19 in the WHO Database

Variables:	Crude		Adjusted
	OR (95% CI)	p value	OR (95% CI)	p value
Sex:
Male	1		1
Female	0.94 (0.62, 1.42)	0.756	1.22 (0.73, 2.03)	0.457
Age Group:
≤ 44 years old	1		1
45–64 years old	1.37 (0.76, 2.48)	0.292	1.52 (0.83, 2.80)	0.174
≥ 65 years old	1.72 (0.93, 3.12)	0.084	2.09 (1.09, 4.00)	0.026
WHO Region:
Americas	1		1
Europe	0.92 (0.64, 1.32)	0.637	0.61 (0.37, 1.00)	0.049
Other regions	0.44 (0.28, 0.68)	<0.001	0.76 (0.36, 1.62)	0.480

Discussion

The present study was conducted to analyze the ADEs reported in the WHO database. The male sex appears more vulnerable. ADE episodes were reported across a wide age group from below 20-year to over 60-years. A significant chunk of ADEs was reported from Europe, followed by the Americas, and then from elsewhere. Most of the ADEs were reported spontaneously and were observed when tocilizumab was administered intravenously.

Tocilizumab has been used in various immunological disorders, but its use in COVID-19 is either on compassionate grounds or under trial [16-24]. Due to the lack of its extensive usage, limited information about its post-approval safety and efficacy is available [21,25,27,28]. Based on the evidence of use in immunological disorders, the ADEs have been classified into very common ADEs like upper respiratory tract infections and hyperlipidemia [14]. Common ADEs include severe infections due to various pathogens such as bacteria, fungi, viruses, protozoa, or any other opportunistic infections (tuberculosis, cryptococcosis, aspergillosis, candidiasis, etc. Pneumocystis jirovecii pneumonia), which can present as cellulitis, pneumonia, urinary tract infection, herpes zoster, and gastroenteritis [13,14]. Other common ADEs include gastrointestinal diseases such as gastritis, abdominal pain, skin disorders including rashes and itching, headache, dizziness, high blood pressure, cough, respiratory distress, conjunctivitis, along with abnormal laboratory parameters, especially raised liver transaminases, elevated total bilirubin, leukopenia, neutropenia, and low fibrinogen levels. Uncommon ADEs are diverticulitis, renal stones, hypothyroidism, stomatitis, and gastric ulcer were reported [13]. Rare ADEs include severe hypersensitivity reactions (anaphylaxis, Stevens-Johnson-Syndrome) and hepatobiliary disorders (drug-induced liver injury and hepatitis) have been noticed [13,14].

In the present study, neutropenia (1.5%) was the most common blood, and lymphatic system disorder observed, followed by hypofibrinogenemia (0.8%) and thrombocytopenia (0.7%). Higher rates of neutropenia were reported in several previous studies conducted by Price et al. (4%), Morena et al. (6%), Stone et al. (13.7%), and Campochiaro et al. (16%) in tocilizumab treated COVID-19 patients [21,25,27,31]. The rate of thrombocytopenia reported by Stone et al. (0.6%) was comparable to the WHO database (0.7%), whereas Morena et al. (14%) reported a comparatively higher rate [27,31]. Anemia was reported among a few patients (0.5%) in the WHO database, whereas a study performed by Campochiaro et al. reported anemia at 64% as the most frequent ADE [25].

Cytokine storm, which is a fatal occurrence in COVID-19 patients where the immune system is hyperactivated leading to highly elevated levels of cytokines like IL-1β, IL-6, IP-10, TNF, INF-γ, MIP- 1α and 1β [38,39]. The common cells that are involved in the pathogenesis of cytokine storm are neutrophils, macrophages, and natural killer cells. The extracellular webs of DNA/histones synthesized by neutrophils are called Neutrophil extracellular traps (NETs) and helpful in controlling infections and are also responsible for worsening inflammation which can end up into cytokine storm [40,41]. In severe COVID-19 cases, an increased level of NETs have been found and is hypothesized that it is a crucial link inducing release of cytokines further leading to multi-organ damage [41-44]. However, on resolution of the infection or inflammation, the neutrophils undergo apoptosis and necrosis to maintain the homeostasis and prevent the body from prolonged damage by the neutrophils and released granules or reactive oxygen species [45]. This step of death of neutrophils in absence of inciting stimuli is crucial and increased rate of neutrophil clearance might need to neutropenia in certain conditions [46,47]. In the present study, the reasons for the events of neutropenia could not ascertained whether it was because of the resolution of the inflammation/cytokine storm or due to the drug tocilizumab.

Increased hepatic enzyme levels accounted for about 4.68% of the ADEs, whereas hepatitis accounted for 2.49%. The majority of the studies on COVID-19 patients reported higher values as compared to the present study. Campochiaro et al. reported a transient rise in liver enzymes in 15% of the tocilizumab treated patients [25]. Morena et al. had 29% of patients with abnormal hepatic enzymes. In contrast, Alattar et al. reported a rise of Alanine aminotransferase (ALT) in 44% of the patients [27,29]. Salvarani et al reported rise in alanine aminotransferase as the most common adverse event with 8% in tocilizumab group in comparison to 3% in standard care group [48]. Rimland et al. reported minimally elevated liver function tests in 64% of the patients, which was higher than other studies [49]. On the contrary, Stone et al. reported a lower rate of ALT (5.0%) and aspartate aminotransferase (AST) rise (3.7%) [31]. In contrast, Guaraldi et al. documented no evidence of AST elevation’s differential rate among treatment groups [18]. In a study performed by Gatti et al on the characterization of the adverse events reported with tocilizumab in the FDA Adverse Event Reporting system, several reports of hepatitis fulminant, acute hepatic failure and hepatic necrosis were observed [50].

This study observed varied rates of infections and infestations in the WHO database such as bacteremia (0.3%), Candida Infection (0.5%), Pneumonia of various etiology (1.6%), Staphylococcal Sepsis (0.40%), Septic Shock Syndrome (0.9%) and Staphylococcal Infection (0.4%). Studies conducted on COVID-19 patients using tocilizumab reported varied results. Bacteremia was reported in 27% of patients by Morena et al., 13% of patients by Campochiaro et al., 13% by Ip et al., 13.7% by Stone et al., and <1% by Guaraldi et al. [18,25,27,31,51]. Bacterial infections, superinfections, and related complications were seen in various studies with various proportions. A survey executed by Quartuccio et al. documented that 43% of patients had bacterial complications [30]. In contrast, Gorgolas et al. reported these in 6 · 3% of the patients [52]. Studies were done by Kimmig et al. (64.3% vs. 31.3%), Somers et al. (54% vs.26%), and Menzella et al. reported that patients treated with tocilizumab were almost twice as prone to developing secondary bacterial infections/superinfections as compared to the non-treated group [20,53,54]. Menzella et al. reported that most superinfections were ventilator-associated pneumonia, and Staphylococcus aureus was found to be the pathogen in about 50% of bacterial pneumonia cases [20]. Studies conducted by Ip et al. reported secondary pneumonia in 9% of the cases, and Campochiaro et al., documented cases of candidemia and invasive pulmonary aspergillosis in patients treated with tocilizumab [25,51]. Toniati et al. reported that two patients developed septic shock and later succumbed to it [24]. There were two reported cases of Herpes infection in the WHO database. Alattar et al., in their study, reported one case of herpes simplex virus reactivation [29]. Guaraldi et al., in their research, reported four cases of invasive aspergillosis, one case of hepatitis B virus reactivation, and four cases of herpes simplex virus reactivation, among which one patient died of severe hepatic failure due to hepatitis owing to severe herpes simplex virus [18].

These infections and superinfections could be due to suppression of the immune system by blocking the IL-6 pathway which is crucial in functioning of immune system by interplay between innate and adaptive immunity [55]. IL-6 as a cytokine which also acts as a differentiation factor for B cells that can instigate the activated B cells to synthesize immunoglobulins [56-58]. As IL-6 is crucial in the synthesis of antibodies which can directly fight against the foreign pathogens like viruses, a drug like tocilizumab which acts via blocking the IL-6 receptors might affect the body’s immune defense against the COVID-19 virus by suboptimal formation of immunoglobulins from the B cells [56,57]. However, literature reveals that studies done by Masiá et al. and Başaran et al. reported that tocilizumab administration in the COVID-19 patients did not lead to decreased antibody response to SARS-CoV-2 [56,59]. In support of the findings, Cabanov et al. also reported that tocilizumab do not hamper the production of anti-SARS-CoV-2 antibodies [60]. This finding was supported by previous study conducted by Mori et al. where they reported that tocilizumab did not affect the production of antibodies after influenza vaccination in patients with rheumatoid arthritis [61].

This study identified intestinal perforation in 1.19% of the patients. Toniati et al. reported that one patient developed gastrointestinal perforation while on treatment with tocilizumab [24]. Salvarani reported one serious adverse event in the form of gastrointestinal tract bleeding in patients receiving tocilizumab [48]. Among the skin and subcutaneous tissue disorders, a rash was reported in 0.60% of the cases in the WHO database. Higher numbers were reported by Morena et al., where a cutaneous rash was seen in 2% of the treated patients [27]. In cardiovascular ADEs, QT prolongation was seen in 0.10% and Atrial fibrillation in 0.2% of the patients in the WHO database. Alattar et al., in their study, reported a comparatively higher proportion of QT prolongation in 5 patients (20%) and Atrial fibrillation in one patient in their tocilizumab treated patients [29]. Acute kidney injury was reported in six patients in the WHO database, whereas Alattar et al. documented a single acute kidney injury case in their study [29]. Hypertriglyceridemia was seen in four cases in the WHO database. Alattar et al., in their series, reported two cases of hypertriglyceridemia, and evidence-based on its previous use in immunological disorders, hypercholesterolemia is among very common ADEs of tocilizumab [29].

On the contrary to the above findings, there were studies conducted by Rossi et al., Colaneri et al., Sciascia et al., Xu et al., and Sanchez-Montalvá et al. which concluded that they failed to note any adverse drug reactions deemed to use of tocilizumab in COVID-19 patients [62-65]. In the study performed by Veiga et al, adverse events were reported in 43% participants receiving tocilizumab in comparison to 34% in patients receiving standard care, out of which serious adverse events were in 16% in the tocilizumab group and 11% in the standard care group. However, they did not find any significant difference in the incidence of any specific adverse event between patients receiving tocilizumab and standard care [66].

Even though we do not have enough data regarding the safety of tocilizumab use in COVID-19 patients, safe prescribing in these patients can be predicted based on the previous safety data of its use in immunological diseases. The results in the WHO database and the trials are based on short-term studies on the COVID-19 patients. Extensive trials are essential to assess the safety of tocilizumab in COVID-19 patients. The publication of the results of tocilizumab use in the RECOVERY trial makes this a treatment option of choice.

Limitation of the study

Tocilizumab has not been used officially and commonly in treating patients with COVID-19 outside the RECOVERY trial; thus, less case information reports are available in the WHO database, which will probably highlight the common ADEs, whereas uncommon ones may be missed. The data in this study was taken from VigiBase where the information comes from varied sources. The probability of a suspected adverse effect to be caused by drug cannot be ascertained in all the cases. The information provided does not represent the opinion of the UMC or the World Health Organization.

Conclusion

Tocilizumab appears to be a relatively safe drug based on the WHO database’s available data, with small overall numbers of ADEs, reported. Neutropenia, elevated liver enzymes, superinfections, pneumonia, reactivation of herpes simplex, tuberculosis or hepatitis, hypertriglyceridemia, acute kidney injury, pulmonary embolism, rash, and cardiac abnormalities are prevalent ADEs in patients with COVID-19 infection, mostly in mild cases. Therefore, to generate evidence, long-term follow-up studies with a large sample size will enlighten medical science about unknown ADEs associated with tocilizumab in COVID-19 patients. According to this study, the findings suggest there are numerous adverse effects. Reports from randomized, double-blind controlled clinical trials will provide more safety information to enable evidence-based decision-making on the use of tocilizumab to treat patients with COVID-19.

In conclusion, tocilizumab is one of the drugs supported by trial data for the treatment of COVID–19. It is essential to assess tocilizumab’s efficacy and safety in COVID-19 based on available data from the trials and spontaneous reports. Patients given tocilizumab should be adequately monitored for altered full blood count, altered liver function, superinfections, and ECG changes during the treatment.

Recommendation

Clinicians using tocilizumab should monitor for the presence of neutropenia, changes in cellular blood values, rise in hepatic enzymes, the possibility of superinfection, reactivation of latent infections, and alteration ECG and plausible drug interactions and drug-disease interaction during the treatment to avoid adverse events and obtain better clinical outcomes.

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