key: cord-1048624-qqa7gwrh
authors: Celik, Ilhami; Eryilmaz‐Eren, Esma; Kilinc‐Toker, Aysin; Eren, Didem; Yildiz, Merve; Kanat, Azade; Topaloglu, Ulas Serkan; Guzeldag, Seda; Kara, Mehmet; Ulu‐Kilic, Aysegul
title: Low‐dose tocilizumab is associated with improved outcome and a low risk of secondary infection in severe COVID‐19 pneumonia
date: 2021-11-11
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14997
sha: e81483bcd7b85c6e535406bb421068de3a23519f
doc_id: 1048624
cord_uid: qqa7gwrh

BACKGROUND: Respiratory failure and death are the leading causes of severe Coronavirus disease 2019 (COVID‐19). Hyper‐inflammation and cytokine storm cause lung damage. This study aimed to compare the low‐dose and high‐dose effects of tocilizumab, an IL‐6 receptor antagonist. METHOD: Patients with severe pneumonia and hyper‐inflammation signs because of COVID‐19 were included in this retrospective study. Patients receiving tocilizumab <200 mg intravenously were classified as the low‐dose group, and receiving ≥200 mg as the high‐dose group, and those not treated with tocilizumab as the control group. Demographic and clinical data of patients who died and survived in both low‐high dose and control patients were compared. According to symptom day and radiological infiltration, patients with tocilizumab were also evaluated in two groups as early and late periods at tocilizumab administration time. RESULTS: A total of 160 patients were included in the study; 70 were treated with a low dose and 50 with high‐dose tocilizumab. Forty patients were in the control group. Age, comorbidity and clinical features were similar in the control, low‐dose tocilizumab and high‐dose tocilizumab groups. The mortality rate (12.9%, 30.0%, 37.5, P = .008) was less in the low‐dose tocilizumab group. The secondary infection rate was higher in the high‐dose group than in the low‐dose tocilizumab and control groups (44.0%, 10.0%, 10.0%, P < .001). Distinguishing between those patients who died and survived, age (OR: 1.1589, P < .001), higher APACHE II scores (OR: 1.225, P = .001) and needs for non‐invasive mechanical ventilation (OR: 14.469, P < .001) were the most critical risk factors. Low‐dose tocilizumab was associated with a lower mortality rate (OR: 0.244, P = .012). CONCLUSION: The use of tocilizumab at a low dose is associated with lower secondary infections and mortality.

Globally, there have been more than 188 million confirmed cases of Coronavirus disease 2019 (COVID- 19) , with more than 4 million deaths have been reported from the first COVID-19 case was identified. 1 The most common symptoms of patients with COVID-19 are fever, cough and dyspnoea. Patients may have severe pneumonia, which leads to respiratory failure and death. 2 Severe COVID-19 patients are known to have cytokine release syndrome (CRS). IL-6, IL-2, IL-7, IL-10 and tumour necrosis factor (TNF) levels were higher in patients who need intensive care. 3 IL-6 levels were correlated with poor clinical outcome and SARS-CoV-2 RNAaemia in severely ill patients. 4 Tocilizumab (TCZ) is an anti-interleukin-6-receptor (IL-6R) monoclonal antibody used in rheumatological diseases. The first case in which TCZ was found effective was reported, in February 2020, in China. 5 Guaraldi et al treated 33 patients with severe pneumonia associated COVID-19, with TCZ and reported a positive effect on survival and respiratory function compared with the control group. 6 There are also reports claiming that the use of TCZ in the treatment of severe COVID-19 is ineffective for survival. 7 There is no consensus yet in the literature and there are different results. 8 TCZ-related side effects have also been reported. 9, 10 As a result of multiple side effects, especially secondary bacterial infections, low-dose TCZ recommendations have been attracting interest. 11, 12 Here, we aimed to evaluate the efficacy on clinical outcome and 28-day mortality, and side effects of low-dose TCZ compared with high doses.

This retrospective study was carried out in a tertiary hospital with a 1607 bed capacity, and 253 intensive care beds. Adult patients (>18 years old) treated with intravenous TCZ because of severe COVID-19 from 1 April 2020 to 31 December 2020 were included in this study.

TCZ treatment indications were determined as follows: lymphopenia (lymphocyte count, <0.80, ×10 9 /L), high CRP levels (>40 mg/ dL) and high D-dimer and ferritin levels.

The case group was defined as patients who received TCZ in addition to antiviral and supportive treatment. The age-and gender-matched control group consisted of the severe COVID-19 pneumonia patients who were followed up in the same period as the patients in the study group and had hyper-inflammation but did not use TCZ. Only antiviral and supportive treatments were given to the control group.

COVID-19 pneumonia was defined as I. SARS-CoV-2 PCR positivity in the upper respiratory tract samples and bilateral peripheral ground glass infiltration (typical for in the thorax computerised tomography (CT); or II. The rapid antibody test was positive and typical infiltration for COVID-19 in thorax CT. 13 Severe COVID-19 pneumonia was defined as fever and respiratory tract infection findings and the presence of one of the following: respiratory rate >30/min, defined as severe respiratory distress (dyspnoea, use of extra respiratory muscles), presence of oxygen saturation <90% in room air (PaO 2 /FiO 2 < 300 in the patient receiving oxygen). 14 Antiviral treatments were used for five days as a standard.

Their doses were, respectively, favipiravir; 3200 mg loading dose followed by 1600 mg/day maintenance dose, hydroxychloroquine; 400 mg/day following 800 mg loading dose and 100 mg/day following remdesivir 200 mg loading dose. Dexamethasone 8 mg/day and methylprednisolone 1 mg/kg were administered.

Patients with absolute contraindications (neutrophils <1 × 10 9 /L, platelets <100 × 10 9 /L, aspartate aminotransferase (AST) >3 × upper limit of normal or severely active bacterial or opportunistic infection)

were not treated with TCZ.

The patients diagnosed with cancer, undergoing any immunosuppressive therapy, mild or moderate COVID-19 clinic and intubated with COVID-19 were excluded from this study.

During the pandemic, a 400 mg vial of TCZ was used. The physicians determined the dose of TCZ. Each vial was divided into two to five patients, used with a 1-hour infusion in 100 cm 3 0.9% saline. Each vial was consumed within 24 hours of opening the vial. After administration of 80 or 100 mg, a further 80 or 100 mg repeat dose was administered within 24-48 hours.

Many patients with COVID-19 have acute lung damage and hypoxic respiratory failure, possibly caused by hyperinflammation. Interleukin-6 (IL-6) blockade was found to be beneficial in this process, but the most important disability of anti-inflammatory treatments are secondary infections.

The appropriate dose of tocilizumab in the COVID19 environment is unknown. In this study, we evaluated different doses of tocilizumab in COVID-19 patients. Randomised TCZ doses <200 were considered a low dose, and ≥200 as a high dose. 12 TCZ administration time was determined according to thorax CT imaging and duration of symptoms. If there was ground glass and duration of symptoms <7 days, it was defined as early period; if there was paving stone or fibrotic band and duration of symptoms >7 days, it was considered the late period. 15 

The collected information was processed using Statistical Package for 

Thirty-nine patients (24.3%) died within 28 days after TCZ infusion.

The differences between the patients who survived and did not survived are presented in Table 1 . Non-survivors were statistically significantly older than survivors (P = .002). Interlobular lines and fibrosis were more common in the non-survivor group (P = .009) and

they needed more non-invasive mechanical ventilation (P = .001) at the time they were included in the study. The rates of secondary infection, secondary bacterial infection and secondary fungal infection within 14 days after TCZ were higher in the non-survivor group (P < .001, P < .001 and P = .021, respectively) ( Table 1) .

In multivariate analysis, the older age (OR: 1.158, P < .001), Laboratory data of all patients are given in Table 2 . Before TCZ infusion, C-reactive protein (CRP) and D-dimer values were higher in the non-survivor group (P = .010 and P = .001). According to the laboratory findings evaluated on the seventh day of study; leukocyte, serum aspartate aminotransferase (AST), CRP, procalcitonin, D-dimer and fibrinogen levels were higher, and lymphocyte parameters were lower in the non-survivor group (P < .001, P = .008, P < .001, P = .001, P < .001, P = .007 and P < .001, respectively) ( Table 2 ).

Older age, demographic data, symptoms at admission, APACHE II scores, corticosteroid or antiviral treatment and respiratory support before TCZ of the patients treated with low-or high-dose TCZ and control group were similar (Table 3) . Within 14 days, secondary infections and secondary bacterial infections were higher in the highdose TCZ group than the low-dose TCZ and control groups (P < .001

and P < .001, respectively). The mortality rate was lower in the lowdose group (12.9%) than in the high-dose (30%) and control group.

The difference was statistically significant (P = .008). In paired comparisons, there was a significant difference between low-dose TCZ and high-dose TCZ groups with P = .036, low-dose TCZ and control groups with P = .004. Non-invasive mechanical Table 4 . The patients who received TCZ later were significantly older (P = .005). Gender, comorbid diseases, symptoms, antiviral and supportive treatment were similar (Table 4 ). More intubation was needed in the late period group was on the seventh day after treatment (36.7% vs 15.6%) (P = .02). The mortality rate with secondary bacterial infections was statistically higher among patients with late initiation (P = .035 and P = .032, respectively). Leukocytosis, CRP and procalcitonin were increased in non-survivor patients, and lymphocytes were decreased. Patients in the nonsurvivor group had higher C-reactive protein (CRP) and D-dimer values before TCZ infusion.

The most important limitation was that the IL-6 level was not measured. Based on previous studies, treatment was determined based on the idea that IL-6 levels were lower than sepsis. In addition, in the early initiation group, 56 patients were treated with low-dose TCZ, 34 patients were high-dose TCZ; in the late initiation group, 14 patients were low-dose treatment and 16 patients were high-dose treatment. In our study, when we divided patients into subgroups, the number of patients was relatively low. Another important limitation was that some clinical data, such as vasopressor dose or fluidelectrolyte balance, were not available because of the retrospective study. Further multicentre and randomised trials are needed to confirm the efficacy and safety of early administration of a low dose of TCZ in larger populations.

Early (within the first seven days of symptoms onset) and low-dose TCZ appear to contribute to recovery in severe COVID-19 pneumonia patients. At this point, the rational use of TCZ is essential. Older age and the need for non-invasive mechanical ventilation are factors affecting mortality. There was a lower secondary infection with lowdose TCZ.

This research was approved by the local ethics committee (Date: 01.10.2020, Number: 171).

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Low-dose tocilizumab is associated with improved outcome and a low risk of secondary infection in severe COVID-19 pneumonia