key: cord-0729057-vmv2xrz7
authors: Keske, Şiran; Tekin, Süda; Sait, Bilgin; İrkören, Pelin; Kapmaz, Mahir; Çimen, Cansu; Uğur, Semra; Çelebi, İrfan; Bakır, Veli Oğuzalp; Palaoğlu, Erhan; Şentürk, Evren; Çağlayan, Benan; Çakar, Nahit; Tabak, Levent; Ergönül, Önder
title: Appropriate use of Tocilizumab in COVID-19 Infection
date: 2020-07-26
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.07.036
sha: 9a82a71b7ca488a6cf73a000307418d7915066d4
doc_id: 729057
cord_uid: vmv2xrz7

OBJECTIVE: We aimed to describe the effectiveness and optimum use of tocilizumab (TCZ) treatment by the support of clinical, laboratory, and radiologic observations. METHODS: All the patients were followed up in the hospital with daily interleukin-6 (IL-6), C-reactive protein (CRP), ferritin, D-dimer, complete blood count, and procalcitonin. Computerized thoracic tomography was obtained on admission, when oxygen support was necessary, and seven days after TCZ start. Disease course of the patients was grouped as severe or critical according to their clinical, laboratory, and radiologic evaluations. RESULTS: In total, 43 patients were included; 70% of the patients was male; the median age was 64 (min-max: 27-94), 6 (14%) patients were fatal. The median duration of oxygen support before the onset of TCZ was shorter among the severe patient group than the critical patient group (1 vs 4 days, p < 0.001). Only 3 cases out of 21 (14%) who received TCZ in the ward were transferred to ICU, and none of them died. The levels of IL-6, CRP, ferritin, D-dimer, and procalcitonin were significantly lower in severe cases group than the critical cases group (p = 0.025, p = 0.002, p = 0.008, p = 0.002, and p = 0.001, respectively). Radiological improvement was observed in severe cases on the seventh day of TCZ. Secondary bacterial infection was detected in 41% of critical cases, but none of the severe ones. CONCLUSION: Earlier use of TCZ in COVID-19 infection is beneficial for survival, length of hospitalization, and duration of oxygen support. Our recommendation for the administration of TCZ is based on the increase in requirement of the oxygen support, progression in the thorax computerized tomography, and elevation of inflammation markers, including IL-6, CRP, ferritin, and D-dimer and decrease in percent of lymphocyte.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus, which was the cause of pneumonia first seen in Wuhan, China, in December 2019 [1] . SARS-CoV-2 pneumonia was reported in many countries of the world, and the World Health Organization (WHO) declared the outbreak as a pandemic on March 11 th , 2020. Patients diagnosed with COVID-19 may have a wide range of symptoms from mild to severe. Fever, cough, and shortness of breath are the most common symptoms that have been reported [2] . Advanced age, underlying comorbidities such as hypertension, diabetes, cardiovascular disease, and cerebrovascular disease are the risk factors that have been reported for developing into severe to critical cases [3, 4] . The acute respiratory distress syndrome (ARDS) may develop in some of the patients, who are more likely to be fatal [5] . The cytokine storm causes ARDS and multiple organ failure, which occurs as a result of the macrophage activating syndrome (MAS) both in sepsis and COVID-19 [6, 7] . It has been reported that the serum levels of the cytokines, including IL-6, are higher in critical patients with COVID-19 [8, 9] . Hence, suppressing the cytokine storm seems to be an effective way to decrease the fatality [10] .

Tocilizumab (TCZ) is an anti-interleukin-6 (IL-6) receptor monoclonal antibody that inhibits signal transduction and used for the treatment of rheumatoid arthritis [11, 12] . Besides, TCZ J o u r n a l P r e -p r o o f has a significant effect on the treatment of infection-induced cytokine storm, and it might be effective in the treatment of critical patients with COVID-19 [13, 14] . However, the right placement and timing of TCZ in the treatment course is necessary.

We aimed to detail the benefit and appropriate timing for TCZ treatment in severe to critical cases with COVID-19 pneumonia. We described the secondary bacterial infections that could be associated with TCZ.

In this retrospective study, the patients who were infected with SARS-CoV-2 and received TCZ from March 10 th to April 14 th , 2020 at American Hospital and Koc University Hospital in Istanbul, Turkey were included. All the patients were followed up for at least 14 days at the hospital after the TCZ treatment. A COVID-19 team including infectious diseases, internal medicine, chest medicine, and intensive care unit physicians managed all the cases with weekly meetings and daily on-call and or bedside consultations.

Case definition of the WHO was used in diagnosis of COVID-19, including probable and confirmed cases [15] . The confirmation was defined as the positive laboratory result of COVID-19 infection, whereas the probable case was defined as inconclusive or a suspect case for whom testing could not be confirmed for any reason.

Blood oxygen level lower than 93% was accepted as decreased oxygen saturation. If necessary, oxygen support was given by nasal cannula, a venture mask, and non-invasive respiratory support or invasive mechanic ventilation.

In our study, the patients were categorized as severe or critical based on the severity of J o u r n a l P r e -p r o o f 5 infection [16] . The features of the severe cases were respiratory distress (≥30 breaths/min) or oxygen saturation ≤ 93% or arterial partial oxygen pressure (PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg. The features of the critical cases were respiratory failure requiring mechanical ventilation or shock or organ failure requiring ICU.

Primary outcomes were duration of oxygen requirement, being transferred to ICU, and the fatality. Secondary outcomes were the duration of oxygen support after using TCZ and the length of hospitalization.

All the suspected or confirmed adult cases with COVID-19 received hydroxychloroquine (or plus azithromycin) on admission according to the national protocol of Ministry of Health ( Figure 1 ). By April 1 st , 2020, since it became available, favipiravir was started to be used as an alternative in case of progression in radiological imaging or requirement of oxygen support.

TCZ was started in suspicion of cytokine storm by evaluating radiological progression, the requirement of oxygen support, CRP, IL-6, procalcitonin, LDH, ferritin, D-dimer level, leucocyte, lymphocyte, and platelet counts.

The initial dose of TCZ was 8 mg/kg based on Chinese Guideline [16] . If the first dose was not effective, one more dose was given at least 12 hours later. Informed consent was obtained from the cases if not available from their relatives. We followed up the cases in terms of adverse events with biosafety monitoring document.

Nasopharyngeal and oropharyngeal samples were tested for SARS-CoV-2 by real-time polymerase chain reaction in the laboratory of Koç University Hospital in Istanbul. 

Categorical variables were compared by using Chi-square test. For the continuous variables, non-parametric Kruskal-Wallis test was used because of the low sample size. The STATA 15v was used for the statistical analysis, and the statistical significance was set as p-value <0.05.

Institutional Review Board of Koç University approved the study with the reference number of 2020.143.IRB1.033.

Forty-three patients were included, 70% of the patients was male, the median age was 64 (min-max: 27-94), 63% was older than 60 years ( Table 1 ). The fever (91%) and cough (60%) were the most common symptoms. All the fatal cases were male and >60 years of age, the median age of fatal cases was higher than the survived ones (75 vs. 61, p=0.016, Table 1 ). Hypertension and diabetes mellitus were the most commonly detected comorbid diseases, and the comorbidities were similar between two groups ( Table 1 ).

The median duration of oxygen support before the onset of TCZ was 3.5 days in fatal cases and two days in survived ones (p=0.12). The duration from the onset of symptoms to the start of TCZ was similar among fatal and survived cases. None of severe cases, but three critical cases died (p=0.01, Table 1 ).

The laboratory results of the patients on the day of TCZ administration among fatal and non-fatal cases were summarized in Table 1 . IL-6 level was 337 pg/mL in fatal cases, while it was 126 pg/mL in survived cases (p=0.04). Ferritin, CRP, and D-dimer were found to be higher among the fatal cases than survived ones, with no statistical significance (Table 1) .

We compared the severe and critical cases ( Table 2) . The groups were similar in terms of age and comorbid diseases, while male gender was higher among critical cases (91% to 52%, p=0.005).

Favipiravir use among the severe and critical cases was similar (p=0.23, table 2). The median duration of oxygen support before the onset of TCZ was shorter among the severe cases than critical cases (1 vs 4 days, p<0.001). The median duration of oxygen support after, length of stay, and the total duration of hospitalization after administration of TCZ was shorter among the severe cases than critical cases (p<0.001, p=0.028 and p=0.001 respectively, Table 2 ). Only 3 severe cases out of 21 (14%) who were transferred to the ICU, and none of them died. In laboratory analysis, IL-6 was 115 in severe cases and 168 in critical cases (p=0.025). CRP, ferritin, D-dimer, and procalcitonin were significantly lower in severe cases (p=0.0029, p=0.008, p=0.002, and p=0.001, respectively). The lymphocyte percentage was 13.5% in severe cases and 11% in critical ones (p=0.007). Radiological imaging with CT was also examined before the onset of TCZ in most of the cases, and radiological improvement was also observed on the seventh day of TCZ in severe cases ( Figure 3 ).

After use of TCZ, the earliest change in laboratory tests was observed in the percentage of lymphocytes, which increased within the first day. The CRP declined one day after TCZ sharply. Two days after TCZ, IL-6 declined sharply, but ferritin and D-Dimer slightly. (Table 3 , Figure 2 ).

During ICU stay, secondary bacterial infections were detected in 9 (41%). In five cases (22%), [18] . IL-6 plays a significant role in cytokine storm [19] . TCZ is an anti-inflammatory drug that has the potential to decrease MAS induced cytokine storm was shown to be beneficial in COVID-19 in some case series [13, 20, 21] and a recent systematic review [22] . In our study, we observed that IL-6 was higher in fatal cases than survived cases.

In the early days of COVID-19 pandemics, because of the off-label use and insufficient data of efficacy and safety of TCZ, we could not start it in the early stages of the disease, so that we commonly used TCZ in ICU, where the cases could be intubated. In later days, the access to the drug became easier, then we started it earlier at the ward. By this application, no fatal cases and very low level of ICU admission was observed ( Table 2 ). The critical decision for TCZ use is the onset of the cytokine storm. After cytokine storm started, oxygen saturation decreased within hours to days by the increase in lung involvement. We compared inflammation parameters such as percent of lymphocyte, IL-6, CRP, ferritin, and D-dimer before and after administration of TCZ. Among severe cases, percent of lymphocyte increased in one day, CRP declined after one day, IL-6 after two days sharply, ferritin and D-Dimer after two days, slightly ( Figure 2 ). However, among the critical cases, IL-6 level did not decline and percent of lymphocyte did not increase (Figure 2 ). J o u r n a l P r e -p r o o f Among 9 out of 22 (41%) patients who were admitted in the ICU, secondary bacterial infections were detected. Secondary bacterial infections could not be related solely to TCZ use. However, secondary bacterial and fungal infections, including tuberculosis, should be kept in mind. The patients whose quantiferon test was positive should be evaluated for INH prophylaxis [23] .

Being an observational pre-post study was one of the limitations. During the study period, in later phase by using our experiences we started to give the TCZ earlier compared to the early phase. However, our patient distribution in severe and critical groups ( Table 1 ) allowed us to make a comparison of starting TCZ in severe or critical patient groups. In our clinical practice we grouped the patients according to clinical, radiological and laboratory criteria, and our categorization was in parallel with Chinese guideline, although this was not validated, yet.

There is no doubt about the need of randomized clinical studies for definite conclusion. 

A novel coronavirus outbreak of global health concern

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med

Cytokine storm and sepsis disease pathogenesis

The pathogenesis and treatment of the `Cytokine Storm' in COVID-19

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

Anti-interleukin 6 receptor antibody treatment in rheumatic disease

A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy

Off-label Use of Tocilizumab in Patients with SARS-CoV-2 Infection

Global surveillance for COVID-19 caused by human infection with COVID-19 virus

Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia

The cytokine release syndrome (CRS) of severe

Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

IL-6 as a keystone cytokine in health and disease

Effective treatment of severe COVID-19 patients with tocilizumab

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in severe patients with COVID-19

Supportive Treatment with Tocilizumab for COVID-19: A Systematic Review

Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics

/mL) 1197

Laboratory (on the day of TCZ) (median, min-max)

We thank to administrators of hospital management, Erhan Bulutçu, Ömür Erçelen, İsmail Bozkurt, Erdal Aksoy, and laboratory manager Erhan Palaoğlu