key: cord-1052686-0ly9ueg1
authors: Sarhan, Rania M.; Harb, Hadeer S.; Abou Warda, Ahmed E.; Salem-Bekhit, Mounir M.; Shakeel, Faiyaz; Alzahrani, Sami A.; Madney, Yasmin M.; Boshra, Marian S.
title: Efficacy of the early treatment with tocilizumab-hydroxychloroquine and tocilizumab-remdesivir in severe COVID-19 Patients
date: 2021-11-02
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.10.024
sha: 72566045f83170d97158ad7ca05350d2106fa377
doc_id: 1052686
cord_uid: 0ly9ueg1

BACKGROUND: The effectiveness of the best combination between different antiviral and anti-inflammatory drugs stills an interest in the treatment of COVID19 infection. PATIENTS AND METHODS: A prospective randomized cohort study comprised 108 adult patients with confirmed PCR COVID 19 infection with systemic hyper inflammation state, divided into two groups according to the treatment regimen, 56 in the tocilizumab- hydroxychloroquine (TCZ-HCQ) treatment, and 52 in the tocilizumab-remdesivir (TCZ-RMV) treatment. The first group received a combination of I.V. TCZ (400–800 mg every 24 hours for only two doses) and HCQ (400 mg twice in the first day then 200 mg twice for 5 days) while the second group of patients received I.V. RMV of 200 mg on day 1 followed by 100 mg once daily infused over 60 minutes for 5 days with the same TCZ regimen used in the first group. All clinical parameters and laboratory investigations were assessed before and after treatment. RESULTS: The CRP was significantly decreased while PaO2/FiO2 (P/F) ratio post-treatment was significantly improved in both treatment groups. TCZ-HCQ group showed a significant decrease in the ferritin, LDH, and D. Dimer levels. The median days of hospitalization with interquartile range (IQR) were 10 (6–16) and 8 (5–12) for TCZ-HCQ and TCZ-RMV groups, respectively. The numbers of mechanically ventilated patients were 25 and 43 for TCZ-HCQ and TCZ-RMV groups, respectively. Therapeutic failure was about 26.8% in the TCZ-HCQ group and 30.8% in the TCZ-RMV group but there was no significant difference between both groups. Some complications were recognized only in TCZ-RMV following treatment including secondary bacterial infections (42.3%), myocarditis (15.4%), and finally pulmonary embolism (7.7%). CONCLUSION: Efficacy of both TCZ-RMV and TCZ-HCQ combinations are observed in the treatment of severe COVID-19 patients; however the increased need for ICU or mechanical ventilation in the TCZ-RMV arm contributed to the appearance of cardiac and thrombotic events. The study was registered at the Clinical Trials registry (ClinicalTrials.gov; NCT04779047).

showed a significant decrease in the ferritin, LDH, and D. Dimer levels. The median days of hospitalization with interquartile range (IQR) were 10 (6-16) and 8 (5) (6) (7) (8) (9) (10) (11) (12) for TCZ-HCQ and TCZ-RMV groups, respectively. The numbers of mechanically ventilated patients were 25 and 43 for TCZ-HCQ and TCZ-RMV groups, respectively. Therapeutic failure was about 26.8% in the TCZ-HCQ group and 30.8% in the TCZ-RMV group but there was no significant difference between both groups. Some complications were recognized only in TCZ-RMV following treatment including secondary bacterial infections (42.3%), myocarditis (15.4%), and finally pulmonary embolism (7.7%).

Conclusion: Efficacy of both TCZ-RMV and TCZ-HCQ combinations are observed in the treatment of severe COVID-19 patients; however the increased need for ICU or mechanical ventilation in the TCZ-RMV arm contributed to the appearance of cardiac and thrombotic events.

Coronavirus disease 2019 (COVID-19) is considered a great issue all over the world nowadays. The elevated mortality rate, in severe acute respiratory syndrome coronavirus, is the core of the challenge (1) . The capacities of intensive care units (ICU) worldwide are challenged to encounter this outbreak. There is no therapy proven to be effective yet. Consequently, there is a great need for more research on treatments that can reduce the mortality rate and the number of critical cases (2) . Also, the rapid spread of COVID-19 infection created an urgent need for effective treatments against this type of viral pneumonia. Antivirals and immunomodulators are the main therapeutic agents that have been proposed for treatment. They are all subjected to many in-vitro, animal, and clinical trials. An improvement in preclinical results was demonstrated with these agents but till now no one of them was approved (3) .

Hydroxychloroquine (HCQ) is one of the immunomodulatory and antimalarial drugs that demonstrated antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (4). The antiviral effect of HCQ is attributed to its J o u r n a l P r e -p r o o f ability to elevate intracellular pH resulting in reduced phagolysosome fusion and impairing glycosylation of the viral receptor. On the other hand, the immunemodulating effect of HCQ is represented in inhibition of signaling of the toll-like receptor and reducing the production of IL-1 and IL-6 (5) . Also, previous studies suggested that HCQ may have an anti-thrombotic effect (6, 7) . Additional Studies, regarding HCQ associated clinical outcomes, are required. If the HCQ treatment is proved to be effective, a great precedent could be achieved in the management of COVID-19 especially in areas that have limited resources for health care (7, 8) On other hand, it was found that hydroxychloroquine was not able to reduce the viral loads in the upper or lower respiratory tract in hospitalized COVID 19 patients, despite its antiviral activity in many in vitro systems (9) .

Remdesivir (RMV), another antiviral drug, was used for the treatment of Ebola fever and Marburg virus disease. It was found to be effective against many single-stranded RNA viruses. It acts by therapeutically targeting RNA-dependent RNA polymerase, needed for RNA virus self-renewal (10) . Some randomized clinical trials suggested that RMV could help in improving the recovery for many hospitalized COVID-19 patients especially those who need supplemental oxygen therapy all over the world (11, 12) .

In many studies, the use of remdesivir in hospitalized COVID-19 patients has been demonstrated variability among health systems due to the differences in the severity of patients' cases and the protocols of treatment. In addition, it was found that it may not be associated with improvements in survival rates but was associated with longer days on hospital beds (13) (14) (15) .

Tocilizumab (TCZ) is a monoclonal antibody that is used in the treatment of systemic juvenile idiopathic arthritis and rheumatoid arthritis. It acts as an antagonist for the IL-6 receptor (16) . The drug was tested in many clinical trials for severe SARS-CoV-2 cases and was found to improve many laboratory parameters including reduction of C-reactive protein (CRP), Interleukin (IL-6), lactate dehydrogenase (LDH), ferritin, and Total Leukocyte Count (TLC). Also, it reduces lung complications, duration of hospitalization, needs for ICU admission and mechanical ventilation, and mortality rate (17) (18) (19) .

The exaggerated immune response and inflammation in severe COVID-19 patients motivate many clinical studies to use a combination of different drugs to be J o u r n a l P r e -p r o o f able to control viral infection (12) . The present study followed this recommendation in an attempt to find the best combination of medicines for severe cases of COVID-19 infection. Randomly, COVID 19 patients with cytokine storm were divided into two groups. Egyptian Ministry of Health COVID-19 protocol was followed in the management of the studied severe COVID-19 subjects. All study patients gave informed written consent and knew that their involvement is voluntary and was informed that they can withdraw from the study at any time.

Different demographic and clinical data were gathered as age, sex, recent exposure history, medical signs and symptoms, different comorbidities such as coronary artery disease, arterial hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and cancer. Blood laboratory test results at the time of admission, were reviewed and abstracted by senior medical physicians and charted in a J o u r n a l P r e -p r o o f computerized database for subsequent verification. The baseline of clinical status included body temperature, need for supplementary oxygen therapy, invasive or noninvasive ventilation, and also need for ICU admission. Chest computed tomographic (CT) scans were carried out for all studied subjects and the ratio of the lesion and its progression were recognized. Besides, serum inflammatory markers as LDH, CRP, and ferritin. Since clinical outcomes are poor predictors of avian influenza severity, as stated by American Thoracic Society guidelines for communityacquired pneumonia, evaluated cases were considered as severe or non-severe COVID-19 because of its worldwide acceptance. Comorbidities were categorized depending on the organ system, counting the respiratory, cardiovascular, and endocrine systems. Our study's endpoint was a composite measure that included the intensive-care unit, invasive ventilation, or death.

Patients included in the study who admitted to intensive care unit with confirmed COVID-19 infection through polymerase chain reaction (PCR); after one week of home isolation or after 7 days of inpatient isolation with significant clinical manifestation of systematic hyper inflammation defined as rapid deterioration in oxygen saturation (SaO 2 ) for less than 92% at ambient air or respiratory rate (RR) for more than 30, or PaO2/FiO2 ratio for less than 250; or in radiological findings of CT chest according to CO-RADS classification defined as worsening of lung involvement as an increase in the number and /or expansion of pulmonary areas of consolidation, need for increased FiO 2 to maintain stable O 2 saturation or worsening O 2 saturation of >3% with steady FiO2, as well as elevation on inflammatory marker C-reactive protein (CRP, ≥ 100 mg/L) or ferritin (≥ 900 ng/mL) and lactate dehydrogenase (LDH, >220 U/L) (20, 21) .

Pregnant or lactating women, known hypersensitivity to all drugs or any ingredients of the formulation, patients with other severe primary diseases, Serious co-morbidities, history of a psychiatric or neurological disorder, history of abuse 

To be eligible, all of the following criteria were essential: a) a normal body temperature for at least three days; b) better respiratory indicators; c) chest radiology indicating significant improvement in respiratory acute exudative lesions, and d) two consecutive negative PCR tests.

The clinical improvement or recovery of the patients was determined depending on many factors which included:

Include a) Oxygenation improvement defined as hospitalization not requiring low supplemental oxygen, or high flow oxygen or noninvasive or invasive ventilation (FiO2 < 40%) b) Duration of hospitalization, and c) Mortality rate. 

Descriptive analysis was performed where quantitative variables were reported as median with interquartile range (IQR) and categorical variables were described as numbers (percentage %). A Mann-Whitney U test was applied to compare clinical parameters between two treatment groups; (TCZ) plus (HCQ) group and TCZ plus (RMV) group. A Chi-square test was performed to locate the difference in categorical data (baseline patient characteristics and study outcomes) between the two groups.

Within the same treatment group, a Wilcoxon Signed Ranks test was used to compare the difference of the clinical parameters before (baseline values) and after drug administration (post-treatment values). A Pairwise Kendall rank correlation test was performed to estimate the correlation between study findings (clinical parameters and J o u r n a l P r e -p r o o f outcomes) and baseline patient characteristics. All tests were achieved using SPSS v 22.0 (SPSS, Chicago, USA) and significance was defined as p <0.05.

The baseline characteristics of patients were summarized in table 1. One hundred and eight patients were included in the study where 56 patients were treated with TCZ-HCQ and 52 patients were treated with the TCZ-RMV group. The median age of the TCZ-HCQ group and TCZ-RMV group was 53 (46-68) and 61 (52- (table 2) A weak correlation was found between the P/F ratio and mechanical ventilation need at entry (r= 0.321, p=0.004) and between the P/F ratio and heart failure comorbidity (r=0.322, p=0.004) in the TCZ-HCQ group. While LDH level following TZC-HCQ therapy was weakly correlated with baseline O2 saturation (r=-0.343, p<0.001) and heart failure (r= -0.319, p= 0.004).

Shifting to study outcomes (table 3) 

In this prospective, cohort study of cases with severe COVID-19, patients were randomly allocated into two treatment groups; either receiving TCZ-HCQ or TCZ-RMV. Both of them showed significant clinical improvement in CRP level and P/F ratio after completion of study doses with nearly similar LOS and mortality. It could be attributed to the significant therapeutic effects of TCZ which prove its superiority when combined with the standard management of moderate to severe COVID-19 cases as repeatedly reported in recent studies (18, 22) . As a monoclonal antibody, it targets the IL-6 pathways to calm the inflammatory storm and decrease mortality (23, 24) . Moreover, both HCQ and RMV were proven to prevent the in-vitro SARS-CoV-2 growth owing to non-specific, antiviral activity (25) .

On the other hand, the decline in LDH level, D-Dimer and ferritin level was only significant in the TCZ-HCQ group. Even worse, the TCZ-RMV group showed a nonsignificant increase in serum ferritin level after receiving therapy. The design of this study may contribute to the poor clinical outcomes of the TCZ-RMV group due to significant differences in baseline clinical parameters between the two groups including; higher age, serum creatinine, mechanical ventilation need, ICU admission, and lower oxygen saturation% in the TCZ-RMV group. Also, there was an unequal distribution of gender in both two groups (including males more than females). The COVID-19 infection more commonly affects older males with comorbidities and can cause fatal respiratory disorders including acute respiratory distress syndrome (ARDS) (26) (27) (28) . On the other hand, more favorable outcomes were expected to be achieved with females if compared to males (29) . Moreover, the higher need for oxygen therapy and mechanical ventilation results in increasing admission in the ICU and affects clinical outcomes despite receiving therapy (27, 30) .

Although the number of COVID-19 patients studied for HCQ in trials was found to be significantly larger than the number of COVID-19 patients studied for RMV; RMV has been reported as an active agent against SARS-CoV-2 in vitro J o u r n a l P r e -p r o o f testing. Also, an adequate clinical safety profile for RMV was reported in about 500 healthy volunteers and patients infected with acute Ebola virus (31, 32) . Also, a previous study has found that RMV can decrease the risk of progression and shorten the time needed for recovery in COVID-19 patients who are early diagnosed with increased risk of hyper inflammation and the need for oxygen supplementation (33) . In our study's findings, there was no significant difference between TCZ-HCQ and TCZ-RMV in both therapeutic failure and mortality rates which is indicating that both HCQ and RMV could be considered equally safe when used for treating severe COVID-19 patients. The mortality rate in both groups was comparable to many previous studies (18, 27) , higher than some reported rates of 4.3-11% (26, 30) , and lower than others reporting mortality of 60.5% (34) , which is attributed to different patient characteristics (18) . On the other hand, other previous studies did not agree with the clinical efficacy of TCZ, RMV, and HCQ in the treatment of COVID-19

patients (35) (36) (37) Liver enzymes (ALT and AST) significantly increased in both treatment groups after therapy. No superiority of RMV in liver injury was found, which disagrees with previous findings (38, 39) . This could be explained on the basis that antivirals were proven to cause hepatocellular injury (39, 40) . Also, there are limited and contradictory data regarding the use of TCZ in COVID-19 treatment in clinical practice. A previous study reported Liver injury and hepatic interactions after TCZ administration in COVID-19 cases, another study observed clinical improvement of respiratory symptoms without any adverse events with its use, while a previous case series reported a resolution of liver function elevation, resulted from previous treatment with different antivirals or as an inflammatory response; after 3 weeks of administration of TCZ (41) (42) (43) . Also, it was repeatedly reported that SARS-CoV-2 infection contributes to aminotransferase elevation which necessitates close monitoring of liver functions in COVID-19 patients especially those with prior liver disease (39, (44) (45) (46) . In addition, previous studies found an exponential increase in aminotransferases with increased disease severity of COVID-19 cases or increased need for intensive care unit admission (47, 48) . Consequently, the definite cause of liver function elevation in all studied patients is difficult to be determined, but it is advisable to make a follow-up for aminotransferases before, during, and after treatment in COVID-19 patients to avoid liver injury. Several studies indicated that cardiac events and myocarditis were common in hospitalized patients due to COVID-19 infection and this was attributed to the elevation in cardiac enzymes as troponin and lactate dehydrogenase (LDH) (51, 52) .

On the other hand, elevation in the level of troponin was observed in hospitalized COVID -19 patients taking remdesivir. Besides, these adverse events were more common for patients who were mechanically ventilated compared to those who were not (31). Wang et al showed that the use of remdesivir therapy was related to hyponatremia and hypokalemia which was the leading cause of discontinuing remdesivir in some patients (53). In addition, as in our study, C Rafaniello showed that remdesivir was associated with a two-fold increased risk in cardiac adverse reactions compared to both hydroxychloroquine and azithromycin (54) . Again, the elevated number of mechanically ventilated patients in the TCZ-RMV group, compared to the TCZ-HCQ group, might contribute to the detection of myocarditis either due to mechanical ventilation or the use of RMV. Taking into consideration the level of LDH as a cardiac enzyme, although the baseline of LDH was elevated in the TCZ-HCQ group than the other group, the decline in LDH level was only significant in the TCZ-HCQ. This can be attributed to the increased need for mechanical ventilation in the TCZ-RMV group. Further studies are required to examine the impact of both HCQ or RMV regarding the appearance of myocarditis taking into consideration the need for mechanical ventilation of patients to clarify their safety.

Although all patients included in the study had cytokine storm, pulmonary embolism was recognized only in the TCZ-RMV group. According to a previous study, despite the reduction in the inflammatory markers by using TCZ and following a proactive anticoagulative way in treatment, in SARS-CoV-2 patients with acute respiratory distress syndrome, thrombotic events were also observed. This can raise concerns regarding the role played by COVID-19 in the coagulative pathways (55) . This fact has been reflected in our study in the arm that included a higher number of mechanically ventilated patients with a higher need for ICU admission. Consequently, it can be assumed that an increased need for ICU or mechanical ventilation may be followed by an increased risk of thrombotic events.

A previous study has been found that the baseline characteristics of patients, such as hypertension and older age, could affect treatment outcomes especially increased mortality (56) . On the other hand, in the present study population, only weak correlations were identified in both treatment groups between study outcomes and baseline patient characteristics in agreement with previous findings, which demonstrated that coexisting conditions, days of symptoms, sex, and enrollment region before initiation of treatment had no significant association with clinical improvement (31) . One explanation of that is the fact that SARS-CoV-2 appears to have tropism for diverse tissues including primarily the respiratory tract but also the heart, brain, liver, and kidney (48). 

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