Receptor Antibody Tocilizumab Research Articles

Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis

Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81–0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.

CNSC-26. GLIOBLASTOMA-NEURONAL CIRCUIT INTEGRATION IS MODULATED BY INTERLEUKIN-6

Abstract The pleiotropic cytokine interleukin-6 (IL-6) is known to be involved in both pro- and anti-inflammatory signaling cascades. In glioblastoma studies using animal and human models, IL-6 promotes immunosuppression and tumor progression and is negatively associated with survival. Intriguingly, IL-6 also contributes to increased synaptogenesis during development and following focal brain injury. Glioblastoma remodeling of neuronal circuits influences patient survival; therefore, it is possible that IL-6 has mechanistic significance. Here, we investigated IL-6 as a driver of activity-dependent glioblastoma proliferation using patient-derived xenograft (PDX) mouse and human glioblastoma models. We assessed neuronal activity by microelectrode arrays and in vitro calcium imaging using weighted mean firing rate (WMFR), network burst frequency (NBF), and synchrony index. Next, we used bulk and single-cell RNA sequencing on 13,731 cells from ten tumors including pair-matched samples to identify differentially expressed genes in intratumoral regions with elevated functional connectivity and found IL6 to be highly upregulated. Mouse embryonic cortical neurons and cerebral organoids co-cultured with primary patient-derived glioblastoma cells demonstrated concentration-dependent neuronal hyperexcitability (increased WMFR and NBF) in IL-6-overexpressing conditions compared to the neuron-only condition. Pharmacological inhibition using the humanized IL-6 receptor antibody tocilizumab reduced network synchrony across models. These findings suggest that IL-6-induced glioma-neuronal hyperexcitability may be inhibited by the FDA-approved tocilizumab, thereby providing preclinical support for its use to treat activity-dependent mechanisms of glioblastoma proliferation. Future studies are needed to uncover mechanisms and clinical efficacy.

IL-6 blockade for Behçet's disease: review on 31 anti-TNF naive and 45 anti-TNF experienced patients.

Despite the remarkable efficacy of anti-TNF agents in Behçet's disease (BD), unmet therapeutic needs for refractory or intolerant patients to these drugs still exist. Based on evidence implicating IL-6 in the pathogenesis of BD, we summarise the current experience on the off-label administration of the anti-IL-6 receptor antibody tocilizumab for BD refractory to disease-modifying anti-rheumatic drugs. We searched PubMed and EMBASE for original articles published through December 2021 reporting on the use of tocilizumab for BD. We retrieved 25 articles fulfilling our search criteria, reporting on a total of 74 patients of whom 31 were anti- TNF naive; 2 additional anti-TNF experienced patients were included. The vast majority (72 of 76) received the standard intravenous dose of tocilizumab, whereas the total follow-up, including also post-treatment follow-up in many patients, ranged from 2 to 84 months without new safety issues. Tocilizumab was given in anti-TNF naive patients predominantly for vascular (n=16), central nervous system (n=7) and ocular involvement (n=5). On the other hand, anti-TNF experienced patients received tocilizumab predominantly for ocular (n=28), central nervous system (n=8) and mucocutaneous involvement (n=6). Tocilizumab was effective in 87% of anti-TNF naive (13 and 14 with complete and partial remission, respectively) and in 80% of anti-TNF experienced patients (17 and 19 with complete and partial remission, respectively). Although preliminary, evidence published so far suggests that IL-6 inhibition is a legitimate therapeutic option for BD patients with refractory ocular, CNS and vascular involvement. Controlled studies are clearly needed.

Tocilizumab for the Treatment of Familial Mediterranean Fever-A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician’s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.

Effect of Tocilizumab on "Ventilator Free Days" Composite Outcome in SARS-CoV-2 Patients: A Retrospective Competing Risk Analysis.

SARS-CoV-2 infection demonstrates a wide range of severity. More severe cases demonstrate a cytokine storm with elevated serum interleukin-6, hence IL-6 receptor antibody tocilizumab was tried for the management of severe cases. Effect of tocilizumab on ventilator-free days among critically ill SARS-CoV-2 patients. Retrospective propensity score matching study, comparing mechanically ventilated patients who received tocilizumab to a control group. 29 patients in the intervention group were compared to 29 controls. Matched groups were similar. Ventilator-free days were more numerous in the intervention group (SHR 2.7, 95% CI: 1.2 - 6.3; p = 0.02), ICU mortality rate was not different (37.9% versus 62%, p = 0.1), actual ventilator-free periods were significantly longer in tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio of death in tocilizumab group (HR 0.49, 95% CI: 0.25 - 0.97; p = 0.04). There was no difference in positive cultures among groups (55.2% in tocilizumab group versus 34.5% in the control; p = 0.1). Tocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated SARS-CoV-2 patients; it is associated with significantly longer actual ventilator-free periods, and insignificantly lower mortality and higher superinfection.

“Ventilator-free days” composite outcome in patients with SARS-CoV-2 infection treated with tocilizumab: A retrospective competing risk analysis

BackgroundSARS-CoV-2 infection demonstrates a wide range of severity, with more severe cases presenting with a cytokine storm with elevated serum interleukin-6; hence, the interleukin-6 receptor antibody tocilizumab was used for the management of severe cases. ObjectiveTo explore the effect of tocilizumab on ventilator-free day composite outcomes among critically ill patients with SARS-CoV-2 infection. MethodsThis retrospective propensity score-matching study compared mechanically ventilated patients who received tocilizumab to a control group. ResultsTwenty-nine patients in the intervention group were compared to 29 controls. The matched groups were similar. The ventilator-free days composite outcome was higher in the intervention group (sub-distribution hazard ratio 2.7, 95% confidence interval [CI]: 1.2–6.3; p = 0.02), the mortality rate in the intensive care unit was not different (37.9% vs 62%, p = 0.1), and actual ventilator-free days were significantly longer in the tocilizumab group (mean difference 4.7 days; p = 0.02). Sensitivity analysis showed a significantly lower hazard ratio for death in the tocilizumab group (HR 0.49, 95% CI: 0.25–0.97; p = 0.04). Positive cultures were not significantly different among the groups (55.2% vs 34.5% in the tocilizumab and control groups, respectively; p = 0.1). ConclusionsTocilizumab may improve the composite outcome of ventilator-free days at day 28 among mechanically ventilated patients with SARS-CoV-2 infection. It is associated with significantly longer actual ventilator-free days, insignificantly lower mortality, and higher superinfection.

A Case of COVID-19 with Acute Exacerbation after Anti-Inflammatory Treatment

A COVID-19 patient (53-year-old woman from Japan) was admitted to our hospital. She had a high fever (38.3 °C), cough, fatigue, and loss of appetite. She was a smoker and took migraine medication. A thoracic computed tomography (CT) scan showed no evidence of pneumonia. She was treated with antibiotics, protease inhibitors, inhalant corticosteroids, and antivirals. Anti-interleukin-6 receptor antibody tocilizumab (TCZ 400 mg) was added on day 2. On day 4, her temperature decreased, but her vital signs suddenly worsened, with an SpO2 of 70% in ambient air, a blood pressure of 70 mmHg (systolic), loss of consciousness, and tachypnea. Her CT showed bilateral lung consolidation and no pulmonary embolism. She was connected to the ventilator. On day 11, her respiratory condition improved (PaO2/FIO2 400), and she was able to withdraw from the ventilator. Her laboratory data (white cell count, ferritin, d-Dimer, C-reactive protein, and β2-microglobulin) did not increase even at the time of exacerbation, except for Galectin-9 (Gal-9). The plasma Gal-9 levels increased 2.3 times from before the administration of TCZ, followed by a swift decrease associated with improvements in respiratory status. She was discharged on day 16. Patients with TCZ-treated COVID-19 require careful observation.

Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade.

Interleukin-6 (IL-6) is implicated in skeletal muscle wasting and in regulating skeletal muscle hypertrophy in the healthy state. This work aimed to determine the role of IL-6 in regulating systemic protein and amino acid metabolism during rest, exercise, and recovery in lean and obese humans. In a nonrandomized, single-blind design, 12 lean and 9 obese individuals were infused first with 0.9% saline (Saline), secondly with the IL-6 receptor antibody tocilizumab (Acute IL-6R ab), and 21 days later with saline while still under tocilizumab influence (Chronic IL-6R ab). Outcome measures were determined before, during, and after 90 minutes of exercise at 40% Wattmax by isotope dilution technique, using primed continuous infusion of L-[ring-D5]phenylalanine and L-[D2]tyrosine. Main outcomes measures included systemic protein turnover and plasma amino acid concentrations. We saw no effect of acute or chronic IL-6 receptor blockade on protein turnover. In lean individuals, chronic IL-6 receptor blockade increased plasma concentrations of total amino acids (rest Δ + 186 μmol/L; 95% CI, 40-332; recovery Δ + 201 μmol/L; 95% CI, 55-347) and essential amino acids (rest Δ + 43 μmol/L; 95% CI, 12-76; recovery Δ + 45 μmol/L; 95% CI, 13-77) independently of exercise but had no such effect in obese individuals (total amino acids rest Δ + 63 μmol/L; 95% CI, -170 to 295, recovery Δ - 23 μmol/L, 95% CI, -256 to 210; essential amino acids rest Δ + 26 μmol/L; 95% CI, -21 to 73, recovery Δ + 11 μmol/L; 95% CI, -36 to 58). IL-6 receptor blockade has no effect on protein turnover in fasting lean and obese humans during rest, exercise, and recovery. Chronic IL-6 receptor blockade increases total and essential amino acid concentrations only in lean individuals.

Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway

Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1−/− explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.

Diagnostics and treatment of giant cell arteritis

Die Riesenzellarteriitis (RZA) ist in der Altersgruppe der über 50-Jährigen die häufigste idiopathische systemische Vaskulitis. Die Erkrankung bedarf einer zeitnahen Diagnostik und Therapie, um schwere Komplikationen wie eine Erblindung oder einen Schlaganfall zu vermeiden. Die Rezidivneigung erfordert eine mehrjährige, zum Teil lebenslange Glukokortikoid(GC)-Therapie, was das Risiko GC-induzierter Langzeitnebenwirkungen erhöht. Daher wird bei der Mehrzahl der Patienten eine additive GC-einsparende Therapie empfohlen. Hierzu steht der Anti-IL-6-Rezeptor-Antikörper Tocilizumab in subkutaner Applikation als zugelassene Substanz zur Verfügung, alternativ kann Methotrexat (MTX) eingesetzt werden (off-label).

1685P COLAR: Results from an intervention study investigating IL-6 blockade with tocilizumab for treatment of immune checkpoint inhibitor induced colitis and arthritis

Immune checkpoint inhibitors (ICIs) may induce serious and even lethal immune related (ir) adverse events (AEs) in any organ. The pathophysiology underlying ir-AEs is not fully explained, however, increased production of proinflammatory cytokines such as interleukin (IL)-6, has a central role. This study investigated the efficacy of the IL-6 receptor antibody tocilizumab (TCZ), for the treatment of ir-arthritis and ir-colitis among cancer patients treated with ICI.

Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men

SummaryLack of interleukin-6 (IL-6) leads to expansion of adipose tissue mass in rodents and humans. The exact underlying mechanisms have not been identified. In this placebo-controlled, non-randomized, participant-blinded crossover study, we use the IL-6 receptor antibody tocilizumab to investigate the role of endogenous IL-6 in regulating systemic energy metabolism at rest and during exercise and recovery in lean and obese men using tracer dilution methodology. Tocilizumab reduces fatty acid appearance in the circulation under all conditions in lean and obese individuals, whereas lipolysis (the rate of glycerol appearance into the circulation) is mostly unaffected. The fact that fatty acid oxidation is unaffected by IL-6 receptor blockade suggests increased re-esterification of fatty acids. Glucose kinetics are unaffected. We find that blocking endogenous IL-6 signaling with tocilizumab impairs fat mobilization, which may contribute to expansion of adipose tissue mass and, thus, affect the health of individuals undergoing anti-IL-6 therapy (Clinicaltrials.gov: NCT03967691).

Drug efficacy and safety of biologics and Janus kinase inhibitors in elderly patients with rheumatoid arthritis.

Elderly patients with rheumatoid arthritis (RA) are frequently associated with higher disease activity and impaired physical function, although they show intolerance for conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, because of their comorbidities. However, the present treatment recommendation based on randomized controlled trials is not distinguished by age or comorbidities. Therefore, this review aimed to investigate the efficacy and safety of biological DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi) in elderly patients. Present bDMARDs, including tumor necrosis factor inhibitors (TNFi), cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (abatacept), interleukin (IL)-6 receptor antibody (tocilizumab and salirumab), and anti-CD20 antibody (rituximab), may be similarly or slightly less effective or safe in elderly patients compared with younger patients. Oral glucocorticoid use, prolonged disease duration, and very old patients appear to be associated with an increased risk of adverse events, such as serious infection. Some recent cohort studies demonstrated that non-TNFi showed better retention than TNFi in elderly patients. Both TNFi and non-TNFi agents may not strongly influence the risk of adverse events such as cardiovascular events and malignancy in elderly patients. Regarding JAKi, the efficacy appears to be similar, although the safety (particularly for serious infections, including herpes zoster) may be attenuated by aging.

Difficulties of biological therapy in the patient with active rheumatoid arthritis and secondary renal amyloidosis: A report of clinical case

A clinical case of a patient with active rheumatoid arthritis (RA) resistant to standard basic therapy is presented, which served as the reason for the appointment of the target drug – Janus kinase, tofacitinib (Jaquinus) and then biological therapy using anti-IL6 receptor antibody tocilizumab (Actemra). This clinical example demonstrates the patient with the presence of several complications, both the course of the disease – amyloid nephropathy with the development of nephrotic syndrome (NS) as a manifestation of secondary amyloidosis with kidney damage, as well as basic therapy – the presence of comorbid infections with hospital pneumonia and infectious (septic) knee arthritis.An additional contribution of NS to the development of infectious complications in patients with RA receiving immunosuppressive therapy is supposed. Current treatment options for resistant RA and the feasibility of early use of biologics before the development of irreversible complications, as well as the difficulties of therapy and the complications associated with immunosuppression are discussed. Preventive measures for immunization with the anti-pneumococcal vaccine and the need to correct hemostatic disorders in patients with RA and NS are important.

Designing a bispecific antibody targeting IL-6Rα and NKG2A receptors via in silico affinity maturation as a strategy to combat severe COVID-19

Abstract High mortality in COVID-19 patients has been encountered with acute respiratory distress syndrome (ARDS). Cytokine storm has been observed as a reason for this severity in critical cases showcasing high levels of circulating cytokines along with a pronounced decrease in cytotoxic T lymphocytes and Natural Killer Cell populations. The Interleukin-6 amplifier, the activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells has been widely discussed as an initiator of this cytokine release syndrome. The anti-IL-6α receptor antibody tocilizumab has shown success in recovery when administered to critical COVID-19 patients. Additionally, increased release of IL-6 is shown to elicit immune cell disproportionation by upregulating inhibitory NKG2A receptors on NK cell surface, causing blunting of the host’s antiviral response. This study proposes a bispecific immuno-modulatory antibody with one Fab blocking IL-6α-receptor and the other blocking NKG2A receptor to counter hyper-inflammatory cascades and recruit NK cells to the site of viral infection, respectively. Computational site directed mutagenesis was performed to design a library of increased binding affinity mutants of tocilizumab and NKG2A inhibitory monalizumab, followed by docking studies, molecular dynamics simulations, MM-PBSA analysis to study stability of the bispecific assembly in physiologically relevant conditions. This approach utilizing immunomodulation for simultaneous recruitment of antiviral immunity and regulation of hyper-inflammatory host responses may present a potent strategy for combatting critical stage COVID-19 and thereby help in curbing COVID-19 related mortality.

Successful Treatment of AA Amyloidosis in Ankylosing Spondylitis Using Tocilizumab: Report of Two Cases and Review of the Literature.

Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis.

The Effect of Tocilizumab on Inflammatory Markers in Patients Hospitalized with Serious Infections. Case Series and Review of Literature.

Background: The human anti-IL-6 receptor antibody tocilizumab (TCZ) has been approved for the treatment of rheumatoid arthritis (RA) and giant cell arteritis (GCA). It is observed that CRP levels drop quickly after starting TCZ treatment. This may lead to misinterpretation of laboratory results when accessing the patient with infectious disease while on TCZ. We conducted this study to report cases treated with tocilizumab who developed serious infections with special reference to levels of CRP and to review the literature on the effect of tocilizumab on acute phase response (APR) during infections. Methods: The files of RA and GCA patients hospitalized in the Tel Aviv medical center between 2009–2019 were reviewed. Cases of patients with RA and GCA treated with tocilizumab who were hospitalized due to severe infections were reviewed with special emphasis on the duration of treatment, type of infection, and APR. Results: We identified nine admissions. Seven patients were treated with tocilizumab for RA, two for GCA. The diagnosis was pneumonia in three cases, osteomyelitis in one, cellulitis in one, endocarditis due to Whipple disease in one, abscess of cervix uteri in one, meningitis in one, and perforated diverticulitis in one. The mean CRP levels on admission were 4.75 mg/L (normal range, up to 5 mg/L). All cases were diagnosed correctly on admission. Conclusions: CRP levels may not correctly reflect the severity of infectious diseases during tocilizumab treatment. Increased awareness of the masking effect of tocilizumab on the APR during infection is needed in order to avoid a delay in the diagnosis.

IL-6: from arthritis to CAR-T-cell therapy and COVID-19.

Blockade of interleukin (IL)-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T cell therapy and COVID-19 is then discussed.

Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial

BackgroundGlobal randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country.MethodsCOVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369).Findings180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference −3·71 [95% CI −18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study.InterpretationRoutine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies.FundingMedanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.

Respiratory virus infections after hematopoietic cell transplantation

Respiratory viral infection is a common disease even among immunocompetent individuals. Moreover, approximately 40% of the hematopoietic cell transplantation (HCT) recipients suffer from a respiratory infection within 100 days after HCT. New respiratory viruses have been continuously identified in the past 20 years, such as new strains of coronaviruses (CoV), human metapneumovirus (HMPV), and human bocavirus (BoV). In 2019, severe acute respiratory syndrome coronavirus (SARS-CoV)-2 that caused the coronavirus disease (COVID)-19 pandemic was identified. The 30-day overall survival after lower respiratory tract disease (LRTD) due to CoV, including SARS-CoV-2 or HMPV, was 60-70%, which is similar to that after LRTD due to influenza or respiratory syncytial virus. However, whether BoV is a pathogen of LRTD remains unclear. Moreover, corticosteroid has been reported as an efficient drug for LRTD due to SARS-CoV-2. Antiviral drug (remdesivir), anti-IL-6 receptor antibody (tocilizumab), and JAK inhibitor (ruxolitinib) are also expected to be efficient for the treatment of COVID-19. Thus, managing respiratory viruses in HCT recipients needs to be learned based on experiences from the COVID-19 pandemic.