We report the first case of coronavirus disease 2019 (COVID-19) in a multiple myeloma patient successfully treated with tocilizumab.Although tocilizumab was effective in the treatment of COVID-19 in this case, randomized controlled trials are needed.
Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6), emerged as an alternative treatment for COVID-19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID-19 infected patients. The demographic, treatment, laboratory parameters of C-reactive protein (CRP) and IL-6 before and after TCZ therapy and clinical outcome in the 15 COVID-19 patients were retrospectively assessed. Totally 15 patients with COVID-19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL-6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL-6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL-6, the repeated dose of the TCZ is recommended.
The COVID-19 pandemic, which has exhausted the momentum in China, is still in the exponential phase in the rest of the world, without even reaching the peak.
There are currently no effective prophylactic or post exposure therapies. In patients infected with SARSCoV-2, it has been described that disease severity and outcomes are related to the characteristics of the immune response. Interleukin (IL)-6 and other components of the inflammatory cascade contribute to host defense against infections. However, exaggerated synthesis of IL-6 can lead to an acute severe systemic inflammatory response known as cytokine release syndrome (CRS). In the pathogenesis of SARS-CoV-2 pneumonia, a study found that a CRS involving a considerable release of pro inflammatory cytokines occurred, including IL-6, IL-12, and tumor necrosis factor α (TNF-α).
The paper published in this issue by Fu et al., reports preliminary data collected from 21 patients with SARSCoV-2- induced ARDS treated with tocilizumab. In this single arm study, patients with moderate to severe COVID-19 disease received one or two doses of tocilizumab (400 mg/dose) in addition to standard therapies used including lopinavir and methylprednisolone as reported in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (6th interim edition). Most patients experienced clinical improvement including lower oxygen requirement (15/21, 75%), decrease of CRP, increase in lymphocyte levels, decreased fever and improved chest tightness. Two patients were taken of the ventilator within 5 days after the treatment with tocilizumab, another one improved significantly.
Until that time, it seems plausible to speculate that the anti-IL6R mAb plays a protective role if given at the time of overly elevated immune response to the virus, thus preventing “anaphylactic toxicity”. Such extreme cytokine reaction is accompanied by infiltration of inflammatory monocytes/macrophages (IMM) into the lung and elevated production of the pro-inflammatory cytokines (IL-1, IL-6, IL-8, CXCL-10, and MCP-1). These events are associated with severe lung damage, characterized by profound vascular leakage, and death. In this context the anti-IL6R may only be controlling the “cytokine storm” without deleterious effect on virus replication.
The world is in the midst of the coronavirus disease 2019 (COVID-19) pandemic. Interleukin 6 (IL-6) inhibitor (tocilizumab) had been suggested for the treatment of acute respiratory distress syndrome (ARDS) patients based on the concept of “cytokine storm” in COVID-19. However, we still lack reliable studies to verify “cytokine storm” in COVID-19 pneumonia. Furthermore, IL-6 inhibitor has potential hazards of inducing infectious diseases. The efficacy of IL-6 monoclonal antibody-directed therapy remains to be fully evaluated.
A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response.
The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10.
In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.
After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways.
Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab.
Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.
A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died.
The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm.
Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.
We report the case of a 57-year-old woman with systemic sclerosis (SSc) who developed COVID-19. Comorbidities were insulin dependent type 2 diabetes mellitus and WHO grade I obesity. The anti-topoisomerase I antibody-positive patient was diagnosed with SSc in 2017. SSc-associated interstitial lung disease (SSc-ILD), with cough and exertion dyspnoea, was the leading organ manifestation, associated with symmetrical, non-erosive polyarthritis, and elevated acute phase reactants. Treatment with the anti-interleukin (IL) 6 receptor blocker tocilizumab, with 8mg/kg body weight every 4 weeks intravenously, was started, leading to a good control of both arthritis and SSc-ILD, with gradual improvement of musculoskeletal and respiratory symptoms, lung function and high resolution CT imaging. At the last annual assessment in January 2020, her forced vital capacity and carbon monoxide lung diffusion capacity were 92% and 70% of the respective predicted values. Tocilizumab was continued at 5-week intervals.
On 12 March 2020, 4 weeks after the last tocilizumab infusion, the patient presented to our hospital’s emergency department with cough, headache and general malaise since about 1week. She reported contact with a patient with COVID-19 2weeks earlier. As she was in relatively good general health condition, subfebrile (37.6°C), with unchanged bibasal lung crackles and no significant dyspnoea, she was allowed to return home with symptomatic treatment only. The nasopharyngeal swab was positive for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) by realtime reverse transcription-PCR. She was quarantined at home and monitored by daily telephone calls, and the upcoming tocilizumab infusion was postponed. The symptoms remained mild, and, 10 days later, she reported to be free of symptoms. A follow-up nasopharyngeal swab for SARS-Cov2 performed on March 26 turned out negative. She was thus declared cured from the infection and scheduled to receive the next tocilizumab dose 4days after the negative test.
In this case, a patient with insulin-dependent type 2 diabetes mellitus and SSc-ILD treated with tocilizumab developed a mild form of COVID-19. Her pre-existing ILD and diabetes are WHOdefined risk factors for a more severe course of COVID-19, while immunosuppressive treatment is currently also regarded as a risk factor. In previous coronavirus outbreaks however, immunosuppression was not a documented risk factor. At present, in patients with COVID-19 from Wuhan, China, higher levels of C reactive protein and IL-6 have been associated with increased mortality.4 Accumulating evidence suggests that a subgroup of patients with severe COVID-19 develop a cytokine storm syndrome. Currently, several ongoing randomised trials study the efficacy and safety of anti-IL-6-receptor monoclonal antibodies in severe COVID-19.5 6 Although these agents are immunosuppressive and thus formally contraindicated in patients with active infections, they may show benefit in certain subgroups of COVID-19-associated severe acute respiratory distress syndrome.
Since December 2019, a viral pneumonia, named coronavirus disease 2019 (COVID-19), from Wuhan, China, has swept the world. Although the case fatality rate is not high, the number of people infected is large and there is still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is an important cause of death. Therefore, treatment of the cytokine storm has become an important part of rescuing severe COVID-19 patients. Interleukin-6 (IL-6) plays an important role in cytokine release syndrome. If it is possible to block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe COVID-19 patients. Tocilizumab is an IL-6 receptor (IL-6R) blocker that can effectively block the IL-6 signal transduction pathway and thus is likely to become an effective drug for patients with severe COVID-19.
In a recent review, the authors synthesized the current evidence for one of the possible therapeutic options for the treatment of SARS-CoV-2 infection, in the context of the urgent need for effective therapies in the current pandemic, particularly in severe cases.
However, there is no systematically recommended treatment for COVID-19. Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R) and is FDA-approved for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome and recently, has been administered intravenous experimentally in the treatment of severe COVID-19 pneumonia in China and Italy with promising results.
A study in two hospitals of Anhui, China that included 21 patients with severe COVID-19 infection treated with Tocilizumab in addition to routine therapy, showed as results a high rate of absorption of lung lesions, decreased C-reactive protein, lymphocytes count in peripheral blood and oxygen requirement and early hospital discharge (13.5 days on average), suggesting that Tocilizumab could be an effective therapy in patients with severe infection, effectively improve clinical symptoms and repress the deterioration of critical patients.
The evolution of the current pandemic is putting strong pressure on health systems around the world in search for effective therapies against COVID-19 infection. Apparently, Tocilizumab provided a new therapeutic strategy for severe and critical cases, although the evidence strength needs to be enhanced, the results of further controlled trial studies will clarify the true clinical impact of this IL-6- blocking treatment on COVID-19 infection.
Younger patients with COVID-19 may experience an exaggerated immune response to SARS-CoV-2 infection and develop cytokine release syndrome (CRS), which may be life threatening. There is no proven antiviral therapy for COVID-19 so far, but profound immunosuppression has recently been suggested as a treatment for COVID-19-associated CRS. We present a case of life-threatening CRS caused by COVID-19 infection with a favourable response to immunosuppressive therapy with tocilizumab (TCZ). The rapid clinical and biochemical improvement following TCZ administration suggests that treatment with immunotherapy can be life-saving in selected patients with COVID-19-induced CRS.
Objectives: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19.
Methods: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded.
Results: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05).
Conclusions: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.
Introduction: No therapy has yet proven effective in COVID-19. Tocilizumab (TCZ) in patients with severe COVID-19 could be an effective treatment.
Method: We conducted a retrospective case-control study in the Nord Franche-Comté Hospital, France. We compared the outcome of patients treated with TCZ and patients without TCZ considering a combined primary endpoint: death and/or ICU admissions.
Results: Patients with TCZ (n=20) had a higher Charlson comorbidity index (5.3 [±2.4] vs 3.4 [±2.6], P=0.014), presented with more severe forms (higher level of oxygen therapy at 13L/min vs 6L/min, P<0.001), and had poorer biological findings (severe lymphopenia: 676/mm3 vs 914/mm3, P=0.037 and higher CRP level: 158mg/L vs 105mg/L, P=0.017) than patients without TCZ (n=25). However, death and/or ICU admissions were higher in patients without TCZ than in the TCZ group (72% vs 25%, P=0.002).
Conclusion: Despite the small sample size and retrospective nature of the work, this result strongly suggests that TCZ may reduce the number of ICU admissions and/or mortality in patients with severe SARS-CoV-2 pneumonia.
Objective: This study aimed to assess the role of Tocilizumab therapy (TCZ) in terms of ICU admission and mortality rate of critically ill patients with severe COVID-19 pneumonia.
Design: Patients with COVID-19 pneumonia were prospectively enrolled in SMAtteo COvid19 REgistry (SMACORE). A retrospective analysis of patients treated with TCZ matched using propensity score to patients treated with Standard Of Care (SOC) was conducted.
Setting: The study was conducted at IRCCS Policlinico San Matteo Hospital, Pavia, Italy, from March 14, 2020 to March 27, 2020.
Participants: Patients with a confirmed diagnosis of COVID-19 hospitalized in our institution at the time of TCZ availability.
Interventions: TCZ was administered to 21 patients. The first administration was 8 mg/kg (up to a maximum 800 mg per dose) of Tocilizumab intravenously, repeated after 12 h if no side effects were reported after the first dose.
Main Outcomes and Measures: ICU admission and 7-day mortality rate. Secondary outcomes included clinical and laboratory data.
Results: There were 112 patients evaluated (82 were male and 30 were female, with a median age of 63.55 years). The 21 patients who received TCZ were matched to 21 patients who received SOC (a combination of hydroxychloroquine, azithromycin and prophylactic dose of low weight heparin). No adverse event was detected following TCZ administration. This study found that treatment with TCZ did not significantly affect ICU admission (OR 0.11; 95% CI between 0.00 and 3.38; p = 0.22) or 7-day mortality rate (OR 0.78; 95% CI between 0.06 and 9.34; p = 0.84) when compared with SOC. Analysis of laboratory measures showed significant interactions between time and treatment regarding C-Reactive Protein (CRP), alanine aminotransferase (ALT), platelets and international normalized ratio (INR) levels. Variation in lymphocytes count was observed over time, irrespective of treatment.
Conclusions: TCZ administration did not reduce ICU admission or mortality rate in a cohort of 21 patients. Additional data are needed to understand the effect(s) of TCZ in treating patients diagnosed with COVID-19.
Interleukin-6 is an important marker of inflammation. We performed a systematic review and meta-analysis to demonstrate the association of elevated IL-6 with severe Coronavirus disease-2019 (COVID-19). A total of 9 studies were included in the systematic review and meta-analysis. Patients with severe COVID-19 had a significantly higher serum IL-6 levels compared to non-severe patients (mean difference (MD): 38.6 pg/mL, 95% CI: 24.3 – 52.9 pg/mL, p <0.001, I2 = 98.5%).
On meta-regression, increasing mean IL-6 level was associated with increased mortality in patients (Coefficient (Q): 0.01, 95% CI: 0.01-0.03, p = 0.03). Given the association of elevated IL-6 with severe COVID-19 and mortality, clinicians should use this as a potential marker to recognize severe disease. IL-6 should be incorporated in a scoring system along with other inflammatory markers to risk stratify the patients for early recognition of severe disease. Our study should encourage researchers to conduct trial evaluating Anti IL-6 antibodies such as Tocilizumab to assess the efficacy in patients with severe COVID-19.
Coronavirus disease 2019 (COVID-19) pneumonia has been poorly reported in solid organ transplanted patients; prognosis is uncertain and best management unclear. We describe the case of a 61-year-old kidney transplant recipient with several comorbidities who was hospitalized and later received a diagnosis of COVID-19 pneumonia; the infection was successfully managed with the use of hydroxychloroquine and a single administration of tocilizumab, after immunosuppression reduction; the patient did not require mechanical ventilation. During the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, transplant clinicians should be readily informed about new cases of COVID-19 pneumonia in solid organ transplant recipients, with focus on therapeutic strategies employed and their outcome.