Tocilizumab in COVID-19: The Cerrahpaşa-PREDICT score

BackgroundCytokine release syndrome (CRS), characterized by overproduction of proinflammatory cytokines in the course of severe coronavirus disease 2019 (COVID-19), has been suggested as the major cause of mortality. Tocilizumab, a recombinant humanized monoclonal antibody against human IL-6 receptor, poses a therapeutic option for the treatment of CRS leading to severe acute respiratory syndrome in coronavirus-2 (SARS-CoV-2) infection.MethodsWe performed a single-center retrospective study to reveal the outcome of COVID-19 patients on tocilizumab and proposed “the Cerrahpaşa-PREDICT score”, a new clinical scoring system using clinical and laboratory parameters that would help predicting the 28-day mortality of COVID-19 patients receiving tocilizumab.ResultsEighty-seven patients (median age: 59 years) were included of whom 75.8% were male. Tocilizumab use significantly improved clinical and laboratory parameters. The 28-day mortality rate on tocilizumab was 16.1%. The Cerrahpaşa-PREDICT score, consisting of platelet counts, procalcitonin, D-dimer levels, SO₂R and the time from symptom onset to tocilizumab administration had a positive predictive value of 94.5% and negative predictive value of 92.9% for anticipating 28-day mortality.ConclusionsSevere COVID-19 should closely be monitored for the signs of hyperinflammation. We showed that administration of tocilizumab early in the course of the disease (prior to ICU admission) resulted in a favorable outcome. Close monitoring usually aids identifying patients who would benefit from tocilizumab. In this regard, the Cerrahpaşa-PREDICT score might serve as a practical tool for estimating the 28-day mortality in COVID-19 patients who received tocilizumab and would facilitate timely recognition of fatal cases to be evaluated for other therapeutic options.     

Effectiveness of adjunctive corticosteroid therapy in patients with severe COVID-19: A retrospective cohort study

BACKGROUNDThe effectiveness of adjunctive corticosteroid use in patients with coronavirus disease 2019 (COVID-19) remains inconclusive.AIMTo investigate the effectiveness of adjunctive corticosteroid therapy in patients with severe COVID-19.METHODSWe conducted a retrospective analysis of the difference in several outcomes between patients with severe COVID-19 who received corticosteroid therapy (the corticosteroid group) and patients with severe COVID-19 who did not receive corticosteroid therapy (the non-corticosteroid group).RESULTSSeventy-five patients were included in this study. Of these, 47 patients were in the corticosteroid group and 28 patients were in the non-corticosteroid group. There were no differences between the two groups in the total length of hospital stay, the length of intensive care unit stay, high-flow oxygen days, non-invasive ventilator days, invasive ventilation days, and mortality rate. Total lesion volume ratio, consolidation volume ratio and ground-glass opacity volume ratio in the corticosteroid group decreased significantly on day 14, while those in the non-corticosteroid group did not show a significant decrease.CONCLUSIONOur results show that adjunctive corticosteroid use did not significantly improve clinical outcomes in severe COVID-19 patients, but might promote the absorption of pulmonary lesions. Larger multicenter randomized controlled studies may be needed to confirm this.     

Effect of pulsed corticosteroids and tocilizumab on hyperinflammation in COVID-19 patients with acute respiratory distress syndrome

Objective: To compare the efficacy of pulsed-dose corticosteroids (≥250 mg methylprednisolone, 3 days) and tocilizumab in treating COVID-19-related hyperinflammation.Methods: This prospective observational study included RT-PCR positive COVID-19 patients with acute respiratory distress syndrome, who were admitted to the COVID-19 Adult Intensive Care Unit of Prof Dr. Murat Dilmener Emergency Hospital (Istanbul, Turkey) between December 1, 2020 and February 28, 2021. Clinical, laboratory and radiological examinations were used to diagnose COVID-19 associated hyperinflammation. Three cohort groups were formed: the pulsed-dose corticosteroids group (250 mg methylprednisolone for 3 days), the tocilizumab group (8 mg/day single dose or 400 mg/day for 2 days), and the combined group (pulsed-dose corticosteroid+tocilizumab). The difference in mortality rates among the groups was compared primarily. The most common cause(s) of death was determined. Furthermore, adverse events (secondary infection, acute kidney injury, arrhythmia, gastrointestinal system bleeding) for 28 days were recorded. Results: A total of 60 patients were included in this study, with 20 patients in each group. There was no statistically significant difference between the 3 groups in mortality rates (55％ in the pulsed corticosteroid group, 60％ in the tocilizumab group, 50％ in the combined group, χ2=0.404, P=0.817). Infectious causes were found to be the most common cause of mortality in all the three groups, and no difference was found between them (χ2=0.404, P=0.817). There was also no difference in the development of adverse events such as secondary infection, acute kidney injury, arrhythmia, and gastrointestinal bleeding among the groups (P>0.05). Conclusions: Corticosteroids can be used instead of tocilizumab to treat hyperinflammation in COVID-19 patients with acute respiratory distress syndrome .     

Machine Learning as a Precision-Medicine Approach to Prescribing COVID-19 Pharmacotherapy with Remdesivir or Corticosteroids

Purpose: Coronavirus disease–2019 (COVID-19) continues to be a global threat and remains a significant cause of hospitalizations. Recent clinical guidelines have supported the use of corticosteroids or remdesivir in the treatment of COVID-19. However, uncertainty remains about which patients are most likely to benefit from treatment with either drug; such knowledge is crucial for avoiding preventable adverse effects, minimizing costs, and effectively allocating resources. This study presents a machine-learning system with the capacity to identify patients in whom treatment with a corticosteroid or remdesivir is associated with improved survival time.Methods: Gradient-boosted decision-tree models used for predicting treatment benefit were trained and tested on data from electronic health records dated between December 18, 2019, and October 18, 2020, from adult patients (age ≥18 years) with COVID-19 in 10 US hospitals. Models were evaluated for performance in identifying patients with longer survival times when treated with a corticosteroid versus remdesivir. Fine and Gray proportional-hazards models were used for identifying significant findings in treated and nontreated patients, in a subset of patients who received supplemental oxygen, and in patients identified by the algorithm. Inverse probability-of-treatment weights were used to adjust for confounding. Models were trained and tested separately for each treatment.Findings: Data from 2364 patients were included, with men comprising slightly more than 50% of the sample; 893 patients were treated with remdesivir, and 1471 were treated with a corticosteroid. After adjustment for confounding, neither corticosteroids nor remdesivir use was associated with increased survival time in the overall population or in the subpopulation that received supplemental oxygen. However, in the populations identified by the algorithms, both corticosteroids and remdesivir were significantly associated with an increase in survival time, with hazard ratios of 0.56 and 0.40, respectively (both, P = 0.04).Implications: Machine-learning methods have the capacity to identify hospitalized patients with COVID-19 in whom treatment with a corticosteroid or remdesivir is associated with an increase in survival time. These methods may help to improve patient outcomes and allocate resources during the COVID-19 crisis.     

Timing of REGEN-COV administration and progression to severe COVID-19

IntroductionSeveral clinical trials have demonstrated that REGEN-COV (casirivimab and imdevimab) decreases the risk of hospitalization and death among COVID-19 patients. However, these trials did not evaluate the optimal timing of its administration, and evidence is limited regarding the relationship between the timing of administration and progression to severe COVID-19 among patients who receive REGEN-COV in a real-world setting. We examined the association between the timing of REGEN-COV administration and progression to severe COVID-19 among patients who received REGEN-COV in Japan.MethodsWe included a total of 342 COVID-19 patients (37 hospitals) who received REGEN-COV between July 19 and September 30, 2021. We calculated the difference between the date of symptom onset and the date of administration as an indicator of the timing of REGEN-COV administration and determined progression to severe COVID-19 after REGEN-COV administration. We conducted a logistic regression analysis, adjusting for potential confounders.ResultsThe proportion of cases progressing to severe COVID-19 increased daily from symptom onset and sharply increased from day 5 of onset. The early administration (days 0–4) decreased the risk of progression to severity compared with late administration (after day 5), with an adjusted odds ratio of 0.29 (95% confidence interval: 0.11–0.56).ConclusionsThe early administration of REGEN-COV was associated with a decreased risk of progression to severe COVID-19 when the delta variant was dominant. The present epidemiological findings indicate that this monoclonal antibody therapy should be implemented very early in the clinical course probably even for emerging variants such as omicron BA.2.     

Low dose vs high dose tocilizumab in COVID-19 patients with hypoxemic respiratory failure

PurposeTocilizumab has been shown to decrease mortality when used concomitantly with steroids in COVID-19 with 8 mg/kg (max 800 mg) being the standard dose. Our study sought to assess whether a low dose (400 mg) shows similar benefit compared to a high dose for COVID patients concurrently on the same median dose of steroids.Materials/MethodsA retrospective, multihospital observational study of COVID-19 patients who received tocilizumab in conjunction with steroids between March 2020 and August 2021 was conducted.ResultsA total of 407 patients were analyzed with low dose group being significantly more ill at baseline as a higher percentage of patients received vasopressors, were admitted to the ICU and on mechanical ventilation. In the propensity-matched analysis, both groups receiving a median dexamethasone equivalent dose of 10 mg showed no difference in 28-day mortality (p = 0.613). The high dose group had a higher rate of fungal and viral infections.ConclusionCompared to low dose tocilizumab, the high dose did not provide additional efficacy and mortality benefit but resulted in higher fungal and viral infections. This study illustrates that low dose tocilizumab can be an alternative to high dose during a drug shortage of tocilizumab without compensating for efficacy and safety, conserving resources for more patients.     

Effect of COVID-19 outbreak on the treatment time of patients with acute ST-segment elevation myocardial infarction

ObjectiveTo explore the effect of COVID-19 outbreak on the treatment time of patients with ST-segment elevation myocardial infarction (STEMI) in Hangzhou, China.MethodsWe retrospectively reviewed the data of STEMI patients admitted to the Hangzhou Chest Pain Center (CPC) during a COVID-19 epidemic period in 2020 (24 cases) and the same period in 2019 (29 cases). General characteristics of the patients were recorded, analyzed, and compared. Moreover, we compared the groups for the time from symptom onset to the first medical contact (SO-to-FMC), time from first medical contact to balloon expansion (FMC-to-B), time from hospital door entry to first balloon expansion (D-to-B), and catheter room activation time. The groups were also compared for postoperative cardiac color Doppler ultrasonographic left ventricular ejection fraction (LVEF),the incidence of major adverse cardiovascular and cerebrovascular events (MACCE),Kaplan-Meier survival curves during the 28 days after the operation.ResultsThe times of SO-to-FMC, D-to-B, and catheter room activation in the 2020 group were significantly longer than those in the 2019 group (P < 0.05). The cumulative mortality after the surgery in the 2020 group was significantly higher than the 2019 group (P < 0.05).ConclusionThe pre-hospital and in-hospital treatment times of STEMI patients during the COVID-19 epidemic were longer than those before the epidemic. Cumulative mortality was showed in Kaplan-Meier survival curves after the surgery in the 2020 group was significantly different higher than the 2019 group during the 28 days.The diagnosis and treatment process of STEMI patients during an epidemic should be optimized to improve their prognosis.     

TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol

BackgroundPneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a “cytokine storm”. IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor.MethodsThis multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h, or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study.ConclusionThis trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020–001110-38; Clinicaltrials.gov ID NCT04317092     

Should timing be considered before abandoning convalescent plasma in covid-19? Results from the Turkish experience

IntroductionsResults with convalescent plasma therapy in coronavirus disease 2019 (COVID-19) have been contradictory. Timing seems to be an important factor for COVID-19 convalescent plasma(CCP) to be effective. Aim of this study is to compare disease outcomes in hospitalized COVID-19 patients who were treated with CCP within first three or seven days of symptoms to patients with symptoms longer than seven days.Material and methodsA multicenter retrospective study was conducted to evaluate disease outcomes in hospitalized COVID-19 patients who received CCP in addition to standard of care (SOC) approach. Patients were subgrouped according to time of CCP administration; within three days of symptoms, seven days of symptoms and after seven days of symptoms. A control group was formed from age, gender and comorbidity matched hospitalized patients who received SOC treatments without CCP. Length of hospital stay, rates of anti-inflammatory treatment initiation, intensive care unit (ICU) admission and mortality was set as outcome measures.ResultsA total of 223 patients were enrolled in this study, 113 patients received CCP (38 within three days, 63 within seven days, 50 after seven days of symptom onset). Rate of anti-inflammatory treatment initiation was significantly lower (38.1 % vs 62.7 %, p = 0.002, relative risk, 0.60,73; 95 % confidence interval [CI], 0.42 to 0.85) and length of hospital stay was significantly shorter (median(IQR) 8(4) days vs 9.5(5.25) days, p = 0.0025) in patients who received CCP within seven days of symptom onset when compared to SOC group.ConclusionCCP therapy may provide better outcomes when applied within seven days of symptoms.     

Timing of convalescent plasma therapy-tips from curing a 100-year-old COVID-19 patient using convalescent plasma treatment: A case report

BACKGROUNDConvalescent plasma therapy is used for the treatment of critically ill patients for newly discovered infectious diseases, such as coronavirus disease 2019 (COVID-19) pneumonia, under the premise of lacking specific treatment drugs and corresponding vaccines. But the best timing application of plasma therapy and whether it is effective by antiviral and antibiotic treatment remain unclear. CASE SUMMARYWe describe a patient with COVID-19, a 100-year-old, high-risk, elderly male who had multiple underlying diseases such as stage 2 hypertension (very high-risk group) and infectious pneumonia accompanied by chronic obstructive pulmonary disease and emphysema. We mainly describe the diagnosis, clinical process, and treatment of the patient, including the processes of two plasma transfusion treatments.CONCLUSIONThis provides a reference for choosing the best timing of convalescent plasma treatment and highlights the effectiveness of the clinical strategy of plasma treatment in the recovery period of patients with COVID-19 pneumonia.     

Effects of corticosteroids in hospitalized patients with Legionella pneumonia: A retrospective cohort study

IntroductionLegionella pneumophila is an important cause of pneumonia, however there is scant literature assessing the therapeutic benefit of corticosteroids in treatment. We sought to investigate the association between corticosteroid use and in-hospital mortality for patients hospitalized with Legionella pneumonia.MethodsData was collected retrospectively from January 2012 to July 2019 at a 705 bed hospital in New York City. Patients were included if they received a positive Legionella test. Exclusion criteria included age <18, concurrent immunosuppression, and HIV diagnosis. We assessed the relationship between corticosteroid use and in-hospital mortality. Statistical analyses were performed in RStudio.ResultsThe study included 160 patients, among which 32 (20%) received steroids. Overall mortality was 7.5% (12.5% among steroid recipients, 6.2% among controls). 25% of patients were admitted to the ICU (37.5% among steroid recipients, 21.9% among controls). Adjusted analysis showed steroid recipients did not have significantly different mortality (aOR = 2.56, p = 0.436). Steroid use was not significantly associated with longer LOS (p = 0.22). Steroid use was significantly associated with hyperglycemia (aOR = 2.91, p = 0.018) and GI bleed (OR = 9.0, p = 0.014).ConclusionsWe found that in patients hospitalized with Legionella pneumonia, corticosteroid administration was not significantly associated with longer hospitalization or mortality. All findings held true when adjusting for known predictors of pneumonia severity. Corticosteroid use was associated with increased rates of hyperglycemia and GIB requiring blood transfusion. The results of this study are consistent with guidelines recommending against routine use of corticosteroids in CAP.     

Elevated blood favipiravir levels are inversely associated with ferritin levels and induce the elevation of uric acid levels in COVID-19 treatment: A retrospective single-center study

IntroductionMeasurement of blood Favipiravir (FPV) levels and accumulation of data in COVID-19 patients are critical for assessing FPV efficacy and safety. We performed a retrospective study based on measurements of blood levels of FPV and related factors in COVID-19 patients admitted to our hospital. Furthermore, we also investigated the association between blood FPV levels and uric acid level alterations before and after FPV administration.MethodsWe enrolled 27 COVID-19 patients who had received FPV treatment at Hokushin General Hospital from April 1 to December 31, 2020. Age, gender, COVID-19 severity, presence of comorbidities, and laboratory data for each subject were investigated to identify factors that correlate with blood FPV levels. Uric acid levels were measured before and after FPV administration and a difference between the levels (i.e., a change of uric acid level) was evaluated.ResultsWhen a significant univariate variable was input by the stepwise method and a combination of variables that maintained statistical superiority was searched, serum ferritin was the only factor that independently affected blood FPV level. Furthermore, in the high-FPV group (20 μg/mL or more), a significant increase in uric acid levels was observed after FPV administration. The increment value was significantly larger than that in the low-FPV group (less than 20 μg/mL).ConclusionsFerritin level was an important independent factor inversely affecting blood FPV level. Furthermore, a high blood FPV level induced the elevation of uric acid levels in COVID-19 treatment.     

Factors associated with high antibody titer following coronavirus disease among 581 convalescent plasma donors: A single-center cross-sectional study in Japan

IntroductionThe ability to predict which patients with a history of coronavirus disease (COVID-19) will exhibit a high antibody titer is necessary for more efficient screening of potential convalescent plasma donors. We aimed to identify factors associated with a high immunoglobulin G (IgG) titer in Japanese convalescent plasma donors after COVID-19.MethodsThis cross-sectional study included volunteers undergoing screening for convalescent plasma donation after COVID-19. Serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S-protein IgG antibodies were measured using a high-sensitivity chemiluminescence enzyme immunoassay.ResultsIgG antibodies were measured in 581 patients, 534 of whom had full information of selected independent variables. Multiple linear regression analysis revealed that increasing age (1.037 [1,025, 1.048]), days from symptom onset to sampling (0.997 [0.995, 0.998]), fever (1.664 [1.226, 2.259]), systemic corticosteroid use during SARS-CoV-2 infection (2.382 [1.576, 3.601]), and blood type AB (1.478 [1.032, 2.117]) predict antibody titer.ConclusionOlder participants, those who experienced fever during infection, those treated with systemic corticosteroids during infection, those from whom samples were obtained earlier after symptom onset, and those with blood type AB are the best candidates for convalescent plasma donation. Therefore, these factors should be incorporated into the screening criteria for convalescent plasma donation after SARS-CoV-2 infection.     

Critically ill patients with COVID-19 in Tokyo,Japan: A single-center case series

IntroductionWe reported, in our previous study, a patient with coronavirus disease 2019 (COVID-19) who was successfully treated with extracorporeal membrane oxygenation. Data on clinical courses and outcomes of critically ill patients with COVID-19 in Japan are limited in the literature. This study aimed to describe the clinical courses and outcomes of critically ill patients with COVID-19 in Tokyo, Japan.MethodsThis is a single-center case series study. Patients with COVID-19 treated with mechanical ventilation (MV) were reviewed retrospectively. Data on baseline characteristics, in-hospital treatment, and outcomes were collected.ResultsBetween February 2, 2020, and June 30, 2020, 14 critically ill patients with COVID-19 were treated with MV. Most patients were male and had comorbidities, especially hypertension or diabetes; 35.7% were overweight and 21.4% were obese. The majority of the patients had dyspnea on admission. The median duration of MV was 10.5 days, and the 28-day mortality rate was 35.7%. In the four patients with COVID-19 who died, the cause of death was respiratory failure.ConclusionsAs in previous reports from other countries, the mortality rate of patients with COVID-19 requiring intensive care remains high in Tokyo. Further study on the appropriate timing of MV initiation and specific treatments for critically ill patients with COVID-19 is needed.     

Complex and prolonged hypercoagulability in coronavirus disease 2019 intensive care unit patients: A thromboelastographic study

BackgroundA high number of thrombotic complications have been reported in critically ill patients with coronavirus disease 2019 (COVID-19) and appear to be related to a hypercoagulable state. Evidence regarding detection, management, and monitoring of COVID-19–associated coagulopathy is still missing. We propose to describe the thrombus viscoelastic properties to investigate the mechanisms of hypercoagulability in patients with COVID-19.MethodsThromboelastography (TEG) was performed in 24 consecutive patients admitted to a single intensive care unit for COVID-19 pneumonia, and 10 had a second TEG before being discharged alive from the intensive care unit.ResultsCompared with a group of 20 healthy participants, patients with COVID-19 had significantly decreased values of reaction time, coagulation time, and lysis index and increased values of α angle, maximum amplitude, clot strength, and coagulation index. Velocity curves were consistent with increased generation of thrombin. These values persisted in surviving patients despite their good clinical course.DiscussionIn patients with COVID-19, TEG demonstrates a complex and prolonged hypercoagulable state including fast initiation of coagulation and clot reinforcement, low fibrinolysis, high potential of thrombin generation, and high fibrinogen and platelet contribution. The antithrombotic strategy in patients with COVID-19 during intensive care hospitalisation and after discharge should be investigated in further studies.     

The effectiveness of high-dose intravenous vitamin C for patients with coronavirus disease 2019: A systematic review and meta-analysis

ObjectivesVitamin C has anti-inflammatory effects. This review aimed to investigate the therapeutic effect of high-dose intravenous vitamin C (HDIVC) in patients with coronavirus disease 2019 (COVID-19).MethodsThe following key phrases were searched for article inclusion: “Vitamin C OR ascorbic acid” AND “COVID-19 OR coronavirus disease 2019 OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2″. Articles that utilized HDIVC for the management of patients with COVID-19 were included, whereas review articles and case reports were excluded from this review. Moreover, we performed a meta-analysis to evaluate whether HDIVC can reduce the length of hospital stay and in-hospital mortality rate of patients with severe COVID-19.ResultsIn total, eight articles were included in this review, and five studies were included in the meta-analysis. The length of hospital stay was not significantly different between the HDIVC and control groups. Also, although our meta-analysis showed a tendency for HDIVC to reduce the in-hospital mortality rate in patients with severe COVID-19, the in-hospital mortality rate was not significantly different between patients treated with HDIVC and those who did not receive HDIVC.ConclusionsEvidence supporting the therapeutic use of HDICV in COVID-19 patients is lacking. Further studies are required for drawing a clear conclusion on this topic.     

The role of corticosteroids in the treatment of Kawasaki disease

ABSTRACT

Introduction: Kawasaki disease (KD) is a form of systemic vasculitis that can lead to complications of coronary artery lesions (CAL). Diagnosis without delay and treatment with intravenous immunoglobulin (IVIG) are vital for a better prognosis. Anti-inflammatory drugs are generally used empirically in pediatric patients as off label. Corticosteroids are effective with anti-inflammatory effects applied in vasculitis.

Areas covered: The timing of corticosteroid treatment in KD has been widely discussed by scholars. Some corticosteroids may still be effective which could be useful for such specific populations as high-risk patients. In this narrative review, we searched clinical studies, meta-analyzes, and systemic reviews using the PubMed database to summarize the available evidence on corticosteroid usage in KD through October 2019 and then discussed the relevant issues.

Expert opinion: Today, the available evidence is more powerful to recommend corticosteroids for KD, moving from an unproven therapy to an effective adjunctive treatment. We suggest using methylprednisolone pulse therapy as an alternative rescue therapy for immunoglobulin-resistant KD, as well as identifying high-risk patients who need initial corticosteroid with IVIG treatment with an adequate route, dose, and duration. In the future, studies that evaluate the precision role of corticosteroids for individualized KD patients with CAL are warranted.