CHARACTERISTICS OF PATIENTS WHO RECEIVED BIOLOGICAL TREATMENT AFTER KIDNEY TRANSPLANTATION AND THE INCIDENCE OF SERIOUS INFECTIONS: A MULTICENTER STUDY

BackgroundKidney transplant patients due to both primary kidney involvement of chronic/autoimmune inflammatory diseases and end-stage kidney disease related to amyloidosis are followed up in rheumatology clinics. Biological agents one of the treatment options in kidney transplant recipients with chronic/autoimmune inflammatory disease.ObjectivesHowever, there is insufficient data on the development of infection in kidney transplant recipients who received biological treatment. Herein, we aimed to determine the incidence of serious infections in patients with kidney transplant recipients who are received biological therapy.MethodsKidney transplant recipients who are received biological agents due to rheumatologic disease were included in the study. Patients' demographic features, transplantation data, biological treatment, development of infection and severity of infection were screened retrospectively. Infections that requiring hospitalization were defined as severe infections.ResultsA total of 31 patients were included in the study, 14 (45%) of whom were female and mean age was 41 ±9 years. Twenty-five patients (80%) of them were non-preemptive kidney transplant and mean duration of hemodialysis before the transplantation was 40 ±40 months. Twenty-three patients (74%) had end stage kidney failure due to FMF-amyloidosis(Figure-1-). Seventeen patients (54%) received anakinra, 11 patients (35%) received canakinumab and 3 patients (10%) received etanercept with other immunosuppressive treatment. Mean treatment duration of biological agents was 4.2±2.6 years. Two patients developed solid organ malignancy and one patient developed hematological malignancy after transplantation. Sixteen of the patients (52%) were hospitalized at least once due to infection and 4 patients (13%) died due to infection. The cause of decease in two patients was COVID-19.ConclusionRheumatic diseases are an important cause of end-stage renal disease and definitive treatment is kidney transplantation. Kidney transplant recipients due to rheumatological disease also use biological agents in the post-transplantation period. Kidney transplant recipients have higher risk for the development of infection since they receive immunosuppressive therapy and use of biologic agents may further increase the risk for development infection. Meyer et al reported that infection developed in 54 of 187 solid organ transplant recipients using biological agents.[1] Mean treatment duration of biological agents was 12 months in this study. The incidence of infection was 54% in our study. Mean treatment duration of biological agent was 4.2 year was considered main reason for higher incidence of infection in our study.Reference[1]Meyer F, Weil-Verhoeven D, Prati C, Wendling D, Verhoeven F. Safety of biologic treatments in solid organ transplant recipients: A systematic review. Semin Arthritis Rheum. 2021 Dec;51(6):1263-1273. doi: 10.1016/j.semarthrit.2021.08.013. Epub 2021 Aug 26. Erratum in: Semin Arthritis Rheum. 2022 Aug;55:152015. PMID: 34507811.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

PERICARDITIS AFTER COVID-19 VACCINATION: A CASE SERIES

BackgroundCOVID-19 vaccination campaigns successfully impacted on viral spreading and in particular on clinical course of the disease. However, secondary to a highly extended vaccination program, several local and systemic adverse events associated with mRNA COVID-19 vaccines have been reported. Pericarditis and myocarditis are examples of cardiac complications related to these vaccines. In particular, cases of pericarditis have occurred after mRNA COVID-19 vaccination (mostly secondary to vaccination with Moderna than Pfizer-BioNTech), especially in male adolescents and young adults, more often after the second dose. The incidence is approximately of 1-2 cases/100.000.ObjectivesAim of our study was to study the clinical profile of pericarditis occurred within 30 days after COVID-19 vaccines in our clinic.MethodsWe present a case series of patients who developed pericarditis after COVID-19 vaccination in the Department of Internal Medicine at Fatebenefratelli Hospital in Milan, followed from December 1, 2021 to April 15, 2022.ResultsTwenty-five individuals, of which 18 (72%) were women and 7 (28%) were males, had vaccine related pericarditis. Two patients were vaccinated with AstraZeneca, 2 with Moderna, the remaining with Pfizer-BioNTech. Median age was of 42 years. Of all patients, one subject was affected by constrictive effusive pericarditis, while another required treatment of pericarditis with Anakinra, switched to Canakinumab after severe skin reactions, because of failure of therapeutic response to first-line treatments.Two patients required hospital admission, in one case for a transient constrictive pericarditis. In the remaining cases clinical symptoms associated with post-vaccines pericarditis were mild and didn't require hospitalization.Chest pain was reported in 100% of cases, whereas pericardial effusion (in one case larger than 10 mm) was evidenced in 30% of subjects. Eighty percent of patients experienced tachycardia, whereas 90% reported asthenia.An increase in indices of inflammation (CRP) was documented in 50% of patients, usually mild.With regard to therapy, 90% of patients were treated with NSAIDs, 95% with colchicine, while 50% of cases required treatment with low-dose steroids.ConclusionCOVID-19 vaccination induces a particular form of pericarditis, often insidious and very troublesome, but with good prognosis. The clinical phenotype showed less typical chest pain, often normal indices of inflammation and little or no instrumental changes, but patients often experimented tachycardia and functional limitation. With regard to therapy, we used NSAIDs at adequate dosages to control the clinical condition, or low-dose colchicine. Low doses of cortisone (e.g., prednisone 5-10 mg a day) were useful in the presence of marked asthenia or systemic symptoms. Beta-blockers or ivabradine were used in the presence of tachycardia.References[1]Barda N, Children 2021, 8(7), 607;Safety of the BNT162b2 mRNA Covid-19 in a Nationwide setting. N Engl J med 2021;385:1078-1090.[2]Diaz GA, Myocarditis and Pericarditis After Vaccination for COVID-19. JAMA 2021;326 (12): 1210-1212.[3]Bibhuti D, Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?. Children 2021, 8(7), 607.[4]Giacomo Maria Viani, Patrizia Pedrotti, Romano Seregni, and Brucato Antonio;Effusive–constrictive pericarditis after the second dose of BNT162b2 vaccine (Comirnaty): a case report;European Heart Journal - Case Reports (2022) 6(2), 1–6.[5]Francesco Perna, Elena Verecchia, Gaetano Pinnacchio, Laura Gerardino, Antonio Brucato, and Raffaele Manna;Rapid resolution of severe pericardial effusion using anakinra in a patient with COVID-19 vaccine-related acute pericarditis relapse:a case report;European Heart Journal - Case Reports (2022) 6, 1–6.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

HIGH DOSE INTRAVENOUS ANAKINRA TREATMENT IS SAFE AND EFFECTIVE IN SEVERE AND CRITICAL COVID-19 PATIENTS: A PROPENSITY SCORE MATCHED STUDY IN A SINGLE CENTER

BackgroundIn COVID-19 severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm.ObjectivesIn this study, we aimed to evaluate the high dose intravenous anakinra treatment response and outcome in patients with severe and critical COVID-19 compared to standard of care.MethodsThis retrospective observational study was carried out at a tertiary referral center. The study population consisted of two groups as follows;the patients receiving high dose intravenous anakinra (anakinra group) between 01.09.2021 and 01.02.2022 and the patients treated with standard of care (SoC, control group) as historical control group who were hospitalized between 01.07.2021 and 01.09.2021.ResultsAfter the propensity score 1:1 matching 79 patients in anakinra and 79 patients in SoC matched and included into the analysis. Mean±SD patient age was 67.4±16.7 and 67.1±16.3 years in anakinra and SoC group, respectively (p=0.9). Male gender was 38 (48.7 %) in anakinra and 36 (46.2 %) SoC (p=0.8). Overall, ICU admission was in 14.1 % (n=11) and 30.8 % (n=24) (p=0.013;OR: 6.2), intubation in 12.8 % (n=10) and 16.7 % (n=13) patients (p=0.5), 14.1 % (n=11) and 32.1 % (n=25) patients died in anakinra and control group, respectively (p=0.008;OR: 7.1)ConclusionIn our study mortality was lower in patients receiving anakinra compared to SoC. Intravenous high dose anakinra is safe and effective treatment in patients with severe and critical COVID-19.Table 1.Baseline clinical and laboratory features of patients receiving standard of care (SoC) and Anakinra before and after propensity score (PS) matchingBefore PS matchingAfter PS matchingVariablesAnakinra (n=148)SoC (n=114)p value (OR)Anakinra (n=78)SoC (n=78)p value (OR)Age (years) (mean±SD)66.8±1763.1±170.0967.4±16.767.1±16.30.9Gender, male (n, %)78 (52.7)45 (39.5)0.033 (4.5)38 (48.7)36 (46.2)0.8Duration of hospitalization (days) (median, IQR)11 (12)9 (7.3)0.027.5 (9)11 (8)0.01Comorbidities (n, %) Diabetes mellitus41/146 (28.1)39 (34.2)0.318 (23)31 (39.7)0.025 (5) Hypertension84/143 (58.7)64 (56)0.730 (61.5)50 (64)0.7 Coronary heart disease27/143 (19)24 (21)0.718 (23)20 (25.6)0.7 Heart failure18/143 (12.6)23 (20)0.114 (18)20 (25.6)0.24 Chronic renal failure31 (21)6 (5.3)<0.001 (13.06)15 (19)6 (7.7)0.035 (4.5) Chronic obstructive lung disease23/144 (16)19 (16.7)0.914 (18)15 (19)0.8 Dementia15/117 (12.8)2 (1.8)0.001 (10.4)3/61 (5)2 (2.6)0.5 Malignancy16/146 (11)8 (7)0.39 (11.5)6 (7.7)0.4 Immunosuppressive usage18/146 (12.3)2 (1.8)0.001 (10.08)5 (6.5)2 (2.6)0.2Disease severity (n, %) NIH score 3 (severe)57 (38.5)68 (59.6)0.001 (11.5)48 (61.5)44 (56.4)0.5 NIH score 4 (critical)91 (61.5)46 (40.4)30 (38.5)34 (43.6) mcHIS score (mean±SD)3.4±1.22.64±1.5<0.0012.9±13.1±1.30.2PS: Propensity score, SoC: Standard of care, OR: Odds ratio, SD: Standard deviation, IQR: Interquartile range, mcHIS: Modified Covid hyperinflammatory syndrome score, NIH: National Institute Health, ALT: Alanin aminotransferase, AST: Aspartate aminotransferaseTable 2.Outcomes of patients receiving SoC and Anakinra before and after PS matchingBefore PS matchingAfter PS matchingVariables (n, %)Anakinra (n=148)SoC (n=114)p value (OR)Anakinra (n=78)SoC (n=78)p value (OR)Pneumothorax3/134 (2.2)00.25*2/73 (2.7)00.5*Myocardial infarction3/132 (2.3)6 (5.3)0.32/72 (2.8)2/56 (3.6)1Pulmonary embolism4/134 (3)11 (9.6)0.034 (4.8)*3/73 (4.1)7 (9)0.3*Intensive care unit60 (40.5)25 (22)0.001 (10.2)11 (14.1)24 (30.8)0.013 (6.2)Intubation54 (36.5)13 (11.4)<0.001 (21.3)10 (12.8)13 (16.7)0.5Mortality56 (37.8)27 (23.7)0.015 (5.96)11 (14.1)25 (32.1)0.008 (7.1)PS: Propensity score, SoC: Standard of care, OR: Odds ratioREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Tocilizumab versus anakinra in COVID-19: results from propensity score matching.

Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

Evaluation of serum interleukin-1 receptor antagonist levels in major depressive disorder: A case-control study.

Background and Aims: Major depressive disorder (MDD) is characterized by the occurrence of one or more depressive episodes lasting a minimum of 2 weeks and is marked by a persistently low mood and a lack of enjoyment in daily activities. The diagnosis of MDD is not possible by a well-established laboratory test or biomarker. A wide range of potential biomarkers for depression have been proposed by many studies, but none of them has adequately described the correlation between the biomarkers and depression. The purpose of this study was to evaluate serum interleukin-1 receptor antagonist (IL-1RA) levels as an early depression risk factor. Methods: The present case-control study included 88 participants. Among them, 44 MDD patients enrolled from the psychiatry department of a public hospital in Dhaka, Bangladesh, and 44 age- and sex-matched healthy controls (HCs) from various sites in Dhaka city. A qualified psychiatrist evaluated the cases and HCs based on the fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5). The Hamilton depression (Ham-D) rating scale was employed to evaluate the intensity of depression. An enzyme-linked immunosorbent assay kit (Boster Bio, USA) was used to determine serum IL-1RA concentrations. Results: We observed no marked alteration in the serum concentration of IL-1RA in MDD patients in comparison to HCs (292.81 ± 24.81 and 288 ± 24.87 pg/mL; p > 0.05). Among MDD patients, we found no noteworthy association between the severity of depression and serum IL-1RA levels. Conclusion: The findings of the present study imply that IL-1RA may not be identified as a promising biomarker for risk assessment of depression. However, its neuroprotective role may be taken into consideration for the understanding of pathophysiology of MDD.

Anakinra for the treatment of COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant human interleukin-1 (IL-1) receptor antagonist Anakinra for the treatment of COVID-19 patients with elevated soluble urokinase plasminogen activator receptor (suPAR). However, the role of Anakinra in COVID-19 remains unanswered, especially in patients receiving different forms of respiratory support. Therefore, the objective of this systematic review is to assess the safety and effects of Anakinra compared to placebo or standard care alone on clinical outcomes in adult hospitalized patients with SARS-CoV-2 infection. METHODS: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, medRxiv, and the Cochrane Central Register of Controlled Trials (CCSR)) and the WHO COVID-19 Global literature on coronavirus disease database to identify completed and ongoing studies from inception of each database to December 13, 2021. Since then, we monitored new published studies weekly up to June 30, 2022 using the CCSR. We included RCTs comparing treatment with Anakinra to placebo or standard care alone in adult hospitalized patients with SARS-CoV-2 infection. RESULTS: We included five RCTs with 1,627 patients (nAnakinra = 888, ncontrol = 739, mean age 59.63 years, 64% male). Random-effects meta-analysis was used to pool data. We found that Anakinra makes little or no difference to all-cause mortality at up to day 28 compared to placebo or standard care alone (RR 0.96, 95% CI 0.64-1.45; RD 9 fewer per 1000, 95% CI 84 fewer to 104 more; 4 studies, 1593 participants; I2 = 49%; low certainty of evidence). CONCLUSIONS: Anakinra has no effect on adult hospitalized patients with SARS-CoV-2 infection regarding mortality, clinical improvement and worsening as well as on safety outcomes compared to placebo or standard care alone. TRIAL REGISTRATION: PROSPERO Registration Number: CRD42021257552.

Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA.

Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in coronavirus disease 2019 (COVID-19). This retrospective, observational study analyses US hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity, and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs. 8 days; P = 0.002) or those who died in hospital (6 vs. 9 days; P = 0.01). Patients with myocardial infarction or renal conditions were six times (P < 0.01) and three times (P = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (P = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes

PURPOSE OF THE STUDY: Given the similarities between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki's disease, most patients with MIS-C have been treated with intravenous immune globulin (IVIG), the standard of care for Kawasaki's disease. However, other immunomodulatory therapies, including corticosteroids and biologics, have been used to counter the cytokine-related inflammatory changes in MIS-C. The purpose of this study was to describe the pattern of immunomodulatory therapies used in patients with MIS-C in the United States and to assess the relative effectiveness of IVIG plus corticosteroids (CSTs), compared with IVIG alone, in the initial treatment of MIS-C. STUDY POPULATION: The Overcoming COVID-19 surveillance registry identified 596 patients as having MIS-C at each of the 58 participating hospitals between March 15 and October 31, 2020. Of these, 518 (87%) were flagged as receiving at least 1 immunomodulatory treatment. The researchers then analyzed longitudinal data collected in this cohort, including demographic characteristics, underlying medical conditions, signs and symptoms at presentation, clinical course, laboratory test results, diagnostic studies, treatments, complications, and outcomes. METHODS: Statistical comparisons between IVIG+CSTs and IVIG treatment groups were done by population sampling using propensity score matching;among the patients treated with IVIG plus glucocorticoids or IVIG alone on day 0, a total of 206 could be matched at a 1:1 ratio and based on propensity scores. To compare the potential effectiveness of initial immunomodulatory treatment, the authors prespecified a primary composite outcome of cardiovascular dysfunction (left ventricular ejection fraction < 55% and/or shock needing vasopressor support) on day 2 or beyond, up until discharge. Secondary outcome measures included the primary outcome components, escalation of immunomodulation treatment after day 1, and recurrent or persistent fever on day 2 and beyond. The potential effectiveness of treatment in primary and secondary outcomes was also assessed using an inverse-probability weighted analysis. RESULTS: Of the patients treated, 241 (47%) received IVIG and CSTs;107 (21%) received IVIG, CSTs, and a biologic (anakinra, etanercept, infliximab, or tocilizumab);89 (17%) received IVIG only;and 81 (16%) received other treatments, including CSTs only, a biologic only, CSTs and a biologic, or IVIG and a biologic. Highest illness severity was seen in the 107 patients who received IVIG, CSTs, and a biologic combined. Treatment patterns changed over time, with an observed decrease in the fraction of cases treated with IVIG alone, offset primarily by an increase in the use of IVIG with CSTs together. In the propensity-score-matched analysis, initial treatment with IVIG + CSTs was associated with a lower risk of cardiovascular dysfunction and less escalation of immunomodulatory treatments later in hospitalization, but the risks of persistent or recurrent fever and length of stay in the ICU were not clearly lower. The inverse-probability-weighted analysis confirmed the findings of the propensity-score-matched analysis. CONCLUSIONS: The authors found that initial treatment with IVIG plus glucocorticoids for MIS-C was associated with a lower risk of cardiovascular dysfunction than initial treatment with IVIG alone.

In Silico Approach for Pro-inflammatory Protein Interleukin 1β and Interleukin-1 Receptor Antagonist Protein Docking as Potential Therapy for COVID-19 Disease

BACKGROUND: Interleukin-1 receptor antagonist (IL-1Ra) also known as Anakinra is a receptor antagonist of IL-1 especially IL-1β. IL-1β increased in infected COVID-19 patient groups. This study aimed that the IL-1Ra contained in Conditioned Medium Wharton’s Jelly Mesenchymal Stem Cells (CM-WJMSCs) has the potential to inhibit IL-1β which is one of the cytokine storms that occur in COVID patients through an in--silico approach. AIM: This study aims to determine the effect of in silico approach pro-inflammatory protein interleukin 1β (IL-1 β) and IL-1Ra protein as cytokine WJ-MSCs for potential treatment of COVID-19 disease. METHODS: 3D structure using the homology modeling method on Swiss Model web-server. Molecular docking was performed to analyze the binding mode of the IL-1β related to COVID-19 with IL-1Ra and the docking results were fixed using FireDock web-server. RESULTS: These results of the docking of proteins between IL-1β and the CM-WJMSCs component, namely IL-1Ra showed that IL-1Ra has criteria for docking on IL-1β such as the good score for QMEAN, good CscoreLB, and BS-score results, and the lowest energy obtained was −585.1 KJ/mol. It can be predicted that IL-1Ra can inhibit IL-1β which causes cytokine storms in COVID-19 patients. CONCLUSION: Based on the result, CM-WJMSC has potential treatment on the severity of COVID-19 infection. © 2022 Wahyu Widowati, Kusworini Handono, Marlina Marlina, Ika Adhani Sholihah, Diana Krisanti Jasaputra, Teresa Liliana Wargasetia, Mawar Subangkit, Ahmad Faried, Ermi Girsang, I Nyoman Lister, Chrismis Novalinda Ginting, Ita Margaretha Nainggolan, Rizal Rizal, Hanna Kusuma, Linda Chiuman.

A case of multisystem inflammatory syndrome in adults following natural infection and subsequent immunization.

Multisystem inflammatory syndrome in adults is a rare and life-threatening complication that follows natural COVID-19 infection and primarily affects young unvaccinated adults. This complication is seldom described following vaccination, which would have important implications for the vaccination timing and platform in this population. COVID-19 vaccines are extremely effective; however, the risk of rare adverse events needs to be balanced with the vaccination benefits.

Diabetes in COVID-19 patients: challenges and possible management strategies

Background The recent pandemic of coronavirus disease 19 (COVID-19) has been causing intense stress among the global population. In the case of hospitalized and ICU-admitted COVID-19 patients with comorbidities, it has been observed that a major portion of them are diabetic. Therefore, researchers had indicated a link between diabetes mellitus (DM) and COVID-19. Furthermore, DM is a potential risk factor for the severity of COVID-19 cases. Thus, in this study, the correlation existing between diabetic patients and COVID-19 was summarized. Main body of the Diabetic patients have a weaker immune system, less viral clearance rate, malfunctions of metabolic activity due to their high blood glucose level, and other associated problems. This does not increase the susceptibility for the patients to be infected with COVID-19. However, the severity of COVID-19 can worsen due to the comorbidity of DM. Short conclusion Proper management, appropriate use of drugs that do not increase the ACE2 expression, lowering blood glucose level, decreasing the susceptibility of SARS-CoV-2, and maintaining a healthy lifestyle could be effective.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients.

BACKGROUND: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. METHODS: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. RESULTS: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. CONCLUSION: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study.

BACKGROUND: A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. METHODS: In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. RESULTS: Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. CONCLUSIONS: Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.