Interleukin-6 Blockade Research Articles

Therapeutic targeting of interleukin-6 for the treatment of COVID-19.

Coronavirus disease 19 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in China and has spread worldwide with a significant rate of infection. Considering the elevated levels of proinflammatory cytokines in COVID-19, it is suggested that cytokine storms play a critical role in its pathogenesis, including acute respiratory distress syndrome (ARDS). However, there is no specific drug for preventing the cytokine release syndrome (CRS) caused by COVID-19. Indeed, interleukin 6 (IL-6) has been highlighted for its many biological functions, such as immune regulation, inflammatory response, and metabolism. Therapeutic blockade of the IL-6 signaling pathway is expected to reduce the excessive immune reponse observed in COVID-19. Currently, the IL-6 receptor antagonists tocilizumab and sarilumab, have been adopted for preventing CRS during the progression of COVID-19, and remarkable beneficial effects were observed by using these humanized monoclonal antibodies. Based on the pathogenesis of COVID-19, we reviewed the biological mechanism of IL-6 blockade in the treatment of SARS-CoV-2 infection and evaluated its clinical applications.

Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19

BackgroundMany COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. MethodsHospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. Results70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. ConclusionsSubcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.

Interleukin-1 blockade in patients with pericardial constriction

Abstract Background Recurrent pericarditis is very difficult to treat, especially when symptoms become refractory to conventional treatments (nonsteroidal anti-inflammatory drugs,colchicine,corticosteroids). Interleukin-1 (IL-1) blockade with anakinra has been proved to be useful in this setting. Indeed, persistent inflammation of the pericardium may lead to pericardial constriction, worsening prognosis. Purpose This study was aimed to assess the incidence and clinical course of pericardial constriction in patients with corticosteroid-dependent, colchicine-resistant recurrent pericarditis (CCRP) undergoing anti IL-1 treatment. Methods We selected patients included in the IRAP (International Registry of Anakinra for Pericarditis). A subgroup of 39 CCRP patients enrolled at the coordinating center underwent echocardiographic and clinical assessment for pericardial constriction. Results Thirty-nine patients were assessed, aged 42±12 years old, 67% females, 74% idiopathic etiology, with a median disease duration of 12 months (IQR 9–20) and a recurrence rate of 2.79 flares-patient/year before starting anakinra. Echocardiographic signs of pericardial constriction were demonstrated in 8 patients (21%). After starting anakinra, in 5/8 patients (63%) a complete resolution of pericardial constriction was observed within a median of 1.2 months,IQR 1–4. In other 3/8 patients (37%) pericardial constriction persisted and became chronic, requiring pericardiectomy within a median of 2.8 months, IQR 2–5. Compared with others, the 8 patients with pericardial constriction hadn't had a greater burden of pericardial flares before anakinra (3.87 flares-patient/year vs. 2.62/patient-year, p=0.07) and after anakinra (0.71 flares-patient/year vs. 0.72/patient-year, p=0.99). However, among 11 patients (28%) with incessant symptoms, an higher incidence of pericardial constriction was observed, compared with patients with recurrent symptoms (respectively 64% vs. 3.6%, RR=47, 95% CI 4.5–492, p<0.01). Conclusions In CCRP patients, pericardial constriction may be reversed by anti IL-1 agents. The risk of pericardial constriction is associated with incessant symptoms rather than simple recurrent course. Funding Acknowledgement Type of funding source: None

Role of Interleukin-1 Family Members and Signaling Pathways in KSHV Pathogenesis.

Kaposi’s sarcoma-associated herpesvirus (KSHV) represents the etiological agent for several human malignancies, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD), which are mostly seen in immunocompromised patients. In fact, KSHV has developed many strategies to hijack host immune response, including the regulation of inflammatory cytokine production. Interleukin-1 (IL-1) family represents a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Furthermore, a broadening list of diseases has revealed the pathologic role of IL-1 mediated inflammation. In the current mini-review, we have summarized recent findings about how this oncogenic virus is able to manipulate the activities of IL-1 signaling pathway to facilitate disease progression. We also discuss the therapeutic potential of IL-1 blockade against KSHV-related diseases and several unsolved questions in this interesting field.

Novel strategies to target the humoral alloimmune response.

Antibody-mediated rejection (ABMR) represents a major cause of late allograft loss in solid organ transplantation worldwide. This process is driven by donor-specific antibodies (DSA), which develop either de-novo or, in sensitized patients, are preformed at the time of transplantation. Effective targeting of ABMR has been hampered by a lack of robust randomized controlled trials (RCT), required for the regulatory approval of new therapeutics. In this review, we discuss the evidence behind the present "standard" of care and recent progress in the development of novel strategies targeting different aspects of the alloimmune humoral response, including naïve and memory B-cell activation, the germinal centre reaction, plasma cell survival and antibody effector functions. In particular, we focus on co-stimulation blockade and its combination with next-generation proteasome inhibitors, new depleting monoclonal antibodies (anti-CD19, anti-BCMA, anti-CD38, anti-CD138), interleukin-6 blockade, complement inhibition and DSA degradation. These treatment modalities, when used in the appropriate clinical context and combination, have the potential to finally improve long-term allograft survival.

Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms

Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention.

Neutrophilic dermatoses with unusual and atypical presentations

Neutrophilic dermatoses (NDs) are a group of reactive, noninfectious autoinflammatory diseases characterized by (1) infiltration of the epidermis, dermis, and or/hypodermis by neutrophils; (2) their association with distinct diseases (eg, hematologic malignancy and chronic inflammatory diseases); (3) potential extracutaneous involvement; and (4) response to anti-inflammatory drugs, such as corticosteroids, dapsone, colchicine, and novel biologic therapies, such as the anti–interleukin-1 blockade. Although distinct NDs have been described, transitional forms with overlapping features are often identified. These justify a simplified classification of NDs with three major forms: superficial (epidermal or pustular) NDs, dermal (en plaques) NDs, and deep NDs.We review selected or novel variants of NDs, including subcorneal pustular dermatosis, the group of immunoglobulin A neutrophilic dermatoses, amicrobial pustular dermatosis of the folds, and neutrophilic urticarial dermatosis, as well as atypical forms of Sweet syndrome and pyoderma gangrenosum closely mimicking severe infectious diseases. Knowledge of these variants is essential for proper diagnosis, adequate management, and avoidance of a dangerous escalation of therapy, such as unnecessary immunosuppression or extensive surgery.

Blockade of Tumor Necrosis Factor by Etanercept Prevents Postoperative Adhesion Formation in Mice.

Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation. Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercept-treated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band. Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation.

Hemophagocytic lymphohistiocytosis in a patient with COVID-19 treated with tocilizumab: a case report

BackgroundThe understanding of coronavirus disease 2019 (COVID-19) is rapidly evolving. Although it is primarily a respiratory illness, other manifestations, such as Guillain-Barré syndrome, immune thrombocytopenia, and immune-mediated thrombotic thrombocytopenic purpura, have been described. We present a case of a patient with hemophagocytic lymphohistiocytosis secondary to COVID-19 treated with tocilizumab with a marked biochemical improvement.Case presentationIn this case report we present a Caucasian patient with COVID-19 who developed a marked elevation of inflammatory parameters with ferritin 36,023 μg/L, but also elevated C-reactive protein 334 mg/L and lactate dehydrogenase 1074 U/L, 1 week after admission to the intensive care unit. He met five of eight criteria for hemophagocytic lymphohistiocytosis, but he lacked the high fever and cytopenia seen in the majority of cases. He was treated with tocilizumab, a monoclonal antibody targeting the interleukin-6 receptor, and over the next days, a rapid decrease in ferritin and C-reactive protein levels was observed. However, his respiratory failure only improved gradually, and he was weaned off the respirator 11 days later.ConclusionCOVID-19 may induce a hyperinflammatory clinical picture and in some cases develop into hemophagocytic lymphohistiocytosis. In our patient’s case, therapeutic interleukin-6 blockade abrogated signs of hyperinflammation but did not seem to improve pulmonary function. Measurement of ferritin and C-reactive protein, as well as quantification of interleukin-6 on indication, should be performed in patients with severe COVID-19. Specific treatment in such patients must also be contemplated, preferably in randomized controlled trials.

Preemptive interleukin-6 blockade in patients with COVID-19

Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.

Deep immunophenotyping at the single-cell level identifies a combination of anti-IL-17 and checkpoint blockade as an effective treatment in a preclinical model of data-guided personalized immunotherapy

BackgroundAlthough immune checkpoint blockade is effective for several malignancies, a substantial number of patients remain refractory to treatment. The future of immunotherapy will be a personalized approach adapted to each...

Cotrimoxazole as adjuvant therapy in critical ill COVID 19 patients

The ongoing pandemic of COVID-19 has forced us to consider using available drugs in the shortfall of vaccines and established treatment. Cotrimoxazole is one of the oldest drugs presently used in the prevention and treatment of opportunistic infections in the human immune deficiency virus (HIV) etc. It is a combination of two drugs Trimethoprim and Sulfamethoxazole. This cost-effective old drug is well tolerated among the population with the concomitant use of folic acid; moreover, it also looks after the secondary infections. To conclude, Cotrimoxazole can be used as critically ill COVID-19 patients.&#x0D; &#x0D; References &#x0D; &#x0D; Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive care Med. 2020;46(5): 846–48. https://doi.org/10.1007/s00134-020-05991-x&#x0D; Rozin A, Schapira D, Braun-Moscovici Y, Nahir AM. Cotrimoxazole treatment for rheumatoid arthritis. Semin Arthritis Rheum. 2001;31(2):133-41.&#x0D; Bourke CD, Gough EK, Pimundu G, Shonhai A, Berejena C, Terry L, et al. Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation. Sci Transl Med. 2019;11(486): eaav0537. https://doi.org/10.1126/scitranslmed. aav0537&#x0D; Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020; 111:102452. https://doi.org/10.1016/j.jaut.2020.102452&#x0D; Vickers IE, Smikle MF. The immunomodulatory effect of antibiotics on the secretion of tumour necrosis factor alpha by peripheral blood mononuclear cells in response to Stenotrophomonas maltophilia stimulation. West Indian Med J. 2006;55(3):138-41. https://doi.org/10.1590/s0043-31442006000300002&#x0D; Onyebuagu PC, Kiridi K, Pughikumo DT. Effects of septrin administration on blood cells parameters in humans. Int. J. Basic Appl. Innov. Res, 2014;3(1): 14 -8. https://www.ajol.info/index.php/ijbair/article/view/104688&#x0D; Ho JMW, Juurlink DN. Considerations when prescribing trimethoprim– sulfamethoxazole. CMAJ. 2011; 183(16):1851-8. https://doi.org/10.1503/cmaj.111152&#x0D; Mahan CS, Walusimbi M, Johnson DF, Lancioni C, Charlebois E, Baseke J, et al. Tuberculosis treatment in HIV infected Ugandans with CD4 counts .350 cells/mm3 reduces immune activation with no effect on HIV load or CD4 count. PLoS one.2010;5(2): e9138. https://doi.org/10.1371/journal.pone.0009138&#x0D; Varney VA, Smith B, Quirke G, Parnell H, Ratnatheepan S, Bansal AS, et al. P49 the effects of oral cotrimoxazole upon neutrophil and monocyte activation in patients with pulmonary fibrosis and healthy controls; does this relate to its action in idiopathic pulmonary fibrosis. Thorax. 2017;72: A109. http://dx.doi.org/10.1136/thoraxjnl-2017-210983.191&#x0D;

Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: A prospective cohort study.

BackgroundThe virological and immunological effects of the immunomodulatory drugs used for COVID-19 remain unknown. We evaluated the impact of interleukin (IL)-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and the antibody response in patients with COVID-19.MethodsProspective cohort study in patients admitted with COVID-19. Serial nasopharyngeal and plasma samples were measured for SARS-CoV-2 RNA and S-IgG/N-IgG titers, respectively.Findings138 patients with confirmed infection were included; 76 (55%) underwent IL-6 blockade. Median initial SOFA (p = 0•016) and SARS-CoV-2 viral load (p<0•001, Mann-Whitney-Wilcoxon test) were significantly higher among anti-IL-6 users. Patients under IL-6 blockade showed delayed viral clearance in the Kaplan-Meier curves (HR 0•35 [95%CI] [0•15–0•81], log-rank p = 0•014), but an adjusted propensity score matching model did not demonstrate a significant relationship of IL-6 blockade with viral clearance (HR 1•63 [0•35–7•7]). Cox regression showed an inverse association between SARS-CoV-2 RNA clearance and the initial viral load (HR 0•35 [0•11–0•89]). Patients under the IL-6 blocker showed shorter median time to seropositivity, higher peak antibody titers, and higher cumulative proportion of seropositivity in the Kaplan Meier curves (HR 3•1 [1•9–5] for S-IgG; and HR 3•0 [1•9–4•9] for N-IgG; log-rank p<0•001 for both). However, no significant differences between groups were found in either S-IgG (HR 1•56 [0•41–6•0]) nor N-IgG (HR 0•96 [0•26–3•5]) responses in an adjusted propensity score analysis.InterpretationOur results suggest that in patients infected with SARS-CoV-2, IL-6 blockade does not impair the viral specific antibody responses. Although a delayed viral clearance was observed, it was driven by a higher initial viral load. The study supports the safety of this therapy in patients with COVID-19.FundingInstituto de salud Carlos III (Spain).

Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study

ObjectivesTo assess the safety and efficacy of interleukin (IL)−6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation.MethodsWe conducted an open-label study of sarilumab in severe COVID-19...

Modulation of Interleukin-1 and -18 Mediated Injury in Donation after Circulatory Death Mouse Hearts

BackgroundDonation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. Materials and methodsFollowing clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. ResultsDeveloped pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. ConclusionsHeart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.

Treatment of Juvenile Spondyloarthritis: Where We Stand

Juvenile spondyloarthritis is a subset of juvenile idiopathic arthritis (JIA) with onset in late childhood and adolescence and a strong association with human leukocyte antigen (HLA) B-27 positivity and familial aggregation that has the potential for axial involvement, potentially leading to ankylosing spondylitis. Current therapy for severe disease relies heavily on tumor necrosis factor inhibitors (TNFi). Treatment paradigms in children largely consist of extrapolation from studies on adults with spondyloarthritis. Additional therapies studied in adults include non-steroidal anti-inflammatory drugs (NSAIDs), blockade of the interleukin-17 (IL-17) and IL-23 axes, blockade of T-cell stimulation, phosphodiesterase (PDE)-4 inhibition, and Janus-activated kinase (JAK) pathway alteration. IL-17 blockade and IL-23 blockade are guideline approved after TNFi failure (and even as an alternative to TNFi) in adults, depending on concomitant inflammatory bowel and skin disease, with JAK and PDE-4 inhibition options following biologic failure. Neither pediatric nor adult guidelines address IL-6 blockade, T-cell co-stimulation blockade, or combination biologic therapy.

Coronavirus Disease 2019 Viremia, Serologies, and Clinical Course in a Case Series of Transplant Recipients

Here we report a single-center cohort of 6 patients (4 kidney only, and 2 simultaneous liver/kidney transplants) diagnosed with COVID-19 at a median of 1.9 years (range = 0.2-9.3 years) post transplant. Five (of 6) patients required inpatient admission, 2 patients (mortality = 33%) died. Among those with mortality, an increased concentration of inflammatory biomarkers (interleukin-6 and C-reactive protein) was noted with a lack of response to interleukin-6 blockade, remdesivir, and/or convalescent plasma. None of the kidney-only transplants (4/6; 67%) had elevation in plasma donor-derived cell-free DNA above the previously published cut-off of 1%, suggesting absence of significant allo-immune injury. Four (of 5) admitted patients had detectable SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) in blood on samples obtained at/during hospitalization. Of the 4 discharged patients, 2 patients with undetectable virus on repeat nasopharyngeal swabs had seroconversion with positive SARS-CoV-2 IgG formation at 30 to 48 days post infection. One patient had prolonged shedding of virus on nasopharyngeal swab at 28 days post discharge despite lack of symptoms. In this preliminary report, we find that immunocompromised transplant patients had higher rates of RNAemia (67%) than reported in the general population (15%), seeming absence of allo-immune injury despite systemic inflammation, and formation of IgG overtime after recovery from infection.

The conundrum of interleukin-6 blockade in COVID-19.

The conundrum of interleukin-6 blockade in COVID-19.

IL-6 (Interleukin 6) Blockade and Heart Rate Corrected QT Interval Prolongation in COVID-19.

IL-6 (Interleukin 6) Blockade and Heart Rate Corrected QT Interval Prolongation in COVID-19.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.