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1.
Ter Arkh ; 94(8): 1028-1035, 2022 Oct 12.
Article in Russian | MEDLINE | ID: covidwho-2091506

ABSTRACT

The Advisory Board chaired by the chief specialist in infectious diseases of the Ministry of Health of Russian Federation, Professor V.P. Chulanov was held on June 18, 2022 in Saint Petersburg. Aim. The main purpose of the Board was following discussion: the analysis of the real-world data of levilimab as an anticipatory therapy for COVID-19 in hospitalized patients; the review of the experience and perspectives of levilimab as an anticipatory anti-inflammatory option for outpatient patients who meet defined clinical and laboratory criteria. Results. The analyzed data on clinical efficacy and safety formed the basis of recommendations proposed by experts for the use of levilimab in the inpatient and outpatient medical care for COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Anti-Inflammatory Agents , Receptors, Interleukin-6
2.
J Clin Pharm Ther ; 2022 Oct 21.
Article in English | MEDLINE | ID: covidwho-2088243

ABSTRACT

Tocilizumab (Actemra®), as the first human interleukin-6 receptor (IL-6R) antagonist, has been used in treating moderate to severe active rheumatoid arthritis (RA) patients who were undertreatment with one or more disease-modifying anti-rheumatic drugs (DMARDs) and did not improve significantly. Tocilizumab also has been administrated and confirmed in several inflammatory-based diseases. Recently, tocilizumab has been prescribed to treat patients with advanced coronavirus disease (COVID-19) and is used as one of the effective drugs in reducing the increased inflammation in these patients. On the other hand, cancer treatment has been considered by researchers one of the most important challenges to human health. Regarding inflammatory-associated malignancies, it has been shown that inflammatory mediators such as interleukin-1 beta (IL-1ß), IL-6, and tumour necrosis factor-alpha (TNF-α) may play a role in tumorigenesis, thus targeting these cytokines as evidence suggested can be useful in the treatment of these types of cancers. This review summarized the role of the IL-6/IL-6R axis in inflammation-based cancers and discussed the effectiveness and challenges of treating cancer with tocilizumab.

3.
Indian Journal of Critical Care Medicine ; 26(10):1069-1071, 2022.
Article in English | EMBASE | ID: covidwho-2066999
4.
Chest ; 162(4):A1856-A1857, 2022.
Article in English | EMBASE | ID: covidwho-2060874

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Biological disease modifying anti-rheumatic drugs (bDMARDs) are commonly used to treat interstitial lung disease (ILD) in patients with connective tissue disease (CTD). These patients often develop concurrent COVID-19 disease and existing data is scarce to guide treatment. We describe a case with a rare anti-Pl-7 Anti-Synthetase Syndrome (ASS) receiving Rituximab treatment for ILD who developed acute respiratory distress syndrome (ARDS) secondary to COVID-19 disease. CASE PRESENTATION: A 58-year-old female presented with worsening shortness of breath, loss of taste and smell, cough and headaches for 1 week. She had pre-existing severe chronic ILD secondary to ASS on Rituximab therapy. She tested positive on SARS-CoV-2 PCR testing, CT chest showed bilateral lung honeycombing, reticulations, traction bronchiectasis along with ground glass opacities consistent with active inflammatory interstitial process superimposed on ILD. She was diagnosed with COVID-19 pneumonia. She was initially started on high-dose Dexamethasone, Remdesivir and supplemental oxygen via high flow nasal cannula and supportive care for ARDS, however level of care was escalated due to worsening respiratory distress. Rituximab was discontinued due to active COVID-19 infection, the decision was made to start Baricitinib at 4 mg daily. She received treatment for 14 days, that led to a significant improvement in her respiratory status. DISCUSSION: ASS is a rare autoimmune condition involving multiple organs, with ILD being the major cause of morbidity. bDMARDS, especially Rituximab, have shown promising results in management of severe and refractory ILD in ASS. However, the role of bDMARDs as protective or risk factor for developing severe COVID-19 disease in these patients is unclear. ARDS in COVID-19 disease involves a vigorous inflammatory response and cytokine production leading to diffuse alveolar damage. Literature supports that use of corticosteroids, IL-1 and IL-6 receptor blockers and Janus Kinase (JAK) inhibitors for severe COVID-19 pneumonia is associated with decreased morbidity. Baricitinib is a JAK1 and JAK2 with anti-cytokine and anti-viral properties and has been associated with reduction in morbidity and mortality in patients with COVID-19 as demonstrated in our case. Generally, use of bDMARDs does not contribute to worse outcomes in COVID-19 disease in patients receiving these agents for rheumatological conditions. However, use of Rituximab and high dose glucocorticoids have been associated with worse outcomes, while Baricitinib may have a protective effect. Therefore, holding Rituximab in those with active COVID-19 infection is recommended. CONCLUSIONS: Management of COVID-19 in patients with CTD is a challenge due to the novel nature of the disease and scarcity of available data. The association of use of bDMARDs in rheumatological disease with outcomes in SARS-CoV-2 infection is yet to be elucidated. Reference #1: Barbosa AN, Silvinato A, Bacha H, Floriano I, Tanni S, Bernardo W. Use of disease-modifying drugs (tocilizumab, tofacitinib, and baricitinib-a biological or synthetic target specific) in patients hospitalized with COVID-19. Rev Assoc Med Bras (1992). 2022;68(1):3-8. Reference #2: Santos CS, Férnandez XC, Moriano Morales C, Álvarez ED, Álvarez Castro C, López Robles A, Pérez Sandoval T. Biological agents for rheumatic diseases in the outbreak of COVID-19: friend or foe? RMD Open. 2021 Jan;7(1):e001439. doi: 10.1136/rmdopen-2020-001439. PMID: 33455920;PMCID: PMC7813407. Reference #3: Galarza-Delgado DÁ, Serna-Peña G, Compeán-Villegas JE, Cardenas-de la Garza JA, Pineda-Sic RA, Colunga-Pedraza IJ, Vega-Morales D, Pérez-Barbosa L, Skinner-Taylor CM, Flores-Alvarado DE. Characteristics and evolution of 38 patients with rheumatic diseases and COVID-19 under DMARD therapy. Clin Rheumatol. 2021 Mar;40(3):1197-1199. doi: 10.1007/s10067-020-05510-9. Epub 2020 Nov 24. PMID: 33231774;PM

5.
Chest ; 162(4):A585-A586, 2022.
Article in English | EMBASE | ID: covidwho-2060638

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: COVID-19 patients requiring admission to an ICU have a higher risk of invasive pulmonary aspergillosis (IPA) with a reported incidence of 19.6%-33.3%. CASE PRESENTATION: A 63-year-old male presented with progressively worsening dyspnea for one week. He has a past medical history of atrial fibrillation, hypertension, and obesity. He was tested positive for COVID about two weeks prior. He did receive a single dose of Moderna vaccine. Initial chest x-ray(CXR) showed diffuse ground-glass opacities. He was initiated on Remdesivir and decadron, and later received a dose of tocilizumab. He was intubated on hospital day 3 for worsened hypoxemia. Repeat CXR suggested some improvement but a new left lower lobe airspace haziness. He also had new-onset leukocytosis with elevated procalcitonin level. He was started on cefepime for concern of superimposed hospital-acquired pneumonia. A second dose of tocilizumab was administered. No clinical improvement was seen, and additional workups were obtained. Serial CXRs revealed increasing diffuse airspace opacities concerning for ARDS. Tracheal aspirate culture grew coagulase-negative staphylococcus and Aspergillosis Fumigatus. Cefepime was changed to vancomycin, and voriconazole and caspofungin were added. Unfortunately, the patient's respiratory status worsened with increasing ventilation requirement. He also developed septic shock and acute renal failure requiring CVVH. He became even more hypotensive after CVVH initiation, and multiple vasopressors were required to maintain his hemodynamics. Unfortunately, he continued to deteriorate and he also developed profound respiratory acidosis. He died shortly afterwards after family decided to withdraw care. DISCUSSION: In this case, in addition to superimposed bacterial pneumonia, pulmonary aspergillosis likely also contributed to his clinical deterioration. The mechanism by which fungal infections develop in COVID-19 infection is not well-understood. Severe COVID-related immune dysregulation, ARDS, and high-dose steroids use are potential culprits for the increased risk of IPA. Tocilizumab, an IL-6 receptor monoclonal antibody used in patients with severe COVID-19 infection, may also predispose the patient to IPA according to post-marketing data. The mortality rate from current case reports is as high as 64.7%. Diagnosis and treatment in such a scenario remain a challenge. Sputum culture, serum Beta-galactomannan, Beta-D glucan, and aspergillosis PCR have low sensitivity. Tissue biopsy and CT scan in critically ill patients are often not feasible. Voriconazole is usually considered the first-line treatment in IPA. CYP3A4-mediated drug interactions between azoles and antiviral agents require further investigation. CONCLUSIONS: Clinicians should be aware that severe COVID-19 patients are at higher risk of IPA. The prognosis is poor. Early detection and treatment in clinically deteriorated patients are warranted. Reference #1: Borman, A.M., Palmer, M.D., Fraser, M., Patterson, Z., Mann, C., Oliver, D., Linton, C.J., Gough, M., Brown, P., Dzietczyk, A. and Hedley, M., 2020. COVID-19-associated invasive aspergillosis: data from the UK National Mycology Reference Laboratory. Journal of clinical microbiology, 59(1), pp.e02136-20. Reference #2: Lai CC, Yu WL. COVID-19 associated with pulmonary aspergillosis: A literature review. J Microbiol Immunol Infect. 2021;54(1):46-53. doi:10.1016/j.jmii.2020.09.004 Reference #3: Thompson Iii GR, Cornely OA, Pappas PG, et al. Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa242. Published 2020 Jun 19. doi:10.1093/ofid/ofaa242 DISCLOSURES: No relevant relationships by Jason Chang No relevant relationships by Jason Chang No relevant relationships by kaiqing Lin No relevant relationships by Guangchen Zou

6.
Chest ; 162(4):A448, 2022.
Article in English | EMBASE | ID: covidwho-2060598

ABSTRACT

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Since the start of Covid-19 pandemic, several respiratory microorganisms have been identified that cause coinfection with Sars-Cov-2. Bacteria like Staphylococcus aureus and viruses like influenza are some of the identified pathogens. Rarely, fungal infections from Aspergillus are also being reported. CASE PRESENTATION: 59-year-old male with past medical history of hypertension and hyperlipidemia was admitted for shortness of breath and was found to be positive for Covid-19. He received Remdesivir, dexamethasone & tocilizumab. He required non-invasive ventilation via continuous positive airway pressure but continued to remain hypoxemic with elevated procalcitonin, he was treated with cefepime for bacterial pneumonia. Patient required emergent intubation and eventually underwent tracheostomy. He developed methicillin-resistant Staphylococcus aureus pneumonia for which he received vancomycin. He was eventually discharged to long term acute care facility. Patient was readmitted after 2 months due to worsening respiratory status. Computed Tomography Angiography of chest was negative for pulmonary embolism but showed pleural effusion. He underwent thoracentesis which showed exudative effusion with negative cultures. Echocardiogram showed right heart failure. Patient's symptoms were believed to be due to Covid-19 fibrosis. He required home oxygen and also received pulmonary rehabilitation. One year after the initial Covid-19 infection, he developed pulmonary hypertension and was referred for lung transplant consultation. However, he developed severe hemoptysis requiring intubation and vasopressors. Galactomannan was positive, Karius digital culture revealed Aspergillus Niger for which he received voriconazole. He was not deemed a suitable candidate for lobectomy. Patient developed arrhythmia and had prolonged QT interval so voriconazole was switched to Isavuconazole. He continued to have hemoptysis and his condition did not improve so family requested to transition care and patient passed away. DISCUSSION: Several studies have proven co-infection of Aspergillus with Covid-19. This case highlights Aspergillus infection approximately 1 year after initial Covid-19 infection. Sars-Cov-2 causes damage to airway lining which can result in Aspergillus invading tissues. IL-6 is increased in severe Covid-19 infection. Tocilizumab is an anti-IL-6 receptor antibody that has been approved for treatment of Covid-19 pneumonia. However, IL-6 provides immunity against Aspergillus so use of tocilizumab decreases protection against Aspergillosis which is usually the reason for co-infection. However, in this case patient developed fungal infection later during Covid-19 fibrosis stage. CONCLUSIONS: Recognizing fungal etiology early on is important in Covid-19 patients as mortality is high and appropriate intervention can reduce morbidity and mortality. Some patient may eventually require lung resection. Reference #1: Kakamad FH, Mahmood SO, Rahim HM, Abdulla BA, Abdullah HO, Othman S, Mohammed SH, Kakamad SH, Mustafa SM, Salih AM. Post covid-19 invasive pulmonary Aspergillosis: a case report. International journal of surgery case reports. 2021 May 1;82:105865. Reference #2: Nasrullah A, Javed A, Malik K. Coronavirus Disease-Associated Pulmonary Aspergillosis: A Devastating Complication of COVID-19. Cureus. 2021 Jan 30;13(1). Reference #3: Dimopoulos G, Almyroudi MP, Myrianthefs P, Rello J. COVID-19-associated pulmonary aspergillosis (CAPA). Journal of Intensive Medicine. 2021 Oct 25;1(02):71-80. DISCLOSURES: No relevant relationships by Maria Haider Baig

7.
Chest ; 162(4):A384, 2022.
Article in English | EMBASE | ID: covidwho-2060578

ABSTRACT

SESSION TITLE: Global Pulmonary Cases SESSION TYPE: Global Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: COVID 19 is associated with hyper- inflammation with levels of IL 6 correlating with the severity of COVID 19. IL6 causes increased vascular permeability and endothelial dysfunction and plays a major role in the development of ARDS.[1] Tocilizumab is a monoclonal antibody against the IL6 receptor which is being used for COVID pneumonia. Large randomized controlled trials including REMAP-CAP and RECOVERY reported a mortality benefit of tocilizumab in certain patients [3]. Aspergillus is a mold that causes variety of pulmonary infections depending on host's immune status. In immunocompromised hosts, it causes invasive pulmonary aspergillosis [2]. Symptoms initially are similar to bronchopneumonia: cough with sputum, dyspnea, fever not responsive to antibiotics. With disease progression, patients experience pleuritic chest pain and hemoptysis. CASE PRESENTATION: 69 y/o female came to ER with complaint of dyspnea and cough. PMH significant for Diabetes. She had a recent admission for COVID 3 weeks ago during which she received tocilizumab. This time, her vitals were HR- 96 RR- 24 Temp- 99.6 BP- 124/72, Sat- 88% on 2L NC. Labs WBC 31.1 D dimer- 2.17 ABG PO2- 61. CT pulmonary angiogram was consistent with left mid lung zone cavitary mass with an air-fluid level measuring 5 x 8 cm in transverse and AP dimension. Patient was started on broad-spectrum antibiotics (vancomycin, cefepime, metronidazole). Sputum cultures, Beta glucan assay, AFB and fungal immunodiffusion panel was ordered. Beta D Glucan assay came positive. Fungal immunodiffusion panel was negative. Bronchoscopy was done and AFB, aspergillus antigen and cultures were collected. BAL aspergillus antigen came positive and KOH fungal culture grew Aspergillus Fumigatus. Voriconazole was started. She was discharged on voriconazole for 12 weeks, ceftriaxone and clindamycin for 6 weeks for antibacterial coverage with plan to repeat CT chest in 3 weeks. DISCUSSION: We use tocilizumab for COVID 19 patients requiring invasive or non invasive mechanical ventilation and CRP ≥7.5 and exclude patients with ANC <2000, platelet <50,000 and history of serious bacterial, fungal or viral infection. This patient did not have any exclusion criteria but developed invasive fungal infection 3-4 weeks later. Due to worsening hypoxia and high D dimer, initial consideration was pulmonary embolism for which CT angiogram was done and a cavitary lesion was found. Differentials were bacterial abscess, tuberculosis or fungal infection. BAL played a crucial role in diagnosing aspergillosis. CONCLUSIONS: In patients presenting with worsening respiratory symptoms post tocilizumab administration we must keep a low index of suspicion for superimposed opportunistic infections including aspergillosis. Appropriate workup including CT chest, sputum or bronchoalveolar lavage for cultures (bacterial, fungal), Beta D Glucan and fungal panel is essential for diagnosis. Reference #1: Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia Ivan O Rosas;Norbert Bräu;Michael Waters;et al. New England Journal of Medicine, v384 n16 (20210422): 1503-1516 Reference #2: Pulmonary aspergillosis: a clinical review M. Kousha, R. Tadi, A.O. Soubani European Respiratory Review 2011 20: 156-174;DOI: 10.1183/09059180.00001011 Reference #3: Interleukin-6 Inhibitors. Available at: https://www.covid19treatmentguidelines.nih.gov. DISCLOSURES: No relevant relationships by Shaylika Chauhan No relevant relationships by Vipul Gidwani

8.
Journal of Comprehensive Pediatrics ; 13(Supplement 1):32, 2022.
Article in English | EMBASE | ID: covidwho-2058346

ABSTRACT

Upon COVID-19 infection, age-specific mortality rates in RADs patients notably began from 35 years old, while in the uninfected population, it was from 55. COVID-19 associated rheumatic signs and symptoms are myalgia, fatigue, Kawasaki-like signs, and skin rashes mimicking vasculitides and pernio (chilblains) like lesions. So a variety of rheumatic diseases may mimic or be mimicked by COVID-19. Rheumatologic Treatments During COVID-19 Epidemic: Prednisone caused an increased hospitalization rate, significantly when the dose exceeded 10 mg per day. It is reasonable to reduce glucocorticoids gradually to 5 - 7.5 mg/day, but discontinuation during the pandemic is not recommended. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) reduce the risk of COVID-19 infection and the cytokine storm emerging in severe cases. Colchicine has reduced the mortality of COVID- 19 patients and the number of severe cases. Tapering or even discontinuing csDMARDs is suggested to recover immunity in severe cases, which may help rapidly eliminate the virus. Hydroxychloroquine is likely to increase survival in SLE patients, and it is not advisable to be discarded. Biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) may help reduce inflammatory cytokine storm under COVID-19 attack. Compared with RADs patients treated with CD20 monoclonal antibody rituximab or IL-17A antagonist secukinumab, patients receiving tumor necrosis factor (TNF) inhibitors etanercept and alemtuzumab or IL- 6 receptor antagonist tocilizumab may experience milder course. Applicable Laboratory Indicators: Elevation of ESR, CRP, ferritin, interleukin 6, and creatine kinase can be seen in COVID-19 and various rheumatic diseases. RADs related autoantibodies may present among non-RAD severe COVID- 19 cases. COVID-19 as a Risk Factor for Rheumatologic Diseases: Cases of Small vessel cardiac vasculitis/endothelium, immunoglobulin A (IgA) vasculitis in patients with Crohn disease, cutaneous vasculitis-like lesions, systemic arterial and venous thromboembolism including cryptogenic strokes and other vasculopathy features, systemic rheumatic diseases such as SLE, inflammatory arthritis, GCA, inflammatory myopathies, APS, Sjogren's syndrome, ANCA-associated vasculitides, seropositive rheumatoid arthritis, and Virus-associated or reactive arthritis and Crystal-related arthritis due to gout or calcium pyrophosphate disease has been reported. COVID-19, in the acute phase, may cause cytokine storm and severe inflammatory response;and in the chronic phase, patients become susceptible to autoinflammatory and autoimmune diseases. If a patient has signs and symptoms of rheumatic diseases after developing COVID-19, do not attribute these complaints entirely to COVID-19;consider starting a real dangerous rheumatic disorder.

9.
HemaSphere ; 6:1038, 2022.
Article in English | EMBASE | ID: covidwho-2032104

ABSTRACT

Background: Vulnerability of patients (pts) with chronic lymphocytic leukemia (CLL) and their susceptibility to Covid-19 infection is documented in several studies with reported case fatality rates (CFRs) up to 40%, but there is still paucity of data on identifying risk factors of their adverse outcome. Aims: To evaluate demographic, patient-related, CLL-related and Covid-19 related risk factors in hospitalized pts with concurrent CLL and Covid-19. Methods: Total of 81 CLL pts were identified in medical records of three University centers in Belgrade: Clinical Hospital Center (CHC) Zemun, CHC Bezanijska kosa and CHC Zvezdara dedicated to treatment of Covid-19 pts during pandemic (from 15 March 2020 to 31 December 2021). Results: For all 81 pts CFR was 32.1%. Age (median age 68 yrs;range 45-90 yrs) and sex (apparent male prevalence: 61 male and 20 female;M:F=3.05) had no influence on outcome. Pts with Charlson comorbidity index >4 (29/81;35.8%) had significantly higher CFR (38% vs 9.5%, p=0,025). Concerning CLL-directed treatment: 26/81(32.1%) pts were on active treatment (5 pts were on Bruton tyrosine kinase inhibitor, 21pts receiving imunochemotherapy), 11/81(13.6%) pts were in remission on previous lines of therapy, while 44/81(54.3%) pts were treatment naive. CLL treatment history had no impact on CFR, as well as anemia (Hb<100g/l) that was present in 29/81(35.8%)pts, hipogammaglobulinemia (21/81;26%pts) and hiperferritinemia>450ng/mL (50/81;61.7%pts). Of evaluated laboratory parameters, high levels of lactate-dehydrogenase (LDH>2xUNL:6/81;7.4%pts), D-dimer (>1000ng/mL:36/81;44.4%pts), and C-reactive protein (CRP>100mg/L: 31/81;38.3%pts) proved to be associated with adverse outcome;p-values 0.002, 0.039 and <0.001, respectively. According to Covid-19 clinical course, the severe Covid-19 score had 35(43,2%)pts, and critical 19(23.5%)pts. Covid-19 infection was treated according to current National guidelines. Corticosteroids were administrated to 81.5% of pts, antiviral agents to 38.3%, IL-6 receptor inhibitor to 11.1%, antiviral monoclonal antibodies to 7.4% and intravenous immunoglobulin to 19.8% of pts. None of listed therapeutic approaches had impact on CFRs. Antibiotics were administrated to 43/81 (53.1%) of pts with documented or highly suspected concomitant bacterial infection (procaltitonin level>0.5ng/mL and/or chest X-Ray image corresponding to bacterial pneumonia), and the bacterial coinfection had adverse impact on CFR (51.2% vs.10.2%;p<0.001). Significantly higher mortality was documented in pts who needed supplemental oxygen (58/81;71%) (CFR 43.1 vs.4.3%;p<0.001), and intensive care unit (ICU) admission (25/81-30.9%;19/25 needed mechanical ventilation) (CFR 88% vs.7.1%;p<0.001). In multivariate analysis, bacterial coinfection and ICU admission proved to be the most significant adverse parameters influencing outcome (p=0.012). Summary/Conclusion: Our study proved the dismal outcome of CLL pts with concurrent Covid-19. That could be mainly attributed to the high proportion of bacterial coinfections reflecting their frailty and sucessibility to both viral and bacterial infections.

10.
Annals of the Rheumatic Diseases ; 81:1696-1697, 2022.
Article in English | EMBASE | ID: covidwho-2009118

ABSTRACT

Background: Human SARS-CoV-2 infection can induce a wide spectrum of organ dysfunctions, including microvascular impairment [1]. S1 subunit of viral receptor-binding domain binds to the angiotensin-converting enzyme 2 receptor on endothelium and S2 subunit allows the virus to enter endothelial cells. The resulting breakdown of barrier integrity drives a cascade of infammatory and thrombotic events, that aggravate the course of COVID-19 together with other risk factors [2-4]. Up to date, a lower capillary density has been reported in several distinct body districts, using sublingual video microscopy, ocular optical coherence tomography angiography, skin functional laser Doppler perfusion imaging and nailfold videocapillaroscopy (NVC) [5-8]. NVC examination has been performed in adult COVID-19 patients, however, without a control group [8]. Objectives: To confrm the statistical signifcance of the reduction in capillary density per linear millimeter evaluated by NVC in comparison with primary Ray-naud's phenomenon (PRP) patients and control subjects (CNT) and to evaluate the impact of an aggressive therapy against COVID-19 on the sparing in the number of capillaries. Methods: Sixty-one COVID-19 survivors, thirty-one PRP patients and thirty CNT age and sex-matched underwent NVC analysis. Demographic and clinical data of COVID-19 survivors were collected with special regard to concomitant therapies, that included antivirals, antibiotics, anticoagulants and anti-infamma-tory/immunomodulant drugs (glucocorticoids, hydroxychloroquine, IL-6 receptor antagonist). COVID-19 survivors were divided in two subgroups according to the severity of the active infection: thirty-four survivors with past mild-moderate disease (either unneedy for oxygen supplementation or need for Venturi mask) and twenty-seven survivors with past severe disease (need for Continuous Positive Airways Pressure and/or mechanical ventilation). The same Rheumatologist performed NVC evaluations in all patients and controls, using an optical probe, equipped with a 200x magnifcation lens and connected to a picture analysis software (Videocap, DS Medica, Milan, Italy). Absolute capillary number per linear millimeter was counted. Results: COVID-19 survivors underwent NVC examination after a mean period of 126±53 days from the disease onset. Multivariate analysis showed differences in absolute capillary number per linear millimeter (p<0.001) after adjusting for age, sex, body mass index, comorbidities and concomitant drugs. The mean (± standard deviation) absolute nailfold capillary number per linear millimeter was signifcantly lower in severe (8.2±1.15) and mild-moderate (8.4±0.75) COVID-19 survivors than in both PRP (8.7±0.68) and CNT subjects (9.3±0.53) (p<0.001). The analysis of the impact of treatments on capillary density in the severe COVID-19 patients showed a positive trend (preservation of the capillary number) with antivirals (no: 7.8±1.53;yes: 8.5±0.64;p=0.35) and anti-IL-6 receptor antagonist administration (no: 7.8±1.36;yes: 8.6±0.74;p=0.16), while none of the other drugs was shown to be effective (glucocorticoids p = 0.46;antibiotics = 0.52;anticoagulants not evaluable as they were used in all COVID-19 patients). Conclusion: SARS-CoV-2 infection seems associated to a signifcant capillary loss as distinctive NVC feature and data concerning the comparison of capillary density pre COVID-19 and post COVID-19 are desirable to reinforce this observation. The positive trend in saving the number of capillaries induced by aggressive anti-infammatory therapies in COVID-19 survivors needs larger cohorts of patients.

11.
Annals of the Rheumatic Diseases ; 81:460-461, 2022.
Article in English | EMBASE | ID: covidwho-2008834

ABSTRACT

Background: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease that primarily affects joints but is also often characterized by extra-articular involvement1. Cardiovascular diseases are the most important causes of sudden death in these patients, which present a risk of developing cardiovascular events increased by 48%2. The causes of increased cardiovascular risk are several and not completely understood, but recent evidence supports the key role of endothelial dysfunction in pathogenesis. In this complex scenario, it is known that IL-6 receptors are present at the endothelial level and can be activated leading to endothelial dysfunction. SARS-Cov-2 is a coronavirus responsible for the disease called 'coronavirus disease 2019' (CoViD-19) characterized by clinical manifestations ranging from a flu-like syndrome up to severe lung damage associated with systemic hyper cytokine syndrome that can lead to multiple organ failure and death. Therefore, both RA and Covid-19 are associated with an increased pro-thrombotic and cardiovascular risk and IL-6 might be crucial in the patho-physiological mechanisms of both diseases. Objectives: The main hypothesis of this study was to evaluate the possible role of IL-6 as a promoter of endothelial dysfunction in RA and CoViD-19. Methods: In vitro experiments were conducted on the endothelial cell line EA. hy926. Cells were treated for 24 h with fetal bovine serum (FBS), a pool of RA patients' sera or a pool of CoViD-19 patients' sera. The expression levels of adhesion molecules (V-CAM1/CD-106, I-CAM/CD-54, p-selectine/CD-62, tissue factor/CD-142) and apoptosis were analyzed using cytofuorimetric technique. In addition, the autophagy level, using the autophagy markers p62 and LC3II, were evaluated through a western-blot analysis. The same experiments were conducted co-treating cells with the same pool of sera in addition to tocilizumab (TCZ), an anti-IL-6 drug, to verify the reversibility of the process and test the role of the aforementioned cytokine. Data are reported as interquartile median values. The Kruskal Wallis test was used for unpaired samples and the Mann-Whitney test for paired samples. P<0.05 values were considered statistically signifcant. Results: EA. hy926 cells, when treated with both RA and CoViD-19 patients' sera, showed increased levels of activation molecules and apoptosis compared to FBS treated cells. In addition, we observed increased levels of both p62 and LC3 proteins after both rheumatoid arthritis and CoViD-19 patients' sera treatment. All these fndings were reversible in the presence of TCZ. The results are presented in Figure 1. Conclusion: Our data showed that treatment with RA and CoViD-19 patients' sera increase the activation and death of endothelial cells in vitro. The increased level of cells death is possibly due to a block of autophagy. The reversibility of the process after blocking IL-6 with TCZ co-treatment confrms the hypothesis that IL-6 can play a key role in the pathogenesis of endothelial damage in patients with RA and CoViD-19.

12.
Indian Journal of Critical Care Medicine ; 26:S94, 2022.
Article in English | EMBASE | ID: covidwho-2006381

ABSTRACT

Aim and background: COVID-19 was a new disease-causing a pandemic and hence generated uncertainty, and a great deal of anxiety with regard to appropriate therapeutic interventions. Many treatment regimens were tried with no evidence supporting the same. Critical and fatal COVID-19 due to immune dysregulation results in severe inflammation or a cytokine storm with markedly elevated pro-inflammatory cytokines like interleukin-6 (IL-6). Tocilizumab, an IL-6 receptor antagonist, is reported to prevent disease progression. However, since this is an expensive intervention, it is important that evidence is reviewed systematically regarding its utility. The India COVID guidelines is a group of experts and methodologists who came together to use a process of evidence synthesis to inform treatment guidelines using an evidence to decision framework (www.indiacovidguidelines.org). We report the data regarding tocilizumab in severe to critical COVID-19 infection. Objectives: To assess the efficacy and safety of tocilizumab in patients with COVID-19. Materials and methods: Search methods: We performed a systematic search till 15.10.2021 of the following databases: Pubmed, WHO ICTRP, L.OVE platform, Cochrane library, and COVID-NMA. Selection criteria: We selected only randomised controlled trials (RCT) evaluating tocilizumab use in COVID-19. Data collection and analysis: Two review authors independently screened and identified studies using Rayyan, did a risk of bias assessment using the Cochrane ROB 2 tool and extracted numerical data from studies for outcomes like all-cause mortality, disease progression, clinical improvement, and adverse events. Meta-analysis was performed using Review Manager 5.4. I2 statistics were used to measure residual heterogeneity. Certainty of evidence was evaluated using GRADE methodology. A group of experts then used the WHO evidence to decision framework to judge values and preferences, and a recommendation for tocilizumab applicable to a lower-middle-income country was generated. Results: Our search retrieved 1408 s from various databases. Twenty-three RCTs were included in this systematic review with 10,583 participants. All participants were hospitalised adults with moderate to severe disease with an average age of 54-65 years. Median C-reactive protein was ≥ 100 mg/L indicating significant systemic inflammation. Prevalence of comorbidities varied and tocilizumab was initiated in rapidly worsening patients within 24-48 hours of admission to intensive care in most trials. More than 80% of participants were administered corticosteroids. Tocilizumabtreated patients showed a significant reduction in mortality with RR 0.88 (95% CI 0.81, 0.94) and reduced disease progression with RR 0.87 (95% CI 0.72, 1.06) with moderate certainty of the evidence, increased clinical improvement with RR 1.04 (95% CI 1.00, 1.09), and reduced time to clinical improvement with HR 1.22 (95% CI 1.14, 1.30) with low certainty of evidence. There was very low certainty in the evidence for adverse events and serious adverse events. Secondary infections were uncommon in most trials with follow-up till 14 or 28 days, which may have been too early to detect the same. Conclusion: A systematic review and meta-analysis which generated efficacy data of tocilizumab was then applied to an evidence to decision framework by subject experts resulting in a robust evidence-informed guideline applicable to any Indian secondary or tertiary healthcare setting.

13.
International Journal of Pharmaceutical Sciences Review and Research ; 75(1):199-203, 2022.
Article in English | EMBASE | ID: covidwho-1970067

ABSTRACT

In severe Covid-19 pneumonia, acute respiratory distress syndrome (ARDS) associated with cytokine storm is the leading cause of death. Tocilizumab was approved for chimeric antigen receptor T-cell therapy induced cytokine release syndrome and it may provide clinical benefit in these severe covid-19 pneumonia. In this retrospective cohort study, we evaluated patients with severe COVID-19 pneumonia admitted between May 2021 and June, 2021. Patients who were received tocilizumab during treatment, were enrolled for the study. Systemic steroids, hydroxychloroquine, and azithromycin were concomitantly used for the patients. The outcome was measured as an improvement in peripheral oxygen saturation by change in mode of oxygen therapy and improvement in laboratory parameters after tocilizumab administration. Out of 23 treated patients (18 Male, 5 Females), 19 patients received a single dose of tocilizumab and another four patients received two doses of it. Of these 23 patients, 3/3 with NRBM (non-rebreather mask) showed improvement and shifted to nasal cannula for oxygenation. 11/12 patients with NIV(non-invasive) showed improvement. 5/8 patients with invasive ventilation showed gradual improvement and shifted to NIV. A total of 4/23 (17%) patients didn’t show any improvement and died. Inflammatory markers like CRP, percentage of lymphocytes, and ferritin also showed significant improvement after administration of tocilizumab. Our study showed that in patients with severe COVID-19, tocilizumab was associated with significant improvement in clinical and laboratory parameters. These findings require further validation from ongoing clinical trials of Tocilizumab in COVID-19 patients.

15.
World J Virol ; 11(3): 113-128, 2022 May 25.
Article in English | MEDLINE | ID: covidwho-1954636

ABSTRACT

Since December 2019, a novel coronavirus that represents a serious threat to human lives has emerged. There is still no definite treatment for severe cases of the disease caused by this virus, named coronavirus disease 2019 (COVID-19). One of the most considered treatment strategies targets the exaggerated immune regulator, and interleukin (IL)-6 is a crucial pro-inflammatory mediator. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases show an elevated level of IL-6 related to disease severity. IL-6 activity can be inhibited by the following: IL-6 itself, IL-6 signaling pathways such as Janus kinase and signal transducer and activator of transcription (JAK-STAT), gp130, IL-6R, and downstream activated ILs, such as IL-17 and IL-6 cytokine. Currently, according to these studies and their results, IL-6 blockade with anti-IL-6 or its receptor antibodies such as tocilizumab in COVID-19 is beneficial in severe cases and may reduce the mortality rate. JAK-STAT inhibitors block the cytokine storm by inhibiting several crucial pro-inflammatory mediators such as TNF-α and IL-6 and have shown various results in clinical trials. IL-6 induces IL-17 secretion, and IL-17 is involved in the pathogenesis of inflammatory processes. Clinical trials of anti-IL-17 drugs are currently recruiting, and anti-gp130 antibody is preclinical. However, this agent has shown positive effects in inflammatory bowel disease clinical trials and could be tested for SARS-CoV-2. This study aimed to review the role of IL-6 in the cytokine storm and studies regarding IL-6 and blockade of its inflammatory pathways in COVID-19 to determine if any of these agents are beneficial for COVID-19 patients.

16.
Open Access Macedonian Journal of Medical Sciences ; 10:1383-1391, 2022.
Article in English | EMBASE | ID: covidwho-1939099

ABSTRACT

BACKGROUND: No gold standard therapy was approved globally for COVID-19 pneumonia to the date of this study. The pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed as a modality to control cytokine release syndrome (CRS). Abnormally high levels of interleukin-6 (IL-6) are a common finding in COVID-19 patients with pneumonia and acute respiratory distress syndrome, so the use of IL-6 antagonist was tested as a therapeutic option in controlling the disease. Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody that can specifically bind the membrane-bound IL-6 receptor and soluble IL-6 receptor, thereby inhibiting signal transduction. Tocilizumab is currently FDA approved for the management of rheumatoid arthritis, giant cell arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. This study is a retrospective analysis of data polled during Phase I of COVID pandemic, adopted by the isolation hospital of Kasr Al-Ainy Medical School, Cairo University, during the period from May to September 2020. AIM: The aim of this study is to evaluate tocilizumab influence in the outcome;in terms of reducing the hospital stay, risk and duration of mechanical ventilation (invasive and noninvasive), mortality, and the incidence of complications related to drugs use (secondary bacterial infection and GIT bleeding) in patients with moderate-to-severe COVID-19. METHODS: This retrospective, observational cohort study included adults (between 18 and 80 years) with moderate-to-severe COVID-19 pneumonia, who were admitted to isolation hospital of Kasr Al-Ainy Medical School, Cairo University, between May and September 2020. We segregated the patients into two groups: Group A: In addition to the standard care protocol according to the local guidelines of the Egyptian Ministry of Health and Population in that period (supplemental oxygen, steroids in a dose of 1–2 mg/kg methylprednisolone for 5–10 days, broad-spectrum antibiotics, vitamins, and prophylactic dose of anticoagulation with low-molecular-weight heparin, proton-pump inhibitor, and poly-vitamins), they received tocilizumab intravenously in a dose of 8 mg/kg bodyweight (up to a maximum of 800 mg per dose), divided in two shots 12–24 h apart. Group B: Those received the standard care protocol alone, noting that guidelines were adjusted later on according to the updated scientific publications and WHO recommendations. The primary endpoint was to evaluate the effect of different regimens in controlling the disease, the need for mechanical ventilation and its duration (either invasive or non-invasive), length of ICU stay, hospital stay, and in-hospital mortality. Comparisons between quantitative variables were done using the non-parametric Mann–Whitney U-test. For comparison of serial measurements within each patient, the non-parametric Wilcoxon signed-rank test was used. For comparing categorical data, Chi-square (2) test was performed. Exact test was used instead when the expected frequency was <5. Correlations between quantitative variables were done using Spearman correlation coefficient. RESULTS: During this period, 166 patients were admitted to ICU, suffering from severe hypoxemia with moderate to severe COVID-19 pneumonia, 10 of them were excluded (three were over 80 years old, other three had advanced stages of malignancy, two were on steroids therapy and non-invasive home ventilation due to chronic chest condition, and two were presented with MODs and deceased in <48 h from admission), thus, 156 were included in the study. Group A: Seventy-six patients (49%) received tocilizumab in addition to standard therapy, Group B: Eighty patients (51%) received standard therapy only. In Group A, the mean length of ICU stay was 8.96 days with mean length of hospital stay 13.76, compared to mean length f ICU stay 9 days in Group B (p = 0.57) and mean length of hospital stay 12.46 days (p = 0.117). In Group A, 35 patients (46%) needed non-invasive mechanical ventilation (MV),12 patients of the 35 needed invasive MV in later stage, compared to 26 patients (32%) in Group B, 14 patients of the 26 needed invasive MV in later stage (p = 0.16). In Group A, 14 patients (18.4%) needed invasive mechanical ventilation, compared to 19 patients (23.7%) in Group B (p = 0.213). In Group A, 6 (7.9%) of 76 patients died, compared to 13 (16.3%) of 80 in Group B p = 0.11. The incidence of secondary bacterial infection in Group A was 16 patients (21%) compared to 21 (26%) in Group B (p = 0.44). CONCLUSION: In this study, we did not detect statistical difference in both groups of patients coming during CRS-associated COVID-19 pneumonia, regarding (ICU stay, need for and length of MV, the incidence of secondary bacterial infection, and in-hospital mortality) for COVID-19 moderate-to-severe pneumonia.

17.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927800

ABSTRACT

Rationale Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterised by an IL-6 driven cytokinemia, associated with a rapidly developing acute respiratory distress syndrome (ARDS). A blunted AAT response to IL-6 in SARS-CoV-2 has been associated with increased morbidity and mortality. One of the main functions of IL-6 is regulation of acute-phase proteins such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the proteaseanti- protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS). In addition, we investigated the effect of anti-IL-6 therapy on anti-protease defence. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma (n=20), airway tissue (n=8) and tracheal secretions (n=13) of people with severe SARS-CoV-2 infection. AAT and IL-6 levels were also evaluated over time in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab (n=30). Results AAT plasma levels doubled in severe SARS-CoV-2 ARDS patients (329g/L +/- 08 g/L as compared to baseline levels 174g/L +/- 011 g/L, P<0001). In lung parenchyma AAT levels were increased. Despite no increase in neutrophils, an increased percentage of neutrophils involved in NET formation were observed in the alveoli. A protease-anti-protease imbalance was detected in tracheal aspirates (TA). NE was active and AAT inactivated, reflecting cleavage and complexation with NE. The major airway anti-protease, secretory leukoprotease inhibitor (SLPI) was decreased in SARS-CoV-2-infected lungs and cleaved in TAs. Induction of AAT in SARS-CoV-2 infection occurred mainly through IL-6 signalling. Tocilizumab (IL-6 receptor antagonist) down-regulated AAT during infection (13g/L+/-0225 from 2469 g/L+/-0197, P<00001) while IL-6 remained elevated (NS=0.0998) as reflected by the IL-6/AAT ratio (P=0046). Conclusion This study shows that the AAT response to SARS-CoV-2 infection is compartmentalized with an appropriate increase in plasma and alveoli but an inadequate response in airways. This underlines a significant, but potentially treatable, protease-antiprotease imbalance in SARS-CoV-2 ARDS as well as highlighting IL-6's importance in SARS-CoV-2 pathology not only as a pro-inflammatory cytokine but as an anti-inflammatory regulator. In conclusion there is unopposed NE activity in the airways of people with SARS-CoV-2 ARDS which could be amenable to AAT therapy. Our data suggest caution in the use of IL-6 blocking therapies in SARS-CoV-2-infected individuals.

18.
Immunologiya ; 43(2):188-196, 2022.
Article in Russian | EMBASE | ID: covidwho-1897333

ABSTRACT

Introduction. Timely prescribing of proactive cytokine storm therapy in patients with COVID-19 using targeted therapy is an important component of success in the treatment of this disease. However, the blockade of receptors to proinflammatory cytokines, in particular to IL-6, leads to shifts in immunoregulatory processes, the nature of which can determine the effectiveness of the therapy and the course of the postCOVID period of rehabilitation of the patient. The aim of the study - to study the dynamics of the parameters of innate and adaptive immunity in a patient with COVID-19 using an IL-6 receptor anatagonist. Material and methods. 30 hospitalized patients were examined with the diagnosis: COVID-19 coronavirus infection (confirmed), moderate form;complication: bilateral polysegmental pneumonia. The comparison group consisted of practically healthy donors (30 people). The dynamics of laboratory parameters (general clinical, biochemical and immunological) were evaluated against the background of therapy with IL-6 blockers. Results. The presence of lymphopenia in the patient, an increase in the level of CRP, LTK, fibrinogen, lactate, IL-6 require the use of proactive anti-cytokine therapy. The timely administration of these drugs (in particular, the IL-6 receptor inhibitor) has a positive effect on the course of the disease and the recovery of patients. In the immune system, after the introduction of monoclonal antibodies to IL-6 receptors, 2 weeks after administration, there is an increase in the maturation of T-lymphocytes, documented by an increase in the content of T-lymphocytes with helper function with a simultaneous decrease in the number of natural killers, B-lymphocytes and disimmunoglobulinemia of IgA, IgM and IgG classes. Conclusion. The use of monoclonal antibodies to IL-6 receptors in patients with a moderate form of COVID-19 leads to dysregulatory processes in the immune system with their gradual normalization by 2 weeks after administration.

19.
Clin Infect Dis ; 75(1): e380-e388, 2022 08 24.
Article in English | MEDLINE | ID: covidwho-1886374

ABSTRACT

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.


Subject(s)
COVID-19 , Adult , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , Prospective Studies , Treatment Outcome
20.
Topics in Antiviral Medicine ; 30(1 SUPPL):178, 2022.
Article in English | EMBASE | ID: covidwho-1880558

ABSTRACT

Background: We aimed to evaluate the efficacy of sarilumab, an IL-6 receptor inhibitor, combined with SOC, in patients (pts) affected by severe COVID-19 pneumonia. Methods: Open-label, Phase III, randomized trial assessing clinical efficacy and safety of intravenous sarilumab in pts with severe COVID-19, at 5 clinical centers in Italy. We included hospitalized pts with SARS-CoV-2 infection and pneumonia, in severe or critical condition (excluding mechanically ventilated). Pts were randomized 2:1 to receive sarilumab 400 mg plus SOC (armA) or to continue SOC (armB). The primary endpoint was time to clinical improvement of 2 points on a 7-point category ordinal scale, ranging from 1 (discharged with resumption of normal activities) to 7 (death). Pts were stratified according to baseline disease severity (PaO2/FiO2 ratio < or ≥ 200 mmHg), C reactive protein (CRP < or ≥ 7 mg/dL) and lymphocytes count (< or ≥ 870/mmc). The key secondary endpoint was time to death. Adverse events (AE) were evaluated as safety outcomes. We used chi square test to compare proportions between arms, and Cox regression stratified by clinical center to estimate the hazard risk (HR) of primary endpoint. Results: Of 191 pts screened, 176 were assigned to armA (121) and B (55). A similar proportion of pts were treated with steroids (44 armA vs 26 armB, p=0.170) and remdesivir (22 armA vs 8 armB, p=0.552). 58/121 (48%) pts underwent to a second dose of sarilumab 12 hours after the first dose. At day 30, no significant differences in the primary endpoint were found between the arms (Figure1). After stratifying for inflammatory parameters, the probability of improvement seemed greater in armA than B, for the strata with CRP <7 mg/dL (88% [95% CI 77-96] vs 79% [63-91], HR 1.55 [0.9-2.6];log-rank p=0.049) and with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7];log-rank p=0.058). Figure2 for interaction tests between strata. There were no significant differences in death probability (armA 5% [2.3-10.9]) and armB 3.6% [0.9-13.8] HR 1.30 [0.41-4.15];log-rank p=0.79) and in the rates of AE (armA 32% [39/121] and armB 23% [14/55], p=0.195) and serious AE (armA 18% [22/121] and armB 11% [7/55], p=0.244). Conclusion: In our population, efficacy of sarilumab in pts with severe COVID-19 was not confirmed, even if some benefits were shown in those treated at an early stage of the disease with lower inflammatory burden. Further trials are needed for identifying targeted subgroups for maximizing benefit of this treatment.

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