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1.
Hemasphere ; 4(6): e492, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1234152

ABSTRACT

Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration <6 µmol/l as the best cutoff-point predicting hospitalization with a sensitivity of 94.7% and a specificity of 67.9%. When stratifying inpatients in a low- and high oxygen demand group serum iron levels differed significantly between these two groups and showed a high negative correlation with the inflammatory parameters IL-6, procalcitonin, and CRP. Unexpectedly, serum iron levels poorly correlate with hepcidin. We conclude that measurement of serum iron can help predicting the severity of COVID-19. The differences in serum iron availability observed between the low and high oxygen demand group suggest that disturbed iron metabolism likely plays a causal role in the pathophysiology leading to lung injury.

2.
Rev Alerg Mex ; 67(4): 338-349, 2020.
Article in Spanish | MEDLINE | ID: covidwho-1106727

ABSTRACT

The clinical manifestations of COVID-19 are reminiscent of those of acute respiratory distress syndrome induced by cytokine release syndrome and secondary hemophagocytic lymphohistiocytosis that is observed in patients with other coronaviruses such as SARS-CoV and MERS-CoV. Neurologists face the challenge of assessing patients with pre-existing neurological diseases who have contracted SARS-CoV-2, patients with COVID-19 who present neurological emergencies, and patients who are carriers of the virus and have developed secondary neurological complications, either during the course of the disease or after it. Some authors and recent literature reports suggest that the presence of neurological manifestations in patients who are carriers of SARS-CoV-2 may be associated with a greater severity of the disease.


Las manifestaciones clínicas de COVID-19 recuerdan las del síndrome de insuficiencia respiratoria aguda inducido por el síndrome de liberación de citocinas y la linfohistiocitosis hemofagocitica observada en pacientes con otros coronavirus como SARS-CoV y MERS-CoV. Los neurólogos tienen el reto de evaluar pacientes con enfermedades neurológicas preexistentes que contraen SARS-CoV-2, pacientes con COVID-19 que presentan emergencias neurológicas y pacientes portadores del virus que desarrollan complicaciones neurológicas secundarias, durante el curso de la enfermedad o posterior a la misma. Algunos autores y reportes en la literatura recientes sugieren que las manifestaciones neurológicas en pacientes portadores de SARS-CoV-2 pueden asociarse con mayor gravedad de la enfermedad.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , Lymphohistiocytosis, Hemophagocytic/etiology , Nervous System Diseases/etiology , SARS-CoV-2 , Adaptive Immunity , Anosmia/etiology , Blood-Brain Barrier , Brain Ischemia/etiology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Encephalitis, Viral/etiology , Headache/etiology , Humans , Immunity, Innate , Leukocytes/immunology , Organ Specificity , Viral Tropism
3.
Front Pharmacol ; 11: 592238, 2020.
Article in English | MEDLINE | ID: covidwho-1082186

ABSTRACT

The cytokine storm or cytokine storm syndrome (CSS) is associated with high mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), for example following sepsis or infectious diseases including COVID-19. However, there are no effective treatments for CSS-associated ALI or ALI/ARDS. Thus, there remains an urgent need to develop effective drugs and therapeutic strategies against CSS and ALI/ARDS. Nasal and inhaled drug delivery methods represent a promising strategy in the treatment of inflammatory lung disease as a result of their ability to improve drug delivery to lungs. Improving the nasal mucosa absorption of poorly water-soluble drugs with poor mucosa bioavailability to a therapeutically effective level is another promising strategy in the fight against ALI/ARDS. Here, chitosan nanoparticles loaded with hesperidin (HPD/NPs) were developed for nasal delivery of the anti-inflammatory HPD compound to inflammatory lungs. In vitro and in vivo, HPD/NPs exhibited enhanced cellular uptake in the inflammatory microenvironment compared with free HPD. In a mouse model of inflammatory lung disease, the HPD/NPs markedly inhibited lung injury as evidenced by reduced inflammatory cytokine levels and suppressed vascular permeability compared with free HPD. Collectively, our study demonstrates that nasal delivery of HPD/NPs suppresses CSS and ALI/ARDS in a murine model of inflammatory lung disease, and that nanoparticle-based treatment strategies with anti-inflammatory effects could be used to reduce CSS and ALI in patients with inflammatory lung injury.

4.
Front Immunol ; 11: 621441, 2020.
Article in English | MEDLINE | ID: covidwho-1081856

ABSTRACT

Although COVID-19 has become a major challenge to global health, there are currently no efficacious agents for effective treatment. Cytokine storm syndrome (CSS) can lead to acute respiratory distress syndrome (ARDS), which contributes to most COVID-19 mortalities. Research points to interleukin 6 (IL-6) as a crucial signature of the cytokine storm, and the clinical use of the IL-6 inhibitor tocilizumab shows potential for treatment of COVID-19 patient. In this study, we challenged wild-type and adenovirus-5/human angiotensin-converting enzyme 2-expressing BALB/c mice with a combination of polyinosinic-polycytidylic acid and recombinant SARS-CoV-2 spike-extracellular domain protein. High levels of TNF-α and nearly 100 times increased IL-6 were detected at 6 h, but disappeared by 24 h in bronchoalveolar lavage fluid (BALF) following immunostimulant challenge. Lung injury observed by histopathologic changes and magnetic resonance imaging at 24 h indicated that increased TNF-α and IL-6 may initiate CSS in the lung, resulting in the continual production of inflammatory cytokines. We hypothesize that TNF-α and IL-6 may contribute to the occurrence of CSS in COVID-19. We also investigated multiple monoclonal antibodies (mAbs) and inhibitors for neutralizing the pro-inflammatory phenotype of COVID-19: mAbs against IL-1α, IL-6, TNF-α, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and inhibitors of p38 and JAK partially relieved CSS; mAbs against IL-6, TNF-α, and GM-CSF, and inhibitors of p38, extracellular signal-regulated kinase, and myeloperoxidase somewhat reduced neutrophilic alveolitis in the lung. This novel murine model opens a biologically safe, time-saving avenue for clarifying the mechanism of CSS/ARDS in COVID-19 and developing new therapeutic drugs.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/immunology , Cytokine Release Syndrome/immunology , Disease Models, Animal , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/pharmacology , Cytokine Release Syndrome/virology , Cytokines/immunology , Male , Mice , Mice, Inbred BALB C , Poly I-C/immunology , SARS-CoV-2/immunology
5.
Cureus ; 12(12): e12290, 2020 Dec 26.
Article in English | MEDLINE | ID: covidwho-1029534

ABSTRACT

Introduction Cytokine release syndrome in COVID-19 is characterized by hyperinflammation, which manifests as acute respiratory distress syndrome (ARDS), multiorgan failure, and high inflammatory parameters. Tocilizumab, an interleukin 6 (IL-6) antagonist has been used in COVID-19 ARDS with conflicting results from different parts of the world. Objective To study the treatment outcomes with tocilizumab in patients with COVID-19 ARDS and hyperinflammation using the World Health Organization (WHO) COVID-19 ordinal scale. Methods An observational study was conducted from Feb 2020 to May 2020 on COVID-19 ARDS patients with hyperinflammation. Results A total of 244 patients with COVID-19 were admitted, out of which 107 had ARDS. Thirty patients had both ARDS and hyperinflammation and received tocilizumab. The mean age was 62.5 years (SD: 13.5) and the majority were male (83%). The mean CRP pre-treatment was 217.5 mg/L and post 48 to 72 hours of tocilizumab treatment was 98.5 mg/L. Twenty-one patients (70%) also received concomitant intravenous (IV) methylprednisolone. Of the 30 patients, seven died and 20 recovered. Ten patients required intensive care unit admission and nine developed nosocomial infections. COVID-19-associated aspergillosis was diagnosed in three patients post tocilizumab treatment. Mortality was significantly higher in patients who developed a nosocomial infection and who required intermittent positive pressure ventilation (IPPV). Post-treatment, clinical improvement was observed in patients who had a median score of 5 on the WHO ordinal scale. Conclusion Our study supports the use of tocilizumab in COVID-19 ARDS patients with a pre-treatment median WHO ordinal severity score of 5 and recommends the monitoring of nosocomial infections and opportunistic infections.

6.
Recent Pat Antiinfect Drug Discov ; 15(2): 104-112, 2020.
Article in English | MEDLINE | ID: covidwho-1013263

ABSTRACT

To date, severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has infected millions of individuals worldwide. This virus causes coronavirus disease 2019 (COVID-19) and has led to numerous deaths worldwide. A large percentage of infected patients present asymptomatically, augmenting the spread of the virus. Symptomatic COVID-19 commonly causes mild to severe respiratory disease and fever, but some individuals experience serious complications resulting in death. Immune compromised, high risk, and elderly individuals are at an increased risk of more severe consequences of the illness such as respiratory failure, organ dysfunction, and shock. Cytokine storm (also known as cytokine release syndrome (CRS)), a systemic inflammatory response that can be triggered by an infection, has been associated with the symptom progression of COVID-19. This review evaluates several published studies that have implemented tocilizumab (TCZ), an IL-6 receptor antibody (US20120253016A1), in COVID-19 treatment. Outcomes and biomarkers of patients treated with TCZ are compared to patients treated with standard of care regimens. Interleukin-6 (IL-6), a prominent inflammatory cytokine involved in CRS in various inflammatory conditions, may have a vital role in the underlying mechanism involved in debilitating SARS-CoV-2 infections and could serve as a viable treatment target. Studies suggest that TCZ may aid in the recovery of patients with COVID-19 and reduce mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/pharmacology , COVID-19/diagnosis , COVID-19/metabolism , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/metabolism , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Receptors, Interleukin-6/metabolism , Treatment Outcome
7.
Cureus ; 12(11): e11555, 2020 Nov 18.
Article in English | MEDLINE | ID: covidwho-1000582

ABSTRACT

BACKGROUND: Considering the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the clinical implications of gastrointestinal (GI) and hepatic manifestations of coronavirus disease 2019 (COVID-19) in the U.S. population require analysis. METHODS: We retrospectively reviewed all adult patients with COVID-19 admitted to our facility. Patients were divided into two groups based on the presence of GI symptoms and transaminitis at presentation. Univariable analysis was performed to assess the differences between study groups. Kruskal-Wallis and Pearson's chi-square tests were used to compare the median of continuous and categorical variables, respectively. Multivariate logistic regression analysis was performed to identify predictors of mechanical ventilation, cytokine release syndrome (CRS), and mortality after adjusting for baseline variables. RESULTS: A total of 84 patients were analyzed. After adjusting for baseline comorbidities, presence of GI symptoms (aOR, adjusted odds ratio 4.2, 95% CI, 1.17-15.60, p=0.03) and transaminitis on admission (aOR 5.69, 95% CI, 1.47-21.99, p=0.01) were associated with CRS. Transaminitis on admission and elevated total bilirubin during hospitalization were associated with an increased need for mechanical ventilation (aOR 6.17, 95% CI, 1.49-25.44, p=0.02 and aOR 7.29, 95% CI, 1.73-30.75, p=0.007, respectively). An elevated aspartate aminotransferase (AST) on admission (aOR 13.41, 95% CI, 1.08-165.69, p=0.04) and elevated total bilirubin during hospitalization (aOR 82.68, 95% CI, 1.67-4074.8, p=0.02) were independently associated with an increased risk of mortality in COVID-19 patients. CONCLUSION: COVID-19 patients with transaminitis on admission had a higher risk of requiring mechanical ventilation and developing CRS. Patients with elevated AST on admission and elevated total bilirubin had higher mortality. Patients with GI symptoms did not have worse outcomes.

8.
Chest ; 158(4): 1397-1408, 2020 10.
Article in English | MEDLINE | ID: covidwho-996748

ABSTRACT

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. STUDY DESIGN AND METHODS: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. RESULTS: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). INTERPRETATION: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/therapy , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Adult , Aged , Aged, 80 and over , Algorithms , COVID-19 , Coronavirus Infections/mortality , Cytokine Release Syndrome/mortality , Female , Hospitalization , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Respiration, Artificial , SARS-CoV-2 , Survival Rate , Treatment Outcome , Young Adult
9.
J Glob Infect Dis ; 12(4): 221-224, 2020.
Article in English | MEDLINE | ID: covidwho-993888

ABSTRACT

Since the beginning of the COVID-19 pandemic, many therapeutic strategies have been tried, with mixed results, to prevent and treat adult multisystem inflammatory syndrome in COVID-19 (AMIS-COVID-19). The reason behind this may the complex web of highly intertwined pathophysiologic mechanisms involved in the SARS-CoV-2 infection and the corresponding human systemic response, leading to end-organ damage, disability, and death. Colchicine, high-dose aspirin, and montelukast are being investigated currently as potential modulators of AMIS-COVID-19 in patients who fail to improve with traditional therapeutic approaches. Here, we present a patient who presented with high fevers, extreme fatigue and dyspnea, and ongoing deterioration. As part of our clinical approach, we used the simultaneous combination of the three agents listed above, capitalizing on their different respective mechanisms of action against AMIS-COVID-19. Following the initiation of therapy, the patient showed symptomatic improvement within 24 h, with the ability to return to daily activities after 72 h of continued triple-agent approach. Based on this experience, we have reviewed the immunomodulatory basis of this regimen, including potential avenues in which it may prevent the development of cytokine release syndrome (CRS) and its clinical manifestation, AMIS-COVID-19. By blocking the early stages of an inflammatory response, via diverse mechanistic pathways, the regimen in question may prove effective in halting the escalation of CRS and AMIS-COVID-19 in acutely symptomatic, nonimproving COVID-19 patients.

11.
J Interferon Cytokine Res ; 40(12): 549-554, 2020 12.
Article in English | MEDLINE | ID: covidwho-990532

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly and become a pandemic. Caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe COVID-19 is characterized by cytokine storm syndromes due to innate immune activation. Primary immunodeficiency (PID) cases represent a special patient population whose impaired immune system might make them susceptible to severe infections, posing a higher risk to COVID-19, but this could also lead to suppressed inflammatory responses and cytokine storm. It remains an open question as to whether the impaired immune system constitutes a predisposing or protective factor for PID patients when facing SARS-CoV-2 infection. After literature review, it was found that, similar to other patient populations with different comorbidities, PID patients may be susceptible to SARS-CoV-2 infection. Their varied immune status, however, may lead to different disease severity and outcomes after SARS-CoV-2 infection. PID patients with deficiency in antiviral innate immune signaling [eg, Toll-like receptor (TLR)3, TLR7, or interferon regulatory factor 7 (IRF7)] or interferon signaling (IFNAR2) may be linked to severe COVID-19. Because of its anti-infection, anti-inflammatory, and immunomodulatory effects, routine intravenous immunoglobulin therapy may provide some protective effects to the PID patients.


Subject(s)
COVID-19/complications , COVID-19/immunology , Immune System , Inflammation , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/immunology , Comorbidity , Disease Susceptibility , Humans , Immunity, Innate , Immunoglobulins, Intravenous/metabolism , Interferon Regulatory Factor-7/metabolism , Pandemics , Receptor, Interferon alpha-beta/metabolism , Risk , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 7/metabolism
13.
Isr Med Assoc J ; 22(8): 505-513, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-972915

ABSTRACT

BACKGROUND: In this review we described the values of commonly available HScore laboratory markers in patients with coronavirus-19 (COVID-19)-pneumonia associated cytokine storm syndrome (CPN-CSS) and compared results with those of other forms cytokine storm syndrome (O-CSS) to determine a pattern for CPN-CSS. Twelve CPN-CSS studies and six O-CSS studies were included. CPN-CSS typically obtained a single HScore value (e.g., aspartate transaminase > 30 U/L) while failing all other HScore criteria. A typical pattern for CPN-CSS was revealed when compared to O-CSS: lymphopenia vs. pancytopenia and increased vs. decreased fibrinogen. Findings, other than HScore commonly found in CPN-CSS studies, showed elevated lactate dehydrogenase, D-dimer, and C-reactive protein. Although CPN-CSS studies describe severely ill patients, the HScore markers are typically less toxic that O-CSS.


Subject(s)
COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Pneumonia/blood , Pneumonia/virology , Aspartate Aminotransferases/blood , C-Reactive Protein/metabolism , Ferritins/blood , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Humans , L-Lactate Dehydrogenase/blood , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Lymphopenia/virology , Pancytopenia/etiology , Patient Acuity , SARS-CoV-2
14.
Front Pharmacol ; 11: 584956, 2020.
Article in English | MEDLINE | ID: covidwho-963117

ABSTRACT

For the initial phase of pandemic of coronavirus disease 2019 (COVID-19), repurposing drugs that in vitro inhibit severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been attempted with overlooked or overestimated efficacy owing to limited clinical evidence. Most early clinical trials have the defects of study design, small sample size, non-randomized design, or different timings of treatment initiation. However, well-designed studies on asymptomatic or mild, or pediatric cases of COVID-19 are scarce and desperately needed to meet the clinical need. However, a trend could be observed based on current clinical evidence. Remdesivir and favipiravir may shorten the recovery time; lopinavir/ritonavir does not demonstrate treatment efficacy in severe patients. Triple therapy of ribavirin, lopinavir, and interferon ß-1b showed early viral negative conversion, and the major effect may be related to interferon. Some small sample-size studies showed that interleukin-6 inhibitors may demonstrate clinical improvement; non-critical patients may benefit from convalescent plasma infusion in small sample-size studies; and the role of hydroxychloroquine or chloroquine in the treatment and prophylaxis of COVID-19 remains unclear. Combination therapy of traditional Chinese medicine with antiviral agents (ex. interferon, lopinavir, or arbidol) may alleviate inflammation in severe COVID-19 patients based on small sample-sized observational studies and experts' opinion. Most of the published studies included severe or critical patients with COVID-19. Combination therapy of antiviral agents and immune-modulating drugs is reasonable especially for those critical COVID-19 patients with cytokine release syndrome. Drugs to blunt cytokine release might not benefit for patients in the early stage with mild disease or the late stage with critical illness. Traditional Chinese medicine with antiviral effects on SARS-CoV-2 and immune-modulation is widely used for COVID-19 patients in China, and is worthy of further studies. In this review, we aim to highlight the available therapeutic options for COVID-19 based on current clinical evidence and encourage clinical trials specific for children and for patients with mild disease or at the early stage of COVID-19.

15.
Cureus ; 12(11): e11442, 2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-948188

ABSTRACT

Background The fatal outcomes by COVID-19 are accompanied by cytokine storm syndrome, and thereby it is reported that disease severity is dependent on the cytokine storm syndrome. This cytokine storm can be assessed by evaluating the serum ferritin levels. The objective of this study was to assess the activities of serum ferritin and treatment outcomes among COVID-19 patients who were treated with dexamethasone and vitamin C.  Materials and methods A single-center, prospective, observational study was conducted among SARS-CoV-2 infected patients from July 2020 to August 2020. The diagnosis was confirmed by real-time polymerase chain reaction (RT-PCR) and computed tomography (CT) imaging of the lungs. Serum ferritin levels were compared with the treatment outcomes of COVID-19 positive patients who were treated with dexamethasone and vitamin C. Results A total of 50 COVID-19 patients were included in the study. The mean age was 41.70 years. The recovery rate (94%) was remarkably high and is a good sign of COVID 19 treatment with vitamin C and dexamethasone as key modalities. The mean serum ferritin levels among recovered and expired patients were 478.81 ng/ml and 1410 ng/ml, respectively. Conclusion The serum activities of ferritin were markedly increased in COVID-19 patients who could not survive as compared to the patients who finally recovered from the infection.

16.
BMJ Open ; 10(11): e039951, 2020 11 14.
Article in English | MEDLINE | ID: covidwho-944946

ABSTRACT

INTRODUCTION: About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive). METHODS AND ANALYSIS: Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days postadministration. A total of 120 patients will be recruited (40 patients in each arm). ETHICS AND DISSEMINATION: The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products. If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing intensive care unit admissions. TRIAL REGISTRATION NUMBER: NCT04357860.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/drug therapy , Adolescent , Adult , Aged , Betacoronavirus , COVID-19 , Clinical Trials, Phase II as Topic , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Interleukin-6/immunology , Male , Middle Aged , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/immunology , Randomized Controlled Trials as Topic , Respiration, Artificial , Respiratory Distress Syndrome/immunology , SARS-CoV-2 , Young Adult
17.
Vaccines (Basel) ; 8(4)2020 Nov 12.
Article in English | MEDLINE | ID: covidwho-918920

ABSTRACT

The outbreak of the SARS-CoV-2 virus in December 2019 has caused the deaths of several hundred thousand people worldwide. Currently, the pathogenesis of COVID-19 is poorly understood. During the course of COVID-19 infection, many patients experience deterioration, which might be associated with systemic inflammation and cytokine storm syndrome; however, other patients have mild symptoms or are asymptomatic. There are some suggestions that impaired cellular immunity through a reduction in Th1 response and IFNG (interferon gamma) expression, as well as cross-reactivity with common cold coronaviruses, might be involved in the differential COVID-19 course. Here, we show that CD4+ cells isolated from unexposed healthy donors that were differentiated towards the Th1 lineage in the presence of SARS-CoV-2 proteins exhibited induction of IFNG. Interestingly, the same cells induced to differentiate towards a Th17 lineage did not exhibit changes in IFNG expression or Th17-related cytokines. This suggests the cellular response to SARS-CoV-2 viral proteins is primarily associated with Th1 lymphocytes and may be dependent on past infections with common cold coronaviruses or vaccinations that induce unspecific cellular responses, e.g., BCG (Bacillus Calmette-Guérin). Thus, our results might explain the high variability in the course of COVID-19 among populations of different countries.

18.
Pharmacol Rep ; 72(6): 1529-1537, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-915270

ABSTRACT

BACKGROUND: This study was aimed to assess the efficacy and safety of tocilizumab (TCZ) and to investigate the factors related to the progress and mortality of patients with a secondary cytokine release syndrome caused by SARS-CoV-2. METHODS: A retrospective descriptive observational study of hospitalised patients with a positive polymerase chain reaction (PCR) result for SARS-CoV-2 and whose clinical evolution required the administration of one or more doses of TCZ was conducted. Demographic variables, clinical evolution, radiologic progress and analytical parameters were analysed on days 1, 3 and 5 after administration the first dose of TCZ. RESULTS: A total of 75 patients with a clinical history of Accurate Respiratory Distress Syndrome (ARDS) were analysed, among whom, 19 had mild ARDS (25.3%), 37 moderate ARDS (49.4%) and 19 severe ARDS (25.3%). Lymphocytopenia and high levels of PCR, D-Dimer and IL-6 were observed in almost all the patients (91.8%). Treatment with TCZ was associated with a reduction of lymphocytopenia, C-reactive protein (CRP) levels, severe ARDS cases and fever. Although a better evolution of PaO2/FiO2 was observed in patients who received two or more doses of TCZ (38/75), there was an increase in their mortality (47.4%) and ICU admission (86.8%). The 30-day mortality rate was 30.7% (20.5-42.4% CI) being hypertension, high initial D-dimer levels and ICU admission the only predictive factors found. CONCLUSION: Based on our results, treatment with TCZ was associated with a fever, swelling and ventilator support improvement. However, there is no evidence that the administration of two or more doses of TCZ was related to a mortality decrease.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Intensive Care Units/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/drug therapy , COVID-19/mortality , Cytokine Release Syndrome/mortality , Female , Humans , Male , Middle Aged , Polymerase Chain Reaction , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome , Young Adult
19.
Arch Acad Emerg Med ; 8(1): e67, 2020.
Article in English | MEDLINE | ID: covidwho-896509

ABSTRACT

The 2019 novel coronavirus (officially known as severe acute respiratory syndrome coronavirus 2, SARS-CoV2) was first found in Wuhan, China. On February 11, 2020, the World Health Organization (WHO) has declared the outbreak of the disease caused by SARS-CoV2, named coronavirus disease 2019 (COVID-19), as an emergency of international concern. Based on the current epidemiological surveys, some COVID-19 patients with severe infection gradually develop impairment of the respiratory system, acute kidney injury (AKI), multiple organ failure, and ultimately, death. Currently, there is no established pharmacotherapy available for COVID-19. As seen in influenza, immune damage mediated by excessive production of inflammatory mediators contributes to high incidence of complications and poor prognosis. Thus, removal or blocking the overproduction of these mediators potentially aids in reducing the deleterious cytokine storm and improving critically ill patients' outcomes. Based on previous experience of blood purification to treat cytokine storm syndrome (CSS) in severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), here we aimed to review the current literature on extracorporeal hemoperfusion as a potential therapeutic option for CSS-associated conditions, with a focus on severe COVID-19.

20.
Curr Transplant Rep ; : 1-11, 2020 Oct 23.
Article in English | MEDLINE | ID: covidwho-893355

ABSTRACT

Purpose of Review: Severe coronavirus disease 2019 (COVID-19) is characterized by the development of a deleterious hyperinflammatory response, in which the pleiotropic cytokine interleukin (IL)-6 plays a pivotal role. The administration of immunomodulatory therapies has been proposed to revert the tissue damage induced by COVID-19-related cytokine release syndrome (CRS). The present review summarizes the biological rationale and available clinical experience with this therapeutic strategy in the specific scenario solid organ transplantation (SOT). Recent Findings: A number of case reports, case series, and non-controlled cohort studies have assessed the efficacy and safety of the anti-IL-6-receptor monoclonal tocilizumab in SOT (namely kidney transplantation) recipients with COVID-19 pneumonia and CRS. Although the heterogeneity in patient management and the lack of a control group limit the interpretation of these results, tocilizumab therapy appears to provide some clinical benefit in post-transplant COVID-19 and to be reasonably safe in terms of bacterial superinfection. A large randomized clinical trial (RCT) has shown survival benefit with adjuvant corticosteroids in non-transplant patients, but supporting evidence is scarce for SOT recipients and confounded by the variable adjustment of baseline immunosuppression. Anecdotal experiences have been reported with the use of the anti-IL-1 agent anakinra and the NLRP3 inflammasome inhibitor colchicine in this population. Summary: Immunomodulation has emerged as a promising option for SOT recipients with COVID-19-related CRS, with available experience mainly restricted to the anti-IL-6 agent tocilizumab. However, the supporting evidence is scarce and of low quality. In the absence of RCT, observational studies including well-matched control groups should be designed in future.

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