Treatment Of Severe COVID-19 Patients Research Articles

Intravenous immunoglobulin treatment for patients with severe COVID-19: a retrospective multicentre study

ObjectivesIntravenous immunoglobulin (IVIG) is commonly used to treat severe COVID-19, although the clinical outcome of such treatment remains unclear. This study evaluated the effectiveness of IVIG treatment in severe COVID-19 patients. MethodsThis retrospective multicentre study evaluated 28-day mortality in severe COVID-19 patients with or without IVIG treatment. Each patient treated with IVIG was matched with one untreated patient. Logistic regression and inverse probability weighting (IPW) were used to control confounding factors. ResultsThe study included 850 patients (421 IVIG-treated patients and 429 non-IVIG-treated patients). After matching, 406 patients per group remained. No significant difference in 28-day mortality was observed after IPW analysis (average treatment effect (ATE) = 0.008, 95% CI –0.081 to 0.097, p 0.863). There were no significant differences between the IVIG group and non-IVIG group for acute respiratory distress syndrome, diffuse intravascular coagulation, myocardial injury, acute hepatic injury, shock, acute kidney injury, non-invasive mechanical ventilation, invasive mechanical ventilation, continuous renal replacement therapy and extracorporeal membrane oxygenation except for prone position ventilation (ATE = –0.022, 95% CI –0.041 to –0.002, p 0.028). DiscussionIVIG treatment was not associated with significant changes in 28-day mortality in severe COVID-19 patients. The effectiveness of IVIG in treating patients with severe COVID-19 needs to be further investigated through future studies.

Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients

Background and objectivesAn effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation.Materials and methodsPatients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin- of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated.ResultsA total of 66 patients, 36 in the study group and 30 in the control group were included in the study. Mutations affecting ivermectin metabolism was detected in genetic tests of six (16.7%) patients in the study group and they were excluded from the study. At the end of the 5-day follow-up period, the rate of clinical improvement was 73.3% (22/30) in the study group and was 53.3% (16/30) in the control group (p = 0.10). At the end of the study, mortality developed in 6 patients (20%) in the study group and in 9 (30%) patients in the control group (p = 0.37). At the end of the follow-up period, the average peripheral capillary oxygen saturation (SpO2) values of the study and control groups were found to be 93.5 and 93.0%, respectively. Partial pressure of oxygen (PaO2)/FiO2 ratios were determined as 236.3 ± 85.7 and 220.8 ± 127.3 in the study and control groups, respectively. While the blood lymphocyte count was higher in the study group compared to the control group (1698 ± 1438 and 1256 ± 710, respectively) at the end of the follow-up period (p = 0.24); reduction in serum C-reactive protein (CRP), ferritin and D-dimer levels was more pronounced in the study group (p = 0.02, p = 0.005 and p = 0.03, respectively).ConclusionsAccording to the findings obtained, ivermectin can provide an increase in clinical recovery, improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.

In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19.

Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively. Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19. Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics. Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.

Efficacy of Tocilizumab in the treatment of severe COVID-19 patients with respiratory failure

Objective: This study aimed to investigate the impact of tocilizumab, an IL6R inhibitor, on clinical features and laboratory tests of subjects admitted with severe COVID-19 and respiratory failure.
 Material and Methods: A total of 30 patients with positive polymerase chain reaction for COVID-19 and respiratory failure were analyzed in a retrospective manner. All patients received 8mg/kg body weight tocilizumab i.v. once in addition to the standard COVID-19 treatment protocol, including Oseltamivir phosphate 75mg twice daily, hydroxychloroquine 200 mg twice daily, and azitromycine 250 mg once daily following a 500 mg loading dose. Demographic characteristics, and clinical features including oxygen saturation, the concentration of oxygen inhalation, body temperature, mean arterial pressure and heart rate, and SpO2, end-tidal CO2, and blood tests including complete blood count, procalcitonin, C-reactive protein (CRP), Troponin-I, D-dimer, and liver and kidney function tests were recorded before and after treatment with tocilizumab.
 Results: A significant increase occurred in SaO2 on first and third days following treatment with tocilizumab (84.3 % and 90.3%, respectively, p<0.001 for both recordings compared to baseline). There was also a significant increase in end-tidal CO2. The increase in mean SaO2 after tocilizumab was followed by a decline in respiratory rate on the first and third days of treatment. A dramatic decline was observed in body temperature from the first day of treatment with tocilizumab. Lymphocyte count increased following tocilizumab and C-reactive protein and Troponin I levels were reduced.
 Conclusion: Tocilizumab appears as an effective therapeutic option for improving oxygenation, symptoms and laboratory surrogates of ongoing inflammation in subjects with severe COVID-19.

Could Eosinopenia be a simple, fast and reliable biomarker in diagnosis of Covid-19?

Objective: Monitoring CBC subsets, particularly eosinophils. and inflammation markers, during admission and treatment of severe COVID-19 patients, can reveal key indicators of disease progression and stage to provide a basis for diagnosis and treatment for clinicians. Method: Our study is a retrospective case-control study. After taking aproval of Ministry of Health and Ethics Committee, the recorded clinical, laboratory and radiological data of 30 patients who were diagnosed with Covid-19, between 15 March and 15 June 2020, were compared with 30 healthy person by using appropriate statistical methods. Results: Both patients and conrols included 10 (33.3%) females and 20 (66.6%) males with a mean age of 57.2 ± 15.46 and 60.07 ± 20.59 respectively. Eosinophil counts of the patients on admission were significantly lower than the controls (p <0.001). Eosinophil counts one week after admission were increased significantly compared to the admission levels (p= 0.004). Neutrophil/Eosinophil ratio, which is a reliable indicator of 'Eosinopenia' in patients on admission was significantly higher than that of one week later (p= 0.041). EO1, NE1, NE2, PLT2/LYM2, LYM1/CRP1 and LYM2/CRP2 were the most predictive indexes. The AUCs of them were; 0.856, 0.778, 0.719, 0.738, 0.747 and 0.702 respectively, the cut-off values were; 0.04, 3.32, 3.21, 144,59, 1.99 and 7.84 respectively, the sensitivity and specificity were 66.7% and 93.3% for EO1; 53.3% and 93.3% for NE1; 46.7% and 93.3% for NE2; and 80.1% and 80.5% for PLT2/LYM2; and 100% and 66.7% for LYM1/CRP1and 100% and 53.3% for LYM2/CRP2; respectively. Conclusions: Tracking of CBC subsets, particularly Eosinophil, and CBC indexes is helpful in the early screening, diagnosis, treatment and follow up of critical COVID-19 patients.

Experience of using tocilizumab for treatment in Indonesian patients with severe COVID-19

COVID-19 is a public health emergency of international concern with millions confirmed cases globally including in Indonesia with more than two hundred thousand confirmed cases to date COVID-19. (1) COVID-19 has wide clinical manifestation ranging from asymptomatic, acute respiratory illness, respiratory failure that necessitates mechanical ventilation and support in an ICU, to MODS. (2) Several comorbidities have been demonstrated to be associated with the development of severe outcomes from COVID-19 infection, such as hypertension, diabetes, cardiovascular disease, dyslipidemia, thyroid disease, and pulmonary disease. (3)–(5) Severe COVID-19 is associated with increased plasma concentrations of IL-6, resulting in cytokine storm. (6) Tocilizumab, an interleukin-6 inhibitor, might alleviates the cytokine storm, prevents significant lungs and organs damage, thus improving clinical outcomes. (7) Therefore, tocilizumab, might be one of the promising therapies for severe COVID-19. (8) However there were limited studies regarding the efficacy in COVID-19 patients, especially with control group. We would like to report our experience in using tocilizumab as treatment in severe COVID-19 patients in Indonesia, which is the first in Indonesia to the best of our knowledge.

Efficacy and safety of convalescent plasma therapy in severe COVID-19 patients with acute respiratory distress syndrome

Since SARS-CoV-2 infection is rapidly spreading all around the world, affecting many people and exhausting health care resources, therapeutic options must be quickly investigated in order to develop a safe and effective treatment. The present study was designed to evaluate the safety and efficacy of convalescent plasma (CP) for treating severe cases of COVID-19 who developed acute respiratory distress syndrome (ARDS). Among 64 confirmed cases of severe COVID-19 with ARDS in this study, 32 patients received CP besides first line treatment. Their clinical response and outcome in regard to disease severity and mortality rate were evaluated and compared with the other 32 patients in the control group who were historically matched while randomly chosen from previous patients with the same conditions except for receiving CP therapy. Analysis of the data was performed using SPSS software. Patients with plasma therapy showed improvements in their clinical outcomes including a reduction in disease severity in terms of SOFA and APACHE II scores, the length of ICU stay, need for noninvasive ventilation and intubation and also showed an increase in oxygenation. They also showed reduction in mortality which was statistically significant in less severe cases with mild or moderate ARDS. Early administration of the convalescent plasma could successfully contribute to the treatment of severe COVID-19 patients with mild or moderate ARDS at risk of progressing to critical state.

Prognostic value of interleukin-18 and its association with other inflammatory markers and disease severity in COVID-19

BackgroundThe effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. ObjectiveTo investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. MethodsPatients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. ResultsThere were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. ConclusionsThe serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients.

&lt;p&gt;Remdesivir is Effective for Moderately Severe Patients: A Re-Analysis of the First Double-Blind, Placebo-Controlled, Randomized Trial on Remdesivir for Treatment of Severe COVID-19 Patients Conducted in Wuhan City&lt;/p&gt;

Remdesivir is Effective for Moderately Severe Patients: A Re-Analysis of the First Double-Blind, Placebo-Controlled, Randomized Trial on Remdesivir for Treatment of Severe COVID-19 Patients Conducted in Wuhan City

GM-CSF in the treatment of COVID-19: a new conductor in the pathogenesis of cytokine storm?

GM-CSF in the treatment of COVID-19: a new conductor in the pathogenesis of cytokine storm?

Translation: Expert Consensus on the Application of Artificial Liver Blood Purification System in the Treatment of Severe and Critical COVID-19

The prevention and treatment of COVID-19 nationwide has entered a tackling phase. Effective treatment of severe and critically ill patients is the key to reducing the fatality of the disease. The artificial liver blood purification system can remove inflammatory factors, alleviate the damage of the inflammatory response to the body, and has important value for the treatment of severe COVID-19. Led by Academician Lanjuan Li, based on the experience of treating patients across the country, integrating the opinions of experts from all over the country, the center summarized and formulated the consensus including the basic principles, treatment indications, relative contraindications, mode selection, monitoring indicators, and efficacy evaluation of artificial liver, which provides reference for treatment of severe COVID-19 patients.

Proteomic and Metabolomic Characterization of COVID-19 Patient Sera

Early detection and effective treatment of severe COVID-19 patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model was validated using 10 independent patients, 7 of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 COVID-19 patients, leading to 16 correct assignments. We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation, complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.

Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Results from SMAtteo COvid19 REgistry (SMACORE).

Objective: This study aimed to assess the role of Tocilizumab therapy (TCZ) in terms of ICU admission and mortality rate of critically ill patients with severe COVID-19 pneumonia. Design: Patients with COVID-19 pneumonia were prospectively enrolled in SMAtteo COvid19 REgistry (SMACORE). A retrospective analysis of patients treated with TCZ matched using propensity score to patients treated with Standard Of Care (SOC) was conducted. Setting: The study was conducted at IRCCS Policlinico San Matteo Hospital, Pavia, Italy, from March 14, 2020 to March 27, 2020. Participants: Patients with a confirmed diagnosis of COVID-19 hospitalized in our institution at the time of TCZ availability. Interventions: TCZ was administered to 21 patients. The first administration was 8 mg/kg (up to a maximum 800 mg per dose) of Tocilizumab intravenously, repeated after 12 h if no side effects were reported after the first dose. Main Outcomes and Measures: ICU admission and 7-day mortality rate. Secondary outcomes included clinical and laboratory data. Results: There were 112 patients evaluated (82 were male and 30 were female, with a median age of 63.55 years). Using propensity scores, the 21 patients who received TCZ were matched to 21 patients who received SOC (a combination of hydroxychloroquine, azithromycin and prophylactic dose of low weight heparin). No adverse event was detected following TCZ administration. This study found that treatment with TCZ did not significantly affect ICU admission (OR 0.11; 95% CI between 0.00 and 3.38; p = 0.22) or 7-day mortality rate (OR 0.78; 95% CI between 0.06 and 9.34; p = 0.84) when compared with SOC. Analysis of laboratory measures showed significant interactions between time and treatment regarding C-Reactive Protein (CRP), alanine aminotransferase (ALT), platelets and international normalized ratio (INR) levels. Variation in lymphocytes count was observed over time, irrespective of treatment. Conclusions: TCZ administration did not reduce ICU admission or mortality rate in a cohort of 21 patients. Additional data are needed to understand the effect(s) of TCZ in treating patients diagnosed with COVID-19.

Effective treatment of severe COVID-19 patients with tocilizumab

After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People's Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.

Respiratory Support in COVID-19 Patients, with a Focus on Resource-Limited Settings.

The ongoing novel coronavirus disease (COVID-19) pandemic is threatening the global human population, including in countries with resource-limited health facilities. Severe bilateral pneumonia is the main feature of severe COVID-19, and adequate ventilatory support is crucial for patient survival. Although our knowledge of the disease is still rapidly increasing, this review summarizes current guidance on the best provision of ventilatory support, with a focus on resource-limited settings. Key messages include that supplemental oxygen is a first essential step for the treatment of severe COVID-19 patients with hypoxemia and should be a primary focus in resource-limited settings where capacity for invasive ventilation is limited. Oxygen delivery can be increased by using a non-rebreathing mask and prone positioning. The presence of only hypoxemia should in general not trigger intubation because hypoxemia is often remarkably well tolerated. Patients with fatigue and at risk for exhaustion, because of respiratory distress, will require invasive ventilation. In these patients, lung protective ventilation is essential. Severe pneumonia in COVID-19 differs in some important aspects from other causes of severe pneumonia or acute respiratory distress syndrome, and limiting the positive end-expiratory pressure level on the ventilator may be important. This ventilation strategy might reduce the currently very high case fatality rate of more than 50% in invasively ventilated COVID-19 patients.

Chinese and western medicine study on vigorous heat of Qi and Ying type in severe COVID-19 patients

Vigorous heat of Qi and Ying type in severe coronavirus disease 2019 COVID-19 patients mainly shows heat syndrome in Qi thermal perturbation syndrome in heart and Ying and stasis heat syndrome in blood it mainly shows dyspnea and or hypoxemia in Western medicine severe cases can be rapidly develop for acute respiratory distress syndrome sepsis shock blood coagulation dysfunction and multiple organ failure and so on. There is a consistency between the vigorous heat of Qi and Ying type in COVID 19 and sepsis in clinical manifestations development and treatment which provides theoretical basis for the treatment of severe COVID19 patients with vigorous heat of Qi and Ying type.