Treatment For Severe COVID-19 Research Articles

The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring invivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

Human placental mesenchymal stromal cell-derived small extracellular vesicles as a treatment for severe COVID-19: A double-blind randomized controlled clinical trial.

The current study aimed to investigate the effects of human placental mesenchymal stromal cell-derived small extracellular vesicles (hPMSC-sEVs) as a treatment for COVID-19. This double-blind, randomized, controlled clinical trial was conducted on two groups of patients with COVID-19-associated acute respiratory distress syndrome. After randomization, the control group received standard treatment and placebo, and the intervention arm received standard treatment plus hPMSC-sEVs. The number of hospital deaths was considered the primary outcome. After meeting the exclusion and inclusion criteria, 21 and 24 patients were allocated to intervention and control arms, respectively. Besides admission SpO2 levels, which were significantly lower in the intervention arm (p=0.008), all the baseline demo-biographic and laboratory variables were similar between the groups. It was shown that hPMSC-sEVs could significantly (p=0.015) decrease the mortality ratio in the intervention group (4/21 [19.04%]) compared to the controls (13/24 [54.16%]). The mean time to death in the intervention and control groups was 28.06 and 11.10 days, respectively (p <0.001). This study showed that hPMSC-sEVs are a possible treatment for critically ill patients with COVID-19.

Long-term effects on swallowing and laryngeal function after treatment for severe COVID-19 disease in intensive care

PurposeThis study aimed to assess swallowing and laryngeal function at long-term follow-up in patients treated for severe COVID-19 in the ICU.MethodsThirty-six patients with severe COVID-19 were prospectively examined with fiberendoscopic evaluation of swallowing (FEES) about 6 and 12 months after ICU discharge. Comparison with initial FEES examinations during the time in hospital was performed in 17 patients. Analysis of swallowing function and laryngeal features was performed from video recordings. Twenty-five participants responded to Eating Assessment Tool, Voice Handicap Index, and the Hospital Anxiety and Depression Scale at follow-up.ResultsPenetration to the laryngeal vestibule (PAS ≥ 3) was seen in 22% and silent aspiration (PAS = 8) in 11% of patients on at least one swallow at follow-up. Fourteen percent had obvious residue in the vallecula and/or pyriform sinuses after swallowing thick liquid or biscuits. Self-reported eating and swallowing difficulties were found in 40% of patients. Abnormal findings in the larynx were present in 53% at follow-up. Thirty-three percent had reduced or impaired vocal fold movement, of whom 22% had bilateral impaired abduction of the vocal folds. Possible anxiety and depression were found in 36% and 24% of responders, respectively.ConclusionAlthough a majority of patients appear to regain normal swallowing function by 1 year after treatment for severe COVID-19, our results indicate that dysphagia, abnormal laryngeal function, and anxiety/depression may remain in a substantial proportion of patients. This suggests that swallowing and laryngeal function, and emotional symptoms, should be followed up systematically over time in this patient group.

Allograft function predicts mortality in kidney transplant recipients with severe COVID-19: a paradoxical risk factor.

Kidney transplant recipients (KTRs) are at a higher risk of severe coronavirus disease (COVID-19) because of their immunocompromised status. However, the effect of allograft function on the prognosis of severe COVID-19 in KTRs is unclear. In this study, we aimed to analyze the correlation between pre-infection allograft function and the prognosis of severe COVID-19 in KTRs. This retrospective cohort study included 82 patients who underwent kidney transplantation at the Sichuan Provincial Peoples Hospital between October 1, 2014 and December 1, 2022 and were diagnosed with severe COVID-19. The patients were divided into decreased eGFR and normal eGFR groups based on the allograft function before COVID-19 diagnosis (n=32 [decreased eGFR group], mean age: 43.00 years; n=50 [normal eGFR group, mean age: 41.88 years). We performed logistic regression analysis to identify risk factors for death in patients with severe COVID-19. The nomogram was used to visualize the logistic regression model results. The mortality rate of KTRs with pre-infection allograft function insufficiency in the decreased eGFR group was significantly higher than that of KTRs in the normal eGFR group (31.25% [10/32] vs. 8.00% [4/50], P=0.006). Pre-infection allograft function insufficiency (OR=6.96, 95% CI: 1.4633.18, P=0.015) and maintenance of a mycophenolic acid dose >1500 mg/day before infection (OR=7.59, 95% CI: 1.0853.20, P=0.041) were independent risk factors, and the use of nirmatrelvir/ritonavir before severe COVID-19 (OR=0.15, 95% CI: 0.030.72, P=0.018) was a protective factor against death in severe COVID-19. Pre-infection allograft function is a good predictor of death in patients with severe COVID-19. Allograft function was improved after treatment for severe COVID-19, which was not observed in patients with non-severe COVID-19.

The real-world effectiveness of fluvoxamine therapy in mild to moderate COVID-19 patients; A historical cohort study (Fluvoxa Trial)

BackgroundFluvoxamine (FVX) has been proposed as a potential treatment for severe COVID-19 by the σ-1 receptor agonist, which can reduce cytokine production. However, the efficacy of FVX remains controversial. MethodsA historical retrospective cohort study was conducted in mild to moderate COVID-19 patients, 2:1 ratio of standard of care (SOC) and FVX treatments to assess the effectiveness of FVX in preventing deterioration by the fifth day of treatment. ResultsOf 752 eligible patients, 234 received FVX while 518 received SOC, and there was no significant difference in the effectiveness of FVX and SOC in preventing clinical deterioration. On the fifth day after treatment, 86.1 % of patients in the FVX-treated group did not experience clinical deterioration compared to 78.7 % in the SOC group. Notably, the FVX group had higher rates of pneumonia development and hospitalization, requiring more oxygen supplementation while showing less reduction in viral shedding than the SOC group. However, no difference in mechanical ventilation use, ICU admission, and survival was observed. ConclusionFluvoxamine treatment is failed to demonstrate effectiveness in preventing deterioration in mild to moderate COVID-19 and may lead to a higher incidence of pneumonia, hospitalization, and oxygen supplementation, necessitating careful consideration before prescribing the drug for COVID-19.

Strongyloides hyperinfection syndrome precipitated by immunosuppressive therapy for rheumatoid arthritis and COVID-19 pneumonia

The COVID-19 pandemic has posed clinical and public health challenges worldwide. The use of corticosteroids has become an evidence-based practice to reduce the hyperinflammatory process involved in severe COVID-19 disease. However, this can result in the reactivation of parasitic infestations, even with a short course. We report the case of a 64-year-old Cuban born patient who passed away from S. stercoralis hyperinfection syndrome following treatment with dexamethasone for severe COVID-19 disease on a background of prolonged immunosuppression for rheumatoid arthritis. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19 and other immunosuppressive therapies. We recommend empiric Strongyloides treatment for those who are from, or who have accumulated risk by travelling to endemic areas, and are being treated with corticosteroids for severe COVID-19 disease.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

Challenges of the Global COVID-19 Pandemic and Invasive Fungal Pathogens in SARS-COV-2 Associations: A Dangerous Relationship

Background: COVID-19 is a rapidly transmissible pneumonia-like illness caused by SARS-CoV-2 that out broke in China in 2019 and is currently circulating worldwide. In the current context of the SARS-CoV-2 pandemic, complications are observed in clinical settings for the treatment of severe COVID-19 disease in nosocomial settings, due to cases of fungal co-infections. Objective: To carry out a review on fungal infections associated with respiratory infections caused by COVID-19 (Sars-Cov-2) and their aggravation. Methodology: The purpose of this study is to inform the reader about the characteristics of SARS-CoV-2 and the main fungal species that are affecting patients undergoing treatment for severe COVID-19, provoking discussion of the importance of the proposed topic, in relation to co-infections by different fungal microorganisms. Result: 80 scientific studies were selected, resulting from patients with COVID-19 and most commonly observed in patients with a history of comorbidities such as diabetes mellitus, hypertension, kidney disease, severe liver disease, oncological diseases, obesity and with severe COVID-19. These data do not represent the total number of records of the disease in the world, but cases reported by researchers in their series, showing the overlapping of fungal co-infection through the compromised immune status due to the use of therapeutic drugs, dysregulation of the microbiota, age of patients and the severity itself of the severe inflammation caused by COVID-19. Conclusion: The immunosuppression caused by the infection of COVID-19 concomitant with its therapy through corticosteroid therapy and comorbidities of the patients made fungal infections more susceptible, and these interfere in the evolution of the case and in the treatment of COVID-19, being relevant to distinguish secondary infections to therapy and the best possible reconstitution of the clinical picture.

Predictors of the Outcomes Following the Tocilizumab Treatment for Severe COVID-19.

Background: Tocilizumab is used in severe COVID-19 yet has significant rates of treatment failure.Objectives: This retrospective study aimed to identify early predictors of the response to tocilizumab therapy.Methods: Biochemical and clinical characteristics of adult patients who received tocilizumab for severe COVID-19 pneumonia were retrospectively examined. A multivariable logistic regression model was constructed to identify factors that could predict the failure of tocilizumab therapy. A predictive nomogram was also created using the selected model.Results: Out of 101 eligible patients, 30 had treatment failure, and 71 survived on a 28-day follow-up. The partial pressure of oxygen to fraction of inspired oxygen ratio (PFR) on the day of tocilizumab administration (100 vs 80.5), lactate dehydrogenase (LDH; 668 vs 507 U/L), neutrophil-to-lymphocyte ratio (NL ratio; 24.7 vs 10), and creatine kinase myocardial band (CKMB; 30.9 vs 22.7 U/L) were significantly different among the non-survivors and survivors, respectively. A logistic regression model was created, identifying LDH, NL ratio, pro-brain natriuretic peptide (ProBNP), and PFR on the day of tocilizumab administration as best predictors of mortality with an optimism-corrected area under the receiver operator characteristics (ROC) curve of 0.82. The model-implied odds ratios for mortality were 1.89 (95% CI 1.13-3.15) for every 100 U/L rise in serum LDH, 2.29 (95% CI 2.2-4.39) for every 10 unit rise in NL ratio, 1.23 (95% CI 0.95-1.58) for every 100 pg/ml increase in ProBNP, and 0.36 (95% CI 0.13-0.95) for every mmHg rise in PFR at intervention.Conclusion: This study identified NL ratio, LDH, CKMB, and PFR at intervention as important markers of risk of treatment failure following the tocilizumab therapy. A multivariable logistic regression model including LDH, NL ratio, ProBNP, and PFR at intervention best predicted the risk of mortality in patients with severe COVID-19 pneumonia treated with tocilizumab.

Effectiveness and safety profile of mesenchymal stem cell secretome as a treatment for severe cases of COVID-19: a randomized controlled trial

Background: Mesenchymal stem cells (MSCs) are known to have immunomodulatory, anti-inflammatory, anti-apoptotic, and angiogenesis effects that are useful for relieving inflammation, recovery, and protection of lung tissues in COVID-19 patients. Secretome, a secretory product of MSCs, has several advantages over MSCs. We conducted a study to investigate secretomes’ effectiveness and safety profile as a treatment for severe COVID-19. Methods: A double-blind, multicenter, randomized, placebo-controlled trial was conducted between February 2021 and July 2021 in three top COVID-19 referral hospitals in the Greater Jakarta area, Indonesia. Eligible subjects (n=40) were randomized in a 1:1 ratio to an intervention group (n=20) and a control group (n=20). The primary outcome of this study was the changes in inflammatory markers and the ratio of inflammatory to anti-inflammatory markers. The secondary outcomes of this study included clinical outcome, laboratory outcome, radiological outcome, RT-PCR result conversion, and safety profile of MSC secretome. Results: Our analysis showed that on the 14th day after placebo administration, IL-6 level in the control group was significantly increased [4.110 (2.403–12.820) at baseline to 13.320 (2.958–33.285) on the 14th day after intervention, p=0.017]. The IL-6/IL-10 ratio in the control group was significantly increased (p=0.036) on the 14th day after placebo administration. We also found that most of the subjects who received placebo had high levels of IL-6 and ferritin (p=0.043) on the seventh day after the intervention. However, we found no significant differences in inflammatory marker levels on the seventh day and 14th day after intervention between both groups. There was no adverse event reported. There were no significant differences in the laboratory outcome, radiology outcome, RT-PCR result conversion, and safety profiles between both groups. Conclusions: MSC secretome can control inflammation in patients with severe COVID-19 and has a good safety profile. MSC secretome is a promising treatment modality for severe COVID-19.

Lack of Difference in Tocilizumab Efficacy in the Treatment of Severe COVID-19 Caused by Different SARS-CoV-2 Variants.

Tocilizumab (TOC) is presumed to be an effective and safe treatment for severe COVID-19, but its usefulness has not been yet investigated for different SARS-CoV-2 variants. This study aimed to evaluate the influence of TOC on mortality in patients with severe COVID-19 caused by Delta and non-Delta SARS-CoV-2 variants. In a retrospective analysis, we compared the medical records of 78 and 224 patients with severe COVID-19 due to Delta and non-Delta variants, respectively. A total of 30 patients with Delta and 84 with non-Delta variants were treated with TOC in addition to standard therapy. There were no statistically significant differences in mortality rate when comparing Delta vs. non-Delta patients nor when comparing those treated with TOC vs. not treated with TOC in both variants. Using a logistic regression model, in the examined population as a whole, we found an increased (p < 0.05) risk of death as leukocyte and erythrocyte counts decreased and as procalcitonin increased. Increased procalcitonin was significant for mortality in the Delta group, while decreased IL-6, leukocytes, and platelets and increased fibrinogen and procalcitonin were significant in the non-Delta group. Tocilizumab efficacy in severe COVID-19 does not differ between Delta or non-Delta virus variants. The Delta variant of SARS-CoV-2 does not increase mortality when compared to other virus strains.

Simultaneously targeting hyperinflammation and hyperglycemia following respiratory viral infection

Abstract Individuals with hyperglycemia are at great risk of developing exaggerated pulmonary inflammation following infection with respiratory viruses including SARS-CoV-2. Conversely, SARS-CoV-2 infection has been linked to the development of new onset of hyperglycemia and diabetes. Despite global vaccination efforts, SARS-CoV-2 infection continues to be a great public health challenge, and corticosteroids targeting hyper-inflammation remain the mainstay treatment for severe COVID-19. However, steroidal medicine arises the risk of hyperglycemia, limiting its usage. Here, we showed that a second-generation thiazolidines drug MSDC-0602K (MSDC), a mitochondrial pyruvate carrier inhibitor, simultaneously decreased excessive pulmonary inflammation and hyperglycemia in normal and obese hosts during influenza infection, as such, reducing host morbidity and mortality. scRNA-seq analysis revealed that MSDC treatment reduced lung macrophage inflammation, and myeloid-specific ablation of MPC2 led to dampened lung inflammation. Further, MSDC inhibited human lung macrophage inflammatory responses following SARS-CoV-2 infection, and dampened inflammation in lung autopsies of COVID-19 patients. Mechanistically, MSDC treatment destabilized HIF-1a protein, a transcription factor promoting inflammatory responses of lung macrophages, by repressing cellular Acetyl-CoA levels and HIF-1a acetylation. Our results suggest that MSDC has the great potential to treat severe COVID-19 or other respiratory viral infection, particularly in patients with underlying metabolic conditions, by simultaneously repressing hyper-cytokinemia and hyperglycemia. Supported by NIH AG069264, NIH AI150599

Reduced ADAMTS13 Activity in Correlation with Pathophysiology, Severity, and Outcome of COVID-19: A Retrospective Observational Study

BackgroundLow ADAMTS13 activity has been suggested to be an interplaying factor in the pathogenesis of COVID-19, considering that it is a thromboinflammatory disease with high risk of microthrombosis. ObjectivesThe study aimed to explore the correlation between ADAMTS13 activity and the pathophysiological pathway of COVID-19. MethodsWe carried out a retrospective observational study of 87 patients with COVID-19 in NMC Royal Hospital, Abu Dhabi, UAE. ADAMTS13 activity was measured and compared with patients’ characteristics and clinical outcomes. ResultsLow ADAMTS13 activity was associated with pneumonia (p = 0.007), severity of COVID-19 (p <0.001), and mechanical ventilation rates (p = 0.018). Death was more frequently observed among patients (5 patients) with low ADAMTS13 activity compared with normal activity (1 patient), as well as inflammatory markers. Decreased ADAMTS13 activity increased with the risk of pneumonia, severity of COVID-19, need for mechanical ventilation, and use of anticoagulants ([OR = 4.75, 95% CI 1.54–18.02, p = 0.011], [OR = 6.50, 95% CI 2.57–17.74; p <0.001], [OR = 4.10, 95% CI 1.29–15.82; p = 0.024], [OR = 8.00, 95% CI 3.13–22.16; p <0.001], respectively). The low ADAMTS13 activity group had a slightly longer time to viral clearance than the normal ADAMTS13 activity group, but it was not statistically significant (20 days, 95% CI 16–27 days vs 17 days, 95% CI 13–22 days; p = 0.08; Log rank = 3.1). ConclusionsLow ADAMTS13 activity has been linked to pneumonia, COVID-19 severity, use of anticoagulants, and need for mechanical ventilation but not to mortality. We propose rADAMTS13 as a novel treatment for severe COVID-19.

Effectiveness and safety profile of mesenchymal stem cell secretome as a treatment for severe cases of COVID-19: a randomized controlled trial

Background: Mesenchymal stem cells (MSCs) are known to have immunomodulatory, anti-inflammatory, anti-apoptotic, and angiogenesis effects that are useful for relieving inflammation, recovery, and protection of lung tissues in COVID-19 patients. Secretome, a secretory product of MSCs, has several advantages over MSCs. We conducted a study to investigate secretomes’ effectiveness and safety profile as a treatment for severe COVID-19. Methods: A double-blind, multicenter, randomized, placebo-controlled trial was conducted between February 2021 and July 2021 in three top COVID-19 referral hospitals in the Greater Jakarta area, Indonesia. Eligible subjects (n=40) were randomized in a 1:1 ratio to an intervention group (n=20) and a control group (n=20). The primary outcome of this study was the changes in inflammatory markers and the ratio of inflammatory to anti-inflammatory markers. The secondary outcomes of this study included clinical outcome, laboratory outcome, radiological outcome, RT-PCR result conversion, and safety profile of MSC secretome. Results: Our analysis showed that on the 14th day after placebo administration, IL-6 level in the control group was significantly increased [4.110 (2.403–12.820) at baseline to 13.320 (2.958–33.285) on the 14th day after intervention, p=0.017]. The IL-6/IL-10 ratio in the control group was significantly increased (p=0.036) on the 14th day after placebo administration. We also found that most of the subjects who received placebo had high levels of IL-6 and ferritin (p=0.043) on the seventh day after the intervention. However, we found no significant differences in inflammatory marker levels on the seventh day and 14th day after intervention between both groups. There was no adverse event reported. There were no significant differences in the laboratory outcome, radiology outcome, RT-PCR result conversion, and safety profiles between both groups. Conclusions: MSC secretome can control inflammation in patients with severe COVID-19 and has a good safety profile. MSC secretome is a promising treatment modality for severe COVID-19.

Tocilizumab Treatment Effect on Iron Homeostasis in Severe COVID-19 Patients

Background: Tocilizumab has been proposed as an effective treatment for severe COVID-19. We aimed to investigate whether tocilizumab administration is associated with increased availability of serum iron which may possibly be associated with adverse effects on clinical outcomes. Methods: We performed an observational, retrospective cohort study. We included adults, who were hospitalized in ICU with the diagnosis of severe COVID-19 infection eligible for tocilizumab treatment. Laboratory data including serum iron, ferritin, transferrin saturation, hemoglobin, and C-reactive protein levels of all patients were collected shortly before and 24 h, 48 h, and 72 h after tocilizumab administration. Results: During the study period, 15 patients fulfilled the inclusion criteria and were eligible to receive tocilizumab treatment. Tocilizumab therapy was associated with a prominent increase in serum iron and transferrin saturation levels (26 ± 13 μg/dL and 15 ± 8% before treatment and 79 ± 32 μg/dL and 41 ± 15% 72 h after treatment, respectively, p < 0.001) and decrease in serum ferritin levels (1,921 ± 2,071 ng/mL before and 1,258 ± 1,140 ng/mL 72 h after treatment, p = 0.027). Conclusion: Treatment of severe COVID-19 patients with tocilizumab is associated with a profound increase in serum iron and ferritin saturation levels along with a decrease in ferritin levels. This may represent an undesirable side effect that may potentiate viral replication.

Cardiac Arrhythmia Associated with Remdesivir in COVID-19

During the pandemic, Remdesivir was approved as a treatment for severe COVID-19. Little is known about its adverse side effects, as it had not been in clinical use prior to the pandemic, and we continue to learn more daily about its impact-both positive and negative-on our patients. In this case report, we present a patient who developed sinus bradycardia on the third day of Remdesivir administration, NSVT on the fifth day of Remdesivir, and whose arrhythmias resolved after cessation of Remdesivir.

Incidence of COVID-19 in outpatient healthcare workers

Currently, work in any medical organization carries a risk of coronavirus infection, and, first of all, this applies to medical organizations dealing with the treatment of patients infected with coronavirus. Medical workers are a group at increased risk of infection with the SARS-CoV-2 virus in the provision of medical care in modern conditions, which determines their incidence of COVID-19 [1-3]. The aim of the study is to explore the prevalence of cases of COVID-19 infection in medical workers providing medical care on an outpatient basis. Materials and methods. The analysis of the incidence of COVID-19 medical workers in one of the large medical organizations of the Samara region during the period of the pandemic was carried out. The medical staff of the medical organization includes 207 doctors. There are 11 subdivisions in the structure of the medical and prophylactic institution. Research methods: content analysis of the modern regulatory framework (2020-2021), statistical, expert. For the period from May 2020 to March 2021 71 cases of infection of medical workers on an outpatient basis with SARS-CoV-2 were identified, of which 32 doctors (45%) and 39 people (55%) nurses. Based on the results of the expert assessment, the insurance nature of the infection case was established in 50 people (70%). Among the medical and nursing categories of medical workers, the largest number of cases was made by doctors and nurses of primary contact - specialists of the district service: general practitioners (40%), pediatricians (32%), doctors - obstetricians-gynecologists (12%), nurses adults (76%) and children (20%) polyclinic departments. A third of health workers received inpatient treatment for severe COVID-19, an average of 60 days. Conclusion. Medical workers are a risk group of COVID-19 who need support measures, since the possibility of occupational infection has been sufficiently proven, and the risk probably depends on the work performed and the conditions of direct contact of medical personnel, which requires further study in the current persisting epidemic conditions.

A role for interleukin-1 receptor antagonism in severe COVID-19?

Early in the COVID-19 pandemic it was noted that a subset of people with severe disease were admitted to hospital with a hyperinflammatory illness.1 Subsequently, trials investigating immunomodulation as a treatment for severe COVID-19 resulted in dexamethasone becoming standard of care for people admitted to hospital with severe COVID-19 and the interleukin (IL)-6 receptor inhibitor tocilizumab being recommended for people requiring supplemental oxygen and with evidence of a significant inflammatory response.

Human Mesenchymal Stem Cells Treatment for Severe COVID-19: 1-Year Follow-Up Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Background The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial.Methods: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6-minute walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102).Findings: Within 3 months, MSC administration exerted numerical improvement in whole-lung lesion volume compared with the placebo, leading to a significant difference of −10.82% (95% CI: −20.69%, −1.46%, P=0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point, with a significant difference of − 9.02% (95%CI: − 17.44%, − 0.10%, P=0.045) at month 9. More interestingly, 17.86% (10/56) of patients in the MSC group had normal CT images at month 12 ( P= 0.013), but none in the placebo group. The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time, particularly sleep difficulties at month 3 (OR 0.19, 95% CI 0.07,0.50; P=0.001), and usual activity at month 12 (OR 0.15, 95% CI 0.03,0.79; P=0.018). Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.55%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups.Interpretation: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients.Trial Registration: This trial was registered with ClinicalTrials.gov (NCT04288102).Funding The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Ethics Committee of the Fifth Medical Center, Chinese PLA General Hospital (2020-013-D).

Metabolic Support for Elderly, Severe COVID-19 Patients With Acute Respiratory Failure: A Case Series

ObjectivesSevere COVID-19 (SvC19) is a syndrome of acute lung injury, respiratory failure, cytokine storm, distributive shock, multi-system organ failure and high mortality. SvC19 disproportionately impacts the elderly, who are also at risk for micronutrient deficiency. After observing a beneficial response to micronutrient repletion (MR) in a 69 year-old male with SvC19, we hypothesized that nutritional deficiencies were linked to the pathogenesis and that correcting them could be beneficial. In this report we detail a case series of 18 older patients with SvC19 treated with MR.MethodsAll patients had SvC19 requiring mechanical ventilation, elevated levels of CRP, D-dimer and neutrophil to lymphocyte ratio. MR consisted of daily parenteral ascorbate, thiamine, pyridoxine and multivitamins, as well as daily ergocalciferol, zinc and carnitine via nasogastric tube.ResultsThe average age was 63.3 years. Six patients were male, 12 female. Disease severity was comparable based on SOFA score. A partial response was observed in 10 of the 18 patients (55.5%). Six (33.3%) were able to wean off blood pressure support. Five (27.7%) had improvement in gas exchange. Four (22.2) were able to wean off ventilator support. Three patients (37.5%) showed improvement in renal dysfunction.ConclusionsMR shows potential promise as an adjunctive treatment for severe COVID-19, particularly in older patients or those with chronic illness in whom nutritional deficiencies are more probable.Funding SourcesNone