Abstract

The emergence of persistent symptoms following SARS-CoV-2 infection, known as long COVID, is providing a new challenge to healthcare systems. The cardinal features are fatigue and reduced exercise tolerance. Vitamin D is known to have pleotropic effects far beyond bone health and is associated with immune modulation and autoimmunity. We hypothesize that vitamin D levels are associated with persistent symptoms following COVID-19. Herein, we investigate the relationship between vitamin D and fatigue and reduced exercise tolerance, assessed by the Chalder Fatigue Score, six-minute walk test and modified Borg scale. Multivariable linear and logistic regression models were used to evaluate the relationships. A total of 149 patients were recruited at a median of 79 days after COVID-19 illness. The median vitamin D level was 62 nmol/L, with n = 36 (24%) having levels 30-49 nmol/L and n = 14 (9%) with levels <30 nmol/L. Fatigue was common, with n = 86 (58%) meeting the case definition. The median Borg score was 3, while the median distance covered for the walk test was 450 m. No relationship between vitamin D and the measures of ongoing ill-health assessed in the study was found following multivariable regression analysis. These results suggest that persistent fatigue and reduced exercise tolerance following COVID-19 are independent of vitamin D.

Abstract

PURPOSE Several patients experience unexplained persistent symptoms after SARS-CoV-2 recovering. We aimed at evaluating if 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was able to demonstrate a persistent inflammatory process. METHODS Recovered adult COVID-19 patients, who complained unexplained persisting symptoms for more than 30 days during the follow-up visits, were invited to participate in the study. Patients fulfilling inclusion criteria were imaged by [18F]FDG positron emission tomography/computed tomography ([18F]FDG-PET/CT). Whole-body [18F]FDG-PET/CT, performed according to good clinical practice, was qualitatively (comparison with background/liver) and semi-quantitatively (target-to-blood pool ratio calculated as average SUVmax artery/average SUVmean inferior vena cava) analyzed. Negative follow-up [18F]FDG-PET/CT images of oncologic patients matched for age/sex served as controls. Mann-Whitney test was used to test differences between groups. SPSS version 26 was used for analyses. RESULTS Ten recovered SARS-CoV-2 patients (seven male and three females, median age 52 years, range 46-80) with persisting symptoms were enrolled in the study. Common findings at visual analysis were increased [18F]FDG uptake in bone marrow and blood vessels (8/10 and 6/10 cases, respectively). [18F]FDG uptake in bone marrow did not differ between cases and controls (p = 0.16). The total vascular score was similar in the two groups (p = 0.95). The target-to-blood pool ratio resulted higher in recovered SARS-CoV-2 patients than in controls. CONCLUSION Although the total vascular score was similar in the two groups, the target-to-blood pool ratio was significantly higher in three vascular regions (thoracic aorta, right iliac artery, and femoral arteries) in the recovered COVID-19 cohort than in controls, suggesting that SARS-CoV-2 induces vascular inflammation, which may be responsible for persisting symptoms.

Abstract

Immune dysregulation is a hallmark of patients infected by SARS-CoV2 and the balance between immune reactivity and tolerance is a key determinant of all stages of infection, including the excessive inflammatory state causing the acute respiratory distress syndrome. The kynurenine pathway (KP) of tryptophan (Trp) metabolism is activated by pro-inflammatory cytokines and drives mechanisms of immune tolerance. We examined the state of activation of the KP by measuring the Kyn:Trp ratio in the serum of healthy subjects (n = 239), and SARS-CoV2-negative (n = 305) and -positive patients (n = 89). Patients were recruited at the Emergency Room of St. Andrea Hospital (Rome, Italy). Kyn and Trp serum levels were assessed by HPLC/MS-MS. Compared to healthy controls, both SARS-CoV2-negative and -positive patients showed an increase in the Kyn:Trp ratio. The increase was larger in SARS-CoV2-positive patients, with a significant difference between SARS-CoV2-positive and -negative patients. In addition, the increase was more prominent in males, and positively correlated with age and severity of SARS-CoV2 infection, categorized as follows: 1 = no need for intensive care unit (ICU); 2 ≤ 3 weeks spent in ICU; 3 ≥ 3 weeks spent in ICU; and 4 = death. The highest Kyn:Trp values were found in SARS-CoV2-positive patients with severe lymphopenia. These findings suggest that the Kyn:Trp ratio reflects the level of inflammation associated with SARS-CoV2 infection, and, therefore, might represent a valuable biomarker for therapeutic intervention.

Abstract

OBJECTIVE To describe the clinical profiles and risk factors for critical illness in hospitalized children and adolescents with coronavirus disease 2019 (COVID-19). STUDY DESIGN Children 1 month to 21 years of age with COVID-19 from a single tertiary care children's hospital between March 15 and April 13, 2020 were included. Demographic and clinical data were collected. RESULTS In total, 67 children tested positive for COVID-19; 21 (31.3%) were managed as outpatients. Of 46 admitted patients, 33 (72%) were admitted to the general pediatric medical unit and 13 (28%) to the pediatric intensive care unit (PICU). Obesity and asthma were highly prevalent but not significantly associated with PICU admission (P = .99). Admission to the PICU was significantly associated with higher C-reactive protein, procalcitonin, and pro-B type natriuretic peptide levels and platelet counts (P < .05 for all). Patients in the PICU were more likely to require high-flow nasal cannula (P = .0001) and were more likely to have received Remdesivir through compassionate release (P < .05). Severe sepsis and septic shock syndromes were observed in 7 (53.8%) patients in the PICU. Acute respiratory distress syndrome was observed in 10 (77%) PICU patients, 6 of whom (46.2%) required invasive mechanical ventilation for a median of 9 days. Of the 13 patients in the PICU, 8 (61.5%) were discharged home, and 4 (30.7%) patients remain hospitalized on ventilatory support at day 14. One patient died after withdrawal of life-sustaining therapy because of metastatic cancer. CONCLUSIONS We describe a higher than previously recognized rate of severe disease requiring PICU admission in pediatric patients admitted to the hospital with COVID-19.

Abstract

BACKGROUND The COVID-19 pandemic has placed an enormous and growing burden on the population and health infrastructure, warranting innovative ways to mitigate risk of contracting and developing severe forms of this disease. A growing body of literature raises the issue of vitamin C and vitamin D as a risk-assessment tool, and therapeutic option, in COVID-19. OBJECTIVE The objective of this pilot study was to measure serum vitamin C and vitamin D levels in a cohort of patients with critical COVID-19 illness in our community hospital ICU, correlate with other illness risk factors (age, BMI, HgbA1c, smoking status), generate hypotheses, and suggest further therapeutic intervention studies. METHOD This pilot study included all 21 critically ill COVID-19 patients hospitalized in May 2020 in the ICU of North Suburban Medical Center, Thornton, Colorado, in whose care the principal investigator (C.A.) was involved. We measured patients' serum vitamin C and vitamin D levels, and standard risk factors like age, BMI, HbA1c, and smoking status. Variables in this study were gauged using descriptive statistics. RESULTS Of 21 critically ill COVID-19 patients (15 males and 6 females, 17 Hispanic and 4 Caucasian, of median age 61 years, range 20-94), there were 11 survivors.Serum levels of vitamin C and vitamin D were low in most of our critically ill COVID-19 ICU patients.Older age and low vitamin C level appeared co-dependent risk factors for mortality from COVID-19 in our sample.Insulin resistance and obesity were prevalent in our small cohort, but smoking was not. CONCLUSION Our pilot study found low serum levels of vitamin C and vitamin D in most of our critically ill COVID-19 ICU patients. Older age and low vitamin C level appeared co-dependent risk factors for mortality. Many were also insulin-resistant or diabetic, overweight or obese, known as independent risk factors for low vitamin C and vitamin D levels, and for COVID-19.These findings suggest the need to further explore whether caring for COVID-19 patients ought to routinely include measuring and correcting serum vitamin C and vitamin D levels, and whether treating critically ill COVID-19 warrants acute parenteral vitamin C and vitamin D replacement.

Abstract

BACKGROUND Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING None.

Abstract

BACKGROUND & AIMS Angiotensin converting enzyme (ACE)-2 is a modulator of adipose tissue metabolism. However, human data of adipose ACE-2 is rarely available. Considering that, ACE-2 is believed to be the receptor responsible for cell entry of SARS-CoV-2, a better understanding of its regulation is desirable. We therefore characterized the modulation of subcutaneous adipose ACE-2 mRNA expression during weight loss and the impact of ACE-2 expression on weight loss induced short- and long-term improvements of glucose metabolism. METHODS 143 subjects (age > 18; BMI ≥ 27 kg/m2) were analyzed before and after a standardized 12-week dietary weight reduction program. Afterwards subjects were randomized to a 12-month lifestyle intervention or a control group (Maintain-Adults trial). Insulin sensitivity (IS) was estimated by HOMA-IR (as an estimate of liver IS) and ISIClamp (as an estimate of skeletal muscle IS). ACE-2 mRNA expression (ACE-2AT) was measured in subcutaneous adipose tissue before and after weight loss. RESULTS ACE-2AT was not affected by obesity, but was reduced in insulin resistant subjects. Weight loss resulted in a decline of ACE-2AT (29.0 (20.0-47.9) vs. 21.0 (13.0-31.0); p = 1.6 ∗ 10-7). A smaller reduction of ACE-2 AT (ΔACE-2AT) was associated with a larger improvement of ISIClamp (p = 0.013) during weight reduction over 3 months, but not with the extend of weight loss. The degree of changes in insulin resistance were preserved until month 12 and was also predicted by the weight loss induced degree of ΔACE-2AT (p = 0.011). CONCLUSIONS Our data indicate that subcutaneous adipose ACE-2 expression correlates with insulin sensitivity. Weight loss induced decline of subcutaneous adipose ACE-2 expression might affect short- and long-term improvement of myocellular insulin sensitivity, which might be also relevant in the context of ACE-2 downregulation by SARS-CoV-2. TRIAL REGISTRATION ClinicalTrials.gov number: NCT00850629, https://clinicaltrials.gov/ct2/show/NCT00850629, date of registration: February 25, 2009.

Abstract

BACKGROUND Coronavirus disease 2019 (COVID-19) continues to spread, with confirmed cases now in more than 200 countries. Thus far there are no proven therapeutic options to treat COVID-19. We report a case of COVID-19 with acute respiratory distress syndrome who was treated with high-dose vitamin C infusion and was the first case to have early recovery from the disease at our institute. CASE REPORT A 74-year-old woman with no recent sick contacts or travel history presented with fever, cough, and shortness of breath. Her vital signs were normal except for oxygen saturation of 87% and bilateral rhonchi on lung auscultation. Chest radiography revealed air space opacity in the right upper lobe, suspicious for pneumonia. A nasopharyngeal swab for severe acute respiratory syndrome coronavirus-2 came back positive while the patient was in the airborne-isolation unit. Laboratory data showed lymphopenia and elevated lactate dehydrogenase, ferritin, and interleukin-6. The patient was initially started on oral hydroxychloroquine and azithromycin. On day 6, she developed ARDS and septic shock, for which mechanical ventilation and pressor support were started, along with infusion of high-dose intravenous vitamin C. The patient improved clinically and was able to be taken off mechanical ventilation within 5 days. CONCLUSIONS This report highlights the potential benefits of high-dose intravenous vitamin C in critically ill COVID-19 patients in terms of rapid recovery and shortened length of mechanical ventilation and ICU stay. Further studies will elaborate on the efficacy of intravenous vitamin C in critically ill COVID-19.