Vitamin D and COVID‐19: A review on the role of vitamin D in preventing and reducing the severity of COVID‐19 infection

Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) is a pathogenic coronavirus causing COVID‐19 infection. The interaction between the SARS‐CoV‐2 spike protein and the human receptor angiotensin‐converting enzyme 2, both of which contain several cysteine residues, is impacted by the disulfide‐thiol balance in the host cell. The host cell redox status is affected by oxidative stress due to the imbalance between the reactive oxygen/nitrogen species and antioxidants. Recent studies have shown that Vitamin D supplementation could reduce oxidative stress. It has also been proposed that vitamin D at physiological concentration has preventive effects on many viral infections, including COVID‐19. However, the molecular‐level picture of the interplay of vitamin D deficiency, oxidative stress, and the severity of COVID‐19 has remained unclear. Herein, we present a thorough review focusing on the possible molecular mechanism by which vitamin D could alter host cell redox status and block viral entry, thereby preventing COVID‐19 infection or reducing the severity of the disease.     

Aging‐related cell type‐specific pathophysiologic immune responses that exacerbate disease severity in aged COVID‐19 patients

Coronavirus disease 2019 (COVID‐19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID‐19 incidence and severity as a function of age. Our analysis leveraged age‐specific COVID‐19 mortality and laboratory testing from a large COVID‐19 registry, along with epidemiological data of ~3.4 million individuals, large‐scale deep immune cell profiling data, and single‐cell RNA‐sequencing data from aged COVID‐19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C‐reactive protein, D‐dimer, and neutrophil–lymphocyte ratio) are significantly associated with age‐specific COVID‐19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID‐19 patients. Older individuals with severe COVID‐19 displayed type I and II interferon deficiencies, which is correlated with SARS‐CoV‐2 viral load. Elevated expression of SARS‐CoV‐2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID‐19 in aged individuals. Mechanistically, we identified strong TGF‐beta‐mediated immune–epithelial cell interactions (i.e., secretory‐non‐resident macrophages) in aged individuals with critical COVID‐19. Taken together, our findings point to immuno‐inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID‐19 patients.     

Effect of ArtemiC in patients with COVID‐19: A Phase II prospective study

Despite intensive efforts, there is no effective remedy for COVID‐19. Moreover, vaccination efficacy declines over time and may be compromised against new SARS‐CoV‐2 lineages. Therefore, there remains an unmet need for simple, accessible, low‐cost and effective pharmacological anti‐SARS‐CoV‐2 agents. ArtemiC is a medical product comprising artemisinin, curcumin, frankincense and vitamin C, all of which possess anti‐inflammatory and anti‐oxidant properties. The present Phase II placebo‐controlled, double‐blinded, multi‐centred, prospective study evaluated the efficacy and safety of ArtemiC in patients with COVID‐19. The study included 50 hospitalized symptomatic COVID‐19 patients randomized (2:1) to receive ArtemiC or placebo oral spray, twice daily on Days 1 and 2, beside standard care. A physical examination was performed, and vital signs and blood tests were monitored daily until hospital discharge (or Day 15). A PCR assessment of SARS‐CoV‐2 carriage was performed at screening and on last visit. ArtemiC improved NEWS2 in 91% of patients and shortened durations of abnormal SpO₂ levels, oxygen supplementation and fever. No treatment‐related adverse events were reported. These findings suggest that ArtemiC curbed deterioration, possibly by limiting cytokine storm of COVID‐19, thus bearing great promise for COVID‐19 patients, particularly those with comorbidities.     

Thalassaemia is paradoxically associated with a reduced risk of in‐hospital complications and mortality in COVID‐19: Data from an international registry

Although numerous patient‐specific co‐factors have been shown to be associated with worse outcomes in COVID‐19, the prognostic value of thalassaemic syndromes in COVID‐19 patients remains poorly understood. We studied the outcomes of 137 COVID‐19 patients with a history of transfusion‐dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID‐19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID‐19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age‐, sex‐ and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in‐hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all‐cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in‐hospital, all‐cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all‐cause mortality. The presence of thalassaemia in COVID‐19 patients was independently associated with lower in‐hospital, all‐cause mortality and few in‐hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.     

Molecular evidence suggesting the persistence of residual SARS‐CoV‐2 and immune responses in the placentas of pregnant patients recovered from COVID‐19

ObjectivesRecent studies have shown the presence of SARS‐CoV‐2 in the tissues of clinically recovered patients and persistent immune symptoms in discharged patients for up to several months. Pregnant patients were shown to be a high‐risk group for COVID‐19. Based on these findings, we assessed SARS‐CoV‐2 nucleic acid and protein retention in the placentas of pregnant women who had fully recovered from COVID‐19 and cytokine fluctuations in maternal and foetal tissues.Materials and MethodsRemnant SARS‐CoV‐2 in the term placenta was detected using nucleic acid amplification and immunohistochemical staining of the SARS‐CoV‐2 protein. The infiltration of CD14+ macrophages into the placental villi was detected by immunostaining. The cytokines in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens at delivery were profiled using the Luminex assay.ResultsResidual SARS‐CoV‐2 nucleic acid and protein were detected in the term placentas of recovered pregnant women. The infiltration of CD14+ macrophages into the placental villi of the recovered pregnant women was higher than that in the controls. Furthermore, the cytokine levels in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens fluctuated significantly.ConclusionsOur study showed that SARS‐CoV‐2 nucleic acid (in one patient) and protein (in five patients) were present in the placentas of clinically recovered pregnant patients for more than 3 months after diagnosis. The immune responses induced by the virus may lead to prolonged and persistent symptoms in the maternal plasma, placenta, umbilical cord, cord blood and amniotic fluid.     

Dynamics of NK,CD8 and Tfh cell mediated the production of cytokines and antiviral antibodies in Chinese patients with moderate COVID‐19

Recent studies have demonstrated a marked decrease in peripheral lymphocyte levels in patients with coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Few studies have focused on the changes of NK, T‐ and B‐cell subsets, inflammatory cytokines and virus‐specific antibodies in patients with moderate COVID‐19. A total of 11 RT‐PCR‐confirmed convalescent patients with COVID‐19 and 11 patients with non‐SARS‐CoV‐2 pneumonia (control patients) were enrolled in this study. NK, CD8⁺ T, CD4⁺ T, Tfh‐like and B‐cell subsets were analysed using flow cytometry. Cytokines and SARS‐CoV‐2‐specific antibodies were analysed using an electrochemiluminescence immunoassay. NK cell counts were significantly higher in patients with COVID‐19 than in control patients (P = 0.017). Effector memory CD8⁺ T‐cell counts significantly increased in patients with COVID‐19 during a convalescent period of 1 week (P = 0.041). TIM‐3⁺ Tfh‐like cell and CD226⁺ Tfh‐like cell counts significantly increased (P = 0.027) and decreased (P = 0.022), respectively, during the same period. Moreover, ICOS⁺ Tfh‐like cell counts tended to decrease (P = 0.074). No abnormal increase in cytokine levels was observed. The high expression of NK cells is important in innate immune response against SARS‐CoV‐2. The increase in effector memory CD8⁺ T‐cell counts, the up‐regulation of inhibitory molecules and the down‐regulation of active molecules on CD4⁺ T cells and Tfh‐like cells in patients with COVID‐19 would benefit the maintenance of balanced cellular and humoural immune responses, may prevent the development of severe cases and contribute to the recovery of patients with COVID‐19.     

Increased risk of COVID‐19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States

Concerns have been expressed that persons with a pre‐existing mental disorder may represent a population at increased risk for COVID‐19 infec­tion and with a higher likelihood of adverse outcomes of the infection, but there is no systematic research evidence in this respect. This study assessed the impact of a recent (within past year) diagnosis of a mental disorder – including attention‐deficit/hyperactivity disorder (ADHD), bipolar disorder, depression and schizophrenia – on the risk for COVID‐19 infection and related mortality and hospitalization rates. We analyzed a nation‐wide database of electronic health records of 61 million adult patients from 360 hospitals and 317,000 providers, across 50 states in the US, up to July 29, 2020. Patients with a recent diagnosis of a mental disorder had a significantly increased risk for COVID‐19 infection, an effect strongest for depression (adjusted odds ratio, AOR=7.64, 95% CI: 7.45‐7.83, p<0.001) and schizophrenia (AOR=7.34, 95% CI: 6.65‐8.10, p<0.001). Among patients with a recent diagnosis of a mental disorder, African Americans had higher odds of COVID‐19 infection than Caucasians, with the strongest ethnic disparity for depression (AOR=3.78, 95% CI: 3.58‐3.98, p<0.001). Women with mental disorders had higher odds of COVID‐19 infection than males, with the strongest gender disparity for ADHD (AOR=2.03, 95% CI: 1.73‐2.39, p<0.001). Patients with both a recent diagnosis of a mental disorder and COVID‐19 infection had a death rate of 8.5% (vs. 4.7% among COVID‐19 patients with no mental disorder, p<0.001) and a hospitalization rate of 27.4% (vs. 18.6% among COVID‐19 patients with no mental disorder, p<0.001). These findings identify individuals with a recent diagnosis of a mental disorder as being at increased risk for COVID‐19 infection, which is further exacerbated among African Americans and women, and as having a higher frequency of some adverse outcomes of the infection. This evidence highlights the need to identify and address modifiable vulnerability factors for COVID‐19 infection and to prevent delays in health care provision in this population.     

Patterns and correlates of patient‐reported helpfulness of treatment for common mental and substance use disorders in the WHO World Mental Health Surveys

Patient‐reported helpfulness of treatment is an important indicator of quality in patient‐centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post‐traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys – 17 in high‐income countries (HICs) and 13 in low‐ and middle‐income countries (LMICs) – carried out as part of the World Health Organization (WHO)’s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help‐seeking if earlier treatments are not helpful.