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      SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels

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          Abstract

          Until treatment and vaccine for coronavirus disease-2019 (COVID-19) becomes widely available, other methods of reducing infection rates should be explored. This study used a retrospective, observational analysis of deidentified tests performed at a national clinical laboratory to determine if circulating 25-hydroxyvitamin D (25(OH)D) levels are associated with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) positivity rates. Over 190,000 patients from all 50 states with SARS-CoV-2 results performed mid-March through mid-June, 2020 and matching 25(OH)D results from the preceding 12 months were included. Residential zip code data was required to match with US Census data and perform analyses of race/ethnicity proportions and latitude. A total of 191,779 patients were included (median age, 54 years [interquartile range 40.4–64.7]; 68% female. The SARS-CoV-2 positivity rate was 9.3% (95% C.I. 9.2–9.5%) and the mean seasonally adjusted 25(OH)D was 31.7 (SD 11.7). The SARS-CoV-2 positivity rate was higher in the 39,190 patients with “deficient” 25(OH)D values (<20 ng/mL) (12.5%, 95% C.I. 12.2–12.8%) than in the 27,870 patients with “adequate” values (30–34 ng/mL) (8.1%, 95% C.I. 7.8–8.4%) and the 12,321 patients with values ≥55 ng/mL (5.9%, 95% C.I. 5.5–6.4%). The association between 25(OH)D levels and SARS-CoV-2 positivity was best fitted by the weighted second-order polynomial regression, which indicated strong correlation in the total population (R 2 = 0.96) and in analyses stratified by all studied demographic factors. The association between lower SARS-CoV-2 positivity rates and higher circulating 25(OH)D levels remained significant in a multivariable logistic model adjusting for all included demographic factors (adjusted odds ratio 0.984 per ng/mL increment, 95% C.I. 0.983–0.986; p<0.001). SARS-CoV-2 positivity is strongly and inversely associated with circulating 25(OH)D levels, a relationship that persists across latitudes, races/ethnicities, both sexes, and age ranges. Our findings provide impetus to explore the role of vitamin D supplementation in reducing the risk for SARS-CoV-2 infection and COVID-19 disease.

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          Puja Mehta, Daniel McAuley, Michael Brown … (2020)
          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            COVID-19 and African Americans

            Clyde Yancy (2020)
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              Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths

              William Grant, Henry Lahore, Sharon McDonnell … (2020)
              The world is in the grip of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing the risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increasing concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced the risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D (25(OH)D) concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome; and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce the risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/mL (100–150 nmol/L). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
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                Author and article information

                Contributors
                Harvey W. Kaufman: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Justin K. Niles: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Martin H. Kroll: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Caixia Bi: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Michael F. Holick:
                ORCID: http://orcid.org/0000-0001-6023-9062
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Sakamuri V. Reddy: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 17 September 2020
                Publication date Collection: 2020
                Publication date PMC-release: 17 September 2020
                Volume: 15
                Issue: 9
                Electronic Location Identifier: e0239252
                Affiliations
                [1 ] Medical Informatics, Quest Diagnostics, Secaucus, New Jersey, United States of America
                [2 ] Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
                Charles P. Darby Children's Research Institute, UNITED STATES
                Author notes

                Competing Interests: HWK, JKN, MHK, and CB are employees of Quest Diagnostics. HWK, MHK and CB own stock in Quest Diagnostics. MFH is a consultant to Quest Diagnostics and was on the speakers’ bureau for Abbott Inc. and Hyatt Pharmaceutical Industries Company PLC.

                Author information
                http://orcid.org/0000-0001-6023-9062
                Article
                Publisher ID: PONE-D-20-23650
                DOI: 10.1371/journal.pone.0239252
                PMC ID: 7498100
                PubMed ID: 32941512
                SO-VID: 7a4d75ed-8951-49a6-a3d4-4604f3f627f3
                Copyright © © 2020 Kaufman et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 29 July 2020
                Date accepted : 3 September 2020
                Page count
                Figures: 3, Tables: 1, Pages: 10
                Funding
                Quest Diagnostics provided support in the form of salaries for authors JKN, BC, MHK, and HWK and consulting fees for MFH but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: RNA viruses
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Biology and life sciences
                Subject: Microbiology
                Subject: Medical microbiology
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Medicine and health sciences
                Subject: Pathology and laboratory medicine
                Subject: Pathogens
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral pathogens
                Subject: Coronaviruses
                Subject: SARS coronavirus
                Subject: SARS CoV 2
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Chemical compounds
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Organic chemistry
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Earth Sciences
                Subject: Geography
                Subject: Cartography
                Subject: Latitude
                Subject: Medicine and Health Sciences
                Subject: Medical Conditions
                Subject: Infectious Diseases
                Subject: Viral Diseases
                Subject: Covid 19
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Virus Testing
                Subject: Medicine and Health Sciences
                Subject: Epidemiology
                Subject: Medical Risk Factors
                Subject: People and Places
                Subject: Population Groupings
                Subject: Ethnicities
                Subject: Hispanic People
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Algebra
                Subject: Polynomials
                Custom metadata
                Data Availability Data underlying the study cannot be made publicly available due to ethical concerns about patient confidentiality. Data will be made available to qualified researchers on request to HealthTrends@ 123456QuestDiagnostics.com .
                Outbreaks COVID-19

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