Introduction Research over the past 30 years has shown that in addition to the well-established functions as a mediator of calcium and bone metabolism, the hormone 1,25 dihydroxyvitamin D has effects on a range of pathological processes [1]. These include associations with pathogenesis of neoplastic, inflammatory, demyelinating, and cardiovascular diseases, as well as diabetes; the aetiology possibly being due to modulation of innate and adaptive immune functions via genes regulated by the transcription factor vitamin D receptor [2,3]. Hypovitaminosis D, identified by low serum levels of biologically inactive 25-hydroxyvitamin D (25-OHD), has a high worldwide prevalence [4]. Crowe et al. [5] studied the prevalence of vitamin D deficiency (<30 nmol/L) between 2005 and 2015 in 210,502 individuals in the UK. A third (69,515 individuals) of the cohort had low hormone concentrations, this prevalence being higher in individuals who were of male gender, younger age, ethnic minorities, and the economically deprived [5].
It can be argued that currently active measures to counter COVID-19 have been mainly focussed on non-pharmaceutical methods, perhaps in view of the acute explosion of the disease worldwide. The association between hypovitaminosis D and COVID-19 appears to have some scientific merit and must be studied further [6]. Low vitamin D concentrations appear related to pneumonia, cytokine burst and acute respiratory distress syndrome, all of which are associated with COVID-19 [7]. Furthermore, low vitamin D appears prevalent in critically ill patients in intensive care units (ICUs) and is associated with increased length of stay, readmission and mortality [8]. Han et al. [8] carried out a pilot randomised controlled trial of 31 subjects admitted to ICU and ventilated and administered either placebo, 50,000 IU or 100,000 IU of vitamin D daily for 5 consecutive days. Length of stay in hospital was significantly correlated to the dose of vitamin D supplements (placebo: length of stay = 36 ±19 days, day 7 vitamin D levels = 52.2 ±28.0 nmol/L; 50,000 IU/day: length of stay = 25 ±14 days, day 7 vitamin D levels = 114.3 ±49.0 nmol/L; 100,000 IU/day: length of stay = 18 ±11 days, day 7 vitamin D levels = 138.0 ±36.0 nmol/L). The other clinical outcomes studied were not statistically different between the 3 groups. Laird et al. [9] found a significant association between mean vitamin D levels and mortality attributed to COVID-19 in various European countries [9]. Interestingly, the Scandinavian countries Norway, Finland, Sweden, although receiving lower levels of sunlight, had higher mean vitamin D concentrations than their Southern European counterparts (owing to widespread fortification of foods) and lower COVID-19 infection and mortality [9]In view of the accumulating evidence there have been recommendations that individuals at risk of COVID-19 should consider treatment with inactive vitamin D to reduce the risk of infection: 10,000 IU/day for a few days followed by 5,000 IU/day to raise serum 25-OHD concentrations to 100–150 nmol/L [6, 10].
However, although a study by Hastie et al. [11] using data from the UK Biobank did show an association between vitamin D levels and COVID-19 infection, this relationship was not sustained when confounders were included in the logistic regression model. Hence, the relationship between vitamin D levels and COVID-19 infection appear complex, and perhaps may only be seen in subgroups. This heterogeneity would make the association very dependent on the cohort studied.
A report from the UK Office for National Statistics suggested that COVID-19 related deaths (20,283 in England and Wales between March 1, 2020 and April 17, 2020) showed a relationship between mortality and deprivation; the age-standardised mortality rate in the most deprived areas of England was 55.1/100,000 population compared with 25.3/100,000 population in the least deprived areas. (https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsinvolvingcovid19bylocalareasanddeprivation/latest - last accessed: 19/05/2020).
Hayden et al. [12] showed that vitamin D deficiency is related to ethnicity and social deprivation; an association (p=0.0001) was observed between the Index of Multiple Deprivation (IMD) and the percentage of patients with serum vitamin D levels <50 nmol/L in Manchester and Trafford, UK. Similarly, Heald et al. [13] showed a similar relationship between IMD and vitamin D levels in individuals aged >70 years.
We obtained data from 104 individuals tested according to UK Public Health England Guidelines for COVID-19 (https://www.gov.uk/government/publications/wuhan-novel-coronavirus-initial-investigation-of-possible-cases/investigation-and-initial-clinical-management-of-possible-cases-of-wuhan-novel-coronavirus-wn-cov-infection - last accessed 10/05/2020); 93.3% were tested within the hospital (the remainder were from either residential care homes or general practice). The aim of this study was to see whether any differences in serum vitamin D and social deprivation, using the IMD scores, existed between the patient groups with and without a SARS-CoV-2 detected PCR test. We also wished to see if an interaction existed between vitamin D concentration and deprivation with regard to COVID-19. Moreover, the analyses were repeated in subgroups associated with a poorer prognosis, in particular male gender and older age.
Patients and Methods Walsall Healthcare NHS Trust provides acute hospital and community health services for people living in Walsall, UK, and the surrounding areas, and serves a population of around 270,000 people. Acute hospital services are provided from Walsall Manor Hospital, a university-affiliated hospital, which has ~600–650 inpatient beds, and provides community health services from over 60 sites including primary care health centres and General Practitioner surgeries.
All 104 patients in this study were tested for COVID-19 between January 31, 2020 and May 7, 2020, in accordance with the UK Public Health England COVID-19 testing criteria, from samples received at the Department of Microbiology, Walsall Manor Hospital.
Clinical samples of the upper- (nasopharyngeal swabs) or lower-respiratory tract (sputum or bronchial washings) were tested for the presence of SARS-CoV-2 after inoculation into viral transport medium, using initially reference laboratory investigational RdRP-gene real-time reverse-transcriptase PCR assay until 6thApril 2020. After this date, detection of SARS-CoV-2 was performed locally on a commercial assay detecting the ORF-1a/b and E-genes with a reported limit of detection of <300 copies/mL (Roche Cobas; Roche Diagnostics GmbH, Manheim, Germany) [14]. The relative clinical sensitivity and specificity of these targets are not yet known.
Vitamin D levels were the most recent for each patient from a period covering 6 months (between September 1, 2019 and April 30, 2020) obtained from the Clinical Biochemistry laboratory database. Liquid chromatography-tandem mass spectrometry (LC-MS/MS; Waters TQD LC-MS/MS; Waters Corporation, UK) was used to quantify serum 25-OHD2 and 25-OHD3 levels (combined to give the total 25-OHD level) (coefficient of variation (CV) was 6.5%, 5.5% and 5.2% for internal quality control (IQC) 25-OHD3 levels of 19.4, 39.5 and 110.1 nmol/L, respectively; the CV was 10.9%, 5.6% and 5.4% for IQC 25-OHD2 levels of 3.7, 37.7 and 108.8 nmol/L, respectively).
The English Indices of Deprivation combine factors of housing, social and economic issues to give a single deprivation score for small areas (known as Lower-Layer Super Output Areas or LSOAs) in England. An overall weighted aggregation index of multiple deprivation (IMD) is generated based on thirty seven separate indicators,
organized across seven distinct domains of deprivation and each area is ranked from the least to most deprived. The criteria and their associated weightings are: Income deprivation, 22.5%, Employment deprivation, 22.5%, Health deprivation and disability 13.5%, Education, skills and training deprivation 13.5%, Barriers to housing and services 9.3%, Crime 9.3% and Living environment deprivation 9.3%. The indices are a widely used standard measure for comparing areas across the country and help to identify areas with high levels of overall deprivation or areas with specific concerns (health for example) that may not be recognised from the overall index. The measures of deprivation are collected nationally and published every 3–4 years. In the IMD 2019, the most deprived LSOA in England is given a rank of 1 and the least deprived is ranked 32,844. Each vitamin D result was aligned with an associated postcode for each patient and linked to its LSOA using the geo-convert tool (http://geoconvert.mimas.ac.uk - last accessed on 19/05/2020). The LSOA is then linked to the 2019 IMD for the specified full postcode [13]. This was not possible using geo-convert for six patients included in this stud. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/835115/IoD2019_Statistical_Release.pdf - last accessed on 20/05/2020)..