TABLE 2.
Characteristics of studies investigated association of vitamin D status with COVID-19 severity1
| First author (ref) | Study date | Country, setting | Design | Sample size, n | Age (y); sex | Objective/study question | Severity definition/vitamin deficiency definition | Time of VitD ascertainment | Adjusting factors |
|---|---|---|---|---|---|---|---|---|---|
| Abrishami (60) | February to April, 2020 | Academic hospital in Iran | Retrospective study | 73 SARS-CoV-2–positive (+) patients | Mean age: 55.18; male: 46.4% | To evaluate the prognostic role of serum 25(OH)D3 on the extent of lung involvement and final outcome in patients with COVID-19 | Lung involvement and mortality; serum 25(OH)D <25 ng/mL | At admission | For mortality, multivariate linear regression analysis adjusted for potential confounders including sex, age, and comorbidity |
| Anjum (62) | March to June, 2020 | A hospital in Pakistan | Prospective | 140 SARS-CoV-2+ patients | Mean age: 42.46; age range: 15–75; male: 58.57% | To determine the association between severe VDD and mortality in patients with COVID-19 | Severity was defined as mortality; severe VDD was defined as 25(OH)D <10 ng/ml | At admission | — |
| Annweiler (56) | March to April, 2020 | Nursing home in France | Quasi-experimental study with mean follow-up of 36 d | 66 frail elderly nursing-home residents: intervention, n = 57; comparator, n = 9 | Experiment: mean age: 87.7; male: 21%Comparator: mean age: 87.4; male: 33% | To evaluate COVID-19 severity and the use of COVID-19 drugs; the primary and secondary outcomes were COVID-19 mortality and OSCI score in acute phase | OSCI score | The intervention group received VitD3 (single dose of 80,000 IU every 2–3 mo) during COVID-19 or in the preceding month; the comparator group corresponded to all other participants | Age, gender, drugs, functional abilities, albuminuria |
| Annweiler (51) | March to May, 2020 | One geriatric acute care unit dedicated to COVID-19 patients in France | Quasi-experimental study | Group 1 (n = 29), group 2 (n = 16), group 3 (n = 32) | Mean age: 88; male: 51% | 14-day mortality and highest (worst) score on the OSCI measured during COVID-19 acute phase | To determine whether vitamin D3 supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was | Group 1 (n = 29): supplemented regularly with VitD over the preceding yearGroup 2 (n = 16): supplemented with VitD after | Potential confounders were age, gender, functional abilities, undernutrition, chronic |
| effective in improving survival among hospitalized frail elderly COVID-19 patients; severe COVID-19 defined as an OSCI score ≥5 | COVID-19 diagnosisGroup 3 (n = 32): comparator received no VitD | disease, drugs; the 3 groups were similar in the treatments used for COVID-19 | |||||||
| Arvinte (63) | May, 2020 | ICU of medical center in Colorado, USA | Cross-sectional, descriptive | 21 critically ill COVID-19 patients hospitalized; 11 survived, 10 died | Median age 61; age range: 20–94; male: 71.4% | To measure serum 25(OH)D2,3 in patients with critical COVID-19 illness and to assess if VDD correlated with other illness risk factors | Severity was defined as mortality | At ICU admission | — |
| Baktash (47) | March to April, 2020 | General hospital in the UK | Prospective cohort study | 70 elderly SARS-CoV-2+ individuals (aged ≥65 y);VDD patients: (n = 39); non-VDD patients: (n = 31) | Mean age: 81.28; Male: 60% in COVID-19 patients and 40% in non–COVID-19 patients | Vitamin D status and outcomes for hospitalized older patients with COVID-19 | Noninvasive ventilation and high-dependency unit; clinical markers of disease severity; 25(OH)D ≤12 ng/mL | Concurrent with SARS-CoV-2 test | Not adjusted for confounders; another limitation is the supplementation of VitD after the acute phase of illness |
| Bagheri (57) | March to May 2020 | University hospital in Iran | Cross-sectional | 103 outpatients and 28 hospitalized patients | Mean age: 43.74 in outpatients and 58.77 in inpatients | The vitamin D supplementation pattern in past history of patients with COVID-19 in a cross-sectional inquiry | Severity was considered as hospitalization | Supplemented or not supplemented with vitamin D | Adjusted for the factors affecting the severity of this disease |
| Carpagnano (64) | March 11 to April 30, 2020 | Italy, hospital policlinic | Retrospective, observational study | 42 patients with ARF due to COVID-19, treated in respiratory intermediate care unit, and no need of intubation or invasive ventilation | Mean age: 65; male: 71% | Assessing any correlations with disease severity and prognosis | Transfer to ICU, death; vitamin D insufficiency, moderate deficiency, and severe deficiency were defined as 25(OH)D concentrations of 20–29, 10–19, and <10 ng/mL, respectively | Measured after SARS-CoV-2 test | — |
| Entrenas Castillo (36) | May, 2020 | University hospital, Spain | RCT | 76 patients hospitalized with SARS-CoV-2 infection (50 in the intervention and 26 in the control) | Mean age: 53; male: 59% | Effect of calcifediol treatment on ICU admission and mortality rate among patients hospitalized for COVID-19 | Admission to ICU, (0.53 mg VitD at admission, 0.26 mg at day 3 and 7, and then weekly until discharge or ICU admission) | Not measured | Adjusted for variables that were different between groups at baseline (HTN, DM); MLR analysis for probability of the ICU admission |
| Cereda (65) | March to April, 2020 | Italian tertiary referral hospital | Single-center cohort study | 129 COVID-19 patients: VDD group, n = 99; non-VDD, n = 30 | Median age: 77 (IQR, 65.0, 85.0); male: 54.3% | To determine the prevalence of VDD in COVID-19 patients and explore its association with clinical outcomes of disease severity | Clinical outcomes (severe pneumonia, admission to ICU and in-hospital mortality) and biochemical markers of disease severity 25(OH)D <20 ng/mL | Within 48 h since hospital admission | Age, sex, CRP, IHD, and severe pneumonia |
| De Smet (42) | March 1 to April 7, 2020 | Belgium, general hospital | Retrospective observational study | 186 hospitalized SARS-CoV-2–infected patients | Age 68.5; male: 58.6% | Are lower 25(OH)D concentrations correlated with COVID-19 severity? | Patients were classified based on the radiological lesion as early stage 1 (ground-glass opacities), progressive stage 2 (crazy paving pattern), or peak stage 3 (consolidation), 25(OH)D <20 ng/mL | Measured after SARS-CoV-2 test | None |
| Haraj (33) | April 17 to May 26, 2020 | Endocrinology service in Morocco | Descriptive observational study | 41 patients admitted to the endocrinology service for additional care after a stay in ICU | Mean age: 55 <45 years (26.8%),45–70 years (48.8%),>70 (24.4%); 51.2% male | To assess the vitamin D status of patients with COVID-19 after a stay in intensive care | — | At the beginning of the study | — |
| Faul (30) | During March, 2020 | Ireland, Connolly Hospital Blanchardstown | Cohort | 33 hospitalized for COVID-19–related pneumonia; cases: patients progressed to ARDS (n = 12); controls: those who did not progress to ARDS (n = 21) | Mean age: 60; male:100% | Does low 25(OH)D contribute to severe disease and progression to ARDS in some patients infected with SARS-CoV-2? | Progression to ARDS, require intubation and mechanical ventilation, death | Measured after admission to hospital | — |
| Ferrari (43) | February 20 to April 7, 2020 | San Raffaele Hospital, Milan, Italy | Retrospective cohort | 128 SARS-CoV-2+ patients: severe disease (n = 16), nonsevere (n = 112) | Mean age: 62.7; male: 64.8% | Association between COVID-19 severity and VitD concentrations | Severity classification was not explained; 25(OH)D <30 ng/mL | VitD concentration measured, at least once, between the 1st of January and the 31st of May, 2020; the average time interval between SARS-CoV-2 test and VitD measurements was 33.5 d | — |
| Gonçalves (32) | March to April, 2020 | ICU in Brazil | Descriptive cross-sectional study | 176 elderly (aged ≥60 y) | Mean age: 72.9; male: 54% | Prevalence of VDD in elderly patients admitted to the ICU due to SARS-CoV-2 | — | In the first day of ICU admission | — |
| Hamza (58) | March to April, 2020 | Medical college hospital in Pakistan | Descriptive cross-sectional study | 168 SARS-CoV-2+ patients | Age ranged from 30 to 80; mean age: 42.26; male: 56% | To determine the VDD in COVID-19 patients and its association with the severity and fatality of COVID-19 disease | The COVID-19 patients were categorized into asymptomatic and symptomatic; the symptomatic patients were categorized into mild, moderate, and severe disease according to questionairre | At the beginning of the study | — |
| Hernández (44) | March 10 to March 31, 2020 | University hospital in Spain | Retrospective case-control study | 197 COVID-19 patients; cases were the patients with VDD (n = 35); control patients with non-VDD (n = 162) | Age, median (IQR): 61.0 (47.5–70.0) in cases, 61.0 (56.0–66.0) in controls; males in both group: 62.4% | To assess serum 25(OH)D3 in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity | Admission to ICU, requirement for mechanical ventilation, or in-hospital mortality; 25(OH)D <20 ng/mL | At admission | Age, smoking, chronic disease, immunosuppression, BMI, serum-corrected calcium, GFR, and the month of vitamin D determination |
| Im (45) | February to June, 2020 | University hospital, South Korea | Case-control | 50 patients with COVID-19, 32 with pneumonia and 18 without pneumonia | Median age: 57.5 in cases and 52.2 in controls; male: 58% | Association of 25(OH)D3 with disease severity (defined by pneumonia) | Progression to pneumonia includes cases with or without an oxygen supply, high-flow nasal cannula, mechanical ventilator, and ECMO/death was considered as severe; 25(OH)D3 ≤20 ng/dL | Within 7 d of admission | — |
| Jain (53) | June 5 to July 20, 2020 | Tertiary COVID-19 care center in India | Prospective observational | Study included both asymptomatic COVID–19 patients (group A, n = 91) and severely ill patients requiring ICU admission (group B, n = 63) | 30–60 y:Group A: mean age: 42.34; male: 58.2%Group B: mean age: 51.41; male: 66.66% | Analysis of vitamin D concentration among asymptomatic and critically ill COVID–19 patients and its correlation with inflammatory markers | Asymptomatic vs. ICU patients; 25(OH)D <20 ng/dL | At the beginning of the study | Not adjusted |
| Karahan (54) | April 1 to May 20, 2020 | Training and research hospital, Turkey | Retrospective observational study | 149 COVID-19 patients; moderate (n = 47), severe–critical (n = 102) | Mean age: 63.5; age range: 24–90; male: 54.4% | To investigate the role of serum 25(OH)D concentration on COVID severity and related mortality | The severity of COVID was classified according to the Chinese Clinical Guideline for classification of COVID-19 severity2; 25(OH)D ≤20 ng/dL | Data were retrieved from the hospital electronic database system | Confounding factors not mentioned |
| Кaronova (55) | April 1 to May 15, 2020 | Hospital in Russia | Cross-sectional | 80 COVID-19 patients; severe: (n = 25), moderate: (n = 55) | All patients:Age range: 18–94; mean age: 53.2; male: 53.8%Severe disease: mean age: 51.8; male: 48%Moderate disease:mean age: 53.7; male: 56.4% | Association of 25(OH)D concentration in patients with COVID-19 hospitalized with community-acquired pneumonia and compare serum 25(OH)D with clinical outcome | 25(OH)D <20 ng/dL | — | — |
| Kerget (50) | March 24 to May 15, 2020 | Two hospitals in Turkey | Case-control | 88 COVID-19 patients;20 patients developed MAS and 35 developed ARDS and 8 died | Mean age:MAS: 70.1; non-MAS: 43.4; ARDS: 67.9; non-ARDS: 38.3 | To determine the relation of serum 25(OH)D to clinical course and prognosis | Developing MAS and ARDS, and death | Fifth day of admission to hospital | — |
| Luo (46) | February to March 2020 | Wuhan Tongji Hospital | Cross-sectional | 335 COVID-19 patients; 74 severe, 261 nonsevere | Severe:Median age: 62.5; IQR: 51.0–75.3 y; male: 58.1%Nonsevere: Median age: 54; IQR: 40–62 y; male: 40.2% | To investigate whether VDD is associated with COVID-19 disease severity | Severity of COVID-19 was determined based on the level of respiratory involvement; based on Commission and State Administration of Traditional Chinese Medicine3; 25(OH)D <30 ng/mL | For the control group, serum 25(OH)D data on the same period from 2018–2019 were used; for the COVID-19 patients, on admission to hospital | Age, sex, comorbidities, smoking status, and BMI |
| Macaya (52) | — | Tertiary hospital in Madrid, Spain | Retrospective | 80 COVID-19 patients(nonsevere, n = 49; severe, n = 31) | Nonsevere: Median age: 63; IQR (50–72); male: 29%Severe:Age: 75 (66–84); male:21% | The association of VDD with a composite of adverse clinical outcomes | Death, admission to the ICU, and/or need for higher oxygen flow than that provided by a nasal cannula; 25(OH)D <20 ng/mL | At admission or within the 3 previous months | Obesity, cardiac disease, and age |
| Maghbooli (38) | Until May 1, 2020 | A hospital in Tehran | Cross-sectional | 235 COVID-19 patients;mild–moderate severity: n = 64; severe–critical severity: n = 172 | Mean age was 58.7; age range: 20–90; male: 61.3% | To investigate the association between serum 25(OH)D and clinical outcomes, parameters of immune function and mortality | CDC criteria4 were used for the disease severity and prognosis; 25(OH)D <30 ng/mL | At admission to the hospital | Age, sex, BMI, smoking, and history of a chronic medical disorder |
| Merzon (40) | February to March, 2020 | Israel, Health Services | Retrospective cohort study | 782 SARS-CoV-2+ | SARS-CoV-2+: mean age: 35.6; male: 49.23%SARS-CoV-2–negative (–): age: 47.4; male: 40.6% | Is VDD a risk factor for COVID-19 hospitalization? | Hospitalization was considered as the marker of severity; 25(OH)D <30 ng/mL | At least 1 previous blood test for plasma 25(OH)D3 concentration | Demographic variables, psychiatric and somatic disorders |
| Panagiotou (59) | — | UK, local clinical care pathway | Retrospective interim audit | 134 SARS-CoV-2+ patients; 42 admitted to ICU; deceased: 16 | Mean age: 65.9; male: 48.7% | The prevalence of VDD among COVID-19 inpatients, and its associations with disease severity | Severe COVID-19 was defined as admission to ICU and mortality; 25(OH)D <20 ng/mL | Measured after COVID-19 testing | Age, gender, comorbidities, and CRP concentrations for mortality |
| Pizzini (61) | Began on April 29, 2020; ongoing | Several hospitals and care centers in Austria | Prospective multicenter observational study | 22 non-hospitalized (mild) and 87 hospitalized patients (moderate: 34; severe: 53); 38% with VDD | Median age: 58; male: 60% | To investigate associations of vitamin D status to disease presentation | Disease severity was categorized as mild for patients in outward treatment; moderate for patients in inward treatment; and severe for patients requiring oxygen supply, respiratory support, or ICU; 25(OH)D <12 ng/mL | The 25(OH)D3 concentration was measured 2 times: the first days of hospital admission and 8 wk after the diagnosis | — |
| Pérez (66) | — | Hospital Central Military Mexico | 172 patients with COVID-19; cases: those who died (n = 35); controls: those who survived | Mean age: 51.44; male: 77.3% | Determine the association between 25(OH)D concentrations and mortality in hospitalized patients with COVID-19 | Mortality was considered as severe; 25(OH)D <20 ng/dL | — | — | |
| Radujkovic (13) | March to June, 2020 | Medical university hospital, Heidelberg, Germany | Cohort | 185 patients;patients with VDD (n = 41); non-VDD (n = 144); outpatients: 92; inpatients: 93 | Median age: 60, IQR (49–70); male: 51% | To explore possible associations of vitamin D status with disease severity and survival | Decision for inpatient vs. outpatient admission was based on spontaneous oxygen saturation, comorbidities, and the overall performance status; based on COVID-19 severity classifications, all inpatients had severe disease (defined as tachypnea, oxygen saturation <93% at rest, or ICU requirement); 25(OH)D <12 ng/mL | At the time of admission | Adjusted for age, gender, and comorbidities |
| Rastogi (14) | — | Tertiary care hospital in north India | RCT | 40 Asymptomatic or mildly symptomatic SARS-CoV-2+ with VDD [25(OH)D3 <20 ng/mL] | Median age in the intervention group: 50.0, IQR (36–51); male: 37.5%Control: 47.5 (39.3 to 49.2); male: 58.3% | Effect of high-dose oral cholecalciferol supplementation on SARS-CoV-2 viral clearance | — | At the beginning of study | — |
| Ye (41) | February to March, 2020 | Guangxi People's Hospital, China | Case-control | 80 healthy controls and 62 patients diagnosed with COVID-19 | Median age in controls: 42, IQR (31–52); male: 40%Age in cases: 43(32–59); male: 37% | To examine the relation between serum 25(OH)D3 concentration and COVID-19 severity, and its clinical case characteristics | Severe COVID-19 case was defined according to the guidelines of the National Health Commission of China5; 25(OH)D <20 ng/dL | At admission | Demographics and comorbidities |
| Yılmaz (35) | March to May 2020 | Turkey, Dicle University Faculty of Medicine | Case-control | 85 children (40 patients who were diagnosed with COVID-19 and hospitalized, 45 healthy children in the control group) | COVID-19 patients: 101.76 ± 27.91 mo; male: 47.5%Controls: 75.68 ± 27.34 mo; male: 60% | To determine the prevalence and clinical importance of VDD in children and adolescent patients who were hospitalized with the diagnosis of COVID-19 | Mild: cases with upper respiratory tract infection with normal respiratory system examinationModerate: pneumonia with fever and cough but without symptoms of dyspnea and hypoxemia or cases with findings of COVID-19 on CT scan without any symptomsSevere: fever and cough in the early period who develop dyspnea and central cyanosisCritical: develop ARDS or RF rapidly25(OH)D < 20 ng/mL | From retrospective file records | None |
1
ARF, acute respiratory failure; ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; GFR, glomerular filtration rate; HTN, hypertension; ICU, intensive care unit; IHD, ischemic heart disease; MAS, macrophage activation syndrome; MLR, multivariate logistic regression; OSCI, Ordinal Scale for Clinical Improvement; PaO2, partial oxygen pressure; RCT, randomized controlled trial; ref, reference; RF, renal failure; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SpO2, oxygen saturation; VDD, vitamin D deficiency; VitD, vitamin D; 25(OH)D, 25-hydroxyvitamin D; 25(OH)D3, 25-hydroxyvitamin D3; 1,25(OH)D, 1,25-hydroxyvitamin D.
2
Chinese Clinical Guideline for classification of COVID-19 severity. Moderate: fever and pulmonary symptoms along with pneumonia on radiologic imaging. Severe: the presence of any of the following criteria: 1) respiratory distress (≥30 breaths/min), 2) oxygen saturation ≤93% at rest, 3) PaO2/FiO2 ≤300 mmHg or chest imaging shows obvious lesion progression >50% within 24–48 h.
3
Commission and State Administration of Traditional Chinese Medicine: 1) mild: mild symptoms with no signs of pneumonia on imaging; 2) moderate: fever, respiratory symptoms with radiological evidence of pneumonia; 3) severe [i.e., meeting any of the following: respiratory distress, respiratory rate ≥30 breaths/min, hypoxemia, SpO2 ≤93% (at rest), or lung infiltrates of >50% within 24–48 h]; and 4) critical (i.e., meeting any of the following criteria: respiratory failure requiring mechanical ventilation, shock, or multiple organ dysfunction requiring ICU monitoring and treatment).
4
CDC criteria were used for the disease severity and prognosis, which includes mild–moderate (mild respiratory symptoms and fever on an average of 5–6 d after infection), severe disease (dyspnea, respiratory frequency ≥30 breaths/min, blood oxygen saturation ≤93%, and/or lung infiltrates >50% of the lung field within 24–48 h) and critical (respiratory failure, septic shock, and/or multiple-organ dysfunction/failure).
5
Per Guidelines of the National Health Commission of China severe cases met at least 1 of the following criteria: 1) respiratory rate >30 breaths/min, 2) pulse oximeter SpO2 ≤93% when breathing ambient air, 3) ratio of PaO2 to FiO2 ≤300 mmHg (1 mmHg = 0.133 kilopascal), and 4) lung imaging showing significant progression of >50% within 24 to 48 h. Critical cases were defined as having at least 1 of the following: 1) respiratory failure (PaO2 <60 mmHg when breathing ambient air), 2) hemodynamic shock (persisting hypotension requiring vasopressors to maintain mean arterial pressure >65 mmHg and serum lactate concentration >2 mmol/L despite volume resuscitation, and 3) organ failure or admittance to ICU.