Effect of Calcium Fortified Foods on Health Outcomes: A Systematic Review and Meta-Analysis.

Calcium supplementation and fortification are strategies widely used to prevent adverse outcome in population with low-calcium intake which is highly frequent in low-income settings. We aimed to determine the effectiveness and cost-effectiveness of calcium fortified foods on calcium intake and related health, or economic outcomes. We performed a systematic review and meta-analysis involving participants of any age or gender, drawn from the general population. We searched PubMed, Agricola, EMBASE, CINAHL, Global Health, EconLit, the FAO website and Google until June 2019, without language restrictions. Pair of reviewers independently selected, extracted data and assessed the risk of bias of included studies using Covidence software. Disagreements were resolved by consensus. We performed meta-analyses using RevMan 5.4 and subgroup analyses by study design, age group, and fortification levels. We included 20 studies of which 15 were randomized controlled trials (RCTs), three were non-randomised studies and two were economic evaluations. Most RCTs had high risk of bias on randomization or blinding. Most represented groups were women and children from 1 to 72 months, most common intervention vehicles were milk and bakery products with a fortification levels between 96 and 1200 mg per 100 g of food. Calcium intake increased in the intervention groups between 460 mg (children) and 1200 mg (postmenopausal women). Most marked effects were seen in children. Compared to controls, height increased 0.83 cm (95% CI 0.00; 1.65), plasma parathyroid hormone decreased -1.51 pmol/L, (-2.37; -0.65), urine:calcium creatinine ratio decreased -0.05, (-0.07; -0.03), femoral neck and hip bone mineral density increased 0.02 g/cm2 (0.01; 0.04) and 0.03 g/cm2 (0.00; 0.06), respectively. The largest cost savings (43%) reported from calcium fortification programs came from prevented hip fractures in older women from Germany. Our study highlights that calcium fortification leads to a higher calcium intake, small benefits in children's height and bone health and also important evidence gaps for other outcomes and populations that could be solved with high quality experimental or quasi-experimental studies in relevant groups, especially as some evidence of calcium supplementation show controversial results on the bone health benefit on older adults.

Management of Primary Hyperparathyroidism With Severe Hypercalcemia During the COVID-19 Pandemic.

PURPOSE: In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely. METHODS: This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19. FINDINGS: Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired. IMPLICATIONS: Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.

Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics.

BACKGROUND: In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. METHODS: A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. RESULTS: The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. CONCLUSIONS: Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.

Serum Calcium and Vitamin D levels: Correlation with severity of COVID-19 in hospitalized patients in Royal Hospital, Oman.

INTRODUCTION: Studies have revealed hypocalcemia and low vitamin D levels in severe covid-19 that warrant further research. OBJECTIVE: Our study investigates the correlation between calcium levels at presentation as a primary endpoint and pre-existing calcium levels as a secondary endpoint to the severity of disease presentation and progression. METHOD: Observational cohort study in adults admitted with COVID-19 from March utill September 2020. Multiple clinical scales and laboratory parameters were used to correlate corrected calcium and vitamin D associations with risk factors and outcomes. RESULTS: Four hundred and forty five patients were included in the study. Hypocalcemic patients had more abnormal laboratory parameters and longer hospitalization duration. Hypocalcemia was in 60-75% of all age groups (p-value 0.053), for which 77.97% were ICU admissions (p-value 0.001) and 67.02% were diabetic (p-value 0.347). There were non-significant correlations between Vitamin D and almost all the parameters except for chronic respiratory diseases, which had a P-value of 0.024. CONCLUSION: It can be concluded that hypocalcemia is a significant and reliable marker of disease severity and progression regardless of underlying comorbidities. Vitamin D levels fail to reflect correlation with severity of COVID-19 infections.

Trace elements and the carotid plaque: the GOOD (Mg, Zn, Se), the UGLY (Fe, Cu), and the BAD (P, Ca)?

Multiple epidemiological studies have suggested that industrialization and progressive urbanization should be considered one of the main factors responsible for the rising of atherosclerosis in the developing world. In this scenario, the role of trace metals in the insurgence and progression of atherosclerosis has not been clarified yet. In this paper, the specific role of selected trace elements (magnesium, zinc, selenium, iron, copper, phosphorus, and calcium) is described by focusing on the atherosclerotic prevention and pathogenesis plaque. For each element, the following data are reported: daily intake, serum levels, intra/extracellular distribution, major roles in physiology, main effects of high and low levels, specific roles in atherosclerosis, possible interactions with other trace elements, and possible influences on plaque development. For each trace element, the correlations between its levels and clinical severity and outcome of COVID-19 are discussed. Moreover, the role of matrix metalloproteinases, a family of zinc-dependent endopeptidases, as a new medical therapeutical approach to atherosclerosis is discussed. Data suggest that trace element status may influence both atherosclerosis insurgence and plaque evolution toward a stable or an unstable status. However, significant variability in the action of these traces is evident: some - including magnesium, zinc, and selenium - may have a protective role, whereas others, including iron and copper, probably have a multi-faceted and more complex role in the pathogenesis of the atherosclerotic plaque. Finally, calcium and phosphorus are implicated in the calcification of atherosclerotic plaques and in the progression of the plaque toward rupture and severe clinical complications. In particular, the role of calcium is debated. Focusing on the COVID-19 pandemia, optimized magnesium and zinc levels are indicated as important protective tools against a severe clinical course of the disease, often related to the ability of SARS-CoV-2 to cause a systemic inflammatory response, able to transform a stable plaque into an unstable one, with severe clinical complications.

Low serum calcium and phosphorus and their clinical performance in detecting COVID-19 patients.

BACKGROUND: This study aimed to evaluate the clinical performance of low serum calcium and phosphorus in discriminative diagnosis of the severity of patients with coronavirus disease 2019 (COVID-19). We conducted a single-center hospital-based study and consecutively recruited 122 suspected and 104 confirmed patients with COVID-19 during January 24 to April 25, 2020. Clinical risk factors of COVID-19 were identified. The discriminative power of low calcium and phosphorus regarding the disease severity was evaluated. Low calcium and low phosphorus are more prevalent in severe or critical COVID-19 patients than moderate COVID-19 patients (odds ratio [OR], 15.07; 95% confidence interval [CI], 1.59-143.18 for calcium; OR, 6.90; 95% CI, 2.43-19.64 for phosphorus). The specificity in detecting the severe or critical patients among COVID-19 patients reached 98.5% (95% CI, 92.0%-99.7%) and 84.8% (95% CI, 74.3%-91.6%) by low calcium and low phosphorus, respectively, albeit with suboptimal sensitivity. Calcium and phosphorus combined with lymphocyte count could obtain the best discriminative performance for the severe COVID-19 patients (area under the curve [AUC] = 0.80), and combined with oxygenation index was promising (AUC = 0.71). Similar discriminative performances of low calcium and low phosphorus were found between suspected and confirmed COVID-19 patient. Low calcium and low phosphorus could indicate the severity of COVID-19 patients, and may be utilized as promising clinical biomarkers for discriminative diagnosis.

Hematological characteristics of patients with novel coronavirus pneumonia in intensive care unit.

BACKGROUND: Toward the end of December 2019, a novel type of coronavirus (2019-nCoV) broke out in Wuhan, China. Here, the hematological characteristics of patients with severe and critical 2019-nCoV pneumonia in intensive care unit (ICU) were investigated, which may provide the necessary basis for its diagnosis and treatment. METHODS: We collected data on patients with confirmed 2019-nCoV pneumonia in the ICU of Leishenshan Hospital in Wuhan from February 25 to April 2, 2020. Real-time reverse-transcription polymerase chain reaction was used to confirm the presence of 2019-nCoV, and various hematological characteristics were analyzed. RESULTS: All patients tested positive for 2019-nCoV using nasopharyngeal swabs or sputum after admission, and interstitial pneumonia findings were noted on chest computed tomography. Sex, age and comorbidities were not significantly different between the severe and critical groups. In terms of prognosis, the survival rate of patients in the severe group reached 100%, whereas that of patients in the critical group was only 13.33% after positive treatment. Furthermore, lymphocyte percentage, blood urea nitrogen, calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels were high-risk factors for disease progression in critical patients. Finally, lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely associated with patient prognosis. CONCLUSIONS: 2019-nCoV pneumonia should be considered a systemic disease. Patients with more complications were more likely to develop critical disease. Lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels can be monitored to prevent progression critical disease.

Serum vitamin D, calcium, and zinc levels in patients with COVID-19.

BACKGROUND AND AIM: COVID-19 is a global public health concern. As no standard treatment has been found for it yet, several minerals and vitamins with antioxidants, immunomodulators, and antimicrobials roles can be sufficient for the immune response against the disease. The present study evaluates the serum vitamin D, calcium, and Zinc levels in patients with COVID-19. MATERIALS & METHODS: This research is a case-control study performed in May 2020 on 93 patients with COVID-19 hospitalized in a Shoushtar city hospital and on 186 healthy subjects with no symptoms of COVID-19. The serum vitamin D, calcium, and zinc levels were collected and analyzed using correlation coefficient and independent t-test via SPSS 18. RESULTS: Vitamin D levels had a significant difference between the case and control groups (p = 0.008). Serum calcium and serum zinc levels also had statistically significant differences between the two groups (p < 0.001). CONCLUSION: The research results showed that serum zinc, calcium, and vitamin D levels in COVID-19 patients are lower than in the control group. The supplementation with such nutrients is a safe and low-cost measure that can help cope with the increased demand for these nutrients in risk of acquiring the COVID-19 virus.

Graft survival effect of HLA-A allele matching parathyroid allotransplantation.

Permanent hypoparathyroidism is an endocrine disease that is mostly associated with the disruption of the parathyroid glands during surgery. Allotransplantation is the most promising approach for treatment particularly for its cost-effective and exact curative potential. Herein our aim was to evaluate human leukocyte antigen (HLA)-A allele matching effect on clinical improvement and graft survival after parathyroid transplantation. We performed parathyroid transplantation between ABO/Rh compatible recipient and an unrelated donor who has chronic kidney disease. Preoperative immunological tests include panel reactive antibody, T-flow cytometry crossmatch, B-flow cytometry crossmatch, autoflow cytometry crossmatch, and complement-dependent cytotoxicity crossmatch tests were performed. After histopathological evaluation, half of the resected parathyroid gland cells were isolated and transplanted to the omentum surface by laparoscopy. The transplantation outcome was followed up throughout 382 days. The recipient discharged 2 days after transplantation without any complication. During follow-up, calcium and vitamin D supplementation reduced to a one-third dose; even the intact PTH levels remained low. However, clinical improvement was observed by serum calcium levels. The recipient still continues with low-dose supplementation after 382 days of post-transplantation. Parathyroid cell transplantation to the omental tissue is the most promising option even with only one allele matching for patients with using lifelong high-dose supplementation. Clinical improvements and long-term effect of HLA-A allele matching should be evaluated with more studies and in larger cohorts as well.

Vitamin D Deficiency and Low Serum Calcium as Predictors of Poor Prognosis in Patients with Severe COVID-19.

BACKGROUND: The severity of Coronavirus Disease 2019 (COVID-19) is a multifactorial condition. An increasing body of evidence argues for a direct implication of vitamin D deficiency, low serum calcium on poor outcomes in COVID-19 patients. This study was designed to investigate the relationship between these two factors and COVID-19 in-hospital mortality. MATERIALS: This is a prospective study, including 120 severe cases of COVID-19, admitted at the department of Reanimation-Anesthesia. Vitamin D was assessed by an immuno-fluoroassay method. Total serum calcium by a colorimetric method, then, corrected for serum albumin levels. The association with in-hospital mortality was assessed using the Kaplan-Meier survival curve, proportional Cox regression analyses and the receiver operating characteristic curve. RESULTS: Hypovitaminosis D and hypocalcemia were very common, occurring in 75% and 35.8% of patients. When analyzing survival, both were significantly associated with in-hospital mortality in a dose-effect manner (pLog-Rank = 0.009 and 0.001 respectively). A cutoff value of 39 nmol/l for vitamin D and 2.05 mmol/l for corrected calcemia could predict poor prognosis with a sensitivity of 76% and 84%, and a specificity of 69% and 60% respectively. Hazard ratios were (HR = 6.9, 95% CI [2.0-24.1], p = 0.002 and HR = 6.2, 95% CI [2.1-18.3], p = 0.001) respectively. CONCLUSION: This study demonstrates the high frequency of hypocalcemia and hypovitaminosis D in severe COVID-19 patients and provides further evidence of their potential link to poor short-term prognosis. It is, therefore, possible that the correction of hypocalcemia, as well as supplementation with vitamin D, may improve the vital prognosis.

Impact of low serum calcium at hospital admission on SARS-CoV-2 infection outcome.

BACKGROUND: Calcium is an essential ion for pathogen survival and virulence and is involved in the regulation of the inflammatory response. Hypocalcemia is a common laboratory finding in critically ill patients. Data regarding levels of calcium in SARS-CoV-2 infection is scarce. Patients with SARS-CoV-2 infection who present with hypocalcemia could have a worse outcome. METHODS: We performed a retrospective analysis of hospitalized patients with SARS-CoV-2 infection and included all patients who had any serum calcium measurement in the first 72h since hospital admission. The main objective was to investigate the relation of low serum calcium with adverse outcome, measured by the requirement of high oxygen support - defined as high flow nasal cannula oxygen, non-invasive mechanical ventilation and/or invasive ventilation - intensive care unit admission or death. RESULTS: A total of 316 patients were included in the study. Median age was 65 years (IQR 55-74); 65% were men. Hypocalcemia within 72h since hospital admission was present in 63% of patients. A higher number of patients in the hypocalcemia group required high oxygen support during hospitalization (49% vs 32%; p=0,01) and were admitted to the ICU (42% vs 26%; p=0,005). No differences in mortality were observed between groups. CONCLUSIONS: Hypocalcemia is frequent in hospitalized patients with SARS-CoV-2 infection and can identify patients who will have a worse outcome. More studies are needed to understand the role of calcium metabolism in SARS-CoV-2 infection and to address the clinical implications and therapeutic interventions it might have.

Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019.

The aim of this study was to investigate the correlations between serum calcium and clinical outcomes in patients with coronavirus disease 2019 (COVID-19). In this retrospective study, serum calcium levels, hormone levels and clinical laboratory parameters on admission were recorded. The clinical outcome variables were also recorded. From February 10 to February 28, 2020, 241 patients were enrolled. Of these patients, 180 (74.7%) had hypocalcemia on admission. The median serum calcium levels were 2.12 (IQR, 2.04-2.20) mmol/L, median parathyroid hormone (PTH) levels were 55.27 (IQR, 42.73-73.15) pg/mL, and median 25-hydroxy-vitamin D (VD) levels were 10.20 (IQR, 8.20-12.65) ng/mL. The serum calcium levels were significantly positively correlated with VD levels (P =0.004) but negatively correlated with PTH levels (P =0.048). Patients with lower serum calcium levels (especially ≤2.0 mmol/L) had worse clinical parameters, higher incidences of organ injury and septic shock, and higher 28-day mortality. The areas under the receiver operating characteristic curves of multiple organ dysfunction syndrome, septic shock, and 28-day mortality were 0.923 (P <0.001), 0.905 (P =0.001), and 0.929 (P <0.001), respectively. In conclusion, serum calcium was associated with the clinical severity and prognosis of patients with COVID-19. Hypocalcemia may be associated with imbalanced VD and PTH levels.

Prevalence and predictive value of hypocalcemia in severe COVID-19 patients.

BACKGROUND: The aim of this study was to investigate the performance and predictive value of hypocalcemia in severe COVID-19 patients. METHODS: We retrospectively investigated the clinical and laboratory characteristics of severe COVID-19 patients. 107 patients were divided into hypocalcemia group and normal serum calcium group. The clinical and laboratory data were compared between two groups. The discriminative power of hypocalcemia regarding poor outcome were evaluated by receiver operating curves (ROC) analyses. RESULTS: Sixty seven patients (62.6%) had hypocalcemia. In hypocalcemia group, leukocytes, c-reactive protein (CRP), procalcitonin (PCT), Interleukin 6 (IL-6), and D-dimer levels was higher, while lymphocytes and albumin (ALB) levels was lower. No significant difference was identified in gender, age, signs and symptoms, comorbidities and other laboratory indicators. Serum calcium levels were negatively correlated with leukocytes, CRP, PCT, IL-6 and D-dimer, while positively correlated with lymphocytes and ALB. Patients with hypocalcemia more commonly presented poor outcome (47.8% (32/67) vs 25% (10/40), p=0.02). Median serum calcium levels were significantly lower in the patients with poor outcome (2.01(1.97-2.05) vs 2.10(2.03-2.20), p<0.001), and it could predict the prognosis with an area under the ROC curve (AUC) of 0.73(95% confidence interval (CI) 0.63-0.83, p<0.001). CONCLUSIONS: Hypocalcemia commonly occurred in severe COVID-19 patients and it was associated with poor outcome.

Clinical characteristics and outcomes of the first 63 adult patients hospitalized with COVID-19: An experience from Oman.

INTRODUCTION: To identify the clinical characteristics and outcomes of hospitalized patients with COVID-19 in Oman. METHODS: A case series of hospitalized COVID-19 laboratory-confirmed patients between February 24th through April 24th, 2020, from two hospitals in Oman. Analyses were performed using univariate statistics. RESULTS: The cohort included 63 patients with an overall mean age of 48±16 years and 84% (n=53) were males. A total of 38% (n=24) of the hospitalized patients were admitted to intensive care unit (ICU). Fifty one percent (n=32) of patients had at least one co-morbidity with diabetes mellitus (DM) (32%; n=20) and hypertension (32%; n=20) as the most common co-morbidities followed by chronic heart and renal diseases (12.8%; n=8). The most common presenting symptoms at onset of illness were fever (84%; n=53), cough (75%; n=47) and shortness of breaths (59%; n=37). All except two patients (97%; n=61) were treated with either chloroquine or hydroxychloroquine, while the three most prescribed antibiotics were ceftriaxone (79%; n=50), azithromycin (71%; n=45), and the piperacillin/tazobactam combination (49%; n=31). A total of 59% (n=37), 49% (n=31) and 24% (n=15) of the patients were on lopinavir/ritonavir, interferons, or steroids, respectively. Mortality was documented in (8%; n=5) of the patients while 68% (n=43) of the study cohort recovered. Mortality was associated with those that were admitted to ICU (19% vs 0; p=0.009), mechanically ventilated (31% vs 0; p=0.001), had DM (20% vs 2.3%; p=0.032), older (62 vs 47 years; p=0.045), had high total bilirubin (43% vs 2.3%; p=0.007) and those with high C-reactive protein (186 vs 90mg/dL; p=0.009) and low corrected calcium (15% vs 0%; p=0.047). CONCLUSIONS: ICU admission, those on mechanical ventilation, the elderly, those with high total bilirubin and low corrected calcium were associated with high mortality in hospitalized COVID-19 patients.

Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19).

BACKGROUND: Early studies have reported various electrolyte abnormalities at admission in patients who progress to the severe form of coronavirus disease 2019 (COVID-19). As electrolyte imbalance may not only impact patient care, but provide insight into the pathophysiology of COVID-19, we aimed to analyse all early data reported on electrolytes in COVID-19 patients with and without severe form. METHODS: An electronic search of Medline (PubMed interface), Scopus and Web of Science was performed for articles comparing electrolytes (sodium, potassium, chloride and calcium) between COVID-19 patients with and without severe disease. A pooled analysis was performed to estimate the weighted mean difference (WMD) with 95% confidence interval. RESULTS: Five studies with a total sample size of 1415 COVID-19 patients. Sodium was significantly lower in patients with severe COVID-19 (WMD: -0.91 mmol/L [95% CI: -1.33 to -0.50 mmol/L]). Similarly, potassium was also significantly lower in COVID-19 patients with severe disease (WMD: -0.12 mmol/L [95% CI: -0.18 to -0.07 mmol/L], I2=33%). For chloride, no statistical differences were observed between patients with severe and non-severe COVID-19 (WMD: 0.30 mmol/L [95% CI: -0.41 to 1.01 mmol/L]). For calcium, a statistically significant lower concentration was noted in patients with severe COVID-19 (WMD: -0.20 mmol/L [95% CI: -0.25 to -0.20 mmol/L]). CONCLUSIONS: This pooled analysis confirms that COVID-19 severity is associated with lower serum concentrations of sodium, potassium and calcium. We recommend electrolytes be measured at initial presentation and serially monitored during hospitalization in order to establish timely and appropriate corrective actions.