Impact of Hypocalcemia on the Prognosis of Patients with Acute Myocarditis.

Acute viral myocarditis is a serious complication of viral infectious diseases, including coronavirus disease 2019 (COVID-19). To better understand the pathogenesis of acute viral myocarditis, we retrospectively analyzed the incidence and prognostic significance of hypocalcemia among patients with acute myocarditis, most of whom were considered to have acute viral myocarditis. We retrospectively reviewed the demographic and clinical data of patients with clinically confirmed acute myocarditis treated in our hospital over a 13-year period from 2006 to 2019, including laboratory results, cardiac imaging findings, and clinical outcomes. These data were compared between lower, middle, and higher calcium groups depending on the minimum calcium level measured during hospitalization. Among the 288 patients with acute myocarditis included, the hypocalcemia group (lower calcium group) had poorer clinical and laboratory results, received more medications and device support, and experienced poorer outcomes, including heart failure, arrhythmias, and death. Specifically, the left ventricular ejection fraction was significantly lower, and the length of hospital stay was significantly longer in the hypocalcemia group than in the other two groups. Furthermore, the incidence rates of atrioventricular block, ventricular tachycardia/ventricular fibrillation, cardiogenic shock, and mortality were significantly higher in the hypocalcemia group. Multivariate Cox regression analysis identified hypocalcemia as an independent risk factor for 30-day mortality in patients with acute myocarditis. In conclusion, the clinical evidence provided by the present study indicates that hypocalcemia is a risk factor for poorer outcomes in patients with acute myocarditis that should be considered carefully in the diagnosis and treatment of these patients.

Baseline electrolyte disorders predict disease severity and mortality in patients with COVID-19.

Distinguishing critical laboratory biomarkers for disease severity at the time of hospital presentation is important for early identification of patients who are most likely to have poor outcomes and effective use of health resources. This study aimed to evaluate whether electrolyte imbalances on hospital admission predict severe disease and mortality in patients with coronavirus disease 2019 (COVID-19). We retrospectively collected data on the blood electrolyte concentrations of 286 COVID-19 patients at admission. The correlations between electrolyte imbalances, inflammation, and thrombosis markers in COVID-19 patients were also evaluated. We assessed the predictive performance of baseline blood electrolyte concentrations for severe disease and death using receiver operating characteristic curve analysis and multivariate logistic regression methods. Abnormalities in serum sodium, calcium, and potassium levels at admission were found at 20.6%, 14%, and 4.2%, respectively in this study. In the receiver operating characteristic curve analyses, hypocalcemia and hyponatremia effectively predicted disease progression to hospitalization (area under the curve 0.82, P < .001 and 0.81, P < .001, respectively) and 30-day mortality (area under the curve 0.85, P < .001 and 0.91, P < .001, respectively). In the multivariate logistic regression analysis, baseline hypocalcemia was identified as an independent risk factor associated with the risk of hospitalization (ß = 2.019, P = .01; odds ratio: 7.53). Baseline hypocalcemia and hyponatremia effectively predicted disease progression toward hospitalization and 30-day mortality in patients with COVID-19. Clinicians should closely follow up or reevaluate COVID-19 patients with baseline electrolyte disorders.

Association between calcium and vitamin D in geriatric patients hospitalized for Covid-19: Results from the GERIA-COVID study (preprint)

The deficiency of 25OH vitamin D (25[OH]D) is common in the older population. It physiologically triggers secondary hyperparathyroidism resulting in normal circulating calcium levels. Adjusted calcium (CaA) is estimated by the PAYNE method and several studies report a misclassification of calcium status by corrected calcium compared to ionized calcium (CaI) in older patients. Hypocalcemia is common in older COVID-19 patients. Blunted secondary hyperparathyroidism explain this high prevalence of hypocalcemia in COVID-19. However, no studies have focused on patients older than 75 years despite the high mortality rate in this population. In the present study, the association between the different types of calcium (CaI, CaA, and total calcium [CaT]) and 25(OH)D deficiency (below 50 nmol/L) was investigated. The study of the correlation between each type of calcium was performed secondarily. Observational monocentric study focused on the GERIA-COVID database during the second wave of COVID-19 in France from October 2020 to March 2021. COVID-19 was diagnosed with RT-PCR and/or chest CT-scan. A population of 181 older COVID-19 patients (86.4 years {+/-} 5.7) was analyzed. Sixty-three patients (34.8%) were deficient in 25(OH)D. The prevalence of total and ionized hypocalcemia was 44.1% and 39.2%, respectively. A negative association was reported in linear regression between 25(OH)D deficiency and CaA ({beta} =-0.052 [-0.093; -0.010], p = 0.015) as well as with CaT ({beta} = -0.05 [-0.09; -0.01], p =0.034) in the multivariate model. No association was found between vitamin D deficiency and CaI. In the multivariate models, there was no association between each type of calcium and PTH. CaI was correlated with CaT (r = 0.39, p < 0.001) and with CaA (r = 0.15, p = 0.043). Secondary hyperparathyroidism was not activated in the context of COVID-19 in this study. After reviewing the literature, this appears to be the first study in older patients to expose such results.

Ionised hypocalcaemia in emergency and acute medicine.

Acute hypocalcaemia can be life-threatening and must be diagnosed promptly. The gold-standard investigation is ionised calcium, which is measured on most blood gas analysers. Total calcium measurements are inaccurate in severe depletion even if 'corrected' or 'adjusted' for albumin. We present an illustrative case of a woman in her 30s with symptomatic hypocalcaemia and a very low ionised calcium on VBG analysis. Emergency calcium replacement was delayed due to a falsely reassuring corrected calcium result. Our discussion includes a systematic literature review on the use of ionised calcium in emergency and acute medical settings. We suggest cognitive biases that may explain clinical over-reliance on corrected calcium, and call for the inclusion of ionised calcium values in major treatment guidelines for acute hypocalcaemia.

Lenvatinib-induced hypocalcaemia due to transient primary hypoparathyroidism.

CONTEXT: Radioiodine refractory differentiated thyroid cancer can be effectively treated with multi-tyrosine-kinase inhibitors (MKIs). Hypocalcaemia has been reported among the side effects of these drugs, but little is known about its pathophysiology and clinical relevance. CASE REPORT: We report the case of a 78-years-old woman with an aggressive papillary thyroid cancer infiltrating perithyroidal structures. The extent of surgery was limited to hemithyroidectomy, RAI treatment could not be performed, and she started lenvatinib treatment. After 4 months of therapy, the patient accessed the Emergency Department for a grade III hypocalcaemia (corrected serum calcium: 6.6 mg/dL, n.v. 8.1-10.4 mg/dL), due to primary hypoparathyroidism (serum PTH: 12.6 ng/L, n.v. 13-64 ng/L). The patient was treated with intravenous calcium infusions and vitamin D supplementation. After discharge, the oral dose of carbonate calcium (CaCO3) was of 6 g/day, and was titrated according to blood exams. Two weeks after discharge, while taking CaCO3 at the dose of 3 g/day, the patient experienced symptomatic grade II hypercalcemia (corrected serum calcium: 11.6 mg/dL), associated to the spontaneous reprise of PTH secretion, and leading to oral calcium withdrawal. During the subsequent follow-up, the patient remained eucalcemic without calcium supplementation. CONCLUSIONS: Though hypocalcaemia has been described as potential side effect of MKI treatment, this is the first report of a lenvatinib-induced primary hypoparathyroidism, in a patient with a documented normal parathyroid function after surgery. The periodical assessment of calcium-phosphorus metabolism is thus warranted to prevent this potentially lethal side effect, in both post-surgical hypoparathyroid and euparathyroid patients.

Serum Glucose and Electrolyte Levels in Children with and without Febrile Seizures: A case-control study (preprint)

Background: Febrile seizures (FS) occur in children aged six to sixty months with a febrile illness not associated with a central nervous system infection or metabolic disorder. Risk factors include; age, history of the disease, certain vaccinations, or iron and zinc deficiencies. Studies show significant hyponatremia, hypocalcemia, and hyperkalemia in children with febrile seizures. Similarly, cerebrospinal fluid hyperglycemia is common in febrile convulsions. This study aimed to retrospectively assess the relationship between febrile seizures, and electrolyte & glucose imbalance among children with fever, and also compare the annual trends of febrile seizure-related admissions pre- and post-Covid 19 pandemics. Methods:  A case-control study was conducted from January 2018 to January 2022 at Zhongnan Hospital of Wuhan University, Hubei, China. 876 children aged 6 to 60 months were divided into 438 cases with febrile seizures (cases) and 438 with fever but without seizures (controls). Serum glucose and electrolyte levels at the time of hospitalization as well as age, gender, birth weight, gestational age, temperature, and causes of fever, in both groups were retrieved, analyzed, and compared. Results: Febrile seizure admissions among children aged 6-60 months were significantly reduced to less than 23.4% during the Covid-19 pandemic. Children with febrile seizures had significantly higher serum glucose levels than those with fever but without seizures (p < 0.05). The serum sodium levels of children with seizures were significantly lower than those without seizures (p < 0.05). Sodium levels were significantly lower among children with complex seizures (p < 0.05). There was no significant difference in the serum electrolyte levels of potassium and calcium between the cases and controls (p > 0.05). A significant positive correlation was found between serum sodium levels and the occurrence of febrile seizures (r = [0.156]; p < 0.05). Conclusion: The study found that admission rates for febrile seizures decreased during Covid-19 and lower sodium levels could be a risk factor for the occurrence of febrile seizures.

Severe Vitamin D Deficiency in Youth with Autism Spectrum Disorder During the COVID-19 Pandemic.

BACKGROUND: Decrease in sunlight exposure during periods of social distancing during the COVID-19 pandemic increased the risk of severe manifestations of vitamin D deficiency (VDD) in a particular "high-risk" population. Our objective was to highlight the importance of vitamin D screening in youth with autism spectrum disorder (ASD) and restrictive eating. CASE PRESENTATION: We describe 3 adolescent male patients with ASD who developed severe manifestations of VDD and hypocalcemia in late 2020 during the COVID-19 pandemic. All spent less time outdoors than in prior years because of isolation at home during the pandemic. Presenting symptoms included seizures and atraumatic fractures. All 3 were found to have hypocalcemia and severe VDD. Limited sun exposure because of isolation indoors during the COVID-19 pandemic was a likely contributing factor to the severity of VDD. All 3 were treated with intravenous calcium acutely, followed by oral calcium and vitamin D. Laboratory tests performed post-treatment showed biochemical resolution of hypocalcemia and VDD. CONCLUSION: These cases highlight the importance of screening "at-risk" youth for VDD. Clinicians should be cognizant that children and adolescents with ASD and restricted eating can have severe manifestations of hypocalcemia and VDD. Decreased sun exposure because of isolating indoors during the COVID-19 pandemic increased their risk for this.

Hypocalcemia in hospitalized patients with COVID-19: roles of hypovitaminosis D and functional hypoparathyroidism.

INTRODUCTION: Despite the high prevalence of hypocalcemia in patients with COVID-19, very limited studies have been designed to evaluate etiologies of this disorder. This study was designed to evaluate the status of serum parameters involved in calcium metabolism in patients with COVID-19 and hypocalcemia. MATERIALS AND METHODS: This cross-sectional study was conducted on 123 hospitalized patients with COVID-19. Serum concentrations of PTH, 25 (OH) D, magnesium, phosphate, and albumin were assessed and compared across three groups of moderate/severe hypocalcemia (serum total calcium < 8 mg/dl), mild hypocalcemia (8 mg/dl ≤ serum total calcium < 8.5 mg/dl) and normocalcemia (serum total calcium ≥ 8.5 mg/dl). Multivariate analyses were performed to evaluate the independent roles of serum parameters in hypocalcemia. RESULTS: In total, 65.9% of the patients had hypocalcemia. Vitamin D deficiency was found in 44.4% and 37.7% of moderate/severe and mild hypocalcemia cases, respectively, compared to 7.1% in the normal serum total calcium group (P = 0.003). In multivariate analysis, vitamin D deficiency was independently associated with 6.2 times higher risk of hypocalcemia (P = 0.001). Only a minority of patients with hypocalcemia had appropriately high PTH (15.1% and 14.3% in mild and moderate/severe hypocalcemia, respectively). Serum PTH was low/low-normal in 40.0% of patients with moderate/severe low-corrected calcium group. Magnesium deficiency was not associated with hypocalcemia in univariate and multivariate analysis. CONCLUSION: Vitamin D deficiency plays a major role in hypocalcemia among hospitalized patients with COVID-19. Inappropriately low/low-normal serum PTH may be a contributing factor in this disorder.

Retrospective case-control study to evaluate hypocalcaemia as a distinguishing feature of COVID-19 compared with other infective pneumonias and its association with disease severity.

OBJECTIVES: To investigate whether calcium derangement was a specific feature of COVID-19 that distinguishes it from other infective pneumonias, and its association with disease severity. DESIGN: A retrospective observational case-control study looking at serum calcium on adult patients with COVID-19, and community-acquired pneumonia (CAP) or viral pneumonia (VP). SETTING: A district general hospital on the outskirts of London, UK. PARTICIPANTS: 506 patients with COVID-19, 95 patients with CAP and 152 patients with VP. OUTCOME MEASURES: Baseline characteristics including hypocalcaemia in patients with COVID-19, CAP and VP were detailed. For patients with COVID-19, the impact of an abnormally low calcium level on the maximum level of hospital care, as a surrogate of COVID-19 severity, was evaluated. The primary outcome of maximal level of care was based on the WHO Clinical Progression Scale for COVID-19. RESULTS: Hypocalcaemia was a specific and common clinical finding in patients with COVID-19 that distinguished it from other respiratory infections. Calcium levels were significantly lower in those with severe disease. Ordinal regression of risk estimates for categorised care levels showed that baseline hypocalcaemia was incrementally associated with OR of 2.33 (95% CI 1.5 to 3.61) for higher level of care, superior to other variables that have previously been shown to predict worse COVID-19 outcome. Serial calcium levels showed improvement by days 7-9 of admission, only in survivors of COVID-19. CONCLUSION: Hypocalcaemia is specific to COVID-19 and may help distinguish it from other infective pneumonias. Hypocalcaemia may independently predict severe disease and warrants detailed prognostic investigation. The fact that decreased serum calcium is observed at the time of clinical presentation in COVID-19, but not other infective pneumonias, suggests that its early derangement is pathophysiological and may influence the deleterious evolution of this disease. TRIAL REGISTRATION NUMBER: 20/HRA/2344.

Associations and prognostic accuracy of electrolyte imbalances in predicting poor COVID-19 outcome: a systematic review and meta-analysis of 28 observational studies (preprint)

BACKGROUND: Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. OBJECTIVES: To systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome. METHODS: PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR+, LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed. RESULTS: We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR=2.08, 95%CI=1.48-2.94, I2=93%, N=8), hypernatremia (OR=4.32, 95%CI=3.17-5.88, I2=45%, N=7) and hypocalcemia (OR=3.31, 95%CI=2.24-4.88, I2=25%, N=6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR+ 4.0, PPV=55%, AUC=0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV=87%, AUC=0.71). Overall quality of evidence ranged from very low to moderate. CONCLUSION: Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.

Predicting ionized hypocalcemia: External validation of an ionized calcium prediction model in patients with COVID-19 and renal failure.

BACKGROUND: Ionized hypocalcemia is common in critically ill patients with COVID-19 and is associated with adverse outcomes. We previously developed a linear model that estimates ionized calcium (ICa) by adjusting total calcium (TCa) for the three components of the anion gap and albumin. On internal validation, it outperformed the popular method that corrects TCa for albumin alone (cTCa) in diagnosing low ICa. In this study, we sought to externally validate our ICa model in hospitalized COVID-19 positive patients. METHODS: We retrospectively studied all 200 patients with COVID-19 who were admitted to the State University of New York Downstate Medical Center between March 11th and April 30th 2020 and referred to the nephrology service for renal failure, and who had ICa measured on a venous blood gas within 25 min of a comprehensive metabolic panel. We compared the performance of the ICa model and cTCa in diagnosing low ICa by ROC analysis, and also examined the accuracy of the absolute values predicted by the two methods relative to measured ICa. RESULTS: On ROC analysis, the ICa model was better than cTCa (area under ROC curve: 0.872 [0.025] vs. 0.835 [0.028]; p = 0.045). The ICa model estimated ICa accurately, but the cTCa method seemed to overcorrect TCa, as a substantial number of patients with clearly normal cTCa values had low ICa. CONCLUSIONS: In an external validation cohort, the ICa model estimated ICa accurately and was better than cTCa in the diagnosis of low ICa. This finding can be useful in guiding direct ICa testing.

Hypocalcemia and Massive Pulmonary Embolism in SLE Patient with COVID-19 Infection, A Case Report (preprint)

A 16-year-old female presented to our ED with fever and coughing of blood for 3 days. She is known to have SLE for 5 months and takes oral prednisone. She was tested positive for COVID19. She developed hypocalcemia with clinically-diagnosed massive pulmonary embolism. She was treated with heparin and recovered.

Hypocalcemia and Massive Pulmonary Embolism in SLE Patient with COVID-19 Infection, A Case Report (preprint)

A 16-year-old female presented to our ED with fever and coughing of blood for 3 days. She is known to have SLE for 5 months and takes oral prednisone. She was tested positive for COVID19. She developed hypocalcemia with clinically-diagnosed massive pulmonary embolism. She was treated with heparin and recovered.

Hypocalcemia in COVID-19 is associated with low vitamin D levels and impaired compensatory PTH response.

BACKGROUND: Hypocalcemia has been identified as a major distinctive feature of COVID-19, predicting poor clinical outcomes. Among the mechanisms underlying this biochemical finding, high prevalence of vitamin D (VD) deficiency in COVID-19 patients reported so far in several studies was advocated. However, robust data in favor of this hypothesis are still lacking. Therefore, aim of our study was to investigate the role of hypovitaminosis D and parathyroid hormone (PTH) levels in the development of hypocalcemia in COVID-19 patients. METHODS: Patients admitted to IRCCS Ospedale San Raffaele for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing calcium and VD metabolism. Serum levels of total calcium (tCa), ionized calcium (Ca2+), 25-OH-VD, and PTH were evaluated at admission. We defined VD deficiency as VD below 20 ng/mL, hypocalcemia as tCa below 2.2 mmol/L or as Ca2+ below 1.18 mmol/L, and hyperparathyroidism as PTH above 65 pg/mL. RESULTS: A total of 78 patients were included in the study. Median tCa and Ca2+ levels were 2.15 and 1.15 mmol/L, respectively. Total and ionized hypocalcemia were observed in 53 (67.9%) and 55 (70.5%) patients, respectively. VD deficiency was found in 67.9% of patients, but secondary hyperparathyroidism was detected in 20.5% of them, only. tCa levels were significantly lower in patients with VD deficiency and regression analyses showed a positive correlation between VD and tCa. CONCLUSIONS: In conclusion, we confirmed a high prevalence of hypocalcemia in COVID-19 patients and we showed for the first time that it occurred largely in the context of marked hypovitaminosis D not adequately compensated by secondary hyperparathyroidism.

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.

Fluid and Electrolyte Disturbances in COVID-19 and Their Complications.

The novel coronavirus disease 2019 (COVID-19) is the cause of an acute respiratory illness which has spread around the world. The virus infects the host by binding to the angiotensin-converting enzyme 2 (ACE2) receptors. Due to the presence of ACE2 receptors in the kidneys and gastrointestinal (GI) tract, kidneys and GI tract damage arising from the virus can be seen in patients and can cause acute conditions such as acute kidney injury (AKI) and digestive problems for the patient. One of the complications of kidneys and GI involvement in COVID-19 is fluid and electrolyte disturbances. The most common ones of these disorders are hyponatremia, hypernatremia, hypokalemia, hypocalcemia, hypochloremia, hypervolemia, and hypovolemia, which if left untreated, cause many problems for patients and even increase mortality. Fluid and electrolyte disturbances are more common in hospitalized and intensive care patients. Children are also at greater risk for fluid and electrolyte disturbances complications. Therefore, clinicians should pay special attention to the fluid and electrolyte status of patients. Changes in fluid and electrolyte levels can be a good indicator of disease progression.

Hypocalcemia in COVID-19: Prevalence, clinical significance and therapeutic implications.

COVID-19 extra-pulmonary features include several endocrine manifestations and these are becoming strongly clinically relevant in patients affected influencing disease severity and outcomes.At the beginning of COVID-19 pandemic no population data on calcium levels in patients affected were available and in April 2020 a first case of severe acute hypocalcemia in an Italian patient with SARS-CoV-2 infection was reported. Subsequently, several studies reported hypocalcemia as a highly prevalent biochemical abnormality in COVID-19 patients with a marked negative influence on disease severity, biochemical inflammation and thrombotic markers, and mortality. Also a high prevalence of vertebral fractures with worse respiratory impairment in patients affected and a widespread vitamin D deficiency have been frequently observed, suggesting an emerging "Osteo-Metabolic Phenotype" in COVID-19.To date, several potential pathophysiological factors have been hypothesized to play a role in determining hypocalcemia in COVID-19 including calcium dependent viral mechanisms of action, high prevalence of hypovitaminosis D in general population, chronic and acute malnutrition during critical illness and high levels of unbound and unsaturated fatty acids in inflammatory responses.Since hypocalcemia is a frequent biochemical finding in hospitalized COVID-19 patients possibly predicting worse outcomes and leading to acute cardiovascular and neurological complications if severe, it is reasonable to assess, monitor and, if indicated, replace calcium at first patient hospital evaluation and during hospitalization.