Which Do Animal Cells Need In Order To Maintain Homeostasis?

Eur J Nutr. 2022; 61(2): 625–636.

The relevance of magnesium homeostasis in COVID-xix

Valentina Trapani,^1, ² Andrea Rosanoff,^three Shadi Baniasadi,^iv Mario Barbagallo,⁵ Sara Castiglioni,⁶ Fernando Guerrero-Romero,^seven Stefano Iotti,⁸ André Mazur,⁹ Oliver Micke,¹⁰ Guitti Pourdowlat,¹¹ Giuliana Scarpati,¹² Federica I. Wolf, ¹ and Jeanette A. Maier ⁶

Valentina Trapani

¹Sezione di Patologia Generale, Dipartimento di Medicina due east Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy

^twoAlleanza Contro Il Cancro, Rome, Italia

Andrea Rosanoff

ⁱⁱⁱCMER Centre for Magnesium Didactics and Research, Pahoa, Hawaii USA

Shadi Baniasadi

⁴Tracheal Diseases Research Heart, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti Academy of Medical Sciences, Tehran, Islamic Republic of Islamic republic of iran

Mario Barbagallo

^fiveGeriatric Unit, Department of Medicine, Academy of Palermo, Palermo, Italia

Sara Castiglioni

⁶Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via Grand.B. Grassi 74, 20157 Milan, Italy

Fernando Guerrero-Romero

⁷Biomedical Research Unit of Mexican Social Security Institute, Durango, Mexico

Stefano Iotti

⁸Department of Pharmacy and Biotechnology (FaBit) National Institute of Biostructures and Biosystems, Università di Bologna, Bologna, Italy

André Mazur

⁹Unité de Nutrition Humaine, INRAE, UNH, Université Clermont Auvergne, Clermont-Ferrand, France

Oliver Micke

¹⁰Department of Radiotherapy and Radiation Oncology, Franziskus Hospital, Bielefeld, Frg

Guitti Pourdowlat

¹¹Chronic Respiratory Diseases Research Heart, National Research Establish of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Islamic Democracy of Islamic republic of iran

Giuliana Scarpati

¹²Anestesiologia e Rianimazione, Dipartimento di Medicina due east Chirurgia, Università Degli Studi di Salerno, Fisciano, Italy

Federica I. Wolf

^aneSezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy

Jeanette A. Maier

⁶Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Via Thou.B. Grassi 74, 20157 Milan, Italian republic

Received 2021 Jun 21; Accustomed 2021 Oct half-dozen.

Abstruse

Purpose

In less than one and a half year, the COVID-nineteen pandemic has almost brought to a collapse our health care and economical systems. The scientific inquiry customs has concentrated all possible efforts to understand the pathogenesis of this complex affliction, and several groups accept recently emphasized recommendations for nutritional support in COVID-19 patients. In this scoping review, we aim at encouraging a deeper appreciation of magnesium in clinical nutrition, in view of the vital role of magnesium and the numerous links between the pathophysiology of SARS-CoV-2 infection and magnesium-dependent functions.

Methods

By searching PubMed and Google Scholar from 1990 to appointment, we review existing evidence from experimental and clinical studies on the role of magnesium in chronic non-infectious disease and infectious diseases, and we focus on contempo reports of alterations of magnesium homeostasis in COVID-19 patients and their clan with disease outcomes. Importantly, we conduct a census on ongoing clinical trials specifically defended to disclosing the office of magnesium in COVID-xix.

Results

Despite many methodological limitations, existing data seem to corroborate an association between deranged magnesium homeostasis and COVID-19, and call for further and better studies to explore the prophylactic or therapeutic potential of magnesium supplementation.

Conclusion

We advise to reconsider the relevance of magnesium, often disregarded in clinical practice. Therefore, magnesemia should be monitored and, in example of imbalanced magnesium homeostasis, an advisable nutritional regimen or supplementation might contribute to protect confronting SARS-CoV-two infection, reduce severity of COVID-19 symptoms and facilitate the recovery after the acute phase.

Keywords: Aging, Chronic not-communicable diseases, Allowed response, Long COVID, Magnesemia, SARS-CoV-2

Introduction

Every bit of June eighteen, 2021, more than than 176 1000000 cumulative confirmed COVID-19 cases take been reported, claiming more than 3.v million lives all over the earth [1], and the numbers are however growing. At an unprecedented speed, vaccines were developed and approved for immunization [two]. Although near 2,310,000,000 vaccines take been administered, nosotros are far from the eradication of the disease. In addition, evidence is accumulating near the lingering effects experienced by recovered COVID-xix patients, fifty-fifty afterwards a mild to moderate disease [iii]. While scientists are searching for a specific therapy to treat the disease, in that location is an urgent need to individuate strategies to reinforce the immune system and forbid the infection, to mitigate the progression of the affliction, and to ameliorate symptoms of long COVID. A balanced diet is essential to strengthen immune responses and to harmonize the microbiota, a complex ecosystem important for health [four]. The nutritional condition of the patient influences the course of COVID-19, even so cognition about the nutritional support of COVID patients is very limited [5].

When the electric current SARS-CoV-2 pandemic began in early 2020, the global magnesium researcher group (MaGNet [6]) was alerted by the hit similarities betwixt COVID-19 risk factors and atmospheric condition linked to magnesium deficit country in humans [seven–9] such as age, diabetes, obesity, high claret pressure, arrhythmias, thrombosis and cardiovascular diseases. These conditions, which are associated with loftier odds of COVID-19 mortality [10, eleven], are common in Western Societies and spreading globally. Indeed, food processing losses resulting in lower dietary magnesium intakes, reduced magnesium availability in the soil and, therefore, in the food chain, long-term prescribed drugs such every bit proton pump inhibitors, all might precipitate subclinical magnesium deficiency [12].

Moreover, we reasoned that magnesium deficiency might play a office in the pathophysiology of COVID-nineteen. Even if the respiratory track is the primary site of the disease, the virus can disseminate to other tissues and complicate the clinical pic, eventually culminating in multi-organ failure [13]. Key mechanisms implicated in the disease include straight viral cytotoxicity, endothelial dysfunction and exaggerated release of inflammatory cytokines. Very early on later on the outbreak of the pandemic, it became evident that endotheliopathy is present in COVID-19 and is likely to be associated with critical disease and decease, to the point that evaluation of endothelial markers is recommended and, in parallel, therapies are sought to preserve endothelial function [14, xv]. Notably, depression magnesium induces a pro-inflammatory, pro-thrombotic phenotype in endothelial cells [16] and promotes platelet aggregation, release of beta-thromboglobulin and thromboxanes, all events that favor the development of thromboembolism [17]. Endothelial injury and hypercoagulable state are key components of the Virchow'south triad and might explain the high incidence of thromboembolic events in COVID-19 patients. Moreover, magnesium deficits may exacerbate the inflammatory response induced past SARS-CoV-2, maintaining and propagating the so-called cytokine storm, a reaction that leads to acute respiratory distress syndrome (ARDS), accentuates endothelial dysfunction and coagulopathy, and promotes multiple organ failure. In addition, other symptoms reported by COVID-nineteen patients, such as asthenia, myalgias, anxiety, depression, indisposition, might be owing to magnesium deficiency [7].

PubMed and Google Scholar were used to pinpoint studies and articles on the topic of interest. Journal articles published between 1990 and June 2021 were reviewed. Keywords included "magnesium", "Sars-CoV-2", "COVID-nineteen", "long COVID", "diabetes", "obesity", "aging", "infectious diseases", "hypertension", "atherosclerosis", "hypomagnesemia", "thrombosis". Nosotros selected merely papers written in English and covering in vitro, animal and human studies.

On these bases, we discuss the physiological role of magnesium, the link between magnesium deficiency and chronic non-communicable diseases which stand for a risk cistron for severe COVID-19, the potential contribution of a depression magnesium status to the pathogenesis of the illness to conclude with a rapid overview of clinical studies available in the literature and a summary of ongoing research on the topic.

Magnesium, a metabolite

The part of magnesium in cell and tissue metabolism is complex and multifactorial. Accumulating evidence suggests that magnesium acts primarily as a key signaling chemical element and metabolite in jail cell physiology. Consequently, the concept that magnesium is an electrolyte is likewise simplistic and obsolete [eighteen–22]. Magnesium is involved in all metabolic and biochemical pathways and is required in a wide range of vital functions, such as bone formation, neuromuscular activity, signaling pathways, bioenergetics, glucose, lipid and poly peptide metabolism, Dna and RNA stability, and cell proliferation. The enzymatic databases list more than 600 enzymes with magnesium indicated as cofactor, and additional 200 are reported in which magnesium acts as an activator [23]. Nevertheless, it should exist specified that, since it interacts direct with the substrate, magnesium is itself a substrate rather than a cofactor [xx, 24]. Indeed, since Mg²⁺ binds to the phosphate moieties of metabolites, the phosphorylated molecules (i.e., ATP, phosphocreatine, equally well as all the other phosphometabolites including those related to carbohydrate metabolism and cellular bioenergetics) form a complex with magnesium. This implies that the actual substrates of the biochemical reactions involving these metabolites are magnesium complexes. This is the reason why magnesium should be regarded as a metabolite and non as a cofactor acting in ancillary fashion in biochemical reactions [20]. As a paradigmatic case, the binding between ATP and Mg²⁺ results in an adequate conformation that allows to weaken the final O–P bond of ATP, thereby facilitating the transfer of phosphate [23]. Hence, the "active species" is not ATP, but MgATP²⁻ [twenty]. This concept is further sustained past the fact that, differently from other ions for which cells maintain transmembrane gradients, intra- and extracellular free magnesium (Mg²⁺) concentrations are comparable [24]. The full (leap + free) intracellular magnesium concentrations range from x to thirty mM. Nevertheless, since most magnesium is bound to polynucleotides, ATP, phosphorylated metabolites and proteins, the concentration of its intracellular ionic (free) form falls in the range of 0.5–i.ii mM [25]. The little amount of intracellular [Mg²⁺], as compared to the intracellular [Na⁺] and [G⁺], which are in the order of 50 and 150 mM respectively [20], strengthens the testify that the contribution of magnesium to the electric accuse of the jail cell is almost negligible. Therefore, it is fourth dimension to revise the concept that magnesium is an electrolyte.

The total body magnesium of an adult is approximately 25 g, of which 50–60% is in os, and the remaining forty%–l% is in the soft tissues, with less than 1% nowadays in the blood [25]. Magnesium is mostly captivated by the modest intestine and to lesser extent by the big intestine, and excreted by kidney through the finely tuned action of many Mg²⁺ transporters [26].

Serum magnesium concentration in claret can be efficiently buffered past renal excretion and, in function, by its release from bones. In addition, magnesium is an intracellular cation whose content depends on the tissue and its metabolic land [27, 28]. Therefore, serum magnesium values within the reference range may not rule out a systemic magnesium-depleted state, and the clinical impact of magnesium deficiency may be easily underestimated [27–29]. Yet, in the absence of a satisfactory and easily measurable biomarker to assess magnesium state, we have to rely on serum magnesium levels, which are found to exist altered in many diseases.

Unfortunately, serum magnesium levels are still not adamant routinely in daily clinical practice. Worldwide, they are measured primarily in critically ill subjects and sometimes in elderly people at hospital admission. In view of the big variety of pathophysiological atmospheric condition associated to a decrease of magnesium availability, we strongly suggest to include magnesium in the evaluation of the blood ionogram.

Magnesium deficit in aging and non-communicable chronic diseases

The overall prevalence of hypomagnesemia in geriatric patients reaches 36% [thirty], among diabetic patients ranges from xix% to 29% [31, 32], and in patients with high claret force per unit area, information technology has been institute to be 63.8% [33]. In addition, information technology has been reported that magnesium deficiency is associated with obesity and the increased incidence of hypertension, cardiovascular affliction, congestive center failure, arrhythmias, and chronic kidney disease, particularly in patients under dialysis [34–36]. Furthermore, information technology has been noted that mortality by cardiovascular deaths in subjects with hypomagnesemia is significantly college as compared with individuals exhibiting normal magnesium levels [37]. Within this context, hypomagnesemia, at the fourth dimension of access in the Intensive Care Unit (ICU), is associated with the length of stay, need for mechanical ventilation, and mortality [38].

Because patients with diabetes, specially the elderly with type 2 diabetes (T2DM), are at a higher gamble of severe disease or death due to SARS-CoV-2 infection than age-matched individuals without diabetes, it is of involvement to recall that a consistent body of evidence has linked magnesium deficiency to alterations of insulin sensitivity, including metabolic syndrome and T2DM [39]. Indeed, T2DM has been associated with several magnesium abnormalities [twoscore, 41]. An umbrella review to map and grade health outcomes linking to magnesium intake and supplementation confirmed that an elevated magnesium intake is associated with a decreased risk of T2DM [42].

Finally, it is important to highlight that magnesium modulates the contractile land of bronchial smooth muscle cells. Hypomagnesemia increases airway reactivity susceptibility to recurrent upper respiratory tract infections, and evolution of pulmonary fibrosis [7, 43]. Magnesium depletion triggers bronchial contraction and spasm, while magnesium supplementation produces bronchial relaxation [xl, 44]. Several possible mechanisms have been postulated for the positive magnesium action to relax bronchial smooth musculus, such every bit its calcium channel blocking action, a decreased sensibility to the depolarizing action of acetylcholine, a stabilization of mast cells and T lymphocytes, and a stimulation of nitric oxide and prostacyclin release [40]. Accordingly, nebulized magnesium sulfate has been used equally a bronchodilator agent in adjuvant care of asthmatic patients [45]. Moreover, because of its vasodilatory, anti-inflammatory and anti-thrombotic effects, magnesium may reduce the respiratory symptoms and ameliorate lung function of COVID-19 patients. All these effects might contribute to the reduction of the ventilation-perfusion mismatch, which is one of the most important reasons for hypoxemia in COVID-19 patients, and to the comeback of oxygenation in these patients [46]. Additionally, considering of the emerging office of mastocytes in driving diffuse alveolar injury in COVID-19 [47], information technology should be recalled that magnesium reduces mastocyte degranulation and, afterwards, prevents the release of inflammatory, pro-thrombotic and fibrotic mediators [48]. Appropriately, famotidine, an antagonist of histamine H2 receptors, seems to mitigate COVID-19 symptoms caused by dysfunctional mast jail cell activation and histamine release [49].

A recent paper demonstrates that low magnesium reduces diaphragm function in an experimental model of sepsis [l]. If confirmed in humans, these results advise that magnesium deficiency might lead to the need of assisted ventilation by impairing diaphragm contraction and, therefore, breathing.

On these bases, there is a plausible pathophysiological basis to support that magnesium is amongst the missing keys linking chronic diseases with the severity and prognosis of COVID-xix.

Magnesium in infectious diseases

Almost findings regarding the direct clan betwixt magnesium condition and immune function are derived from creature models. In humans, the fundamental importance of magnesium in immunity and the underlying mechanisms take been highlighted by the discovery of the master immunodeficiency XMEN (Ten-linked immunodeficiency with magnesium defect, Epstein–Barr virus infection, and neoplasia), which is characterized by chronic Epstein-Barr virus infection [51]. Nonetheless, general testify that magnesium deficiency may confer a higher predisposition to infectious diseases is more often than not indirect [34]. An optimal magnesium status is necessary for the synthesis, send, and activation of vitamin D [52]. Vitamin D is an immunomodulatory hormone, and vitamin D deficit has been linked to various infectious diseases, including upper respiratory and enteric infections, pneumonia, otitis media, Clostridium infections, vaginosis, urinary tract infections, sepsis, influenza, dengue, hepatitis B, hepatitis C, and HIV infections [53]. Accordingly, a number of clinical trials aiming to determine the efficacy of administration of vitamin D and its metabolites for treatment of these diseases have been conducted, merely have rarely shown benefits as therapeutic or preventive measures. Nevertheless, an important exception to the general tendency is for upper respiratory tract infections. A meta-analysis involving 25 randomized controlled trials (RCTs) and data from x,933 participants showed that vitamin D supplementation reduced the hazard of acute respiratory tract infection among all participants [54]. The shut human relationship betwixt magnesium and vitamin D suggests that the college incidence of infectious diseases associated with vitamin D deficiency can be at least in part explained by a deficit of magnesium, and this may be especially relevant in the respiratory tract.

Altered magnesium status also seems to have a prognostic part in older people affected past bacterial pneumonia. Hypomagnesemia and hypermagnesemia were both associated with excessive brusque-term mortality, 18.4% and 50%, respectively, compared to normal values of serum magnesium [55]. Moreover, low serum magnesium status was a significant predictor of frequent readmissions for acute exacerbation of chronic obstructive pulmonary disease in a retrospective report on older adults [56].

More than relevantly, in a cohort of 144 adults who were hospitalized with SARS-CoV-1 infection in the greater Toronto area in the 2003 epidemic, hypomagnesemia was found in many patients on access, and tended to worsen during hospitalization [57]. It was unclear whether this represented the natural history of the disease or was secondary to effects of ribavirin or other therapies on renal tubular function. Indeed, after adjusting for SARS-CoV-one ‐related prognostic factors and corticosteroid use, ribavirin use in 306 SARS patients was strongly associated with hypomagnesemia, and the take a chance of hypomagnesemia attributable to ribavirin utilise was 45% [58]. Since ribavirin is as well currently employed for compassionate utilise in COVID-19 patients with respiratory distress, these findings stress the importance of evaluating and, if necessary, correcting magnesemia. Although in a different context, an beast study suggested that hypomagnesemia might be a mutual adverse event of other antiviral therapies, and might potentiate the risk of cardiovascular complications, while magnesium supplementation is protective [59].

On the other hand, in quest of more constructive outset-line treatments for COVID-19, several in silico docking studies take been published for the repurposing of existing antivirals. Interestingly, binding of several candidate drugs to their viral target is dependent on magnesium, which is not surprising in view of its biochemical properties [60, 61]. Information technology is tempting to speculate that the pharmacological activity of the drugs under investigation for treatment of COVID-19 patients might be dependent on the intracellular magnesium concentration and that magnesium deficits may reduce efficacy.

In determination, very trivial is known on the prevalence and significance of hypomagnesemia in infectious diseases. Nevertheless, the current pandemic has raised unprecedented research efforts that are unveiling intriguing relationships between magnesium status and the clinical course of COVID-19.

Links between magnesium derangements and COVID-nineteen pathogenesis

Every bit knowledge about the pathogenesis of COVID-19 has increased, more than hints illuminate the potential office of dysregulated magnesium homeostasis in the prevention and clinical trend of the illness (Fig.1).

An external file that holds a picture, illustration, etc. Object name is 394_2021_2704_Fig1_HTML.jpg

How magnesium might contribute to protecting confronting COVID-19. Magnesium modulates innate and adaptive immunity and gut microbiota limerick, and is essential for Vitamin D activation and its consistent anti-inflammatory activity. Crucial steps of SARS-CoV-2 infection might exist directly affected by magnesium

Beginning issue to recall is that magnesium tunes the activity of the innate and adaptive allowed systems.

It stabilizes the membranes of mastocytes, localized in the submucosa of the airways and the alveolar septa, thereby preventing their degranulation and the release of a myriad of mediators [62]. Magnesium regulates the activeness of neutrophils and macrophages, inhibits their priming and oxidative burst, and too hinders the Toll-similar receptor iv/NFκB axis [62]. In lymphocytes, magnesium controls the amounts of IP3 and DAG, of import second messengers activated later on the engagement of B and T prison cell receptors [63]. Chiefly, magnesium protects against viral infections because adequate intracellular magnesium concentrations are required for the cytotoxic activity of T lymphocytes and natural killer (NK) cells [64]. Beyond potentiating and harmonizing immune function, it is emerging that magnesium levels might influence initial events of SARS-CoV-2 infection. The viral fasten (S) protein binds the entry receptor, the angiotensin-converting enzyme 2 (ACE2), expressed in many tissues, thus accounting for pulmonary and extrapulmonary manifestations of COVID-19 [13]. For fusion between viral and prison cell membranes to occur, the South protein needs to be proteolytically broken by host prison cell proteases, mainly the transmembrane protease serine protease two (TMPRSS2) and the pre-protein convertase furin [65]. Magnesium might play a office in inhibiting the activeness of these enzymes. Preliminary results suggest that magnesium treatment increases the methylation of the promoter of TMPRSS2, thus hindering transcription and, consequently, reducing the expression of the enzyme [66]. Moreover, thanks to its calcium antagonistic function, magnesium might hamper the activity of the calcium-dependent furin [67]. Information technology follows that magnesium deficiency may promote virus infectivity. Once the infection is ongoing, magnesium deficiency can exacerbate the inflammatory response contributing to the so-chosen cytokine storm that is involved in the pathogenesis of astringent SARS-CoV-2 clinical manifestations. The immune system reaction to the coronavirus may be so overwhelming and inappropriate as to jeopardize the lungs and the other tissues more than the virus itself, endangering the survival of patients. Notably, low levels of magnesium acquaintance likewise with increased amounts of inflammatory mediators [16, 62], among which platelet activating factor (PAF) [68]. PAF is a key thespian in COVID-19, being implicated in generating microthrombosis and promoting respiratory distress [69, 70].

Although some controversies exist, a recent metanalysis reports that depression serum levels of 25-hydroxyvitamin D (25-OHD) are associated with a higher susceptibility to SARS-CoV-two infection, COVID-19 severity and bloodshed [71]. Indeed, as highlighted in the previous section, vitamin D is necessary for a salubrious immune system. The action of vitamin D is strictly intertwined with magnesium [34]. Conspicuously, magnesium deficiency leads to reduced amounts of active vitamin D, thus generating a fertile soil for SARS-CoV-2 infection.

A final issue to mention is the recent finding that magnesium deficiency alters the delicate residuum between gut microbiota and the host [72, 73], thus influencing the airway microbiota and the immune response [74]. Lately, the relation between microbiota dysbiosis and COVID-19 severity has attracted the attention of the scientific community [75, 76] and hopefully new hints will shortly be bachelor.

Magnesium in COVID-19: clinical studies

As delineated in the previous sections, the key role of magnesium in maintaining proper immune, vascular and pulmonary part strongly supports the hypothesis that magnesium condition may affect the susceptibility and the response to SARS-CoV-ii. Indeed, a few recent reports have analyzed magnesium levels in COVID-19 patients and assessed their association with disease outcomes (Table one).

Table 1

Existing clinical studies showing alterations of magnesium levels in COVID-19 patients

Report Pattern	Number of patients	Outcome	References
Retrospective	300	Severe cases have lower magnesium levels than mild and moderate cases	[73]
Retrospective	459	Depression magnesium levels are associated to mortality	[74]
Prospective	300	48% of hospitalized patients are hypomagnesemic, but hypermagnesemia is more than prevalent in ICU cases	[75]
Prospective	200	In pregnant women, SARS-CoV2 infection was associated to higher magnesemia in the kickoff and third semester in comparison to not-infected subjects	[76]
Cross-sectional	58	An altered magnesium condition (either hypomagnesemia or hypermagnesemia) was more than frequent in ICU cases	[77]
Retrospective	ninety	Patients show levels of calcium and magnesium lower than controls	[78]
Retrospective	320	Serum calcium and magnesium concentration were significantly lower in hypokalemic than normokalemic patients	[79]
Case report	1	Persistent hypokalemia and hypomagnesemia, which continued for more than than 5 months later on the initial infection and its resolution	[80]

Zeng et al. [77] analyzed over 300 patients and found that severe cases (divers every bit those having oxygen saturation ≤ 93% at rest, or PaO_ii/FiO_two ≤ 300 mmHg, or requiring ICU care) showed significant lower levels of magnesium than balmy and moderate cases, though all values remained within the reference range. Such difference was plant consistently over the clinical form since disease onset. In addition, depression magnesium levels were indicated every bit risk factor for mortality in COVID-19 patients. A retrospective research on a total of 459 confirmed cases found that in the 63 expired individuals magnesium levels on access were significantly lower than in the 396 survivors (1.61 ± 0.19 vs. one.81 ± 0.23 mg/dl, respectively) [78]. Quilliot et al. [79] performed a detailed analysis of magnesemia and associated factors in a cohort of 300 patients. Amidst these, 48% had a magnesemia below 0.75 mmol/50, including thirteen% of severely hypomagnesemic patients (0.65 mmol/L)¹; on the other hand, a minor proportion of patients (ix.six%) was hypermagnesemic (> 0.95 mmol/L). In this study, in moderate cases of COVID-xix, serum magnesium concentrations were significantly lower and the prevalence of hypomagnesemia was significantly higher than in disquisitional cases, whereas the prevalence of hypermagnesemia was significantly increased in ICU cases. It is intriguing that in pregnant women, SARS-CoV2 infection was associated to significantly higher magnesemia in the first and third semester in comparison to non-infected subjects; however, magnesium levels did not correlate with disease severity in this cohort [80].

A frequent misreckoning factor in the cited studies may be that individuals with comorbidities, such as hypertension, cardiovascular diseases, diabetes, and obesity, who are more prone to develop severe COVID-19, oft show altered magnesium levels. In this respect, information technology is worth mentioning a minor cohort study by Sarvazad et al. [81]. They analyzed the electrolyte condition in COVID-xix patients on hospital access, only patients with a history of cancer, diabetes, hypertension, or cardiovascular and renal disorders were excluded from the study. Overall, out of fifty patients with no previous underlying disease, 32% were found to exist hypomagnesemic (1.26%–one.7 mg/dl), 6% were severely hypomagnesemic (< 1.25 mg/dl) and fourteen% were hypermagnesemic (> 2.6 mg/dl). Almost importantly, an altered magnesium condition (either hypomagnesemia or hypermagnesemia) was more frequently found in the ICU cases compared to the outpatients.

Derangement in magnesium homeostasis may have multifold consequences. Secondary to hypomagnesemia, disturbances of potassium and calcium handling are often detected; when serum magnesium levels are low, hypokalemia and hypocalcemia may be refractory to treatment past supplementation unless magnesemia is concomitantly corrected [25]. Both Yard⁺ and Ca²⁺ imbalances have been described in COVID-19 patients, and in some instances were associated to contradistinct magnesium levels. Al-Hakeim et al. [82] reported preliminary findings showing lower levels of both calcium and magnesium in 60 COVID-nineteen patients in comparison to 30 matched controls. Importantly, calcium and magnesium levels positively correlated with oxygen saturation levels. A retrospective, observational report was conducted on 320 non-critically sick patients [83]. In this cohort, serum calcium and magnesium concentration were significantly lower in hypokalemic than normokalemic patients, and 18.four% of hypokalemic patients was also frankly hypomagnesemic. Furthermore, patients who experienced hypokalemia had significantly longer hospitalization than controls. A case report [84] suggested that electrolyte imbalances may persist in the long term. A COVID-nineteen patient was admitted with depression potassium levels, only normal magnesiuim levels, only during his hospitalization adult persistent hypokalemia and hypomagnesemia, which continued for more 5 months after the initial infection and its resolution.

It is difficult to extrapolate a univocal conclusion from the existing evidence, that was obtained from a variety of populations, employing different measuring techniques and different reference values. The long-standing contend about the magnesium reference range, as well as the lack of consensus most the nigh appropriate indicators of magnesium status, are just ane side of the story [6]. The main trouble lies in the paucity of studies that have been appositely designed to investigate the role of magnesium in COVID-19 clinical grade. All the studies that nosotros have reviewed then far have inherent flaws, mostly due to their observational nature. In near studies, anomalies in magnesium were simply incidental findings that did not undergo farther analysis. Magnesium levels in adequately matched controls were rarely provided. Notably, in most cases, magnesium values were simply "snapshot" values, taken on admission or at an undetermined time during hospitalization. We practice not know magnesium levels before infection, nor their development during the grade of the illness. Data on nutritional habits, medications or dietary supplements is missing.

Despite all limitations, existing data seem to approve an association betwixt deranged magnesium homeostasis and COVID-19. The occurrence of hypermagnesemia in ICU cases in the absence of nephropathy, evidenced past two studies [79, 81], is an intriguing finding that might be related to rapid mobilization from soft tissues in patients with sepsis or to necrotic events due to microvascular thrombosis. Therefore, this finding may not necessarily exist in contrast with data that indicate hypomagnesemia as a risk factor for developing complications.

Unfortunately, now we do non possess enough knowledge to answer to some fundamental questions. Is magnesium deficiency a risk factor for developing COVID-19? In other words, are magnesium-deficient individuals more prone to infection? Or vice versa, does infection lower magnesium levels? And in either case, practice magnesium levels affect the clinical course of the disease? An affirmative and conclusive reply to these questions would offering new rubber or therapeutical opportunities by an intervention as simple as magnesium supplementation. Therefore, nosotros urgently demand to design further and meliorate studies to clarify these issues. At present, nosotros are aware of just i interventional study involving magnesium supplementation in COVID-19 patients that has been published [85]. In a cohort of 43 patients (> 50 years of age), seventeen patients received a combination of vitamin D, magnesium and vitamin B12 (DMB) earlier requiring any form of oxygen therapy, intensive intendance support, or both. The intervention group showed a significant reduction in the proportion of patients clinically deteriorating. The protective result of DMB supplementation was retained after adjusting for age and hypertension. Farther promising work is ongoing [86–88] (Table 2).

Table 2

Ongoing clinical studies investigating the role of magnesium in COVID-19

Study Blueprint	Clinical Centre	Number of Patients	Outcome
Interventional RCT [84]	Masih Daneshvari Infirmary, Shahid Dr. Labbafinejad Hospital, Shahid Sadoughi Hospital, Iran	100	Improvement of respiratory function and symptoms upon inhalation of MgSO₄
Interventional RCT	Mexican Social Security Institute at Durango, Mexico	100	Reduction of the probability of infection and the need for hospitalization and/or mortality upon administration of MgCl₂ plus vitamin D
Interventional	Academy of Minnesota, The states	NA	Efficacy of Mg supplementation for preventing sudden cardiac death in hypertensive patients
Prospective	AOU San Giovanni di Dio e Ruggi D'Aragona, University of Salerno, Italy	100	Correlation betwixt full and ionized serum Mg levels and outcomes in ICU patients
Prospective	National Research Constitute of Tuberculosis and Lung Diseases, Islamic republic of iran	200	Correlation between serum Mg/Ca level and CRP in ICU patients
Retrospective and Prospective [85]	University of Diet and Dietetics / George Mason University, USA	250	Correlation between nutrition standard care practices and outcomes in ICU patients
Retrospective	Academy of Milan – Ospedale Sacco, Italia	430	Correlation between Mg levels and the course of COVID-19
Retrospective	AUSL-IRCCS Reggio Emilia, Italy	241	Correlation between Mg levels and COVID-19 outcomes
Retrospective [86]	University Hospital of Puebla, United mexican states	118	Correlation between renal role, serum magnesium levels and mortality in T2D patients
Retrospective	Comenius University in Bratislava –Biomedical Middle Martin at Jessenius Faculty of Medicine, and the Hospitals of Žilina cocky-governing region, Slovakia	300	Correlation between Mg levels (and of other bio-elements) and the class of COVID-19
Retrospective	Indiana Academy, USA	NA	Associations between nutritional status of vitamin D, iron, and magnesium and disease severity of COVID-xix
Cross-sectional	Mexican Social Security Institute at Durango, Specialty Hospital from the National Medical Heart Century XXI, Mexican Social Security Institute at Mexico City, Mexico	450	Correlation betwixt hypomagnesemia and COVID-nineteen mortality

NA Not available

Magnesium and Postal service-Astute COVID-19 Syndrome

Similarly to mail-acute viral syndromes observed in survivors of other virulent coronavirus epidemics (east.g., SARS and MERS), increasing reports draw persistent and prolonged furnishings after acute COVID-xix [3]. Long COVID affects the lungs, the encephalon, the middle, the gastrointestinal arrangement, and the kidney. Patients most commonly feel pilus loss, fatigue, muscular weakness and joint pain, arthralgia, followed by dyspnea/coughing, and chest pain/palpitation. Neurological symptoms are also frequent: headache, slumber disorders, anxiety/low and cognitive disturbances, in particular clouding of consciousness called "brain fog" (Fig.2). Co-ordinate to epidemiological studies, a loftier percentage of hospitalized and not-hospitalized COVID-nineteen survivors take at to the lowest degree one symptom up to two–6 months after infection. Overall, these symptoms lead to a reject in the quality of life and increase frailty, and represent a current concern calling for multidisciplinary management of the post-acute phase of the disease.

An external file that holds a picture, illustration, etc. Object name is 394_2021_2704_Fig2_HTML.jpg

How magnesium deficiency might contribute to the long COVID-19 syndrome. Among the symptoms of mail service-acute COVID-nineteen syndrome summarized in the figure, many are frequently associated to hypomagnesaemia, i.e., muscular-related symptoms, pulmonary distress, neurologic and behavioral disorders, some arrhytmias, hypercoagulation disorders. These symptoms may benefit from a magnesium-rich diet or, if necessary, magnesium supplementation. PTSD Mail service Traumatic Stress Disorders, including physical, cognitive, and psychiatric symptoms

The mechanisms involved in the pathophysiology of long COVID syndrome are multifactorial and include direct virus-induced alterations, immunologic abnormality and inflammatory damage in response to the acute infection, as well as ischemia due to microvascular thromboembolism, immobility and metabolic derangements, the latter existence associated with the PTSD (Post Traumatic Stress Disorder). The simultaneous occurrence of chronic fatigue, dyspnea, pain and cough propose the possibility of alterations in the encephalon. Interestingly, SARS-CoV-2 has neuro-invasion capacity and sensory neurons seem to be its entry point to the fundamental nervous arrangement (CNS) [89]. Furthermore, neuroinflammatory events driven by the cytokine storm are likely to affect diverse regions of the CNS [90].

In this context, it is noteworthy that in the brain magnesium affects multiple biochemical processes involved in cognitive functions, cell membrane stability and integrity, NMDA-receptor response to excitatory stimuli. It also exerts a calcium-antagonist action and combats neuroinflammation [40]. Consistently, magnesium arrears determines anxiety, insomnia, hyperemotionality, low, headache, light-headedness [forty], symptoms included in the mail-acute COVID-19 syndrome. Moreover, magnesium deficits have been suggested to cause weakness and muscle hurting. This is not surprising since magnesium is key for all the enzymes utilizing or synthesizing muscle ATP, and thus for the product of musculus energy, and besides regulates contraction and relaxation [25]. Additionally, magnesium assures the regenerative chapters of skeletal muscle fibers [91].

In decision, an altered magnesium homeostasis might reasonably contribute to and beal long COVID syndrome (Fig.ii). Therefore, assessing and, if necessary, correcting magnesaemia is essential to back up full recovery. Information technology is clear that care for patients with COVID-19 does not end at the time of hospital belch, and comprehensive intendance of recovered patients is needed in the outpatient setting besides.

In this respect, magnesium supplementation is a rubber and cost-effective intervention that could help restoring the severely deranged homeostatic equilibrium of the body.

Conclusions

The ongoing SARS-CoV-2 pandemic dramatically impacted on wellness and economic system, and has significantly constrained social and cultural rights. Intervention strategies to cope with SARS-CoV-2 infection are in their early stages and we need proof of clinical efficacy. We propose to consider the relevance of magnesium, ofttimes overlooked in clinical do. It is therefore relevant to include magnesium in the ionogram to diagnose alterations of magnesium homeostasis, which might represent one of the many dowels that contribute to complete the circuitous mosaic of signs and symptoms of astute and long COVID-nineteen.

Monitoring and restoring magnesium homeostasis through an appropriate nutritional regimen or eventually by supplementation should therefore be taken in account for the general population, in particular during the current pandemic, as magnesium might contribute to prevent SARS-CoV-2 infection, to reduce severity of COVID-19 symptoms and to facilitate the recovery after the acute phase.

Acknowledgements

The Authors wish to give thanks Martin Kolisek, Massimo Galli, Stefano Rusconi, Stefania Caronni, Letizia Oreni, Lucia Merolle, Roberto Baricchi, Paolo Giorgi Rossi, Pamela Mancuso, Tommaso Fasano, Ornella Piazza, Taylor Wallace, Nana Gletsu-Miller, Martha Rodriguez-Moran, and Moises Mercado-Atri for their contribution in the clinical studies listed in Table ii.

Author contributions

JAM and FIW conceptualization; JAM and VT writing-original typhoon; all authors, writing-review and editing.

Funding

This work did not receive external funding.

Declarations

Conflict of interest

The authors declare no conflict of involvement.

Footnotes

^oneMagnesemia is expressed in mmol/50 or mg/dL (conversion: mmol/L = mg/dL × 0.4114).

Contributor Information

Federica I. Wolf, Email: ti.ttacinu@period.aciredef.

Jeanette A. Maier, Email: ti.iminu@reiam.ettenaej.

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