A systematic review: The relationship of COVID-19 to iron, zinc, and vitamin D

Abstract

Background:

Primary care physicians are crucial in identifying SARS-CoV-2 infection and transferring suspected cases since they are on the front lines of health care. Micronutrients are used as an adjunctive treatment for viral respiratory infections. Because there is currently no effective antiviral therapy for COVID-19, micronutrients such as iron, zinc, and vitamin D may be important for the survival of critically ill patients.

Objective:

To establish and emphasize a relationship between iron, zinc, and vitamin D to COVID-19.

Materials and Methods:

PubMed database was used for articles selection. All relevant articles to our review with the topics regarding the use of iron, zinc and vitamin D in COVID-19 patients. We excluded other articles, which are not related to this field and did not match inclusion criteria. The data extracted according to specific form and double reviewed by the group members.

Results:

The search of the mentioned database returned a total of 3614 studies that were included for title screening. 2910 of them were included for abstract screening, which lead to the exclusion of 1064 articles. The remaining 1846 publications full texts were reviewed. The full-text revision led to the exclusion of 1812 studies, and 34 were enrolled for final data extraction.

Conclusion:

This study raised the idea of employing zinc, iron, and vitamin D as ingredients to either protect SARS-CoV-2 patients or to speed up recovery, decrease symptoms severity and decrease mortality rates.

Introduction

COVID-19 in 2020 brought challenges to the public health system with an emerging virus with respiratory contagion called SARS-CoV-2. COVID-19 is characterized by the symptoms of viral pneumonia, such as fever, fatigue, dry cough, and lymphopenia. Patients have reported comorbidities such as diabetes, cardiovascular disease, liver disease, kidney disease, and malignant tumors. This disease also affects physical activity, sedentary action, and psychological emotion.[1]

The goal of primary health care is to offer all residents access to affordable, high-quality medical treatment. A well-integrated primary health care and public health system is crucial for a coordinated response. Growing evidence of the influence of primary care physicians on health promotion shows that they play a crucial role in epidemic management.[2]

Primary care has a crucial role to play in managing ambulatory COVID-19 and identifying patients who are more likely to experience severe symptoms so that outpatient monoclonal antibodies can be started or patients can be admitted to the hospital. Systematic solutions and extra resources are crucial for addressing the new primary care difficulties brought about by the introduction of the vaccination, the accompanying hesitation, and social hurdles. Primary care has the power to go over vaccine obstacles and engage with hard-to-reach people since it is the trusted source for health care and has new tools to reach out into the community.[3]

The concern of today’s communities is to find a way to prevent or treat COVID-19 and reduce its symptoms in the patients. However, the genetic mutations and more resistant strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerge; the designed vaccines and adjuvant therapies would potentially control the symptoms and severity of COVID-19.[4]

An appropriate diet and good nutritional status are essential for an optimal immune response to prevent infections. On the other hand, a poor diet and deficiency of these nutrients will increase the disease burden. Evidence proposes that nutrients are involved in the development of COVID-19.[5]

Micronutrients are used as an adjunctive treatment for viral respiratory infections. Because there is currently no effective antiviral therapy for COVID-19, adjuvant intervention may be important for the survival of critically ill patients.[4] It has been indicated that some nutrients, including vitamin D, magnesium, and zinc are essential in the modulation of the immune system and interferon (IFN) signaling pathway.[3]

The well-known essential role of vitamins, minerals, metalloids, and other micronutrients in many biological, biochemical, and molecular processes along with in vivo studies demonstrating a significant role of several micronutrients in COVID-19, led clinicians use micronutrients as a promising adjuvant therapy against SARS-CoV-2 severe pneumonia.[5]

Recent reviews agree that micronutrients play a crucial role in COVID-19 progression, prognosis, and survival, as in multiple other viral infections that primarily affect the respiratory tract. The already studied nutritional interventions for SARS-CoV and MERS-CoV infections and the underlying mechanism via which micronutrients inhibit these viruses are encouraging, as SARS-CoV-2 shares a 79.5% sequence identity with SARS-CoV and 50% with MERS-CoV.[4]

Materials and Methods

Sample and study groups

Exploratory research with a quantitative approach is included in this Integrative Literature Review (ILR). ILR is a method for gathering previously published studies with the goal of synthesizing evidence on a topic; it is widely used in the health sciences to find healthcare methods and determine innovations, allowing for the application of evidence-based services, ensuring quality, and promoting patient safety. It comprises six steps that must be completed in order: Explanation of the study issue; inclusion and exclusion criteria; sample definition; evaluation of included studies; findings interpretation; and presentation of the ILR synthesis.

The PICO (Patient, Intervention, Comparison, and Outcome) technique is commonly used in evidence-based practice, and it was utilized to develop the research question. The PICO strategy advises that problems observed in clinical practice, research, and teaching be divided into four elements: Patient, Intervention, and Treatment, Outcome, Comparison (PICO). The construction of these pieces allows for more flexibility in the design made to answer to the problem at hand.

The papers that answered the research question were reviewed in depth after searching and defining the sample. Following data collection, the information was grouped in a table, allowing the profile of the articles to be described and the main points were highlighted.

PubMed central Information Service was chosen as the search databases for the publications used within the study, as they are high-quality sources. PubMed being one of the largest digital libraries on the internet developed by the National Center for Biotechnology Information (NCBI), which is a part of the United States National Library of Medicine. The founded articles were screened by titles and reviewing the abstracts.

Inclusion criteria: The articles were selected based on the relevance to the project, which should include one of the following topics; zinc, iron, vitamin D, COVID-19, SARS-CoV-2. Studies included in PubMed central database, published less than a year ago, and English language were included.

Exclusion criteria: All articles that were not signed in PubMed central database, studies that do not have one of these topics as their primary end, or repeated studies, studies published more than one year, and studies in language other than English were excluded. Review articles as well as studies published more than a year ago were excluded.

Statistical analysis

No software was utilized to analyze the data. The data were extracted based on specific form that contains (title of the publication, author’s name, objective, summary, results, and outcomes). Double revision of each member’s outcomes was applied to ensure the validity and minimize the mistakes. During article selection, studies were doubled-reviewed, and their results to assure that we enroll the studies related to the objective of our study, and to avoid or minimize errors in the results.

Results

Figure 1 shows the selection and identification of studies. The search of the mentioned databases returned a total of 3614 studies that were included for title screening. 2910 of them were included for abstract screening, which lead to the exclusion of 1064 articles. The remaining 1846 publications full texts were reviewed. The full-text revision led to the exclusion of 1812 studies, and 34 were enrolled for final data extraction [Tables 1-3].

Figure 1.

Prisma chart for included studies. The included studies had different study designs

Table 1.

Author, year of publication, study design, micronutrient (iron), and study outcomes

Author, year	Study design	Micronutrients	Study participants	Outcomes
Uta, M., et al. (2022)[6]	A case-control study	Iron Supplementation	446 expectant mothers. 95 pregnant women were found to have COVID-19, which is markedly more common in people with iron-deficient anemia.	In COVID-19 patients, anemia was much more common and was closely connected to puerperal infection, emergency c-sections, and small for gestational age. It is advised to supplement these two’s nutritional intake in order to promote the newborn’s healthy development and growth and prevent a host of problems during pregnancy in the case of a COVID-19 pandemic.
Bastin, A., et al. (2021)[7]	A case-control study	Iron Chelator and Iron Supplement	147 patients with a positive PCR test result and 39 normal individuals	It is possible to think of using iron chelators to lower iron intake as a therapeutic objective. Measuring Fe and ferritin is also helpful for identifying the condition and gauging its severity.
Zhao, K., et al. (2020)[8]	A Retrospective Study	Iron	50 patients in hospitals with COVID-19 confirmed. The impact of serum iron on COVID-19 severity and death was assessed.	The COVID-19 patients had serum iron insufficiency, which was found. Serum iron levels were closely associated with the severity and mortality of the illness. In COVID-19 patients, low serum iron concentration was an independent risk factor for death.
Campione E., et al. (2021)[9]	A clinical trial	Lactoferrin	Three sets of 92 mild-to-moderate COVID-19 patients (67/92) and asymptomatic (25/92) patients were assembled. 32 hospitalized patients got just standard-of-care (SOC) treatment; 28 patients in home-based isolation received no medication; and 32 patients (14 hospitalized and 18 in home-based isolation) received only oral and intranasal liposomal bLf. 32 healthy, untreated, COVID-19 negative participants were also added for additional analysis.	A substantial reduction in serum ferritin, IL-6, and D-dimers levels was seen in individuals receiving bLf treatment. Negative incidents were not reported. These findings prompted us to hypothesize that bLf might play a role in the treatment of mild-to-moderate COVID-19 individuals who are asymptomatic.
Tojo K., et al. (2021)[10]	Two-center observational study	Iron	136 adult hospitalized COVID-19 patients	Serum iron levels and RF severity are inversely correlated in COVID-19 hospitalized patients. Higher blood iron levels are linked to the emergence of severe RF, suggesting that a deficient response to reduced serum iron may be a COVID-19 aggravating factor.
Algahtani F. D., et al. (2021)[11]	A randomized, prospective, interventional pilot study	Lactoferrin	54 patients with COVID-19 who had mild to moderate symptoms that were confirmed in the lab. Only participants in the treatment group received lactoferrin at various doses for seven days; participants in the control group received the approved Egyptian COVID-19 management protocol.	The results prevent drawing any firm conclusions about its potential advantages as a support therapy.
Rosa L., et al. (2021)[12]	A retrospective study	Lactoferrin	121 patients.	Lf is safe and well-tolerated by all patients, making it a potential crucial adjunctive therapy in the fight against SARS-CoV-2 infection.

Table 3.

Author, year of publication, study design, micronutrient (Zinc) and study outcomes

Author, year	Study design	Micronutrients	Study participants	Outcomes
Szarpak, L. et al. (2021)[27]	A meta-analysis	Zinc	1474 patients included in 4 studies	Zinc supplementation did not have any beneficial impact on the course of COVID-19 evaluated as survival to hospital discharge and in-hospital mortality. The zinc-supplemented group had longer hospital stay despite shorter ICU stay.
Tabatabaeizadeh S. A. (2022)[28]	A meta-analysis	Zinc	1506 participants in case and control groups were included in meta-analysis.	zinc supplementation is associated with a lower mortality rate in COVID-19 patients. Zinc supplementation could be considered as a simple way and cost benefit approach for reduction of mortality in COVID-19 patients.
Razeghi Jahromi, S., et al. (2021)[29]	An observational study	Zinc	84 patients diagnosed with COVID-19 presenting to the emergency ward	Results suggest that increasing levels of Zn were accompanied by a decrease in serum CRP level. However, the significant association between Zn and disease severity was lost after adjusting for confounding factors.
Arrieta, F., et al. (2021)[30]	A retrospective study	Zinc	Thirty-five people with COVID-19 in need of PN were studied	Serum zinc concentrations during PN support were inversely associated with length of hospital stay but not with mortality.
Singh, S., et al. (2021)[31]	Cross-sectional study	Zinc	The study analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150-fold difference in death rates)	results suggest a positive correlation between populations’ Zn-sufficiency status and COVID-19 mortality as well as incidence. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19.
Razeghi Jahromi, S., et al. (2021)[32]	An observational study	Zinc	84 COVID-19 patients	Results suggest that increasing levels of Zn was accompanied by a decrease in serum CRP level. However, the significant association between Zn, and disease severity was lost after adjusting for confounding factors.
Verschelden, G., et al. (2021)[33]	An observational study	Zinc	139 eligible patients were included	Zinc concentration is significantly correlated with only the length of hospital, but not with mortality or morbidity. As such, findings do not support the role of zinc as a robust prognostic marker among hospitalized COVID-19 patients who in our cohort presented a high prevalence of zinc deficiency.
Al Sulaiman, K., et al. (2021)[34]	A two-center propensity-score matched study	Zinc	164 patients were included, 82 patients received zinc.	The use of zinc sulfate as an additional treatment in critically ill COVID-19 patients may improve survival. Furthermore, zinc supplementation may have a protective effect on the kidneys.
Ekemen Keleş, Y., et al. (2022)[35]	A prospective observational study	Zinc	100 children with confirmed COVID-19 and 269 children in the control group participated in the study.	Fasting status, diurnal fluctuation, exercise, and sex are just a few of the variables that might affect serum zinc levels, which can reflect the zinc status of the population as a whole rather than the individual. Given that individuals with COVID-19 and low serum zinc levels were more likely to be hospitalized, it is likely that these patients need a thorough evaluation of their living conditions.
Gordon, A. M., and Hardigan P. C. (2021)[36]	An ambulatory, interventional, prospective, single-blind study	Zinc	104 participants	Zinc is a relatively inexpensive mineral nutrient that is an effective prophylactic agent to prevent and mitigate the potentially deadly symptomatic SARS-CoV-2 infection.
Balboni, E., et al. (2022)[37]	A systematic review	Zinc	four randomized clinical trials using zinc supplementation	studies on the effects of zinc supplementation did not confirm efficacy
Ali, N., et al. (2021)[38]	A retrospective study	Zinc	Asian and European population	there is not enough evidence on the association between individual zinc status and COVID-19 infections and mortality.
Hunter, J., et al. (2021)[39]	A systematic review and meta-analysis of randomized controlled trials	Zinc	28 RCTs with 5446 participants were included	Zinc may help to avoid the signs and symptoms of and lessen the duration of respiratory tract infections. Some people may find their tolerance is limited by minor unpleasant effects. Different zinc formulations and dosages did not appear to have comparable efficacy or effectiveness.

Table 1 provides information on the severity of symptoms, prognosis, and use of iron supplements in COVD-19 cases. The use of iron during pregnancy to prevent problems during pregnancy in the COVID-19 pandemic context was validated by a study[6] on pregnant women. Serum iron levels were highly linked with the disease’s severity and mortality.[8] A therapeutic objective was reportedly to use iron chelators to lower iron intake.[7] While the results of one trial prevented drawing any firm conclusions regarding lactoferrin’s potential benefits as a support therapy,[11] it was discovered to be a significant supplemental treatment in the fight against SARS-CoV-2 infection.[9,12]

Table 2 shows data regarding vitamin D supplementation use and serum iron level in severity of symptoms and prognosis of COVD-19 cases. Vitamin D status seems to be strongly associated with COVID-19 clinical severity[13,14,15,16,17,18,19,20,21,22,23,24,25,26] as it shortened hospital stay and decreased mortality in COVID-19 cases.[13,16-18,21,25,26] Vitamin D was also associated with better COVID-19 outcomes.[15,18,20,26]

Table 2.

Author, year of publication, study design, micronutrient (Vit D), and study outcomes

Author, year	Study design	Micronutrients	Study participants	Outcomes
Gönen, M. S., et al. (2021)[13]	A retrospective then a prospective study	Vit D	Retrospective data analysis was used in the study to examine 867 COVID-19 cases. After then, a prospective study with 210 cases and 23 healthy subjects was carried out. 95 of the 163 instances that received vitamin D supplements underwent a 14-day follow-up.	Vitamin D treatment shortened hospital stay and decreased mortality in COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is effective on various target parameters; therefore, it is essential for COVID-19 treatment.
Bania, A., et al. (2022)[14]	A Systematic Review	Calcifediol	11 Studies	Future research should concentrate on calcifediol, which is given to COVID-19 patients after diagnosis and is by far the most promising treatment.
Oristrell, J., et al. (2022)[15]	A population-based, cohort study	Cholecalciferol and calcifediol	We compared propensity score-matched untreated controls to all people under the age of 18 residing in Barcelona-Central Catalonia (n=4.6 million) who had cholecalciferol or calcifediol supplements.	Patients receiving cholecalciferol or calcifediol supplements and reaching serum 25OHD levels below 30 ng/ml had improved COVID-19 outcomes.
Shah, K., et al. (2022)[16]	Systematic reviews and meta-analysis	Vit D	10 Studies	Vitamin D supplementation is effective in reducing COVID-19 severity. Hence vitamin D should be recommended as an adjuvant therapy for COVID-19.
Hosseini, B., et al. (2022)[17]	A Systematic Review and Meta-Analysis	Vit D	Primary prevention is covered in five studies (one RCT, four NRISs), secondary prevention is covered in five (two RCTs, three NRISs), and tertiary prevention is covered in thirteen (six RCTs, seven NRISs).	While vitamin D supplementation exhibited protective effects against death and ICU admission in COVID-19 patients, it had no discernible effect on the chance of infection with COVID-19.
Varikasuvu, S. R., et al. (2022)[18]	A systematic review and meta-analysis	Vit D	A total of 6 RCTs with 551 COVID-19 patients were included.	When all the results from all RCTs were combined, vitamin D consumption was linked to a statistically significant decline in the frequencies of COVID-19-related incidents. The relative risk of ICU admission and death outcomes following vitamin D treatment, however, showed no meaningful difference.
Gallelli, L., et al. (2021)[19]	A multicenter real practice study	Vit D	117 subjects	In order to treat male patients with an acute COVID-19 infection, 1,25(OH) 2D3 may be administered.
Rawat, D., et al. (2021)[20]	A systematic review and meta-analysis”	Vit D	Total 5 studies (3 RCTs and 2 Quasi-experimental) including n=467 patients were included.	No significant difference with vitamin-D supplementation on major health-related outcomes in COVID-19. Well-designed RCTs are required addressing this topic.
Ben-Eltriki, M., et al. (2021)[21]	A Meta-Analysis of Observational Studies	Vit D	Twenty-four observational studies containing 3637 participants were included	The study reported a potential increased risk of developing severe COVID-19 infection among patients with low vitamin D levels.
Nimavat, N., et al. (2021)[22]	A case-control study at a tertiary care hospital	Vit D	Total 156 cases and 204 controls were enrolled in the study	Vitamin D status appears to be strongly associated with COVID-19 clinical severity.
Parant, F., et al. (2022)[23]	An observational retrospective cohort	Vit D	228 older hospitalized patients during the first wave of the COVID-19 pandemic.	VitD supplementation taken during the 3 months preceding the infection onset may have a protective effect on the development of severe COVID-19 forms in older adults.
Dror, A. A., et al. (2022)[24]	A retrospective study	25- hydroxyvitamin D3	1176 patients admitted with COVID-19 were categorized according to disease severity and level of 25(OH) D.	Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality.
Ma, W., et al. (2022)[25]	Prospective study	Vit D	Among 39,315 participants, 1768 reported a positive test for SARS-CoV-2 infection.	study provides suggestive evidence on the association between higher predicted circulating 25(OH) D concentrations and a lower risk of SARS-CoV-2 infection. Greater intake of vitamin D supplements was associated with a lower risk of hospitalization. Our data also support an association between exposure to UV-B or UV-A, independently of vitamin D and SARS-CoV-2 infection
Lin, L. Y., et al. (2022)[26]	A cohort study using UK Biobank	Vit D	307,512 participants	The study found no evidence of an association between historical vitamin D status and hospitalization or mortality due to COVID-19, along with inconsistent results for any association between vitamin D and diagnosis of COVID-19.

Table 3 provides information on blood iron levels, zinc supplementation, and the severity of symptoms in COVD-19 cases. A decreased mortality rate in COVID-19 patients, the prevention of symptoms of respiratory tract infections, and a shorter incubation period have all been linked to zinc supplementation.[28,34,35,39] Others, however, reported improved symptoms without any changes to the mortality rate.[30,33] Unexpected findings from one investigation indicate a relationship between COVID-19 incidence and mortality and populations’ Zn sufficient level.[31] Insufficient data prevented two trials from confirming efficacy in COVID-19 cases.[37,38] According to one study,[27] zinc had no positive effects on the progression of COVID-19.

Discussion

SARS-CoV-2 infection rates with newer variations are still devastating most of the world after more than a year of the COVID-19 pandemic. High positive patient numbers are overwhelming the world’s healthcare systems. Many hospitalized patients’ COVID-19 mortality is caused by silent hypoxia, which is followed by rapid deterioration and, in some circumstances, septic shock. Understanding the interactions and linkages with human host components during pathogenesis and immune evasion tactics is urgently needed. Except for the Omicron variety, which requires a recent booster, acquired immunity through vaccination or earlier infection is currently sufficient to protect against the new SARS-CoV-2 variations. The severity of illness presentations and viral loads in new strains have both increased.[40]

Micronutrients include vitamins, minerals, trace elements, and other substances that affect the frequency and function of innate and adaptive immune cells, the production and development of virus-specific antibodies, the production of pro- and anti-inflammatory cytokines, the oxidative burst reaction, and other processes. These processes are involved in initiating, maintaining, and regulating host immune reactions to virus infections.[41]

The pathophysiology of COVID-19 is being linked more and more to iron excess. Indeed, a number of the symptoms of COVID-19, including inflammation, hypercoagulation, hyperferritinemia, and immunological dysfunction, are also evocative of iron excess. Even while iron is necessary for all living cells, it can be harmful because it contributes to the production of reactive oxygen species, which makes free unbound iron, which results from iron dysregulation and overload, particularly reactive (ROS).[42,43] Activating either acute or chronic inflammatory processes, which are linked to a number of clinical diseases, ROS interact with and destroy cellular lipids, nucleic acids, and proteins. Furthermore, ferroptosis, a recently identified non-apoptotic cell death, is directly caused by iron-catalyzed lipid degradation.[44] Unlike apoptosis, ferroptosis is immunogenic and, in addition to causing increased cell death, also encourages a number of inflammatory-related reactions. In therapeutic situations defined by iron overload, iron chelators have been shown to be generally safe and to protect patients.[42,45] Additionally, iron chelators’ antiviral properties are well supported by a wealth of evidence. In addition, the naturally occurring iron chelator lactoferrin (Lf) has anti-inflammatory and immunomodulatory properties. It can bind to a number of coronavirus receptors, preventing the entry of the virus into host cells. Thus, during the current COVID-19 pandemic, iron chelators may be highly helpful.[42,46]

Although there is a lot of info regarding the relationship between a patient’s zinc status and viral and respiratory tract infections, study evidence regarding COVID-19 is still lacking. However, it can be assumed based on previous reports and is discussed in this perspective, which focuses on how zinc supplementation can rebalance the immune system. Particularly, there has not been much discussion of the effect of zinc in virally produced vascular problems.[47] It is interesting to note that the majority of the COVID-19 risk groupings identified are also groups that have been linked to zinc deficiency.[48] Zinc deficiency can likely be added to the factors that predispose people to infection and the harmful progression of COVID-19 because zinc is necessary to maintain natural tissue barriers like the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, and for a healthy function of the immune system. Last but not least, it may be considered that administering zinc is advantageous for the majority of the population, particularly those with poor zinc status, due to its direct antiviral characteristics.[49,50]

Zinc’s capacity to prevent viral replication has been shown in numerous research. The common cold (typically a coronavirus variety), respiratory syncytial virus infections, cytomegalovirus infections, and herpes labialis are among these viruses. More crucially, zinc can stop the development of the SARS coronavirus (SARS-CoV) and the equine arteritis virus (EAV) in laboratory-grown cells. Zinc may help in the later stages of an infection by reducing the effects of immune system dysregulation, inflammation, and oxidative stress brought on by hypoxia.[51-53] Zinc controls immunological response, is anti-inflammatory, aids in the recovery of patients with severe pneumonia, and protects against hypoxia-induced ischemia reperfusion injury, according to numerous studies. Therefore, it has been suggested that zinc supplementation would be advantageous for COVID-19 patients given the possibility that zinc can target various pathways involved in the intricate pathophysiology of COVID-19 infection.[54-56]

Traditional research has connected vitamin D to healthy bones and calcium absorption. However, over the past ten years, it has become increasingly clear how important vitamin D is in controlling immune function and inflammation. Despite this important function, vitamin D deficiency is still common, affecting about 25% of US and Australian populations, as well as close to 40% of Canadian and European populations, with 25-hydroxyvitamin D (25(OH)D) levels below 50 nmol/L (the standard threshold for defining vitamin D deficiency).[57]

Vitamin D may play a complex and evolving function in the management or treatment of COVID-19. Vitamin D has the ability to affect the severity and results of COVID-19 via influencing a variety of immune system functions. SARS-CoV-2 infections cause the downregulation of ACE2, which results in a toxic buildup of Ang II and ultimately causes ARDS. The interactions between SARS-CoV-2 and the RAAS have been shown to be mitigated by vitamin D.[58] Vitamin D is able to stimulate the vasorelaxant ACE2/Ang-(1-7)/Mas receptor axis, which protects against acute lung injury and ARDS, as a negative endocrine regulator on the RAAS. By attaching to the VDR and blocking the production of renin-producing enzymes and proteins, vitamin D inhibits the biosynthesis of renin. It has also been demonstrated that vitamin D promotes ACE2 expression. There is data that suggests that differing expressions of ACE2, which generate a heightened and more robust immunological response in females, may be the reason for the differential presentation of COVID-19 between males and females (higher likelihood of ICU admissions and death in males).[59,60] At this point, it is established that ACE2 is expressed in higher amounts in males than in females, and the effect of ACE2 expression on COVID-19 severity is assessed.[61]

Conclusion

By rendering the virus effects and functioning as indicators for the severity, this study raised the idea of employing zinc, iron, and vitamin D as ingredients to either protect SARS-CoV-2 patients or to speed up recovery, decrease symptoms severity, and decrease mortality rates. Although there were some studies did not support the beneficial effects of these supplements in COVID-19 cases and some few others reported negative effects of these supplements, the vast majority of studies recommended their usage in COVID-19 management. Large-scale studies with larger sample size are recommended in this field.

Key points

• Primary care physicians are crucial in identifying SARS-CoV-2 infection and transferring suspected cases since they are on the front lines of health care. However, a primary care physician’s knowledge and attitude of their duty can affect how well they function.

• Iron supplementations induce better prognosis and prevention of COVID-19 infection.

• Zinc supplementations induce better prognosis and prevention of COVID-19 infection.

• Vit D supplementations induce better prognosis and prevention of COVID-19 infection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.