Advertisement
  • Loading metrics

Zinc against COVID-19? Symptom surveillance and deficiency risk groups

Zinc against COVID-19? Symptom surveillance and deficiency risk groups

  • Marcin P. Joachimiak
PLOS
x

Abstract

A wide variety of symptoms is associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and these symptoms can overlap with other conditions and diseases. Knowing the distribution of symptoms across diseases and individuals can support clinical actions on timelines shorter than those for drug and vaccine development. Here, we focus on zinc deficiency symptoms, symptom overlap with other conditions, as well as zinc effects on immune health and mechanistic zinc deficiency risk groups. There are well-studied beneficial effects of zinc on the immune system including a decreased susceptibility to and improved clinical outcomes for infectious pathogens including multiple viruses. Zinc is also an anti-inflammatory and anti-oxidative stress agent, relevant to some severe Coronavirus Disease 2019 (COVID-19) symptoms. Unfortunately, zinc deficiency is common worldwide and not exclusive to the developing world. Lifestyle choices and preexisting conditions alone can result in zinc deficiency, and we compile zinc risk groups based on a review of the literature. It is also important to distinguish chronic zinc deficiency from deficiency acquired upon viral infection and immune response and their different supplementation strategies. Zinc is being considered as prophylactic or adjunct therapy for COVID-19, with 12 clinical trials underway, highlighting the relevance of this trace element for global pandemics. Using the example of zinc, we show that there is a critical need for a deeper understanding of essential trace elements in human health, and the resulting deficiency symptoms and their overlap with other conditions. This knowledge will directly support human immune health for decreasing susceptibility, shortening illness duration, and preventing progression to severe cases in the current and future pandemics.

Introduction

At the moment, the pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is wreaking havoc worldwide. This is already the third instance of a coronavirus originating from a zoonotic reservoir and crossing into humans in the 21st century [1,2]. In fact, after the SARS epidemic in 2003/2004, researchers predicted further coronavirus epidemics as early as 2007 [3]. With an increasing world population and progressive urbanization, this is expected to continue. Multiple reports detailing the incidence and fatalities of the Coronavirus Disease (COVID-19) by age group indicate that older patients and those with preexisting underlying conditions are most at risk [49]. Newer results are showing that approximately half of infected individuals are asymptomatic [1012]. It is likely that many of these “asymptomatic” individuals present with subtle, transient, or symptoms not considered to be hallmarks of COVID-19 by the research community or the affected individual. In general, the human phenotype and disease symptom landscape is complex, including multifactorial effects of genetics and the environment, as well as differing severity and subfeatures of phenotypes. However, even if COVID-19 symptoms overlap or are masked by other conditions such as stress and insomnia, the large number of cases worldwide provides a rich dataset and opportunity for learning.

The SARS-CoV-2 virus has presented us with a major challenge to find effective ways to mitigate and ultimately end this pandemic. Epidemiological features, such as the relatively high transmission rates (R0 = approximately 2–3 [13,14]), the high frequency of asymptomatic cases [10,11], many different symptomatic presentations with unknown biomarkers and progression [15], and prolonged viral shedding in convalescents [16], all uniquely complicate this viral outbreak. A deficit of research on vaccines, infectious diseases, and their mechanisms, in particular for viral diseases, and a general lack of international and national collaborative frameworks for biomedical data and knowledge exchange have been contributing factors to slow the progress against COVID-19. Similarly, technological, social, and political difficulties have resulted in the limited availability, timeliness, and performance of reverse transcription PCR (RT-PCR) tests for presence of virus, serological tests for viral antigens, and antibody tests for host immune response. Given these challenges, one of the hopes is that individuals at higher risk of infection or progressing to severe cases can be identified early to improve healthcare management and clinical outcomes. Information on symptom grouping, overlaps, and progression can be leveraged to find associations and build models explaining even subsets of cases. Such knowledge and models can support symptom surveillance, triage for interventions, and predictions of patient outcomes in a more realistic manner, for example, considering symptom overlaps and potential mechanisms. Here, we consider COVID-19 and zinc deficiency, with their related symptoms as an example, and show that knowledge about symptom overlap and underlying mechanisms provides a needed path for enhanced risk mitigation and diagnosis during a pandemic.

COVID-19 symptoms versus human phenotypes related to zinc deficiency

Reports from healthcare workers on the front lines have identified a variety of human phenotypes that appear to be associated with SARS-CoV-2 infection, with new symptoms being recognized over time [17]. Symptoms of severe cases of COVID-19 appear to be better characterized and more consistent, accounting for roughly 20% of cases [18,19]. On the other hand, symptoms for milder cases appear to show greater variation, as expected for the larger number of individuals who present as a mild or “asymptomatic” COVID-19 disease [18,19]. These data are still being collected and reviewed. However, there are multiple mobile symptom tracking efforts that should help standardize the collection and deployment of this important knowledge, even when it is being reported directly by patients or healthcare workers (e.g., https://covid.joinzoe.com/us, https://www.apple.com/covid19/, https://coronavirus.health.ok.gov/symptom-tracker, and https://intermountainhealthcare.org/covid19-coronavirus/covid19-symptom-checker/). We believe that many COVID-19 cases described as “asymptomatic” may be harboring subtle and/or transient symptoms, some of which may be difficult for an individual to notice or report. In other cases, they may also present with noticeable symptoms that overlap or are masked by other conditions. For example, among reported COVID-19 symptoms, there is a growing number of anecdotal reports of asymptomatic or mild cases associated with a decrease or loss of sense of smell and/or taste [2025]. Recently, it was confirmed that 87% of mild to moderate COVID-19 cases exhibited a loss of smell [26]. These symptoms correspond to the human phenotypes of hyposmia (reduced ability to smell), anosmia (loss of ability smell), dysgeusia (distortion of taste), and ageusia (loss of taste). These sensory symptoms have been known to occur post-viral infection and are usually associated with viral infection of the nasal passages and sinusitis [22]. With over 51 million infected individuals as of November 10, 2020 [27], congestion is one of the many possible COVID-19 symptoms [28]. Recently, it has been shown that sensory neurons are not a likely target for SARS-CoV-2 due to lack of angiotensin-converting enzyme 2 (ACE2) expression [29]. Nevertheless, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons and in certain populations of stem cells and blood vessel cells [29]. This finding suggests a potential mechanism for the disruption of olfactory signaling in COVID-19 via neuron-supporting cells.

Symptoms can overlap between different human conditions or diseases and individuals can present with different symptoms for the same condition or disease. COVID-19 appears especially challenging in this regard due to the large variety of symptoms and organs involved [15,30]. Dedicated funding and research efforts are needed so we can learn these distributions of symptoms and their context across the landscape of diseases and individual patient cases. The new COVID-19 mobile symptom tracking apps are one example fitting into this effort, and another are newly established public consortia aiming to harmonize data across institutions [31]. Data and resulting knowledge from these efforts will help to identify actionable information in support of disease surveillance, diagnosis, and clinical outcome management.

One example of a rich collection of human symptoms collected across populations and time are those related to specific nutritional deficiencies. An important focus for COVID-19 is immune activity and health, which is often linked to zinc [32,33]. There are a number of zinc deficiency symptoms, including developmental growth retardation, hypogonadism, cognitive impairment [34], loss of appetite, impaired immune function, and also potentially hair loss, diarrhea, impotence, eye and skin lesions, delayed healing of wounds, the aforementioned taste abnormalities, and mental lethargy [35]. Many of these symptoms overlap with symptoms known to occur during viral infections as well as other diseases.

An intriguing set of overlapping symptoms has to do with loss of taste and smell perception. Gustatory dysfunction is most commonly associated with allergic rhinitis, chronic rhinosinusitis, and upper respiratory infection [36,37], the latter two involving infections and all three involving inflammatory immune response. There have also been multiple reports linking the loss of taste or smell to zinc deficiency, either due to chemotherapy and metal chelating agents [3840], or due to nutritional deficiencies, especially in older populations [41,42], also caused by medical procedures such as dialysis [43]. As a result, zinc has been proposed in the treatment of taste disorders [44,45]; however, zinc supplementation for chemotherapy-induced loss of smell or taste, which is often transient, has not led to improvements in this condition [38,39].

We know that cellular inflammation causes cellular loss of zinc [46,47] and conversely that zinc deficiency leads to increased inflammation [48]. However, the mechanism by which zinc deficiency causes loss of smell or taste is unknown, making it difficult to design effective therapies. While it may be unlikely that COVID-19–related changes in smell or taste perception are related to zinc deficiency, recent data suggest a possible indirect link through reduced odorant receptor levels in response to innate immune signaling [49]. Intriguingly, it has been proposed that olfactory receptor neurons may initiate rapid immune responses at early stages of disease [50], which would be consistent with functional coevolution of human immune response with viral disease vectors associated with early detection at viral entry points into the body. Combined with known effects of inflammation leading to loss of cellular zinc, a testable hypothesis emerges regarding a sustained and massive immune response resulting in depletion of zinc levels. For COVID-19 specifically, this is further supported by symptoms known to enhance risk for zinc deficiency including sweating, loss of appetite, vomiting, diarrhea, inflammation, and increased metabolic demands due to oxygen deficiency. One problem in COVID-19 research, and more broadly emerging diseases, is the large number of proposed hypotheses with varying support and lacking clear and accessible avenues for validation. The potential loss of olfactory perception via zinc deficiency can be directly tested by monitoring zinc levels and tracking sensory perception improvements in response to supplementation. This would allow to rule out spurious symptom overlaps and with the additional benefit of identifying cases of zinc deficiency during a critical period for optimal immune health.

Zinc is essential for human immune function and activity against infectious pathogens

Zinc is an essential trace element for all kingdoms of life [51]. It is even involved as a structural ligand in recently solved SARS-CoV-2 crystal structures including for proteins considered as primary drug targets: the main protease [52,53]; RNA-dependent RNA polymerase [54]; the papain-like protease [55]; nonstructural protein 10 (NSP10) [56]; and the complex of NSP12, NSP7, and NSP8 [57]. After iron, zinc is the second most common trace element found in the human body. It plays multiple roles in human biology, predicted to be involved in >10% of human proteins [58], including special roles in the immune system. The importance of zinc for the immune system has been reviewed elsewhere [3234,5971]. Briefly, zinc is important for the skin’s barrier functionality, for gene regulation in lymphocytes, and for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells [60]. The broad impact of zinc on key features of human immunology is based on the panoply of roles for zinc, including in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation, and related to potentiation of apoptosis, as well as antioxidant and membrane stabilizing properties. Perhaps most relevant to COVID-19, severe zinc deficiency causes lymphopenia and increased apoptosis of lymphocytes [72], effectively leading to a form of immunodeficiency. Additionally related to symptoms of severe COVID-19, zinc is a known anti-inflammatory agent and decreases production of inflammatory cytokines and oxidative stress biomarkers [73]. There is also evidence that zinc levels are involved in a negative feedback loop controlling immune response via nuclear factor kappa B (NF-κB), implicating zinc deficiency in sepsis and excessive inflammation [74]. Nevertheless, we know relatively little about the hierarchical importance and interdependencies of trace elements for human health and disease, warranting more studies and enhanced data collection.

COVID-19: Immune health and zinc deficiency risk groups

How might this be relevant to the novel SARS-CoV-2 virus, a human pathogen to which we are exposed for the first time in history? A recent review focused on the role of zinc supplementation for COVID-19, mostly regarding promising direct antiviral effects which unfortunately still lack clinical data [61]. Others have mentioned zinc along with other supplementation as an adjunct therapy to support immune health [62,7582]. Even in mild COVID-19 cases, our immune response is acting to recognize, neutralize, and clear viral particles, and with increasing disease severity, these responses are intensified or perhaps short-circuited [83]. For severe COVID-19 cases, this may eventually lead to Acute Respiratory Distress Syndrome (ARDS) amid serious side effects caused by the body’s own immune system. However, even for mild cases, there are reports of the infection occurring in cycles where people feel alternately better and then worse [84], likely due to cycles of viral replication, estimated to be about 10 hours [44], and possibly also due to waves of host immune response. Furthermore, SARS-CoV-2 infection appears to have a prolonged incubation period and disease course even for mild cases [85], elevating the importance of interventions which can shorten infectivity and duration. As mentioned earlier, COVID-19 symptoms include multiple additional risks for zinc deficiency, which may exacerbate existing risk groups. Elderly [63] and nutritionally challenged populations are known to have higher rates of zinc deficiency [86], which has been associated with poor outcomes for pneumonia [87,88]. Interestingly, over-supplementing zinc can also cause loss of smell or taste, apparently associated with nasal applications of zinc (now discontinued [8993]). Assuming no zinc deficiency, the daily Food and Drug Administration (FDA) tolerable upper limit (TUL) dose of zinc is <40 mg, while the Recommended Daily Allowance (RDA) is 8 mg for women and 11 mg for men, for persons 18 years or older [35]. However, many available supplements have multiple times the RDA amount [94], while others do not contain this essential trace element at all.

Zinc deficiency is known to impact immune function resulting in an increased susceptibility to infections [32,33]. Some aspects of zinc supplementation are well studied, although studies of effects on the duration of the common cold have been inconclusive, perhaps because of improper dosing, timing, or delivery route [95]. Multiple human trials have shown conflicting evidence for zinc supplementation improving outcomes in patients with pneumonia. In some cases, zinc supplementation shortened the duration of viral infections and improved outcomes in children with lower respiratory infections [60,9698] but not in others [99], and even in some cases for elderly patients with pneumonia [100] but not in others [52]. In addition to undernourished children and the elderly, vegan and vegetarian populations are particularly susceptible to zinc deficiency, as plant-based diets will contain more phytates which are known to interfere with zinc bioabsorption [44,45,101,102]. As a result, vegetarians are recommended to increase their RDA amount by 50% [103] and use techniques for increasing zinc bioavailability such as soaking and sprouting grains and seeds [104,105]. In addition, the main dietary sources of zinc are certain seafood (oysters (673%), crab (49%), lobster (31%)), beef (64%), and chicken (22%), with only beans (26%) and pumpkin seeds (20%) providing strict vegetarians with significant amounts (percentages are FDA daily value per serving) [35]. This may also suggest that people who eat more meat and seafood are less likely to suffer from zinc deficiency and may potentially have more robust immune systems, consistent with some reports of immune system problems in vegetarians [106,107]. However, phytates are common in cereal grains; thus, zinc malabsorption effects are likely to extend across a wide range of diets [102]. These dietary effects may be masked or enhanced by genotype and local environmental effects, but should be considered in multifactorial analysis of COVID-19 susceptibility and clinical outcomes.

Unfortunately, zinc deficiency is common in the developing world, with over 2 billion affected individuals [108]. It is less well known that more moderate zinc deficiencies are observed in many regions worldwide [86]. Therefore, minimally, in the case of the elderly, immunocompromised, or undernourished populations, existing data supports the hypothesis that zinc supplementation during the SARS-CoV-2 pandemic would be a safe, inexpensive, and adjunct treatment to reduce the risk of infection and severe disease progression. We highlight populations and groups at risk of zinc deficiency in Table 1 and note that these risk factors may frequently compound, e.g., nutritional deficiency combined with preexisting conditions or environmental exposure. Not all zinc deficiency mechanisms are known, and we list what are considered to be known causes. Some multivitamins supplements lack zinc because the flavor of zinc is considered unpleasant [104]; thus, even people who regularly take supplements may have insufficient zinc levels.

There also exist dependencies, which are not fully understood, with other essential nutrients, such as vitamin D3, which is thought to regulate homeostasis of some trace elements including zinc [134]. A recent study also showed benefits of vitamin D supplementation for suppression of COVID-19 cytokine storm [135]. However, newer research is revealing that it may be severe immunosuppression and not cytokine storm that is the characteristic of COVID-19 [136], leading to immune enhancement as a focus of therapy. As more studies are performed and hypothesis tested, we may learn whether such potentially conflicting results are due to missing context or misled hypothesis. To this end, nutritional deficiency risk groups with their associated mechanisms or features can aid in studies and analysis by providing a source of categorized factors. Such factors can be linked to clinical and epidemiological data and thus enhance the granularity and explanatory power of statistical analysis or machine learning results.

Strategies for zinc supplementation and monitoring in COVID-19

While zinc is relatively nontoxic, its excess can cause malabsorption of other elements (e.g., copper [137]). In addition, there are a number of known drug interactions with zinc, the most severe being with two HIV inhibitors raltegravir and elvitegravir, along with 32 more moderate interactions [138]. Excess zinc is excreted, hence the continual need for dietary and supplementary sources including supplementing daily with repeated smaller doses. These are some crucial considerations to determine and monitor proper zinc supplementation regimens. Thus, rational nutritional supplementation should take into account dynamic changes such as those due to symptoms associated with enhanced risk for specific deficiencies (e.g., sweating or diarrhea leading to increased loss of zinc), tuned to the expected context for a specific disease such as COVID-19.

While we may not know the optimal zinc supplementation for an individual in the context of COVID-19, supplementation in the context of nutritional deficiency has been demonstrated to offer many positive outcomes for the immune system and specifically the ability to resist infectious pathogens [60, 139146]. However, it is important to distinguish between chronic zinc deficiency in contrast to zinc deficiency acquired upon viral infection, since different monitoring and supplementation strategies are required. The former requires prophylactic therapy to correct a nutritional deficiency and improve immune health, likely resulting in lower infection rates and less severe disease progression. The latter is an adjunct therapy, used to maintain immune health during viral infection, and requiring careful monitoring and dynamic interventions in response to, for example, episodes of symptoms known to lead to zinc deficiency (e.g., sweating or diarrhea).

Unfortunately, current zinc clinical measurements do not accurately reflect intracellular zinc levels [147]. Monitoring zinc levels is complicated by the fact that zinc is distributed as a cofactor across a wide range of macromolecules [148]. However, even if there is no accepted biomarker for zinc deficiency [149], zinc levels can be easily, if not necessarily very accurately, monitored using blood serum, washed scalp hair, urine, saliva, and fingernails [150]. Performing multiple zinc assay types should be considered to improve accuracy. Even if these measurements do not reflect well the intracellular concentration, they provide a relative measure of zinc levels and thus can help assess supplementation effects. The question of optimal and nontoxic levels of zinc will need to be addressed on a per patient basis. Going forward, nutritional status and supplementation effects of key nutrients should be considered a vital component of all personalized health initiatives.

Current status of zinc supplementation and therapies for COVID-19

Despite the unprecedented speed of research and clinical trials for new antiviral drugs and symptom treatments for COVID-19, which are also occurring in parallel with vaccine development efforts, the timeframe for being able to produce results with confidence may unfortunately still be measured in years. As of August 28, 2020, there are at least 12 ongoing or proposed clinical trials in the United States for COVID-19 that involve zinc as either a preventative or combination therapy [151]. There is an intriguing mechanistic hypothesis that providing zinc along with zinc ionophores as antiviral therapy may lead to a combined beneficial effect [152156]. There has been one case study report describing beneficial effects of zinc supplementation for COVID-19 progression [157], and more recently, the first in vivo evidence of zinc supplementation for better COVID-19 outcomes [158]. It has also been reported that COVID-19 patients had significantly lower zinc levels compared with healthy individuals, and this was associated with a greater than 5-fold increased likelihood of developing complications [159]. Since supplementation strategies will be different for preexisting zinc deficiency versus a deficiency acquired during SARS-CoV-2 infection, with acute deficiency during viral infection requiring active monitoring and interventions, it is important to distinguish these cases and their combination.

Accelerating literature analysis: Toward automating nutritional deficiency risk tables

The rate of published research related to COVID-19 has been at the unprecedented level of thousands of papers per week [160]. This is in addition to the already available biomedical literature on, for example, related viruses. Moreover, many aspects of human health are complex and multifactorial with interdependencies between genetics, environment, nutrition, life course, and lifestyle, to name a few factors. Given this volume of knowledge and expected complexities, future efforts will need to make use of computational approaches such as natural language processing (NLP) to provide more machine-friendly compilations of knowledge for public health. These methods encompass automatic concept recognition from literature supported by existing ontologies and vocabularies [161], as well as discovery of similar and related literature concepts by learning vector representations [161,162]. The application of these tools would allow to more efficiently create updatable nutritional deficiency risk tables outlining specific susceptible groups and potential mechanisms, across a wide range of important molecules important for human nutrition. This research direction can contribute to harnessing the available knowledge in literature to better expose complex biological relationships, such as between trace elements, nutritional deficiencies, and aspects of immune health. An effective organization of our existing scientific knowledge, and in particular capabilities of linking to new data, would be a significant advance for combating pandemics caused by a novel species.

Conclusions

Current estimates are that 40% to 70% individuals worldwide will become infected over the course of this pandemic in the absence of strong mitigation efforts [163]. We believe that there is a critical need for research and guidance on enhancing baseline human health and specifically the function of the human immune system for individuals worldwide. So far, there have only been limited reports of providing immunity-enhancing supplementation and neither included zinc: one was for National Health Service (NHS) healthcare workers [164] and another for COVID-19 patients over 50 years of age in Singapore [165]. Based on an extensive review of the existing literature presented here, zinc should be included as part of preventative supplementation for COVID-19 and in general for support of immune health. Even given the limited clinical data on zinc as an adjunct therapy for COVID, based on its known safety and limited drug interactions, zinc supplementation should also be considered in the context of zinc deficiency acquired during a viral infection and host immune response.

Healthy individuals with a robust immune system have clearly a better starting point for the difficult COVID-19 viral infection, with expected positive effects on clinical outcomes such as shortening the duration of even just the sub-severe cases. This, in parallel with other efforts and interventions, is likely to decrease the number of severe COVID-19 cases overall, due to a more robust immune response in the population. This is especially critical for vulnerable populations, also in developed countries [166], where safe and cheap interventions are desperately needed. Our limited testing capability for virus presence and the resulting symptom triage for performing a test (e.g. fever, shortness of breath) can potentially delay treatment and increase the number of severe cases. Therefore, actions focused on understanding and improving the human immune system are a critical step to help mitigate negative outcomes. At this point in the pandemic, an important goal is shortening the illness duration and decreasing the risk of severe disease, to alleviate pressures on healthcare systems and ultimately achieve widespread immunity to SARS-CoV-2 in the human population. These strategies will be highly relevant for future emerging viral and other pathogens.

Methods

Literature searches were performed using the PubMed, Google Scholar, and COVIDscholar [167] literature search engines. For zinc in the context of COVID, we based literature search results on COVIDscholar, which returned 241 articles, documents, and clinical trials for zinc related to COVID-19 (September 17, 2020). We supplemented these searches with PubMed and Google Scholar (September 17, 2020). Clinical trials for COVID-19 involving zinc were obtained from the National Institutes of Health (NIH) clinical trials site [168]. For informing specific sections of the manuscript and construction of Table 1, the following queries were performed: “zinc deficiency,” zinc AND nutrition, zinc AND aging, zinc AND immune, zinc AND antiviral, zinc AND virus, zinc AND infection, zinc AND pneumonia, zinc AND “drug interactions.” All searches were performed between July 2 and November 9, 2020. Query results were curated by selecting the most recent publications and removing redundancy, as well as articles with fewer citations or from lower impact journals.

Key Learning Points

  • Zinc is the second most abundant essential trace element in the human body with critical roles in immune health and response to infectious diseases.
  • Zinc deficiency is common even in the developed world and risks for deficiency can compound.
  • Overlap between symptoms in different conditions, for example, a nutritional deficiency versus Coronavirus Disease 2019 (COVID-19), can be used to suggest clinical tests, diagnosis, and triage interventions.
  • Zinc provides a safe and cheap alternative to enhance immunity worldwide, both to correct chronic nutritional deficiencies and to address acute deficiencies resulting from a viral infection and host immune response.

Top Five Papers

  1. Heyneman CA. Zinc deficiency and taste disorders. Ann Pharmacother. 1996;30:186–187.
  2. Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. 2017;9.
  3. Baum MK, Lai S, Sales S, Page JB, Campa A. Randomized, controlled clinical trial of zinc supplementation to prevent immunological failure in HIV-infected adults. Clin Infect. Dis. 2010;50:1653–1660.
  4. Carlucci PM, Ahuja T, Petrilli C, Rajagopalan H, Jones S, Rahimian J. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. J Med Microbiol. 2020;69:1228–1234.
  5. Jothimani D, Kailasam E, Danielraj S, Nallathambi B, Ramachandran H, Sekar P, et al. COVID-19: Poor outcomes in patients with Zinc deficiency. Int J Infect Dis. 2020.

Acknowledgments

We would like to thank Emily Ho, Maureen Hoatlin, Melissa A. Haendel, Nomi L. Harris, Lauren E. Chan, Nicole A. Vasilevsky, Monica Munoz-Torres, and Chris J. Mungall for discussion, suggestions, and editing.

References

  1. 1. Ye Z-W, Yuan S, Yuen K-S, Fung S-Y, Chan C-P, Jin D-Y. Zoonotic origins of human coronaviruses. Int J Biol Sci. 2020;16:1686–97. pmid:32226286
  2. 2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med. 2020;26:450–2. pmid:32284615
  3. 3. Cheng VCC, Lau SKP, Woo PCY, Yuen KY. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev. 2007;20:660–94. pmid:17934078
  4. 4. Wu C, Chen X, Cai Y, Jia’an X, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020. pmid:32167524
  5. 5. Mao R, Liang J, Shen J, Ghosh S, Zhu L-R, Yang H, et al. Implications of COVID-19 for patients with pre-existing digestive diseases. Lancet Gastroenterol Hepatol. 2020;5:426–8. pmid:32171057
  6. 6. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan. China JAMA Cardiol. 2020. pmid:32211816
  7. 7. Emami A, Javanmardi F, Pirbonyeh N, Akbari A. Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2020;8:e35. pmid:32232218
  8. 8. Du R-H, Liang L-R, Yang C-Q, Wang W, Cao T-Z, Li M, et al. Predictors of Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective Cohort Study. Eur Respir J. 2020. pmid:32269088
  9. 9. Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe disease and death. BMJ. 2020:m1198. pmid:32217618
  10. 10. Nishiura H, Kobayashi T, Suzuki A, Jung S-M, Hayashi K, Kinoshita R, et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). Int J Infect Dis. 2020. pmid:33303095
  11. 11. Day M. Covid-19: identifying and isolating asymptomatic people helped eliminate virus in Italian village. BMJ. 2020;368:m1165. pmid:32205334
  12. 12. Day M. Covid-19: four fifths of cases are asymptomatic. China figures indicate. BMJ. 2020;369:m1375. pmid:32241884
  13. 13. Sanche S, Lin YT, Xu C, Romero-Severson E, Hengartner N, Ke R. High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2. Emerg Infect Dis. 2020;26. pmid:32255761
  14. 14. D'Arienzo M, Conigliob A. Assessment of the SARS-CoV-2 basic reproduction number, R0, based on the early phase of COVID-19 outbreak in Italy. Biosafety and Health. 2020 [cited 9 May 2020]. pmid:32835209
  15. 15. Sudre CH, Lee K, Lochlainn MN, Varsavsky T, Murray B, Graham MS, et al. Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app. MedRxiv 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.06.12.20129056v1?rss=1%22.
  16. 16. Hartman WR, Hess AS, Connor J. Prolonged viral RNA shedding after COVID-19 symptom resolution in older convalescent plasma donors.
  17. 17. Website. [cited 18 Jun 2020]. Available from: “Coronavirus Disease 2019 (COVID-19) CDC—Symptoms of Coronavirus.” n.d. Accessed June 18, 2020. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html.
  18. 18. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.
  19. 19. Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020. pmid:32109013
  20. 20. Kwong E, Aubrey A, Godoy M. Is Loss Of Smell And Taste A Symptom Of COVID-19? Doctors Want To Find Out. NPR. 26 Mar 2020. Available from: https://www.npr.org/sections/goatsandsoda/2020/03/26/821582951/is-loss-of-smell-and-taste-a-symptom-of-covid-19-doctors-want-to-find-out. Accessed 24 Apr 2020.
  21. 21. Menni C, Valdes A, Freydin MB, Ganesh S, El-Sayed Moustafa J, Visconti A, et al. Loss of smell and taste in combination with other symptoms is a strong predictor of COVID-19 infection. Epidemiology medRxiv. 2020.
  22. 22. Machado C, Gutierrez JV. Anosmia and Ageusia as Initial or Unique Symptoms after SARS-COV-2 Virus Infection. Medicine & Pharmacology. 2020.
  23. 23. Eliezer M, Hautefort C, Hamel A-L, Verillaud B, Herman P, Houdart E, et al. Sudden and Complete Olfactory Loss Function as a Possible Symptom of COVID-19. JAMA Otolaryngol Head Neck Surg. 2020. pmid:32267483
  24. 24. Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. 2020. pmid:32215618
  25. 25. Lao WP, Imam SA, Nguyen SA. Anosmia, hyposmia, and dysgeusia as indicators for positive SARS-CoV-2 infection. World J Otorhinolaryngol Head Neck Surg. 2020. pmid:32313712
  26. 26. Lechien JR, Chiesa-Estomba CM, Hans S, Barillari MR, Jouffe L, Saussez S. Loss of Smell and Taste in 2013 European Patients With Mild to Moderate COVID-19. Ann Intern Med. 2020. pmid:32449883
  27. 27. JHU CSSE COVID-19 Dashboard. [cited 28 Apr 2020]. Available from: https://coronavirus.jhu.edu/map.html
  28. 28. CDC COVID-19 symptoms. [cited 28 Apr 2020]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html
  29. 29. Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfaory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020:eabc5801. pmid:32937591
  30. 30. Prates ET, Garvin MR, Pavicic M, Jones P, Shah M, Alvarez C, et al. Confronting the COVID-19 Pandemic with Systems Biology. bioRxiv. 2020. p. 2020.04.06.028712.
  31. 31. Melissa H, Christopher C, Kenneth G. The National COVID Cohort Collaborative (N3C): Rationale, Design, Infrastructure, and Deployment. J Am Med Inform Assoc. 2020. pmid:32805036
  32. 32. Wessels I, Maywald M, Rink L. Zinc as a Gatekeeper of Immune Function. Nutrients. 2017;9. pmid:29186856
  33. 33. Maares M, Haase H. Zinc and immunity: An essential interrelation. Arch Biochem Biophys. 2016;611:58–65. pmid:27021581
  34. 34. Prasad AS. Impact of the discovery of human zinc deficiency on health. J Trace Elem Med Biol. 2014;28:357–63. pmid:25260885
  35. 35. NIH Office of Dietary Supplements. NIH Office of Dietary Supplements Zinc fact sheet. [cited 2020]. Available from: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
  36. 36. Maheswaran T, Abikshyeet P, Sitra G, Gokulanathan S, Vaithiyanadane V, Jeelani S. Gustatory dysfunction. J Pharm Bioallied Sci. 2014;6:S30–3. pmid:25210380
  37. 37. Malaty J, Malaty IAC. Smell and taste disorders in primary care. Am Fam Physician. 2013;88:852–9. pmid:24364550
  38. 38. Lyckholm L, Heddinger SP, Parker G, Coyne PJ, Ramakrishnan V, Smith TJ, et al. A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders. J Pain Palliat Care Pharmacother. 2012;26:111–4. pmid:22764846
  39. 39. Henkin RI, Schecter PJ, Friedewald WT, Demets DL, Raff M. A double blind study of the effects of zinc sulfate on taste and smell dysfunction. Am J Med Sci. 1976;272:285–99. pmid:797259
  40. 40. Ripamonti C, Zecca E, Brunelli C, Fulfaro F, Villa S, Balzarini A, et al. A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer. 1998;82:1938–45. pmid:9587128
  41. 41. Pisano M, Hilas O. Zinc and Taste Disturbances in Older Adults: A Review of the Literature. Consult Pharm. 2016;31:267–70. pmid:27178656
  42. 42. Heyneman CA. Zinc deficiency and taste disorders. Ann Pharmacother. 1996;30:186–7. pmid:8835055
  43. 43. Atkin-Thor E, Goddard BW, O’Nion J, Stephen RL, Kolff WJ. Hypogeusia and zinc depletion in chronic dialysis patients. Am J Clin Nutr. 1978;31:1948–51. pmid:707353
  44. 44. Bar-On YM, Flamholz A, Phillips R, Milo R. SARS-CoV-2 (COVID-19) by the numbers. elife. 2020. pmid:32228860
  45. 45. Yagi T, Asakawa A, Ueda H, Ikeda S, Miyawaki S, Inui A. The role of zinc in the treatment of taste disorders. Recent Pat Food Nutr Agric. 2013;5:44–51. pmid:23305423
  46. 46. Costarelli L, Muti E, Malavolta M, Cipriano C, Giacconi R, Tesei S, et al. Distinctive modulation of inflammatory and metabolic parameters in relation to zinc nutritional status in adult overweight/obese subjects. J Nutr Biochem. 2010;21:432–7. pmid:19427184
  47. 47. Olechnowicz J, Tinkov A, Skalny A, Suliburska J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci. 2018;68:19–31. pmid:28965330
  48. 48. Wong CP, Rinaldi NA, Ho E. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Mol Nutr Food Res. 2015;59:991–9. pmid:25656040
  49. 49. Rodriguez S, Cao L, Rickenbacher GT, Benz EG, Magdamo C, Ramirez Gomez LA, et al. Innate immune signaling in the olfactory epithelium reduces odorant receptor levels: modeling transient smell loss in COVID-19 patients. medRxiv. 2020. pmid:32587994
  50. 50. Butowt R, Bilinska K. SARS-CoV-2: Olfaction, Brain Infection, and the Urgent Need for Clinical Samples Allowing Earlier Virus Detection. ACS Chem Neurosci. 2020:1200–3. pmid:32283006
  51. 51. Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and human health: an update. Arch Toxicol. 2012:521–34. pmid:22071549
  52. 52. Sharafi S, Allami A. Efficacy of zinc sulphate on in-hospital outcome of community-acquired pneumonia in people aged 50 years and over. Int J Tuberc Lung Dis. 2016;20:685–8. pmid:27084825
  53. 53. 6yt8. [cited 9 May 2020]. Available from: https://www.rcsb.org/structure/6yt8
  54. 54. 7btf. In: https://www.rcsb.org/structure/7btf.
  55. 55. 6w9c. [cited 9 May 2020]. Available from: https://www.rcsb.org/structure/6w9c
  56. 56. 2fyg. [cited 9 May 2020]. Available from: https://www.rcsb.org/structure/2fyg
  57. 57. 6nur. [cited 9 May 2020]. Available from: https://www.rcsb.org/structure/6nur
  58. 58. Andreini C, Banci L, Bertini I, Rosato A. Counting the zinc-proteins encoded in the human genome. J Proteome Res. 2006;5:196–201. pmid:16396512
  59. 59. Ibs K-H, Rink L. Zinc-altered immune function. J Nutr. 2003;133:1452S–6S. pmid:12730441
  60. 60. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998;68:447S–63S. pmid:9701160
  61. 61. Skalny AV, Rink L, Ajsuvakova OP, Aschner M, Gritsenko VA, Alekseenko SI, et al. Zinc and respiratory tract infections: Perspectives for COVID-19 (Review). Int J Mol Med. 2020. pmid:32319538
  62. 62. Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C, Ranasinghe P. Enhancing immunity in viral infections, with special emphasis on COVID-19: A review. Diabetes Metab Syndr. 2020;14:367–82. pmid:32334392
  63. 63. Mocchegiani E, Romeo J, Malavolta M, Costarelli L, Giacconi R, Diaz L-E, et al. Zinc: dietary intake and impact of supplementation on immune function in elderly. Age. 2013;35: 839–860. pmid:22222917
  64. 64. Prasad AS. Zinc and Immunity. Biochemistry of Zinc. 1993:165–92. _9
  65. 65. Haase H, Rink L. Zinc and Immunity. Encyclopedia of Metalloproteins. 2013:2375–80. _213
  66. 66. Prasad A. Zinc, Health, and Immunity. Metabolic Medicine and Surgery. 2014:579–94.
  67. 67. Shetty P. Zinc deficiency and infections. Nutrition, immunity and infection:101–13.
  68. 68. Haase H. An Element of Life: Competition for Zinc in Host-Pathogen Interaction. Immunity. 2013:623–4. pmid:24138875
  69. 69. Hirano T, Murakami M, Fukada T, Nishida K, Yamasaki S, Suzuki T. Roles of Zinc and Zinc Signaling in Immunity: Zinc as an Intracellular Signaling Molecule. Adv Immunol. 2008:149–76. pmid:18501770
  70. 70. Gammoh NZ, Rink L. Zinc and the Immune System. Nutrition and Immunity. 2019:127–58.
  71. 71. Kloubert V, Rink L. Zinc Regulation of the Immune Response. Nutrition, Immunity, and Infection. 2017:245–78.
  72. 72. Kolenko VM, Uzzo RG, Dulin N, Hauzman E, Bukowski R, Finke JH. Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes. Apoptosis. 2001;6:419–29. pmid:11595831
  73. 73. Prasad AS. Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health. Front Nutr. 2014;1:14. pmid:25988117
  74. 74. Liu M-J, Bao S, Gálvez-Peralta M, Pyle CJ, Rudawsky AC, Pavlovicz RE, et al. ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Rep. 2013;3:386–400. pmid:23403290
  75. 75. Alschuler L, Weil A, Horwitz R, Stamets P, Chiasson AM, Crocker R, et al. Integrative considerations during the COVID-19 pandemic. Explore. 2020. pmid:32229082
  76. 76. Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence. 2020 [cited 4 May 2020]. pmid:32256705
  77. 77. Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol. 2020:479–90. pmid:32052466
  78. 78. Zhang J, Xie B, Hashimoto K. Current status of potential therapeutic candidates for the COVID-19 crisis. Brain Behav Immun. 2020. pmid:32334062
  79. 79. Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020;395:e35–6. pmid:32035018
  80. 80. Adams KK, Baker WL, Sobieraj DM. Myth Busters: Dietary Supplements and COVID-19. Ann Pharmacother. 2020;54:820–6. pmid:32396382
  81. 81. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections. Nutrients. 2020;12. pmid:32340216
  82. 82. de Faria C-RC, Corgosinho FC, Sanches FLFZ, Prado CMM, Laviano A, Mota JF. Dietary recommendations during the COVID-19 pandemic. Nutr Rev. 2020. pmid:32653930
  83. 83. Arunachalam PS, Wimmers F, Mok CKP, Perera RAPM, Scott M, Hagan T, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 2020;369: 1210–20. pmid:32788292
  84. 84. Chen J, Qi T, Liu L, Ling Y, Qian Z, Li T, et al. Clinical progression of patients with COVID-19 in Shanghai, China J Infect 2020;80: e1–e6. pmid:32171869
  85. 85. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med 2020. pmid:32150748
  86. 86. Wessells KR, Brown KH. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS One 2012;7: e50568. pmid:23209782
  87. 87. Barnett JB, Hamer DH, Meydani SN. Low zinc status: a new risk factor for pneumonia in the elderly? Nutr Rev 2010;68: 30–37. pmid:20041998
  88. 88. Brooks WA, Yunus M, Santosham M, Wahed MA, Nahar K, Yeasmin S, et al. Zinc for severe pneumonia in very young children: double-blind placebo-controlled trial. Lancet 2004;363: 1683–1688. pmid:15158629
  89. 89. Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol 2004;18: 137–141. pmid:15283486
  90. 90. Tisdall FF, Brown A, Defries RD. Persistent anosmia following zinc sulfate nasal spraying. J Pediatr 1938;13: 60–62.
  91. 91. DeCook CA, Hirsch AR. Anosmia due to inhalational zinc: a case report. Chem Senses 2000;25: 659.
  92. 92. Alexander TH, Davidson TM. Intranasal Zinc and Anosmia: The Zinc-Induced Anosmia Syndrome. Laryngoscope. 2006:217–220. pmid:16467707
  93. 93. Davidson TM, Smith WM. The Bradford Hill criteria and zinc-induced anosmia: a causality analysis. Arch Otolaryngol Head Neck Surg 2010;136: 673–676. pmid:20644061
  94. 94. Offit P. The Vitamin Myth: Why We Think We Need Supplements. The Atlantic. 19 Jul 2013. Available from: https://www.theatlantic.com/health/archive/2013/07/the-vitamin-myth-why-we-think-we-need-supplements/277947/. Accessed 27 Apr 2020.
  95. 95. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2013; CD001364. pmid:23775705
  96. 96. Qasemzadeh MJ, Fathi M, Tashvighi M, Gharehbeglou M, Yadollah-Damavandi S, Parsa Y, et al. The effect of adjuvant zinc therapy on recovery from pneumonia in hospitalized children: a double-blind randomized controlled trial. Scientifica. 2014;2014: 694193. pmid:24955282
  97. 97. Bhandari N, Bahl R, Taneja S, Strand T, Mølbak K, Ulvik RJ, et al. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ 2002;324: 1358. pmid:12052800
  98. 98. Brown KH, Hess SY, Vosti SA, Baker SK. Comparison of the Estimated Cost-Effectiveness of Preventive and Therapeutic Zinc Supplementation Strategies for Reducing Child Morbidity and Mortality in Sub-Saharan Africa. Food Nutr Bull. 2013:199–214. pmid:23964393
  99. 99. Bose A, Coles CL, Gunavathi, John H, Moses P, Raghupathy P, et al. Efficacy of zinc in the treatment of severe pneumonia in hospitalized children <2 y old. Am J Clin Nutr. 2006:1089–1096. pmid:16685051
  100. 100. Meydani SN, Barnett JB, Dallal GE, Fine BC, Jacques PF, Leka LS, et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr 2007;86: 1167–1173. pmid:17921398
  101. 101. Lönnerdal B. Dietary factors influencing zinc absorption. J Nutr 2000;130: 1378S–83S. pmid:10801947
  102. 102. Sandstead HH, Freeland-Graves JH. Dietary phytate, zinc and hidden zinc deficiency. J Trace Elem Med Biol 2014;28: 414–417. pmid:25439135
  103. 103. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc external link disclaimer. National Academy Press; 2001.
  104. 104. Yang HH-L, Lawless HT. Descriptive analysis of divalent salts. J Sens Stud 2005;20: 97–113. pmid:16614749
  105. 105. American Dietetic Association; Dietitians of Canada. Position of the American Dietetic Association and Dietitians of Canada: Vegetarian diets. J Am Diet Assoc. 2003;748–765. pmid:12778049
  106. 106. Neubauerova E, Tulinska J, Kuricova M, Liskova A, Volkovova K, Kudlackova M. The Effect of Vegetarian Diet on Immune Response. Epidemiology. 2007:S196.
  107. 107. Craddock JC, Neale EP, Peoples GE, Probst YC. Vegetarian-Based Dietary Patterns and their Relation with Inflammatory and Immune Biomarkers: A Systematic Review and Meta-Analysis. Adv Nutr 2019;10: 433–451. pmid:30947338
  108. 108. Kumssa DB, Joy EJM, Ander EL, Watts MJ, Young SD, Walker S, et al. Dietary calcium and zinc deficiency risks are decreasing but remain prevalent. Sci Rep 2015;5: 10974. pmid:26098577
  109. 109. Fairweather-Tait SJ, Harvey LJ, Ford D. Does ageing affect zinc homeostasis and dietary requirements? Exp Gerontol 2008;43: 382–388. pmid:18079083
  110. 110. Haase H, Mocchegiani E, Rink L. Correlation between zinc status and immune function in the elderly. Biogerontology 2006;7: 421–428. pmid:16953331
  111. 111. Ekholm P, Virkki L, Ylinen M, Johansson L. The effect of phytic acid and some natural chelating agents on the solubility of mineral elements in oat bran. Food Chem 2003;80: 165–170.
  112. 112. Barve S, Chen S-Y, Kirpich I, Watson WH, Mcclain C. Development, Prevention, and Treatment of Alcohol-Induced Organ Injury: The Role of Nutrition. Alcohol Res 2017;38: 289–302. pmid:28988580
  113. 113. Marreiro D do N, Cruz KJC, Morais JBS, Beserra JB, Severo JS, de Oliveira ARS. Zinc and Oxidative Stress: Current Mechanisms. Antioxidants (Basel). 2017;6. pmid:28353636
  114. 114. Amin KA, Al-Shehri FS. Toxicological and safety assessment of tartrazine as a synthetic food additive on health biomarkers: A review. Afr J Biotechnol 2018;17: 139–149.
  115. 115. Maverakis E, Fung MA, Lynch PJ, Draznin M, Michael DJ, Ruben B, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol 2007;56: 116–124. pmid:17190629
  116. 116. Van Biervliet S, Küry S, De Bruyne R, Vanakker OM, Schmitt S, Vande Velde S, et al. Clinical zinc deficiency as early presentation of Wilson disease. J Pediatr Gastroenterol Nutr 2015;60: 457–459. pmid:25825851
  117. 117. Prasad AS. Zinc deficiency in patients with sickle cell disease. Am J Clin Nutr. 2002;181–182. pmid:11815307
  118. 118. Gray NA, Dhana A, Stein DJ, Khumalo NP. Zinc and atopic dermatitis: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2019;33: 1042–1050. pmid:30801794
  119. 119. Katz RL, Keen CL, Litt IF, Hurley LS, Kellams-Harrison KM, Glader LJ. Zinc deficiency in anorexia nervosa. J Adolesc Health Care 1987;8: 400–406. pmid:3312133
  120. 120. Dutta SK, Procaccino F, Aamodt R. Zinc Metabolism in Patients with Exocrine Pancreatic Insufficiency. J Am Coll Nutr. 1998. 556–563. pmid:9853534
  121. 121. Bo S, Lezo A, Menato G, Gallo M-L, Bardelli C, Signorile A, et al. Gestational hyperglycemia, zinc, selenium, and antioxidant vitamins. Nutrition 2005;21: 186–191. pmid:15723747
  122. 122. Damianaki K, Lourenco JM, Braconnier P, Ghobril J-P, Devuyst O, Burnier M, et al. Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline. Nephrol Dial Transplant 2020;35: 1163–1170. pmid:31006015
  123. 123. Himoto T, Masaki T. Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease. Nutrients 2018;10. pmid:29342898
  124. 124. Farooq DM, Alamri AF, Alwhahabi BK, Metwally AM, Kareem KA. The status of zinc in type 2 diabetic patients and its association with glycemic control. J Family Community Med 2020;27: 29. pmid:32030076
  125. 125. Hendricks KM, Walker WA. Zinc deficiency in inflammatory bowel disease. Nutr Rev 1988;46: 401–408. pmid:3070446
  126. 126. Caulfield LE, Zavaleta N, Shankar AH, Merialdi M. Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival. Am J Clin Nutr 1998;68: 499S–508S. pmid:9701168
  127. 127. Krebs NF. Update on zinc deficiency and excess in clinical pediatric practice. Ann Nutr Metab 2013;62 Suppl 1: 19–29. pmid:23689110
  128. 128. Elbaz F, Zahra S, Hanafy H. Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egyptian Journal of Medical Human Genetics 2017;18: 153–163.
  129. 129. Hernández-Camacho JD, Vicente-García C, Parsons DS, Navas-Enamorado I. Zinc at the crossroads of exercise and proteostasis. Redox Biol 2020;35: 101529. pmid:32273258
  130. 130. Ahangar N, Naderi M, Noroozi A, Ghasemi M, Zamani E, Shaki F. Zinc Deficiency and Oxidative Stress Involved in Valproic Acid Induced Hepatotoxicity: Protection by Zinc and Selenium Supplementation. Biol Trace Elem Res 2017;179: 102–109. pmid:28124216
  131. 131. Braun LA, Rosenfeldt F. Pharmaco-nutrient interactions—a systematic review of zinc and antihypertensive therapy. Int J Clin Pract 2013;67: 717–725. pmid:23279674
  132. 132. Jeejeebhoy K. Zinc: an essential trace element for parenteral nutrition. Gastroenterology 2009;137: S7–12. pmid:19874952
  133. 133. Lee BE, Choi BY, Hong DK, Kim JH, Lee SH, Kho AR, et al. The cancer chemotherapeutic agent paclitaxel (Taxol) reduces hippocampal neurogenesis via down-regulation of vesicular zinc. Sci Rep 2017;7: 11667. pmid:28916767
  134. 134. Claro da Silva T, Hiller C, Gai Z, Kullak-Ublick GA. Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016;163:77–87. pmid:27107558
  135. 135. Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy HK, Backman V. The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients.
  136. 136. Remy KE, Mazer M, Striker DA, Ellebedy AH, Walton AH, Unsinger J, et al. Severe immunosuppression and not a cytokine storm characterize COVID-19 infections. JCI Insight 2020. pmid:32687484
  137. 137. Fischer PW, Giroux A, L’Abbé MR. The effect of dietary zinc on intestinal copper absorption. Am J Clin Nutr 1981;34: 1670–1675. pmid:7282591
  138. 138. www.drugs.com/drug-interactions. [cited 2020]. Available from: https://www.drugs.com/drug-interactions/zinc-sulfate,zinc-index.html
  139. 139. Cárcamo C, Hooton T, Weiss NS, Gilman R, Wener MH, Chavez V, et al. Brief Report: Randomized Controlled Trial of Zinc Supplementation for Persistent Diarrhea in Adults With HIV-1 Infection. JAIDS Journal of Acquired Immune Deficiency Syndromes 2006;43: 197. pmid:16940855
  140. 140. Baum MK, Lai S, Sales S, Page JB, Campa A. Randomized, controlled clinical trial of zinc supplementation to prevent immunological failure in HIV-infected adults. Clin Infect Dis 2010;50: 1653–1660. pmid:20455705
  141. 141. Basnet S, Shrestha PS, Sharma A, Mathisen M, Prasai R, Bhandari N, et al. A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children. Pediatrics 2012;129: 701–708. pmid:22392179
  142. 142. Howie S, Bottomley C, Chimah O, Ideh R, Ebruke B, Okomo U, et al. Zinc as an adjunct therapy in the management of severe pneumonia among Gambian children: randomized controlled trial. J Glob Health 2018;8: 010418. pmid:29713463
  143. 143. Shah GS, Dutta AK, Shah D, Mishra OP. Role of zinc in severe pneumonia: a randomized double bind placebo controlled study. Ital J Pediatr 2012;38: 36. pmid:22856593
  144. 144. Green JA, Lewin SR, Wightman F, Lee M, Ravindran TS, Paton NI. A randomised controlled trial of oral zinc on the immune response to tuberculosis in HIV-infected patients. Int J Tuberc Lung Dis 2005;9: 1378–1384. pmid:16466061
  145. 145. Zeng L, Zhang L. Efficacy and safety of zinc supplementation for adults, children and pregnant women with HIV infection: systematic review. Tropical Med Int Health 2011;16: 1474–1482. pmid:21895892
  146. 146. Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, et al. Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat 2001;8: 367–371. pmid:11555194
  147. 147. King JC, Brown KH, Gibson RS, Krebs NF, Lowe NM, Siekmann JH, et al. Biomarkers of Nutrition for Development (BOND)-Zinc Review. J Nutr 2015;146: 858S–885S. pmid:26962190
  148. 148. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. [cited 3 Aug 2020]. Available from: https://www.covid19treatmentguidelines.nih.gov/
  149. 149. Wieringa FT, Dijkhuizen MA, Fiorentino M, Laillou A, Berger J. Determination of zinc status in humans: which indicator should we use? Nutrients 2015;7: 3252–3263. pmid:25954900
  150. 150. Ward NI, Soulsbury KA, Zettel VH, Colquhoun ID, Bunday S, Barnes B. The Influence of the Chemical Additive Tartrazine on the Zinc Status of Hyperactive Children—a Double-blind Placebo-controlled Study. Journal of Nutritional Medicine. 1990;51–57.
  151. 151. US NLM ClinicalTrials.gov. In: US NLM ClinicalTrials.gov [Internet]. [cited 2020]. Available from: www.clinicaltrials.gov
  152. 152. Derwand R, Scholz M. Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win todays battle against COVID-19? Med Hypotheses 2020;142: 109815.
  153. 153. Jing Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding W. Chloroquine Is a Zinc Ionophore. PLoS One 2020;9.
  154. 154. te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, et al. Zn2 Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. PLoS Pathog. 2010;e1001176. pmid:21079686
  155. 155. Rahman MT. Potential benefits of combination of Nigella sativa and Zn supplements to treat COVID-19. Journal of Herbal Medicine 2020;23: 100382. pmid:32834942
  156. 156. Rahman MT, Idid SZ. Can Zn Be a Critical Element in COVID-19 Treatment? Biol Trace Elem Res 2020; 1–9. pmid:32458149
  157. 157. Finzi E. Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. Int J Infect Dis 2020. pmid:32522597
  158. 158. Carlucci PM, Ahuja T, Petrilli C, Rajagopalan H, Jones S, Rahimian J. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. J Med Microbiol. 2020;69:1228–1234. pmid:32930657
  159. 159. Jothimani D, Kailasam E, Danielraj S, Nallathambi B, Ramachandran H, Sekar P, et al. COVID-19: Poor outcomes in patients with Zinc deficiency. Int J Infect Dis 2020. pmid:32920234
  160. 160. Kambhampati SBS, Vaishya R, Vaish A. Unprecedented surge in publications related to COVID-19 in the first three months of pandemic: A bibliometric analytic report. J Clin Orthop Trauma 2020;11: S304–S306. pmid:32405191
  161. 161. Furrer L, Jancso A, Colic N, Rinaldi F. OGER++: hybrid multi-type entity recognition. J Cheminform 2019;11: 7. pmid:30666476
  162. 162. Chen Q, Lee K, Yan S, Kim S, Wei C-H, Lu Z. BioConceptVec: Creating and evaluating literature-based biomedical concept embeddings on a large scale. PLoS Comput Biol 2020;16: e1007617. pmid:32324731
  163. 163. Anderson RM, Heesterbeek H, Klinkenberg D, Hollingsworth TD. How will country-based mitigation measures influence the course of the COVID-19 epidemic? Lancet 2020;395: 931–934. pmid:32164834
  164. 164. Frontline Immune Support. In: Frontline Immune Support [Internet]. [cited 18 Jun 2020]. Available from: https://www.frontlineimmunesupport.com/.
  165. 165. Tan CW, Ho LP, Kalimuddin S, Cherng BPZ, Teh YE, Thien SY, et al. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. pmid:33039952
  166. 166. Wilder JM. The Disproportionate Impact of COVID-19 on Racial and Ethnic Minorities in the United States. Clin Infect Dis 2020. pmid:32648581
  167. 167. COVID-19 literature search powered by advanced NLP algorithms. In: COVIDscholar [Internet]. [cited 17 Sep 2020]. Available from: https://covidscholar.org/.
  168. 168. ClinicalTrials.gov Zinc Trials. In: ClinicalTrials.gov [Internet]. [cited 4 May 2020]. Available from: https://www.clinicaltrials.gov/ct2/results?cond=COVID&term=zinc&cntry=&state=&city=&dist=.