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Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2

Corresponding Author

thiagojmg@yahoo.com.br

orcid.org/0000-0001-8229-7917

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

Corresponding Author:

Thiago Jose Martins Gonçalves, MD, Rua Lourenço Marques, 158 – Vila Olímpia, São Paulo – SP, Brazil.

Email: thiagojmg@yahoo.com.br

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Sandra Elisa Adami Batista Gonçalves MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Andreia Guarnieri MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Rodrigo Cristovão Risegato MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Maysa Penteado Guimarães MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Daniella Cabral de Freitas MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Alvaro Razuk-Filho MD, PhD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Pedro Batista Benedito Junior MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Eduardo Fagundes Parrillo MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Thiago Jose Martins Gonçalves MD,

Corresponding Author

thiagojmg@yahoo.com.br

orcid.org/0000-0001-8229-7917

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

Corresponding Author:

Thiago Jose Martins Gonçalves, MD, Rua Lourenço Marques, 158 – Vila Olímpia, São Paulo – SP, Brazil.

Email: thiagojmg@yahoo.com.br

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Sandra Elisa Adami Batista Gonçalves MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Andreia Guarnieri MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Rodrigo Cristovão Risegato MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Maysa Penteado Guimarães MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Daniella Cabral de Freitas MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Alvaro Razuk-Filho MD, PhD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Pedro Batista Benedito Junior MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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Eduardo Fagundes Parrillo MD,

Department of Nutrology and Clinical Nutrition, Sancta Maggiore Hospital, Prevent Senior Private Health Operator, São Paulo, Brazil

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First published: 23 December 2020

https://doi.org/10.1002/ncp.10612

Citations: 6

Financial disclosure: None declared.

Conflicts of interest: None declared.

Abstract

Background

We verify the prevalence of low zinc levels among critically ill patients infected by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the intensive care unit (ICU) who required invasive mechanical ventilation, as well as its association with severity of acute respiratory distress syndrome (ARDS).

Methods

This is an observational study composed of patients admitted to the ICU. Demographics, anthropometric data for calculating body mass index (BMI), and laboratory data were obtained at admission: blood count, ferritin, arterial blood gas, serum zinc levels, and C-reactive protein. Also, arterial oxygen tension (PaO₂) divided by fractional inspired oxygen (FiO₂) was calculated by the first arterial blood gas after intubation. A diagnosis of severe ARDS was determined if the PaO₂/FiO₂ ratio was ≤100 mm Hg. Low zinc levels were established if zinc levels were <70 μg/dL.

Results

A total of 269 patients met inclusion criteria; 51.3% were men; median age was 74 (66–81) years; 91.1% (245 of 269) were elderly. The median BMI was 30.1 (24.7–32.1) kg/m², with 59.9% (161 of 269) of patients having overweight and obesity. The prevalence of low zinc levels was 79.6% (214 of 269) and severe ARDS was 56.5% (152 of 269). There was an association of low zinc levels and severe ARDS (odds ratio [OR], 14.4; 95% CI, 6.2–33.5; P < .001), even after adjusting for baseline variables (OR, 15.4; 95% CI, 6.5–36.3; P < .001).

Conclusion

Critically ill patients infected by SARS-CoV-2 with severe ARDS have a high prevalence of low serum zinc levels.

Introduction

The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified on December 29, 2019, when the first cases were reported, which were all linked to the Huanan (Southern China) Seafood Wholesale Market and identified by local hospitals using a surveillance mechanism for “pneumonia of unknown etiology” that was established in the wake of the 2003 severe acute respiratory syndrome (SARS) outbreak with the aim of allowing timely identification of novel pathogens such as the coronavirus disease 2019 (COVID-19) .^{1, 2} Common symptoms at the onset of disease included fever, cough, myalgia, and fatigue. In severe cases, the disease can progress to organic disorders including acute respiratory distress syndrome (ARDS), acute cardiac injury, liver injury, kidney injury, and even death.³

ARDS is a clinical condition characterized by an intense systemic inflammatory state and refractory hypoxemia, which can progress to multiorgan failure and death.⁴ There is an excessive release of proinflammatory cytokines, activation of procoagulating factors, and increased oxidative stress.^{5, 6} Consequently, the alveolar edema produced reduces lung compliance, explaining the need to use prolonged invasive mechanical ventilation. ARDS also is associated with profound loss of epithelial mechanical barrier function. The injury and loss of the epithelium is a constitutional event that occurs at the onset of ARDS and includes apoptosis of epithelial cells, resulting in barrier dysfunction and increased permeability.⁷

Severe diseases are characterized by inflammation, oxidative stress, and immune failure.^{8, 9} Inflammatory reactions may lead to the loss of intestinal mucosal integrity, which may decrease the absorption of essential nutrients and increase oxidative stress, resulting in a worsened condition.¹⁰ Critically ill patients develop severe stress and a clinical state that may raise the utilization and metabolic replacement of many nutrients and, especially for zinc, depleting their body reserves.¹¹ In addition, trace element–dependent enzymes are of great importance in the network of antioxidant defense mechanisms to protect cells from reactive oxygen species (ROS) and nitric oxide.^{12, 13}

Zinc is one of the most important essential nutrients because it is involved in numerous biological functions, and it is considered as a multipurpose trace element because of its capacity to bind to >300 enzymes and >2000 transcriptional factors.^{14, 15} It is extensively involved in protein, fat, and nucleic acid metabolism and gene transcription. Its role within the human body is extensive in reproduction, immune function, wound repair, and, on the microcellular level, macrophage, neutrophil, natural killer cell, and complement activity.^{16, 17}

It is estimated that up to 17% of the global population is at risk for inadequate zinc intake, whereas in South Asia, up to 30% of the population may be deficient.¹⁸ Deficiency can occur from decreased intake, inability to absorb the micronutrient, excessive loss, or increased metabolic requirement, as occurs in critically ill patients.¹¹

Low zinc levels have been associated with an increased susceptibility to infectious diseases, including viral infections and impaired activation and maturation of lymphocytes; disturbance of the intercellular communication via cytokines’ weakening of the innate host defense^{19, 20}; and modulation of cytokine-induced epithelial lung cell barrier permeability.⁷

In the light of the current pandemic of COVID-19, the purpose of this study is to evaluate the prevalence of low zinc levels among critically ill patients infected by SARS-CoV-2 and its association with the severity of ARDS.

Methods

Study Design and Setting

This is an observational study, and patients were enrolled consecutively in the moment at admission to the intensive care unit (ICU) between March 15 and May 3, 2020. The inclusion criteria consisted of age equal to or older than 18 years; data collected in the first day at ICU admission; diagnosis of ARDS, defined as a ratio of arterial oxygen tension over fractional inspired oxygen (PaO₂/FiO₂) ≤300 mm Hg; positive swab from the nasal cavity and oropharynx for detection of viral RNA for COVID-19 using the reverse-transcription polymerase chain reaction technique and computed tomography scan of the chest showing bilateral interstitial infiltrate pulmonary with a typical “ground-glass” pattern. The exclusion criteria were patients who had previously used zinc supplements for any reason in the last 3 months, presence of acute or chronic liver failure, or patients with chronic kidney in dialysis.

All included critically ill patients were intubated and required mechanical ventilation in the first 24 hours after admission to the ICU. The patients were receiving the same drug prescription (hydroxychloroquine, azithromycin, corticosteroids, and unfractionated heparin), and early enteral nutrition therapy was established as soon as the patients were hemodynamically compensated.

The study was reviewed and approved by the Local Research Ethics Committee (CAAE 30608,020.9.0000.8114). All procedures were performed following the Declaration of Helsinki.

Variables and Measures

Data of interest were collected for analysis of the population affected by COVID-19: demographic data (sex, age); anthropometric data such as weight (kilograms) and height (meters); severity score in the ICU such as Simplified Acute Physiology Score III (SAPS III)²¹; PaO₂/FiO₂ ratio after orotracheal intubation and mechanical ventilation; the presence of comorbidities (hypertension, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, asthma, heart diseases, neurological, oncological); and laboratory data collected on the first day at admission in the ICU: blood count, C-reactive protein (CRP), and serum zinc levels. The data on weight and height were obtained from a survey with the family member or companion who lived with the patient. From the anthropometric data, body mass index (BMI) was calculated by dividing weight by height squared (kg/m²).

For ARDS severity stratification, we used the Berlin definition²² based on degree of hypoxemia: mild (200 mm Hg < PaO₂/FiO₂ ≤ 300 mm Hg), moderate (100 mm Hg < PaO₂/FiO₂ ≤ 200 mm Hg), and severe (PaO₂/FiO₂ ≤ 100 mm Hg). There were 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H₂O), positive end-expiratory pressure (≥10 cm H₂O), and corrected expired volume per minute (≥10 L/min).

The zinc levels were measured only once at admission in the ICU. The test requested for the analysis of zinc was the serum zinc levels measured by inductively coupled plasma–mass spectrometry (ICP-MS). The definition of zinc deficiency was standardized according to the criteria of the International Zinc Nutrition Consultative Group (IZiNCG)²³ defined by a zinc serum concentration <70 μg/dL. Thus, zinc levels <70 μg/dL were used as a cutoff for low serum zinc levels.

Statistical Analysis

First, for descriptive analysis, the variables were tested for normality using the Shapiro-Wilk test (P > .05 for normality). Nonparametric data were described as median and interquartile range, and categorical data were expressed as a percentage of proportion. The comparison of percentage distribution of categorical variables was performed using the Pearson χ² test. The comparison of data that were not normally distributed with independent groups was performed using the Mann-Whitney U test. Correlations between groups in quantitative variables were studied using Spearman coefficient of correlation. A logistic regression analysis was used to adjusting for baseline variables in calculating the odds ratio (OR). Statistical significance was set at P < .05 and a 95% confidence interval (CI). Observational data were statistically analyzed using SPSS 24.0 software (version 24.0, SPSS Inc, Chicago, IL).

Results

Between March 15 and May 3, 2020, data were collected from critically ill patients infected by COVID-19 at admission in the ICU. The baseline characteristics of patients admitted to the ICU by SARS-CoV-2 who required invasive mechanical ventilation by diagnoses of ARDS are shown in Table 1.

Table 1. Baseline Characteristics of Patients Admitted to the Intensive Care Unit by SARS-CoV-2 Who Required Invasive Mechanical Ventilation

Characteristics	Total (n = 269)
Age, y	74 (66–81)
Sex, n (%)
Male	138 (51.3)
Female	131 (48.7)
Weight, kg	80 (70–90)
BMI, kg/m²	30.1 (24.7–32.1)
Nutrition status, n (%)
Low weight	29 (10.8)
Normal weight	79 (29.4)
Overweight/obesity	161 (59.9)
Hb, g/dL	13.2 (11.8–14.5)
Ht, %	38.8 (34.7–42.3)
CRP, mg/L
First day	131.3 (68.8–210.5)
Third day	192.8 (110.2–261.7)
Ferritin, ng/mL	1223.3 (731.3–1650)
Zinc, μg/dL	59.8 (49.7–67.7)
SAPS III	69 (53–85)
PaO₂/FiO₂ ratio, mm Hg	100 (88–155.5)
Comorbidities, n (%)
Hypertension	199 (74)
Diabetes	114 (42.4)
Pulmonary	75 (27.9)
Cardiovascular	74 (27.5)
Neurological	46 (17.1)
Chronic kidney disease	35 (13)
Oncological	14 (5.2)

Continuous values expressed in median and interquartile range and categorical data as a percentage of proportion.
Reference laboratory values: Hb, 12.0–15.5 g/dL; Ht, 35%–45%; CRP, <5 mg/L; ferritin, 30–300 ng/mL; zinc level: 70–120 μg/dL.
BMI, body mass index; CRP, C-reactive protein; FiO₂, fractional inspired oxygen; Hb, hemoglobin; Ht, hematocrit; PaO₂, arterial oxygen tension; SAPS III, Simplified Acute Physiology Score III; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

A total of 269 patients were enrolled during the study period. Regarding demographic and anthropometric data, 51.3% (138 of 269) of patients were men; median age was 74 (66–81) years; 91.1% (245 of 269) of patients were elderly (≥60 years old); median BMI was 30.1 (24.7–32.1) kg/m²; and 59.9% (161 of 269) of patients were classified as having obesity or overweight by BMI.

Regarding the severity score calculated at admission to the ICU, SAPS III was used with a median value of 69 (53–85), which corresponds to a predicted mortality risk in the ICU of 68.9%.

The PaO₂/FiO₂ ratio, according to the arterial blood gas analysis after intubation and initiation of invasive ventilatory support, had a median of 100 (88–155.5) mm Hg, and 56.5% (152 of 269) of critically ill patients were defined as having severe ARDS (PaO₂/FiO₂ ≤ 100 mm Hg).

The main comorbidities associated were hypertension (74%), diabetes (42.4%), pulmonary diseases such as asthma or chronic obstructive pulmonary disease (27.9%), and cardiovascular diseases such as heart failure or cardiomyopathies (27.5%).

The serum zinc levels were analyzed with a median of 59.8 (49.7–67.7) μg/dL. The prevalence of low zinc levels among critically ill patients infected by SARS-CoV-2 was 79.6% (95% CI, 74.7%–84%).

There was a negative bivariate correlation between zinc levels and age (ρ = −0.180; P = .003) and between PaO₂/FiO₂ ratio and SAPS III (ρ = −0.448; P = .015). There was a positive bivariate correlation between zinc levels and PaO₂/FiO₂ ratio (ρ = 0.217; P < .001). There was no correlation between zinc levels and SAPS III or CRP on the first and third day.

According to the comparison between categorical variables for the presence or absence of low zinc levels (Table 2), there was an association between low zinc levels and severe ARDS (OR, 14.4; 95% CI, 6.2–33.5; P < .001). After performing logistic regression analyses, adjusted for the variables age, sex, BMI, and SAPS III, the chance was even higher that critically ill patients with low zinc levels would present a diagnosis of severe ARDS (OR, 15.4; 95% CI, 6.5–36.3; P < .001). There was no statistically significant difference between critically ill patients with normal or low zinc levels and CRP concentrations on the first and third day in the ICU.

Table 2. Comparison of Critically Ill Patients With Normal Zinc Levels and Low Zinc Levels Admitted to the Intensive Care Unit by SARS-CoV-2

Variables	Normal zinc levels (n = 55)	Low zinc levels (n = 214)	P-value
Age, y	70.5 (62.8–79)	75 (67–81)	.017
Sex, n (%)
Female	25 (45.5)	106 (49.5)	.589
Male	30 (54.5)	108 (50.5)
Weight, kg	80 (70–96.5)	80 (69.9–90)	.378
BMI, kg/m²	29.4 (23.8–34.8)	30.1 (24.8–31.7)	.729
CRP, mg/L
First day	169.2 (91.1–247.2)	121.4 (63.3–201.2)	.080
Third day	191.6 (108.4–263.6)	192.8 (109.9–256.8)	.933
SAPS III	67 (51.3–85.3)	69 (50–85)	.964
Mild ARDS, n (%)	27 (49.1)	23 (10.7)	<.001
Moderate ARDS, n (%)	21 (38.2)	46 (21.5)	.011
Severe ARDS, n (%)	7 (12.7)	145 (67.8)	<.001

Continuous values expressed in median and interquartile range and categorical data as a percentage of proportion.
ARDS, acute respiratory distress syndrome; BMI, body mass index; CRP, C-reactive protein; SAPS III, Simplified Acute Physiology Score III; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Discussion

In view of the global COVID-19 pandemic and the risk of progression in infected patients to severe cases of the disease, our study showed a high prevalence of low zinc levels (79.6%; 95% CI, 74.7%–84%) among 269 patients admitted to the ICU, being that 91.1% (245 of 269) were elderly. In addition, the study showed an association between low zinc levels and the diagnosis of severe ARDS in critically ill patients (OR, 15.4; 95% CI, 6.5–36.3; P < .001).

In light of the high prevalence of zinc deficiency in the world (up to 17%), its impact on the population's health is considered a significant issue,²⁴ and some groups, including elderly and critically ill patients, are considered to be at risk for zinc deficiency, with worse clinical outcomes. Linko et al showed that low serum zinc was very common at the onset of acute respiratory failure in the ICU (95.8%) but had no predictive value for 30-day mortality, ICU length of stay, and time of invasive mechanical ventilation.²⁵ In another study, plasma zinc correlated with measures of inflammation (CRP) on day 3 and was associated with the degree of multiorgan failure on day 3 in the ICU,²⁶ according to our hypothesis of association between low zinc levels and ARDS severity.

A prospective, randomized, double-blind, placebo-controlled study has confirmed that micronutrient status is altered at admission in critically ill patients with multiorgan failure.²⁷ Cander et al demonstrated that in 89% of 34 critically patients, serum zinc levels were lower than the reference values at admission to the ICU, and zinc concentration was found to inversely correlate with Sequential Organ Failure Assessment (SOFA) score.¹² However, our study found no correlation between serum zinc levels and acute disease severity scores in the ICU (SAPS III), which is in agreement with the pharmaconutrition study of Heyland et al.¹³ and Linko et al.²⁵

Regarding the association between low zinc levels and pneumonia severity, Saleh et al demonstrated that, in a total of 100 patients, 28 had severe pneumonia, with 26 belonging to the group with low plasma zinc levels (59%) and the remaining 2 belonging to the group with normal plasma zinc levels (3.5%); the difference between the 2 groups was statistically significant (P = .001).²⁸

Critically ill patients experience oxidative stress due to a drastic increase of ROS. The patients have reduced plasma and intracellular levels of antioxidants and free electron scavengers, and the decreased activity of the enzymatic system involved in ROS detoxification²⁹ that causes the critical conditions of patients is associated with worsening oxidative stress. Some studies suggest that in critical illness, a redistribution of zinc levels occurs, and this process includes a decrease in serum zinc and an increase in liver zinc concentration, and both aspects seem to benefit the host's defense.^30-32 Therefore, despite our findings of a high prevalence of low serum zinc levels in critically ill patients at ICU admission, we cannot demonstrate that there is effectively a zinc deficiency proven only by a single blood measurement of serum zinc levels.

Previous studies on micronutrients in critically ill patients have already shown that the prevalence of low serum zinc levels is higher especially in elderly patients³³ and that, in general, patients have a decrease in muscle function and functionality with detrimental effects on respiratory function; a low serum zinc level also has been shown to increase respiratory tract infections.¹² Persistent zinc deficiency in elderly patients is a common condition and is associated with higher susceptibility to infections due to impaired immune response.^{34, 35} Prasad et al demonstrated that, among elderly patients with zinc deficiency, after supplementation the patients had a lower incidence of infections, lower production of inflammatory cytokines, and lower production of oxidative stress markers compared with the placebo group.³⁶

Zinc is essential for immune cell function by a multitude of signal pathways and plays an important role in cellular metabolism such as protein synthesis, DNA repair, and cytoprotection.¹⁷ Zinc deficiency impairs immune function and is associated with a higher susceptibility to infections.^{30, 37} Besecker et al showed higher concentration of inflammatory cytokines and an increased severity of sepsis in critically patients with lower serum zinc levels.³⁸ In addition, an impaired immune response and inefficient microorganism clearance cause zinc deficiency to exacerbate the acute inflammatory response, and the overamplification leads to increased organ damage and consecutively higher mortality.^{38, 39}

It is important to mention that zinc ions are involved in many cellular processes, activity of various cellular enzymes, and transcription factors. Zinc ions are probably an important cofactor for numerous viral proteins as well.^{40, 41} In cell culture studies, elevated intracellular zinc ions and the addition of compounds that stimulate cellular were found to inhibit the replication of numerous RNA viruses such as influenza virus, respiratory syncytial virus, and several picornaviruses.^{42, 43} Although zinc has direct antiviral properties, it is also critical in generating both innate and humoral antiviral responses. Zinc is an important cofactor of many viral enzymes, proteases, and polymerases, regulating cellular and systemic zinc distribution to inhibit viral replication and dissemination.¹⁵

Although our findings have shown low serum zinc levels in critically ill patients infected by SARS-CoV-2, empirical zinc replacement should be avoided because of the risk of high-level toxicity (zinc levels ≥120 μg/dL).⁴⁴ Excessive zinc intake has been associated with loss of appetite, nausea, and diarrhea. Ingesting high doses of elemental zinc for prolonged periods interferes with copper metabolism.⁴⁵

Zinc-induced cooper deficiency has been reported because of copper's competition for the same absorption site.^{44, 45} In addition, high oral zinc intake induces the production of metallothionein, which binds oral copper and excretes it from the body.⁴⁵ Also, zinc supplements can adversely affect the lipoprotein metabolism, including cholesterol, high-density lipoprotein, and low-density lipoprotein levels.⁴⁶

However, some limitations in our study are recognized. Initially, we did not control the fasting time at admission to the ICU or the food intake at the baseline of the study. We therefore cannot rule out the effect of sample time or fasting status to serum zinc values in this study. Another limitation was that only baseline serum zinc levels were measured, and because of our study design, blood sampling was timed to reflect the moment as soon as possible after the start of invasive mechanical ventilation by the acute respiratory failure and not to a fixed time of day. Furthermore, a simple sample of low serum zinc levels in critically ill patients may reflect a redistribution of the serious disease itself, such as inability to absorb, excessive loss, or increased metabolic demand and not simply a zinc deficiency at admission to the ICU.

Conclusion

Low serum zinc concentration is very prevalent at admission to the ICU for critically ill patients infected by SARS-CoV-2, and it also has been associated with a degree of organ failure manifested with severe ARDS. In addition, inflammation plays the key role in viral infection pathogenesis both at local (pulmonary) and systematic (cytokine storm) levels. This study may shed light on the development of clinical trials to establish therapeutic nutrition interventions with zinc for critically ill patients with COVID-19.

Acknowledgment

The authors wish to thank the volunteers for their participation.

Statement of Authorship

T. J. M. Gonçalves, S. E. A. B. Gonçalves, A. Guarnieri, M. P. Guimarães, and D. C. de Freitas equally contributed to the conception and design of the research; R. C. Risegato, A. Razuk-Filho, P. B. Benedito, and E. F. Parrillo contributed to the acquisition and analysis of the data; T. J. M. Gonçalves, S. E. A. B. Gonçalves, A. Guarnieri, M. P. Guimarães, and D. C. de Freitas drafted the manuscript. All authors critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.

References

1Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020; 382(13): 1199- 1207.
Crossref CAS PubMed Web of Science®Google Scholar
2Thompson R. Pandemic potential of 2019-nCoV. Lancet Infect Dis. 2020; 20(3): 280.
Crossref CAS PubMed Web of Science®Google Scholar
3Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol. 2020; 92(9): 1549- 1555.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
4Dushianthan A, Cusack R, Burgess VA, Grocott MP, Calder P. Immunonutrition for adults with ARDS: Results from a Cochrane systematic review and meta-analysis. Respir Care. 2020; 65(1): 99- 110.
Crossref PubMed Web of Science®Google Scholar
5Butt Y, Kurdowska A, Allen TC. Acute lung injury: A clinical and molecular review. Arch Pathol Lab Med. 2016; 140(4): 345- 350.
Crossref CAS PubMed Web of Science®Google Scholar
6Hughes KT, Beasley MB. Pulmonary manifestations of acute lung injury: more than just diffuse alveolar damage. Arch Pathol Lab Med. 2017; 141(7): 916- 922.
Crossref PubMed Web of Science®Google Scholar
7Bao S, Knoell DL. Zinc modulates cytokine-induced lung epithelial cell barrier permeability. Am J Physiol Lung Cell Mol Physiol. 2006; 291(6): L1132- 1141.
Crossref CAS PubMed Web of Science®Google Scholar
8Preiser JC, van Zanten AR, Berger MM, et al. Metabolic and nutritional support of critically ill patients: consensus and controversies. Crit Care. 2015; 19(1): 35.
Crossref PubMed Web of Science®Google Scholar
9Manzanares W, Langlois PL, Hardy G. Update on antioxidant micronutrients in the critically ill. Curr Opin Clin Nutr Metab Care. 2013; 16(6): 719- 725.
Crossref CAS PubMed Web of Science®Google Scholar
10Lee YH, Bang ES, Lee JH, et al. Serum concentrations of trace elements zinc, copper, selenium, and manganese in critically ill patients. Biol Trace Elem Res. 2019; 188(2): 316- 325.
Crossref CAS PubMed Web of Science®Google Scholar
11Florea D, Molina-Lopez J, Hogstrand C, et al. Changes in zinc status and zinc transporters expression in whole blood of patients with systemic inflammatory response syndrome (SIRS). J Trace Elem Med Biol. 2018; 49: 202- 209.
Crossref CAS PubMed Web of Science®Google Scholar
12Cander B, Dundar ZD, Gul M, Girisgin S. Prognostic value of serum zinc levels in critically ill patients. J Crit Care. 2011; 26(1): 42- 46.
Crossref CAS PubMed Web of Science®Google Scholar
13Heyland DK, Jones N, Cvijanovich NZ, Wong H. Zinc supplementation in critically ill patients: a key pharmaconutrient? JPEN J Parenter Enteral Nutr. 2008; 32(5): 509- 519.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
14Chasapis CT, Ntoupa PA, Spiliopoulou CA, Stefanidou ME. Recent aspects of the effects of zinc on human health. Arch Toxicol. 2020; 94(5): 1443- 1460.
Crossref CAS PubMed Web of Science®Google Scholar
15Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr. 2019; 10(4): 696- 710.
Crossref PubMed Web of Science®Google Scholar
16Baltaci AK, Yuce K, Mogulkoc R. Zinc metabolism and metallothioneins. Biol Trace Element Res. 2018; 183(1): 22- 31
Crossref CAS PubMed Web of Science®Google Scholar
17Lee SR. Critical role of zinc as either an antioxidant or a prooxidant in cellular systems. Oxid Med Cell Longev. 2018; 2018:9156285.
Crossref PubMed Web of Science®Google Scholar
18Wessells 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(11):e50568.
Crossref PubMed Web of Science®Google Scholar
19Jayawardena 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(4): 367- 382.
Crossref PubMed Web of Science®Google Scholar
20Calder 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(4): 1181.
Crossref CAS Web of Science®Google Scholar
21Moreno RP, Metnitz PG, Almeida E, et al. SAPS 3–From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005; 31(10): 1345- 1355.
Crossref PubMed Web of Science®Google Scholar
22Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. Jama. 2012; 307(23): 2526- 2533.
PubMed Web of Science®Google Scholar
23Brown KH, Rivera JA, Bhutta Z, et al. International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull. 2004; 25(1 suppl 2): S99- 203.
PubMed Google Scholar
24Bailey RL, West KP, Jr., Black RE. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015; 66(suppl. 2): 22- 33.
Crossref CAS PubMed Web of Science®Google Scholar
25Linko R, Karlsson S, Pettilä V, et al. Serum zinc in critically ill adult patients with acute respiratory failure. Acta Anaesthesiol Scand. 2011; 55(5): 615- 621.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
26Cvijanovich NZ, King JC, Flori HR, Gildengorin G, Wong HR. Zinc homeostasis in pediatric critical illness. Pediatr Crit Care Med. 2009; 10(1): 29- 34.
Crossref PubMed Web of Science®Google Scholar
27Berger MM, Soguel L, Shenkin A, et al. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care. 2008; 12(4): R101.
Crossref PubMed Web of Science®Google Scholar
28Saleh P, Sadeghpour A, Mirza-Aghazadeh-Attari M, Hatampour M, Naghavi-Behzad M, Tabrizi A. Relationship between plasma levels of zinc and clinical course of pneumonia. Tanaffos. 2017; 16(1): 40- 45.
PubMed Google Scholar
29Abiles J, de la Cruz AP, Castano J, et al. Oxidative stress is increased in critically ill patients according to antioxidant vitamins intake, independent of severity: a cohort study. Crit Care. 2006; 10(5): R146.
Crossref PubMed Web of Science®Google Scholar
30Alker W, Haase H. Zinc and sepsis. Nutrients. 2018; 10(8): 976.
Crossref Web of Science®Google Scholar
31Knoell DL, Liu MJ. Impact of zinc metabolism on innate immune function in the setting of sepsis. Int J Vitam Nutr Res. 2010; 80(45): 271- 277.
Crossref CAS PubMed Web of Science®Google Scholar
32Souffriau J, Libert C. Mechanistic insights into the protective impact of zinc on sepsis. Cytokine Growth Factor Rev. 2018; 39: 92- 101.
Crossref CAS PubMed Web of Science®Google Scholar
33Sriram K, Lonchyna VA. Micronutrient supplementation in adult nutrition therapy: practical considerations. JPEN J Parenter Enteral Nutr. 2009; 33(5): 548- 562.
Wiley Online Library CAS PubMed Web of Science®Google Scholar
34Pepersack T, Rotsaert P, Benoit F, et al. Prevalence of zinc deficiency and its clinical relevance among hospitalised elderly. Arch Gerontol Geriatr. 2001; 33(3): 243- 253.
Crossref CAS PubMed Web of Science®Google Scholar
35Marcellini F, Giuli C, Papa R, et al. Zinc status, psychological and nutritional assessment in old people recruited in five European countries: Zincage study. Biogerontology. 2006; 7(5-6): 339- 345.
Crossref CAS PubMed Web of Science®Google Scholar
36Prasad AS, Beck FW, Bao B, et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007; 85(3): 837- 844.
Crossref CAS PubMed Web of Science®Google Scholar
37Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. 2017; 9(6): 624.
Crossref Web of Science®Google Scholar
38Besecker BY, Exline MC, Hollyfield J, et al. A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr. 2011; 93(6): 1356- 1364.
Crossref PubMed Web of Science®Google Scholar
39Hoeger J, Simon TP, Beeker T, Marx G, Haase H, Schuerholz T. Persistent low serum zinc is associated with recurrent sepsis in critically ill patients – A pilot study. PLoS One. 2017; 12(5):e0176069.
Crossref PubMed Web of Science®Google Scholar
40te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010; 6(11):e1001176.
Crossref PubMed Web of Science®Google Scholar
41Xia X. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. 2020; 9(6): 624.
Google Scholar
42Uchide N, Ohyama K, Bessho T, Yuan B, Yamakawa T. Effect of antioxidants on apoptosis induced by influenza virus infection: inhibition of viral gene replication and transcription with pyrrolidine dithiocarbamate. Antiviral Res. 2002; 56(3): 207- 217.
Crossref CAS PubMed Web of Science®Google Scholar
43Suara RO, Crowe JE Jr. Effect of zinc salts on respiratory syncytial virus replication. Antimicrob Agents Chemother. 2004; 48(3): 783- 790.
Crossref CAS PubMed Web of Science®Google Scholar
44Irving JA, Mattman A, Lockitch G, Farrell K, Wadsworth LD. Element of caution: a case of reversible cytopenias associated with excessive zinc supplementation. CMAJ. 2003; 169(2): 129- 131.
PubMed Web of Science®Google Scholar
45Shaikhkhalil AK, Curtiss J, Puthoff TD, Valentine CJ. Enteral zinc supplementation and growth in extremely-low-birth-weight infants with chronic lung disease. J Pediatr Gastroenterol Nutr. 2014; 58(2): 183- 187.
Crossref PubMed Web of Science®Google Scholar
46Maret W, Sandstead HH. Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol. 2006; 20(1): 3- 18
Crossref CAS PubMed Web of Science®Google Scholar

Citing Literature

Volume36, Issue1

Enteral Nutrition Tolerance in Critical Illness

February 2021

Pages 186-191

This article also appears in:

Nutrition Support and Implications of COVID-19

Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study Design and Setting

Variables and Measures

Statistical Analysis

Results

Discussion

Conclusion

Acknowledgment

Statement of Authorship

References

Citing Literature

References

Information

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Association Between Low Zinc Levels and Severity of Acute Respiratory Distress Syndrome by New Coronavirus SARS-CoV-2

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study Design and Setting

Variables and Measures

Statistical Analysis

Results

Discussion

Conclusion

Acknowledgment

Statement of Authorship

References

Citing Literature

References

Related

Information