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Effects of Micronutrients or Conditional Amino Acids on COVID-19-Related Outcomes: An Evidence Analysis Center Scoping Review

      Abstract

      Recent narrative reviews have described the potential efficacy of providing individuals infected with coronavirus disease 2019 (COVID-19) with additional micronutrients to reduce disease severity. Although there are compelling reasons why providing additional micronutrients or conditional amino acids may affect COVID-19-related outcomes, evidence is lacking. The objective of this scoping review is to explore and describe the literature examining the effect of providing additional micronutrients or conditional amino acids (glutamine, arginine) in adults with conditions or infections similar to COVID-19 infection on COVID-19-related health outcomes. A literature search of the MEDLINE database and hand search of Cochrane Database of systematic reviews retrieved 1,423 unique studies, and 8 studies were included in this scoping review. Four studies examined a target population with ventilator-related pneumonia and acute respiratory distress syndrome, and the other 4 studies included patients who were at risk for ventilator-associated pneumonia. Interventions included intravenous ascorbic acid, intramuscular cholecalciferol, enteral and intramuscular vitamin E, enteral zinc sulfate, and oral and parenteral glutamine. In 6 of the 8 included studies, baseline status of the nutrient of interest was not reported and, thus, it is uncertain how outcomes may vary in the context of nutrient deficiency or insufficiency compared with sufficiency. In the absence of direct evidence examining efficacy of providing additional micronutrients or conditional amino acids to standard care, registered dietitian nutritionists must rely on clinical expertise and indirect evidence to guide medical nutrition therapy for patients infected with COVID-19.
      The coronavirus disease 2019 (COVID-19) pandemic has resulted in immeasurable adverse health effects across the world. Recent narrative reviews have described the potential efficacy of providing additional micronutrients to reduce disease severity in individuals infected with COVID-19.
      • Zhang L.
      • Liu Y.
      Potential interventions for novel coronavirus in China: A systematic review.
      • Grant W.B.
      • Lahore H.
      • McDonnell S.L.
      • et al.
      Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
      • Cheng R.Z.
      Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?.
      Suspected efficacy of providing additional micronutrients to patients to reduce disease severity is based on known mechanisms of micronutrients, including optimizing the immune system and reducing inflammation, as well as results from trials with humans infected with other viruses and in animal models of coronavirus. These narratives describe compelling reasons why providing micronutrients, particularly ascorbic acid (vitamin C) and cholecalciferol (vitamin D), may treat underlying insufficiencies or deficiencies to benefit immune function prior to and after contracting COVID-19 infection.
      In addition to optimizing immune function, another key consideration when providing medical nutrition therapy (MNT) to critically ill patients infected with the COVID-19 virus is the increased risk for malnutrition. Nutrition support is in high demand for critically ill patients being treated in intensive care units during the current pandemic.
      • Laviano A.
      • Koverech A.
      • Zanetti M.
      Nutrition support in the time of SARS-CoV-2 (COVID-19).
      • Martindale R.P.J.
      • Taylor B.
      • Warren M.
      • McClave S.
      Nutrition therapy in the patient with COVID-19 disease requiring ICU care. American Society for Parenteral and Enteral Nutrition, Society of Critical Care Medicine.
      • Iyer R.
      • Bansal A.
      What do we know about optimal nutritional strategies in children with pediatric acute respiratory distress syndrome?.
      Although conditional amino acids are not essential in healthy individuals, needs are increased during critical illness, and these amino acids become essential. Although nutrition support provides essential nutrients, it is possible that providing conditional amino acids, which become essential in the context of critical care, above those provided in standard nutrition support may allow for increased capacity for recovery and maintenance or improvement of nutritional status.
      • Morris C.R.
      • Hamilton-Reeves J.
      • Martindale R.G.
      • Sarav M.
      • Ochoa Gautier J.B.
      Acquired amino acid deficiencies: A focus on arginine and glutamine.
      However, evidence is lacking regarding the effect of providing additional conditional amino acids in the context of critical illness due to COVID-19 infection.
      To provide evidence-based practice, it is important to determine the evidence available to support nutrition interventions. In the absence of direct evidence to support nutrition interventions for the population of interest, practitioners must depend upon their clinical expertise and indirect evidence. Although there is ample evidence to suggest that supplementing or fortifying nutrition support with micronutrients or conditional amino acids may be beneficial for COVID-19 patients, there is little evidence directly testing these interventions in this population. Therefore, the objective of this scoping review is to explore and describe the literature examining the effect of providing additional micronutrients or conditional amino acids (glutamine, arginine) on COVID-19-related health outcomes in adults with conditions or infections similar to COVID-19 infection.

      Methods

      This scoping review followed the protocols developed by Arksey and O’Malley
      • Arksey H.
      • O’Malley L.
      Scoping studies: Towards a methodological framework.
      and refined by Levac
      • Levac D.
      • Colquhoun H.
      • O’Brien K.K.
      Scoping studies: Advancing the methodology.
      et al and the Joanna Briggs Institute.
      • Peters MDJ G.C.M.P.
      • Baldini Soares C.
      • Khalil H.
      • Parker D.
      Chapter 11: Scoping reviews (2020 version).
      The protocol for this scoping review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review checklist
      • Tricco A.C.
      • Lillie E.
      • Zarin W.
      • et al.
      PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation.
      and was registered on Open Science Framework (https://osf.io/9rm6u/).
      • Rozga M.
      The effect of micronutrient and single amino acid supplementation on coronavirus-related outcomes: A scoping review. Open Science Framework.

      Eligibility Criteria

      This scoping review defined the research question and eligibility criteria according to the Population-Concept-Context approach.
      • Peters MDJ G.C.M.P.
      • Baldini Soares C.
      • Khalil H.
      • Parker D.
      Chapter 11: Scoping reviews (2020 version).
      The populations of interest were humans infected with a type of coronavirus (COVID-19, severe acute respiratory syndrome, Middle East respiratory syndrome), with acute respiratory distress syndrome (ARDS), or those at risk of contacting or with ventilator-associated pneumonia, because findings in these populations may inform individuals currently infected with the COVID-19 coronavirus. The concept of this scoping review is provision of additional micronutrients or the conditional amino acids glutamine or arginine. The context was left open to capture all potential articles examining populations of interest. There were no limits on publication dates. Only articles published in English were included in this scoping review due to resource constraints. Additional eligibility criteria can be found in Figure 1.
      Figure 1Eligibility criteria for a scoping review examining the effect of providing micronutrients or conditional amino acids in COVID-19
      COVID-19 = coronavirus disease 2019.
      -related conditions on COVID-19-related outcomes.
      CategoryInclusion criteriaExclusion criteria
      Study typePeer-reviewed literatureGray literature
      PopulationIndividuals with suspected or confirmed viral infections related to the coronavirus (COVID-19
      COVID-19 = coronavirus disease 2019.
      , SARS
      SARS = severe acute respiratory syndrome.
      , MERS
      MERS = Middle East respiratory syndrome.
      ) or ARDS
      ARDS = acute respiratory disease.
      or who are at risk for or who have ventilator-associated pneumonia

      Human
      Individuals with no suspected or confirmed viral infections related to the coronavirus (COVID-19, SARS, MERS) or ARDS or who are not at risk for or who have ventilator-associated pneumonia

      Newborn or preterm human infants

      Animal studies; cell or in vitro studies
      InterventionVitamins and mineral supplements, including thiamine, ascorbic acid, cholecalciferol, and vitamins A and E; zinc; colloidal silver; multivitamin

      Single amino acids: glutamine, arginine
      Does not examine the effect of specified nutrient

      Herbal supplements
      ComparisonNo limitsNo limits
      OutcomesMortality

      Quality of life

      Development of COVID-19 or ventilator-associated pneumonia

      Hospital admission

      Intubation

      Days on ventilator

      Length of stay

      Symptom severity

      Nutrition or BMI
      BMI = body mass index.
      status

      Other coronavirus- and nutrition-related outcomes
      Outcomes that are not coronavirus- or nutrition-related
      SettingNo limitsNo limits
      Sample sizeNo limitsNo limits
      Study designsIntervention and observational primary studies

      Systematic review and meta-analyses
      Narrative reviews, commentary, editorials, letters to the editor, conference abstracts
      Year rangeNo limitsNo limits
      LanguageEnglishNon-English
      a COVID-19 = coronavirus disease 2019.
      b SARS = severe acute respiratory syndrome.
      c MERS = Middle East respiratory syndrome.
      d ARDS = acute respiratory disease.
      e BMI = body mass index.

      Search Plan

      MEDLINE (EBSCO) database was searched on April 21, 2020, to identify titles and abstracts with both the population and concept of interest. Search terms for the coronavirus were adapted from a recent search strategy developed by the National Institute for Health and Care Excellence for this project.
      The National Institute for Health and Care Excellence (NICE)
      Interim process and methods for developing rapid guidelines on COVID-19, 7 Appendix: Search strategy for Medline (Ovid Platform).
      Additional search terms included “micronutrient,” “ascorbic acid,” “vitamin D,” “zinc,” “multivitamin,” “glutamine,” and “arginine.” The only filter used was for the English language. A detailed search plan can be found in Figure 2. Relevant systematic and narrative reviews as well as the Cochrane Database of Systematic Reviews were hand searched for potentially included studies not identified in the MEDLINE search.
      Figure 2MEDLINE search plan for scoping review examining efficacy of providing additional micronutrients and conditional amino acids on coronavirus disease 2019–related outcomes. Date searched: April 21, 2020; limits: English language.
      Search no.Query
      S21S10 AND S20
      S20S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19
      S19(MH “Glutamine+”) OR (MH “Alanine+”) OR (MH “Arginine+”)
      S18colloidal silver
      S17(MH “Zinc+”)
      S16(MH “Vitamin E+”)
      S15(MH “Vitamin D+”)
      S14(MH “Ascorbic Acid+”)
      S13(MH “Vitamin B 12+”) OR (MH “Vitamin B 6+”) OR (MH “Thiamine+”) OR (MH “Vitamin B Complex”)
      S12(MH “Vitamin A+”) OR (MH “beta Carotene”)
      S11(MH “Micronutrients+”)
      S10S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9
      S9(MH “Respiratory Distress Syndrome, Adult”)
      S8(MH “Pneumonia, Ventilator-Associated”)
      S7(MH “Middle East Respiratory Syndrome Coronavirus”)
      S6(MH “Severe Acute Respiratory Syndrome”) OR (MH “SARS Virus”)
      S5((outbreak∗ or wildlife∗ or pandemic∗ or epidemic∗) adj1 (China∗ or Chinese∗ or Huanan∗))
      S4(((respiratory∗ adj2 (symptom∗ or disease∗ or illness∗ or condition∗)) or “seafood market∗” or “food market∗”) adj10 (Wuhan∗ or Hubei∗ or China∗ or Chinese∗ or Huanan∗))
      S3((corona∗ or corono∗) adj1 (virus∗ or viral∗ or virinae∗))
      S2(coronavirus∗ or coronovirus∗ or coronavirinae∗ or Coronavirus∗ or Coronovirus∗ or Wuhan∗ or Hubei∗ or Huanan or “2019-nCoV” or 2019nCoV or nCoV2019 or “nCoV-2019” or “COVID-19” or COVID19 or “CORVID-19” or CORVID19 or “WN-CoV” or WNCoV or “HCoV-19” or HCoV19 or CoV or “2019 novel∗” or Ncov or “n-cov” or “SARS-CoV-2” or “SARSCoV-2” or “SARSCoV2” or “SARS-CoV2” or SARSCov19 or “SARS-Cov19” or “SARSCov-19” or “SARS-Cov-19” or Ncovor or Ncorona∗ or Ncorono∗ or NcovWuhan∗ or NcovHubei∗ or NcovChina∗ or NcovChinese∗)
      S1(MH “Coronavirus Infections+”) OR (MH “Coronavirus+”)

      Study Selection and Data Extraction

      Title and abstract screening were conducted in 2 phases using Rayyan, an online software program.
      • Ouzzani M.
      • Hammady H.
      • Fedorowicz Z.
      • Elmagarmid A.
      Rayyan-a web and mobile app for systematic reviews.
      In the first phase, a reviewer (M.R.) excluded studies with animals or cells as the population of interest as well as studies that were not primary research studies or systematic reviews. Any remaining abstracts were reviewed by 2 independent reviewers. Full texts of potentially included articles were reviewed for eligibility by 2 reviewers (M.R. and F.W.C.), and discrepancies were settled through consensus. Each stage of the review process was documented in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.
      The following data were extracted from included studies: bibliographic information; details on the target population including disease or illness status, ventilator status, and age; details on the intervention including the nutrient, dose, mode, and duration; outcomes of interest reported; and summary of study results. These data were extracted onto a standardized study characteristics table. Studies with similar populations or interventions were grouped and described narratively. As is customary for scoping reviews, no critical appraisal of study quality was conducted.

      Results

      There were 1,423 unique studies identified with the database search; full texts of 11 studies were examined for inclusion, and 8 studies were included in this scoping review (Figure 3).
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • et al.
      Effect of vitamin D supplementation on procalcitonin as prognostic biomarker in patients with ventilator associated pneumonia complicated with vitamin D deficiency.
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      The majority of the studies identified in the initial search were excluded during title and abstract screening. Primary reasons for exclusion included the following: studies in animals or cells; human studies not examining a population of interest; and studies not being primary research studies (eg, narrative reviews and commentaries).
      Figure thumbnail gr1
      Figure 3Preferred Reporting Items for Systematic Reviews and Meta-Analyses Flow diagram for scoping review examining the effect of micronutrients and conditional amino acids in coronavirus disease 2019–related conditions on coronavirus disease 2019–related outcomes.
      Characteristics of the 8 included studies are shown in the Table. There were 5 randomized controlled trials represented in 6 publications
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      ,
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      ,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      ,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • et al.
      Effect of vitamin D supplementation on procalcitonin as prognostic biomarker in patients with ventilator associated pneumonia complicated with vitamin D deficiency.
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      and 3 nonrandomized controlled studies
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      ,
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      ,
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      published between 1987
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      and 2019.
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      The number of participants ranged from 14
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      to 186.
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      Although all studies included critically ill patients, the sample characteristics differed slightly. For example, Lin et al included patients in burn shock resuscitation,
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      and Kaya et al included ventilated patients in neurosurgical intensive care units.
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      TableStudy characteristics and major results for studies included in a scoping review examining efficacy of providing additional micronutrients or conditional amino acids on coronavirus-related outcomes
      StudyPopulationInterventionComparison groupOutcomes reportedMajor results
      Ascorbic acid
      Fowler et al 2019
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.


      RCT
      RCT = randomized controlled trail.


      PMID
      PMID = PubMed ID.
      31573637
      N = 167 ICU
      ICU = intensive care unit.
      patients with sepsis and acute respiratory distress syndrome

      Plasma ascorbate levels at baseline were marginally deficient in both groups

      Mean ± SD
      SD = standard deviation.
      age: 54.8 ± 16.7
      Nutrient: ascorbic acid

      Dose: 50 mg/kg in dextrose 5% in water

      Mode: intravenous infusion

      Duration: every 6 h for 96 h
      Placebo (dextrose 5% in water only)Organ failure (modified SOFA
      SOFA = sequential organ failure assessment.
      score), C-reactive protein levels, thrombomodulin levels
      Compared with placebo, ascorbic acid did not significantly improve reported outcomes.
      Lin et al 2018
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.


      Retrospective case-control

      PMID 29931212
      N = 80

      Patients in burn shock resuscitation

      Baseline ascorbic acid status not reported

      Mean ± SD age: 41±15 (intervention group) and 42.4 ± 17 (comparison group)
      Nutrient: high-dose ascorbic acid

      Dose: started at a dose of 66 mg/kg/h

      Mode: intravenous infusion

      Duration: mean time 4:01 ± 15 h
      No treatmentVentilator-associated pneumonia, mortalityThere were no significant differences in the incidence of ventilator-associated pneumonia or mortality between the 2 groups.
      Cholecalciferol
      Miroliaee et al 2017
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • et al.
      Effect of vitamin D supplementation on procalcitonin as prognostic biomarker in patients with ventilator associated pneumonia complicated with vitamin D deficiency.
      , 2018
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.


      RCT

      PMID 29248753

      29201115
      N = 49

      Patients with ventilator-related pneumonia and cholecalciferol deficiency

      Mean ± SD age: 57.83 ± 18.84 (intervention group) and 56.45 ± 20.70 (comparison group)
      Nutrient: cholecalciferol

      Dose: 300,000 U

      Mode: intramuscular

      Duration: N/A
      N/A = not available.
      PlaceboIL-6
      IL-6 = interleukin-6.
      , CRP
      CRP = C-reactive protein.
      , CPIS
      CPIS = Clinical Pulmonary Infection Score.
      score (pneumonia score), SOFA score, mortality
      Compared with placebo, cholecalciferol group had significantly lower IL-6 levels and mortality, but not CRP level and SOFA or CPIS score.
      Vitamin E
      Hajimahmoodi et al 2009
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.


      RCT

      No PMID
      N = 20

      ICU patients with acute respiratory distress syndrome

      Vitamin E status at baseline not reported

      Mean ± SD age: 51.2 ± 6.41
      Nutrient: vitamin E (600 IU/d)

      Mode: intramuscular

      Duration: 3 d
      Placebo (normal saline)APACHE
      APACHE = Acute Physiology and Chronic Health Evaluation.
      II score
      Vitamin E appeared to be beneficial in decreasing APACHE II score (significant changes in APACHE II in the intervention group).
      Seeger et al 1987
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.


      Before-after study

      PMID 3117857
      N = 14

      Ventilated and intubated acute respiratory failure patients in ICU

      Vitamin E status at baseline was not reported

      Participant ages not reported
      Nutrient: vitamin E (d,1-alpha-tocopherylacertate)

      Dose: 3 g/d

      Mode: enteral (liquid oil directly in gastric tube in 6 doses)

      Duration: 10 d or if mechanical ventilation is not needed before 10 d
      No comparison groupMortalityNo difference seen in mortality according to the increase in plasma tocopherols from the intervention.
      Zinc
      Hasanzadeh et al 2017
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.


      Prospective cohort study

      PMID 28197049
      N = 186

      Adult mechanically ventilated trauma patients in the ICU

      Zinc status at baseline not reported

      Zinc

      24.4% <30 y

      51.2% 30-65 y

      24.4% >65 y

      No zinc

      21.2% <30 y

      50% 30-65 y

      28.8% >65 y
      Nutrient: zinc sulfate

      Dosage: 60-90 mg/d

      Mode: nasogastric tube

      Duration: 1 y
      No zinc sulfateOccurrence of ventilator-associated pneumonia measured with CPISPatients receiving zinc sulfate had a smaller hazard of progression to ventilator-associated pneumonia.
      Glutamine
      Aydoğmuş et al 2012
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.


      RCT

      PMID 25207045
      N = 40 in glutamine and comparison groups

      Patients on mechanical ventilator support for at least 7 d in the ICU

      Mean ± SD age:

      Nonglutamine group: 45 ± 18.2 y

      Glutamine group: 36.35 ± 16.37 y
      Nutrient: glutamine

      Dose: 40 g/d

      Mode: TPN
      TPN = total parenteral nutrition.


      Duration: 7 d
      TPN without glutamineDevelopment of ventilator-associated pneumonia, CRPThere was no difference development of ventilator-associated pneumonia or CRP levels between groups.
      Kaya et al 2017
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.


      RCT

      PMID 28096000
      N = 88

      Ventilated patients in neurosurgical ICU; expected to be ventilated at least 5 d

      Mean ± SD age: 48.57 ± 17.36
      Nutrient: glutamine

      Concentration: 5%

      Mode: oral care

      Duration: 5 d
      Oral care with 2% chlorhexidine gluconate solutionVentilator-related pneumonia measured with Clinical Infection Score (chest x-rays; endotracheal aspirate cultures), acute

      APACHE II score
      No difference between groups at day 1, 3, or 5 (P > .05)
      a RCT = randomized controlled trail.
      b PMID = PubMed ID.
      c ICU = intensive care unit.
      d SD = standard deviation.
      e SOFA = sequential organ failure assessment.
      f N/A = not available.
      g IL-6 = interleukin-6.
      h CRP = C-reactive protein.
      i CPIS = Clinical Pulmonary Infection Score.
      j APACHE = Acute Physiology and Chronic Health Evaluation.
      k TPN = total parenteral nutrition.
      Four studies focused on patients who had ventilator-related pneumonia or ARDS,
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      ,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      ,
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      ,
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      and the remaining 4 studies included patients who were at risk for ventilator-associated pneumonia.
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      ,
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      ,
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      ,
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      Study interventions were heterogeneous. Fowler et al
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      and Lin et al
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      examined the effect of vitamin C or ascorbic acid via intravenous infusion, and the remaining included studies investigated other single nutrients delivered through various modes: glutamine orally
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      or parenterally,
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      vitamin D or cholecalciferol intramuscularly,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      vitamin E (d,1-alpha-tocopherylacertate) enterally
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      or intramuscularly,
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      and zinc sulfate enterally.
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      The duration of the intervention also varied (Table).
      Except for Lin et al
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      and Seeger et al,
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      all other 6 studies had a comparison group.
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      ,
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      ,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      ,
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      Among the 8 included studies, reported outcomes included organ failure, inflammatory and vascular injury markers, pneumonia score, ventilator-related pneumonia, and mortality.
      Five studies did not find any improvement in their reported outcomes.
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      • Kaya H.
      • Turan Y.
      • Tunalı Y.
      • et al.
      Effects of oral care with glutamine in preventing ventilator-associated pneumonia in neurosurgical intensive care unit patients.
      • Lin J.
      • Falwell S.
      • Greenhalgh D.
      • Palmieri T.
      • Sen S.
      High-dose ascorbic acid for burn shock resuscitation may not improve outcomes.
      ,
      • Seeger W.
      • Ziegler A.
      • Wolf H.R.
      Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.
      ,
      • Aydoğmuş M.T.
      • Tomak Y.
      • Tekin M.
      • Kati I.
      • Huseyinoglu U.
      Glutamine supplemented parenteral nutrition to prevent ventilator-associated pneumonia in the intensive care unit.
      In 3 studies, the authors reported a potential benefit of the intervention on outcomes: intramuscular cholecalciferol on mortality,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      intramuscular vitamin E on Acute Physiology and Chronic Health Evaluation score in patients with ARDS,
      • Hajimahmoodi M.
      • Mojtahedzadeh M.
      • GhaffarNatanzi N.
      • et al.
      Effects of vitamin E administration on APACHE II Score in ARDS patients.
      and zinc sulfate on the incidence of ventilator-associated pneumonia in ventilated patients in intensive care units.
      • Hasanzadeh Kiabi F.
      • Alipour A.
      • Darvishi-Khezri H.
      • Aliasgharian A.
      • Emami Zeydi A.
      Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study.
      In 2 studies, authors indicated deficiency of the nutrient of interest at baseline,
      • Fowler 3rd, A.A.
      • Truwit J.D.
      • Hite R.D.
      • et al.
      Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The CITRIS-ALI randomized clinical trial.
      ,
      • Miroliaee A.E.
      • Salamzadeh J.
      • Shokouhi S.
      • Sahraei Z.
      The study of vitamin D administration effect on CRP and interleukin-6 as prognostic biomarkers of ventilator associated pneumonia.
      but baseline status of the intervention nutrient was not described in the remaining studies.

      Discussion

      This scoping review included 8 unique studies examining the effect of providing additional micronutrients or conditional amino acids on COVID-19-related health outcomes in individuals with ARDS and in individuals with or at risk for ventilator-associated pneumonia. Although the search plan included individuals infected with a form of coronavirus (COVID-19, severe acute respiratory syndrome, Middle East respiratory syndrome), there were no studies identified with these target populations. Overall, sparse evidence of heterogeneous interventions described some benefit of intramuscular cholecalciferol and vitamin E and zinc via a nasogastric tube on coronavirus-related outcomes, but findings should be interpreted with caution because this scoping review did not critically analyze risk of bias or certainty of evidence. In addition, most studies did not report the baseline status of the nutrients being supplemented. Thus, it is unclear if results would have been different if participants were exclusively insufficient or deficient vs sufficient. It is possible that treating baseline deficiency may result in improved outcomes,
      • Marik P.E.
      • Kory P.
      • Varon J.
      Does vitamin D status impact mortality from SARS-CoV-2 infection?.
      although providing additional nutrients to a sufficient individual would result in no effect. Hence, further investigation is warranted.
      There has been considerable interest in the efficacy of micronutrient therapy to reduce the severity and symptoms of COVID-19 infection, particularly in the context of critical illness.
      • Zhang L.
      • Liu Y.
      Potential interventions for novel coronavirus in China: A systematic review.
      • Grant W.B.
      • Lahore H.
      • McDonnell S.L.
      • et al.
      Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
      • Cheng R.Z.
      Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?.
      ,
      • Weng H.
      • Li J.-G.
      • Mao Z.
      • Zeng X.-T.
      Randomised trials of vitamin D 3 for critically ill patients in adults: systematic review and meta-analysis with trial sequential analysis.
      ,
      • Molloy E.J.
      • Murphy N.
      Vitamin D, Covid-19 and children.
      Recent reviews include comprehensive discussion of the potential effects of providing additional micronutrients to individuals with COVID-19,
      • Zhang L.
      • Liu Y.
      Potential interventions for novel coronavirus in China: A systematic review.
      particularly ascorbic acid
      • Cheng R.Z.
      Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?.
      ,
      • Boretti A.
      • Banik B.K.
      Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome.
      and cholecalciferol.
      • Grant W.B.
      • Lahore H.
      • McDonnell S.L.
      • et al.
      Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.
      ,
      • Weng H.
      • Li J.-G.
      • Mao Z.
      • Zeng X.-T.
      Randomised trials of vitamin D 3 for critically ill patients in adults: systematic review and meta-analysis with trial sequential analysis.
      ,
      • Molloy E.J.
      • Murphy N.
      Vitamin D, Covid-19 and children.
      In these reviews, the authors provide compelling logic that patients infected with COVID-19 or with comparable conditions could benefit from addition of these nutrients. Authors describe biological functions of these micronutrients and discuss how supplementation has been effective in treating other viruses such as the common cold or influenza, particularly in the context of insufficiency or deficiency. Authors also provide evidence describing efficacy of providing micronutrients in the context of animal models of coronavirus. However, human trials examining efficacy of providing micronutrients and conditional amino acids were lacking, which was supported by the dearth of evidence discovered in this scoping review.
      There is minimal available evidence to guide nutrition care for registered dietitian nutritionist (RDNs) working with patients infected with COVID-19. Indeed, there is little evidence to guide practice for individuals with similar conditions, including alternative versions of the coronavirus, ARDS, or ventilator-associated pneumonia. In these circumstances, it is critical for RDNs to rely on their scientific training and clinical expertise and the nutrition care process to determine if a patient is deficient in an essential nutrient and if treating the respective deficiency is a priority. RDNs can also extrapolate evidence from populations presenting with similar signs and symptoms, such as those with critical illness or on mechanical ventilation, to inform practice for individuals with COVID-19 infections. RDNs should consider how baseline nutrient status may affect outcomes, because treating a deficiency or insufficiency may result in improved outcomes, although providing nutrients above meeting needs may have no effect.
      In the current COVID-19 crisis, it is not possible to wait until clinical trials are published on each intervention delivered before implementing the intervention with a patient, as would ideally be the case in standard care. Instead, RDNs must use ingenuity and innovation and work as part of a multidisciplinary team to determine priorities and risk-benefit ratio of interventions when collaborating to manage health condition in adults infected with COVID-19.

      COVID-19 Research Moving Forward

      In a recent consensus report, the Expert Group on Clinical Treatment of New Corona Virus Disease in Shanghai described that high-dose intravenous ascorbic acid treatment is recommended for patients with light or general symptoms
      Shanghai Expert Group on Clinical Treatment of New Coronavirus Diseases
      Expert consensus on comprehensive treatment of cornoavirus diseases in Shanghai in 2019 comprehensive treatment of coronavirus disease expert consensus.
      to prevent and control cytokine storms. Several trials have been registered examining the effect of providing antioxidants,
      ClinicalTrials.gov
      Anti-inflammatory/antioxidant oral nutrition supplementation in COVID-19 (ONSCOVID19); NCT04323228. National Library of Medicine (US).
      ascorbic acid,
      ClinicalTrials.gov
      Early infusion of vitamin C for treatment of novel COVID-19 acute lung injury (EVICT-CORONA-ALI); NCT04344184. National Library of Medicine (US).
      ClinicalTrials.gov
      Administration of intravenous vitamin C in novel coronavirus infection (COVID-19) and decreased oxygenation (AVoCaDO); NCT04357782. National Library of Medicine (US).
      ClinicalTrials.gov
      Pharmacologic ascorbic acid as an activator of lymphocyte signaling for COVID-19 treatment; NCT04363216. National Library of Medicine (US).
      ClinicalTrials.gov
      Use of ascorbic acid in patients with COVID 19; NCT04323514. National Library of Medicine (US).
      ClinicalTrials.gov
      Vitamin C infusion for the treatment of severe 2019-nCoV infected pneumonia; NCT04264533. National Library of Medicine (US).
      and cholecalciferol.
      ClinicalTrials.gov
      Vitamin D on prevention and treatment of COVID-19 (COVITD-19); NCT04334005. National Library of Medicine (US).
      ClinicalTrials.gov
      Impact of zinc and vitamin D3 supplementation on the survival of aged patients infected with COVID-19 (ZnD3-CoVici); NCT04351490. National Library of Medicine (US).
      ClinicalTrials.gov
      COvid-19 and vitamin D supplementation: A multicenter randomized controlled trial of high dose versus standard dose vitamin D3 in high-risk COVID-19 patients (CoVitTrial); NCT04344041. National Library of Medicine (US).
      Thus, although there is no research to support evidence-based recommendations at this time, evidence to inform provision of additional micronutrients for individuals with COVID-19 infections may be available moving forward. There were no registered trials found directly examining the effects of glutamine or arginine.
      To provide evidence-based practice for RDNs, it is crucial that RDNs participate in COVID-19-related research when possible. In addition to participating in formal research studies, RDNs can contribute their experiences in delivering MNT to this population by documenting care and outcomes in the Academy of Nutrition and Dietetics Health Informatics Infrastructure. RDNs working with COVID-19 patients are essential workers and are likely stressed for time. However, any documentation of current practices can help contribute to a growing pool of evidence supporting the efficacy of MNT in COVID-19-affected patients.

      Strengths and Limitations

      This scoping review followed a rigorous process and examined the availability of interventions of potential utility in populations that may be comparable and applicable to the COVID-19-infected population. A limitation of this scoping review included the lack of evidence available in target populations and lack of documentation of baseline nutrient status of participants in included articles. Moving forward, authors of scoping and systematic reviews examining potential efficacy of interventions in patients with COVID-19 infection should consider including a broader population base, including those with critical illness or respiratory infections, to identify evidence that can be extrapolated to the population of interest. Another limitation of this scoping review was searching the MEDLINE database and Cochrane Database of Systematic Reviews only in the interest of providing information to practitioners in a rapid manner. However, studies cited in the included articles or in any relevant narrative reviews were evaluated for inclusion. This scoping review did not cover all nutrients that may be beneficial to COVID-19 patients, including probiotics or oral nutrition supplements.

      Conclusion

      Individuals infected with COVID-19 may have baseline nutrient deficiencies or increased nutrient needs due to COVID-19 pathology. Current reviews and registered trials discuss the potential utility of providing additional micronutrients and glutamine in contexts that may apply to those infected with COVID-19. However, evidence in human subjects is very limited, and it is unclear if results may vary according to baseline nutrient status. RDNs must work with the multidisciplinary team and rely on clinical expertise and indirect evidence to guide MNT for patients infected with COVID-19 to reduce adverse effects from COVID-19 infection.

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      Biography

      M. Rozga is a nutrition researcher, Academy of Nutrition and Dietetics Evidence Analysis Center, Chicago, IL.
      F. W. Cheng is a nutrition researcher, Academy of Nutrition and Dietetics Evidence Analysis Center, Chicago, IL.
      L. Moloney is a nutrition researcher, Academy of Nutrition and Dietetics Evidence Analysis Center, Chicago, IL.
      D. Handu is senior scientific director, Academy of Nutrition and Dietetics Evidence Analysis Center, Chicago, IL.