key: cord-310239-mmvuij3k authors: Arentz, Susan; Yang, Guoyan; Goldenberg, Joshua; Beardsley, Jennifer; Myers, Stephen P.; Mertz, Dominik; Leeder, Stephen; Hunter, Jennifer title: Clinical significance summary: Preliminary results of a rapid review of zinc for the prevention and treatment of SARS-CoV-2 and other acute viral respiratory infections date: 2020-08-01 journal: Adv Integr Med DOI: 10.1016/j.aimed.2020.07.009 sha: doc_id: 310239 cord_uid: mmvuij3k nan Zinc may potentially reduce the risk of SARS-CoV-2 infections and shorten the duration and severity of illness, including recovery from stroke, through several mechanisms. Indirect evidence from systematic reviews have found zinc supplementation is effective for the prevention of acute respiratory infections in young children and zinc lozenges may reduce the duration of the common cold in adults. Safety concerns associated with high doses or prolonged intake of zinc include anosmia (loss of smell) and copper deficiency. As of the 9 June 2020, the preliminary findings of a rapid review of zinc for the prevention or treatment Pending any definitive evidence, clinicians might consider assessing the zinc status of people with chronic disease co-morbidities and older adults as part of a SARS-CoV-2 clinical work-up, as both groups have a higher risk of zinc deficiency/insufficiency and poorer outcomes from SARS-CoV-2. Supplementation might be indicated for those with low or borderline low results, low dietary intake and/or increased needs. The global COVID-19 pandemic has prompted an urgent search for pharmaceutical and traditional, complementary and integrative medicine (TCIM) interventions. Data from all countries indicate that the case fatality and morbidity rates from SARS-CoV-2 increases with age and for those with noncommunicable chronic disease co-morbidities. [1] [2] [3] [4] Notably, zinc deficiency/insufficiency is prevalent in populations aged over 71 years, [5] [6] [7] [8] [9] , in people with chronic diseases [10] [11] [12] including diabetes, [10, 12, 13] and cardiovascular diseases [10, 12] and hospitalised patients following stroke [14] -see Box 1. [ INSERT BOX 1] J o u r n a l P r e -p r o o f South-East Asia, Sub-Saharan and Central and South American regions, however, marginal deficiencies are also prevalent in developed regions. [33, 34] Assessment of zinc status is notoriously difficult due to absence of sensitive and precise biochemical indicators. The most reliable methods involve combining a clinical assessment with laboratory tests assessing tissue concentrations of zinc in plasma or hair. [35] Clinical manifestations of mildmoderate zinc deficiency include recurrent infections, slow tissue repair, rough skin, mental lethargy, irritability, headaches and reduced lean body mass. [36] Assessment of dietary zinc with validated food frequency instruments may help identify dietary insufficiency [37] however zinc status is still likely to be underestimated due to individual physiological characteristics. [31] For instance, whilst zinc insufficiency/deficiency is known to diminish antibody and cell-mediated immunity in humans that in turn increases the risk of infections, this may only become apparent upon immune system provocation. [38, 39] Through several mechanisms, zinc has the potential to reduce the risk of viral respiratory tract infections, including SARS-CoV-2, and shorten the duration and severity of illness. The authors of a recent non-systematic narrative review of the underlying mechanisms postulate that along with its direct antiviral properties, zinc has the potential to reduce inflammation, improve mucocillary clearance, prevent of ventilator-induced lung injury, and modulate antiviral immunity. In vitro studies have demonstrated that zinc can inhibit the enzymatic activity and replication of SARS-CoV RNA polymerase and may inhibit angiotensin-converting enzyme 2 (ACE2) activity. [40, 42, 43] The antiviral effects of zinc are also hypothesised to potentiate the therapeutic effects of chloroquine, [44] , as chloroquine acts as a zinc ionophore increasing Zn 2+ influx into the cell. [40] Zinc may also modify the host's response to an infection as it is an essential co-factor element with a broad range of functions in the body. Zinc has an essential role in immune and airways function, wound healing and tissue repair that in turn, may delay or prevent recovery from viral respiratory illnesses. [45] [46] [47] [48] [49] [50] [51] Other consequences of zinc deficiency include an increased risk of vitamin A deficiency that is also critical for immune function, due to carrier proteins and activation enzymes being dependant on sufficient zinc status. [52] The potential role of zinc as an adjuvant therapy for SARS-CoV-2 may be broader than just antiviral and/or immunological support. Zinc also plays a complex role in haemostatic modulation acting as J o u r n a l P r e -p r o o f an effector of coagulation, anticoagulation and fibrinolysis . [53, 54] Zinc is also essential for neurological function and normalisation of zinc intake has been shown to improve neurological recovery following stroke. [14] The effectiveness of zinc in preventing or treating SARS-CoV-2 infections is yet to be systematically evaluated and, along with other nutritional supplements, was not mentioned in a recent narrative review of TCIM for the treatment of coronavirus disease 2019 . [55] The findings of systematic reviews of related populations are promising; however, the reviews are limited by population, intervention, or are out of date. [56] [57] [58] A 2016 Cochrane review of six RCTs concluded zinc supplementation was effective for the prevention of pneumonia in children aged two to 59 months. [57] Unlike an earlier review in 2000 of seven RCTs with adult participants and one RCT with children, [59] an updated 2011 systematic review of 13 RCTs found a dose-dependent effect of zinc lozenges compared to placebo controls for reduced duration of common colds in adults. [60] Daily dosages less than 75mg of zinc had no significant effect on duration of colds, however, daily dosage over 75mg reduced the duration of colds by 42% (95% CI: 35% to 48%). In a subsequent 2017 systematic review of seven RCTs of zinc lozenges with a daily dose >75mg, a smaller reduction of 33% (95% CI 21% to 45%) in the duration of common colds was found. [61] No differences in duration were found for daily doses of 192-207mg compared to doses of 80-92mg. Other formats of zinc for preventing or treating upper respiratory infections were examined in three Cochrane systematic reviews, however, all were withdrawn. [56, 62, 63] A protocol for the systematic review of zinc for prevention and treatment of common colds was withdrawn in 2019 due to noncompletion within the editorial time-frame. [64] Search Strategy: The primary objective of this rapid review was to assess the effects of zinc on the incidence, duration and severity of acute upper or lower respiratory tract infections caused by SARS-CoV-2 infection in people of any age and of any zinc status when used as a preventive supplement or as a therapy. The secondary objectives are to assess the effects of zinc on the incidence, duration and severity of assessed RoB and extracted data for each study. Primary studies included were randomized controlled trials (RCTs) and quasi-randomised controlled trials. There were no date nor language restrictions, however, studies published in languages other than English or Chinese are yet to be translated. Included were any zinc conjugates, such as salts or amino-chelates as a single ingredient, in any form (e.g. tablet, syrup, lozenge, gel, spray, liquid), dose and duration, administered via oral, intranasal, sublingual, transdermal, intramuscular or intravenous routes. Excluded Excluded were systematic reviews, non-randomised studies of interventions and studies without a concurrent control, such as case series and case reports. Excluded were people with respiratory tract infections or other upper/lower respiratory illnesses when the cause was confirmed not to be a viral infection, or a non-viral cause is common. Excluded were co-interventions and zinc administered alongside other nutraceuticals, herbs or pharmaceuticals unless both the intervention and control groups received the co-intervention. The exception were co-ingredients with the primary purpose to facilitate absorption (e.g. vitamin B12) or cellular retention (e.g. vitamin B6 or magnesium) of zinc. The A total of 1,625 records were retrieved from the database searches, of which 1,182 records remained after duplicates were removed. A further 981 records were excluded at title and abstract screening, and 80 following full-text screening (due to ineligible study design n=29, population n=11 or intervention n=32; full-text not available n=7; or awaiting translation n=1), leaving 121 records reporting 122 primary studies (86 published in English and 35 in Chinese). One study published in Spanish is pending translation. Four trials specific to SARS-CoV-2 were included, all of which are currently ongoing, and the investigators have been contacted are yet to report their results. A further 15 ongoing trials were excluded as the interventions used zinc in combination with other nutraceuticals (most commonly vitamin C and D) and/or as an agonist (additive) to hydroxychloroquine. As such, the independent effects of zinc cannot be determined. Of the remaining 118 published studies, none investigated zinc for prevention or treatment of acute respiratory infections caused only by a coronavirus infection. Most of the studies (79%) evaluated zinc for treating or preventing upper and/or lower acute respiratory infections in children. (Table 1 ). All the studies of adult participants were for acute upper respiratory infections i.e. the common cold (Table 1) , of which 21 were naturally occurring infections and six inoculated the participants with human rhinovirus species. The prevention effect of zinc was assessed in a variety of ways, mostly as the incidence or recurrence of respiratory infections as reported by study clinicians, the participants' physician or other healthcare workers, parents or self-reports, hospitalisation and/or laboratory tests. Treatment effects for severity and duration included time to symptom resolution, fever or respiratory distress, time in hospital, viral shedding, and self or clinician reported clinical severity. A wide range of zinc formulations and dosages were used, including lozenges, nasal gels and sprays, and oral zinc delivered in syrup, tablet or capsule formats. Only one study evaluated intravenous zinc. is a four-arm pragmatic RCT comparing zinc gluconate only, zinc gluconate and Vitamin C, Vitamin C only, and usual care (standard prescribed medication/supplements). The dose of zinc gluconate is 50mg daily, taken at bedtime. The primary outcome is the number of days required to reach a 50% reduction in symptom severity score (derived from a composite self-rating score of fever, cough, shortness of breath and fatigue rated on a 0-3 scale). Secondary outcomes are time to symptom resolution for each symptom, total symptom composite score at day 5, proportion requiring hospitalisation, use of prescribed adjunctive medicines, and adverse events. Methodological limitations include subjective primary outcome measures from unblinded participants, potential uncertainty around the quality and quantity of the ingredients in the supplements, [68] a potentially insufficient dose of elemental zinc and that the usual care group may use any combination of readily available prescribed medications / supplements, including zinc or vitamin C. Strengths of the pragmatic design include a capacity to inform 'real-world' decisions about any benefits and risks of additional zinc supplementation using products that are readily available compared to usual care alone. The second study, "High-dose intravenous zinc (HDIVZn) as adjunctive therapy in COVID-19 positive critically ill patients: A pilot randomized controlled trial" (ACTRN12620000454976), is being conducted in a hospital setting in Australia. HDIVZn is a two-arm, double-blind RCT comparing intravenous zinc chloride (0.5mg/kg/d) or placebo in 250ml saline bags infused daily over 3-6 hours for seven days. HDIVZn aims to recruit 160 patients who are hospitalised with SARS-CoV-2 infection. The primary outcome is oxygenation. Secondary outcomes are concerned with feasibility, including adequacy of blinding, availability/delivery/storage of the zinc infusions and per-patient costs. Methodological strengths include blinding and the use of an objective primary outcome measure. Limitations include not assessing any other clinical outcomes listed in the core outcome set (COS) for clinical trials on COVID-19. [4] The dose of zinc, approximately 50% more than the minimum daily requirement and without an intracellular transporter co-factor, may be insufficient to effect change of the outcome measurements. [69] Given this is a single-centre trial located in Australia with a low incidence of SARS-CoV-2, as of the 14 th June 2020, no eligible participants had been recruited to the study; and, according to the investigator A/Professor Ischia, "due to the low numbers of COVID-19 infections, the trial is unlikely to reach full recruitment to achieve its desired statistical power." [70] Prevention of SARS-CoV-2 is being evaluated in a multicentre trial of 660 military health professionals exposed to SARS-CoV-2 and located in Tunisia (NCT04377646: A Study of Hydroxychloroquine and Zinc in the Prevention of COVID-19 Infection in Military Healthcare Workers (COVID-Milit)). Participants will be randomized to one of three study arms; either hydroxychloroquine and zinc, hydroxychloroquine and placebo, or two placebo controls. In COVID-Milit, hydroxychloroquine 400 mg will be administered at day 1 and day 2, then as a weekly dose for up to 2 months. Zinc will consist of 15mg per day for up to two months. The primary outcome is the frequency of infection at two months, secondary outcomes are frequency of ten symptoms and adverse events. The low dose of zinc will provide minimum intake required for health. The treatment of SARS-CoV-2 with either hydroxychloroquine plus zinc compared to hydroxychloroquine alone will be evaluated in 80 hospitalised adults with confirmed SARS-CoV-2. This study, registered on the Iranian clinical registry (IRCT20180425039414N2; The effect of zinc on the treatment and clinical course of patients with SARS-cov2 (COVID-19)), is being conducted at the Amin Hospital in Isfahan. Participants will be randomised to either Hydroxychloroquine 200 mg every 12 hours plus zinc 220mg twice daily, or to hydroxychloroquine alone during their hospital stay. Outcomes include mortality rates, length of hospital stay and the clinical course of SARS-CoV-2 (fever, shortness of breath, cough, blood oxygenation (SaO2) and hemodynamic parameters). The treatment J o u r n a l P r e -p r o o f study was designed to ensure that all study participants diagnosed with SARS-CoV-2 received treatment. Preliminary findings of this rapid systematic review found limited direct evidence evaluating zinc for the prevention or treatment of SARS-CoV-2, as the results of the four registered RCTs that were identified are pending. Once available, the findings from the COVIDAtoZ trial that is evaluating the comparative effectiveness of zinc supplements against vitamin C and usual care for treatment of mild to moderate symptoms of community-based SARS-CoV2-19 infections, will be relevant to the general population who can self-prescribe, along with a wide range of health practitioners who provide TCIM advice. The findings from the HDIVZn trial that is evaluating the efficacy and safety of intravenous zinc infusions for hospitalised patients may provide safer and less expensive therapeutic options compared to pharmaceuticals currently being evaluated. Delivery of the intervention, however, requires medical oversight that will restrict its application to hospital settings and perhaps a few primary care settings. The two comparative effectiveness studies will not explain the preventative or treatment effects of zinc as a stand-alone therapy, however they will explain the potential benefits of zinc adjunct to hydroxychloroquine in populations at high risk of zinc deficiency, [34] for the prevention of SARS-CoV-range of functions in the body that modulate immunity, respiratory tract inflammation, coagulation and neurological function to name a few. [14, [38] [39] [40] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] Pending any definitive evidence, it might be reasonable for clinicians to consider assessing the zinc status of people with chronic disease co-morbidities and older adults as part of a SARS-CoV-2 clinical work-up, as both groups have a higher risk of zinc deficiency/insufficiency and poorer outcomes from SARS-CoV-2. Zinc status can be assessed by taking a diet and clinical history (see Box 1), clinical examination and laboratory tests. Plasma zinc may be more reliable than serum zinc and whilst hair mineral analysis is another option a timely result may not be available. [35] For prevention of SARS-CoV-2 and most importantly for general health, given that zinc supplements are readily available, they may be indicated for people with low or borderline low results, low dietary intake and/or increased needs. To optimise safety, a daily dose lower than the tolerable upper limits (<7mg for children aged 1-3 years up to 22mg for those aged 15-17 years) should be used along with dietary modifications whenever possible. In adults, doses up to the no observed adverse effect level (NOAEL) of 50 mg/day should be considered. [28] At this stage, it is unclear if there is any additional benefit from supplementing zinc for the prevention of SARS-CoV-2 or other viral respiratory infections in low risk populations nor for people with normal zinc status. It is also unclear if there are any benefits from supplementing with zinc for the treatment of SARS-CoV-2. There is limited indirect evidence from viral upper respiratory infections that zinc lozenges with a daily dose of >75mg of zinc may shorten the duration of the common cold. However, there are risks with higher doses above the NOAEL including permanent loss of smell. [28] Therefore, a daily dose higher than 100mg of elemental zinc in a lozenge is probably not advisable, as it is questionable whether there are any additional therapeutic effects. [61] Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement. 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