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Deep Dive: Micronutrients with micro-effects for preventing and treating acute respiratory infections

This meta-analysis found evidence that supplementing vitamins C and D may prevent the risk of acute respiratory infections, but only by a tiny amount. Zinc has a more sizable effect, but only once symptoms have set in.

Study under review: Effect of micronutrient supplements on influenza and other respiratory tract infections among adults: a systematic review and meta-analysis

Introduction

Acute respiratory tract infections (ARIs) are the third leading cause of death globally, accounting for approximately 4 million deaths worldwide each year. ARIs are primarily caused by viruses[1] (e.g., rhino, corona, adeno, and influenza) infecting the respiratory tract, meaning the nose, sinuses, throat, and lung. To date, there are over 200 viruses[2] known that cause ARIs. Common symptoms of RTIs[3] include coughing, a sore throat, nasal congestion, runny nose, sneezing, and fever. In severe cases, ARIs can become life-threatening, especially in people with an underlying health condition or a weakened immune system[4]. One of the most common and severe ARIs is seasonal influenza[5], with an annual 3–5 million cases and more than 300,000 deaths globally[6]. Since antibiotics are useless for treating ARIs caused by respiratory viruses, other potential prevention and treatment options[7] are of substantial public health interest. The current COVID-19 pandemic[8] highlights the urgency of finding effective, safe, and widely available ways to prevent and treat ARIs.

Supplementation with micronutrients[9] is one possible strategy for preventing and treating ARIs. Decades of research have accumulated a large body of evidence on various micronutrients, most notably vitamin C[10], which has been researched for over 80 years. Micronutrients with the most robust evidence for immune support are vitamins C and D and zinc[11]. However, there remains a substantial controversy concerning the effectiveness of supplemented micronutrients for preventing and treating ARIs. Here is a quick look at the current literature on the three main micronutrients used for the prevention and treatment of ARIs:

Vitamin C

Vitamin C (ascorbic acid)[12] is a water-soluble essential nutrient and a very popular dietary supplement due to its antioxidant properties, safety, and low price. In 1970, Nobel laureate Linus Pauling[13] claimed that vitamin C prevents the onset and alleviates symptoms of the common cold. Over 50 years later, many researchers ask: Was he right? A recent Cochrane meta-analysis[2] found that vitamin C supplementation did not influence getting a cold, but once infected, vitamin C reduced the duration of symptoms by 8% in adults and 14% in children, and lowered the severity of symptoms. In contrast, marathon runners, skiers, and soldiers showed a 50% decreased risk of getting a cold when supplementing vitamin C. However, the authors advise treating these findings with caution, as their practical relevance still seems unclear. Why is that? Overall, the current evidence and low level of benefit do not justify long-term supplementation in its own rights, the authors claim. Yet, given its low cost and high safety, vitamin C supplementation may be worth considering for people prone to infections and in periods of intensified stress, such as physical exertion. Two recent[14] meta-analyses[15] also concluded that vitamin C does not prevent the incidence of the common cold and has minimal or no effect on its duration. Overall, the use of vitamin C for ARI prevention or treatment remains a subject of considerable controversy.

Vitamin D

Low levels of vitamin D are linked to worse immune function[16] and increased incidence rates of ARIs[17], suggesting that supplementation could prevent them. A recent review[18] outlines the mechanisms of vitamin D’s modulatory effects on innate and adaptive immunity in the context of viral infections. Based on its immunomodulatory functions, the authors concluded that vitamin D is a safe and inexpensive form of adjunct therapy. Indeed, there is a large body of evidence on vitamin D’s ability to prevent and treat ARIs. Two major-meta-analyses support this idea:

A preprint of the most recent meta-analysis[19] from November 2020 investigated the effect of vitamin D supplementation in 46,331 participants ages 0–95 years from 45 randomized controlled trials (RCTs). In this study, vitamin D reduced the odds of incident ARI by 9% (odds ratio, OR 0.91). Interestingly, this effect was independent of baseline vitamin D levels, dose frequency, dose size, and study duration. Furthermore, the researchers also reported a significant heterogeneity across trials (I2 = 37%) and potential publication bias. Using subgroup analysis, they found that vitamin D’s protective effects were most notable when given at a daily dose of 400–1,000 IU (OR 0.70) for up to 12 months (OR 0.82). A subsequent exploratory analysis of RCTs fulfilling these criteria yielded a more significant protective effect of vitamin D (OR 0.58) without significant heterogeneity. These findings indicate that dose and duration could matter when it comes to vitamin D supplementation to prevent ARIs.

Another previous meta-analysis from 2017[20] covered in Study Deep Dives #31 (May 2017) analyzed individual participant data from 25 studies. This study also showed that vitamin D supplementation (daily or weekly, but not in large bolus) lowered the odds of ARI if vitamin D levels were deficient (less than 10 ng/mL or less than 25 nmol/L), but not in people with greater than 10 ng/mL (greater than 25 nmol/L) levels. Combined with the meta-analysis from 2020, these findings suggest that dose and duration, as well as frequency and baseline levels, may matter when it comes to judging the efficacy of vitamin D supplementation.

Zinc

Zinc is an essential mineral that plays numerous roles in the body, most notably as a catalytic and structural cofactor in hundreds of metalloproteins[21]. Often regarded as the gatekeeper of immune function[22], zinc plays an essential role in regulating pathways involved in innate and adaptive immunity. When taken in small doses repeatedly over the day, total daily doses of 10–40 mg zinc seem to substantially reduce the duration of common colds, as suggested by a recent meta-analysis[23]. However, it’s unclear if zinc also reduces the risk of getting colds. Furthermore, high doses may have notable side effects[24], including nausea, diarrhea, and vomiting. In severe cases, chronic zinc toxicity[25] (ingestion of more than 1 gram of zinc once or long-term supplementation with more than 100 mg zinc daily) manifests as copper and iron deficiency, with case[26] studies[27] reporting fatal outcomes.

In summary, the evidence suggests that zinc, vitamin C, and D supplementation may have some benefits for preventing and treating ARIs. Yet, the influence of dose and combinations of multiple micronutrients on individuals of different age groups remains mostly unclear. Understanding these influences is crucial to develop suitable supplementation strategies for effective and safe prevention and treatment of ARIs. The present systematic review and meta-analysis was thus designed to synthesize the current evidence from RCTs on micronutrient supplementation to prevent and treat ARIs in adults.

Figure 1: The lowdown on previous evidence about vitamin C, vitamin D, and zinc
Does it prevent ARIs?Does it reduce symptoms?Which dosing regimen has the best chance of working?

Vitamin C

Not for most people, but probably in highly active athletes.

Not duration, but maybe severity: around 8% in adults, and 14% in children.

1–8 grams daily at the onset of symptoms, ceasing after symptom resolution.

Vitamin D

Reduces odds of infection by around 9%, with better outcomes over longer time periods, lower dose, or in people with lower baseline levels

Unclear: not well studied.

400–1,000 IU daily over the longer term.

Zinc

Probably not.

Maybe severity, but more likely duration, which is cut by roughly three days.

Lozenges containing zinc acetate or gluconate at the onset of symptoms and ceasing after symptom resolution.
Daily total dose above 75 mg of elemental zinc daily may work best.
There’s some reason to suspect zinc acetate may be more effective than the gluconate salt, but there’s evidence that both work.

References: Hemilä et al. Cochrane Database Syst Rev. 2013 Jan.[2]
Martineau et al. BMJ. 2017 Feb.[20]
Jolliffe et al. medRxiv. 2020 Nov.[19]
Wang et al. Am J Trop Med Hyg. 2020 Jul.[23]
Hemilä et al. Open Forum Infect Dis. 2017 Apr.[28]

ARIs are a leading cause of death globally. Supplementation with micronutrients such as vitamin C, vitamin D, and zinc may be a beneficial, relatively safe, and cost-effective strategy to prevent and treat ARIs. However, the evidence remains mostly obscure, specifically regarding the influence of dosage and combinations of micronutrients in various age groups.

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