Sara Grossman, PharmD

In March 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus was declared a global pandemic. Since then, the scientific community has been searching for methods of prevention, diagnosis, and treatment of the newfound virus. In the absence of proven treatments for coronavirus disease 2019 (COVID-19), a variety of pharmaceutical agents have been explored for their potential benefit. Alongside these pharmaceutical agents, a number of dietary supplements, such as vitamin C, zinc, and magnesium have been used as well. One particular vitamin that has caught the attention of both health care professionals and consumers is vitamin D. In this article, we will review the evidence describing a possible link between vitamin D and COVID-19.

Vitamin D is a fat-soluble secosteroid hormone that is primarily responsible for the maintenance of calcium and phosphorus homeostasis, which is important for bone health.

 Vitamin D3, or cholecalciferol, is produced in the skin through exposure to sunlight. Cholecalciferol is then converted to calcidiol (25-hydroxyvitamin D3) in the liver and then further converted in the kidneys to calcitriol (1,25-dihydroxyvitamin D3), the physiologically active form of vitamin D. 

In addition to the natural production of vitamin D3 in the body, exogenous vitamin D3 can also be obtained from dietary sources, such as eggs and fish, or from OTC supplements. Vitamin D2 (ergocalciferol) is another form of vitamin D that is available as prescription-only supplements. The serum concentration of vitamin D generally considered adequate for bone and overall health in healthy individuals is > 50 nmol/L (>20 ng/mL).

 It is estimated that 24% of the US population has vitamin D levels that are lower than 50 nmol/mL.

Groups at risk for having low vitamin D levels include older adults, those with limited sun exposure, individuals with dark skin, individuals with conditions that limit fat absorption, and those who are obese or have undergone gastric bypass surgery.

The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine established recommended dietary allowances (RDAs) that are necessary to maintain proper bone health and calcium metabolism in healthy individuals.

 The daily RDA for vitamin D for adults 18 through 70 years of age is 15 mcg (600 IU). The RDA for adults 71 years and older is 20 mcg (800 IU) per day.

In addition to its impact on bone health, vitamin D’s actions on genes expressed by immune cells, coupled with circumstantial but considerable evidence linking vitamin D deficiency with COVID-19 severity, have led to speculations that vitamin D status may play a role in the management of COVID-19.

 To identify literature that examined the relationship between vitamin D and COVID-19, we conducted a search of PubMed using combinations of the following search terms: 

COVID, COVID-19, coronavirus, vitamin D, deficiency, SARS-CoV-2, cholecalciferol,

 In order to obtain the highest level of evidence, we limited our search to meta-analyses.

In a systematic review and meta-analysis of 6 retrospective studies

 Munshi et al. examined the relationship between vitamin D serum levels and COVID-19 severity and prognosis.

 The investigators reported that based on data from 376 patients who were included in the studies, a low vitamin D level was significantly associated with poorer patient outcomes and prognosis. The investigators thus concluded that diagnosis of vitamin D deficiency could be a helpful adjunct in assessing patients' potential for developing severe COVID-19.

In a systematic review and meta-analysis by Pereira et al, the investigators explored the association between vitamin D deficiency and the prevalence of COVID-19 as well as its association with disease severity.

 A total of 25 observational studies involving 8176 patients with COVID-19 were included in the meta-analysis. The investigators reported that vitamin D deficiency was not associated with the development of COVID-19 infection. In contrast, the investigators did observe a positive association between vitamin D deficiency and disease severity. The investigators also noted that there was no support for vitamin D supplementation in individuals with normal blood vitamin D values with the aim of prevention, prophylaxis, or reducing the severity of the disease.

Liu et al. performed a systematic review and identified 10 case-controlled studies that were included in a meta-analysis aimed at examining the association between COVID-19 and vitamin D deficiency; a total of 376,596 subjects were included in this analysis.

The investigators reported that vitamin D deficiency or insufficiency was associated with an increased risk for COVID-19 infection. Furthermore, they noted that COVID-19 infected individuals had lower vitamin D levels than those who were not infected. The investigators thus concluded that low serum vitamin D status might be related to an increased risk for COVID-19.

A systematic review and meta-analysis by Shah et al. examined the relationship between vitamin D supplementation and the severity of COVID-19 illness, as measured by intensive care unit (ICU) stay and mortality outcomes.

 The meta-analysis included 2 randomized controlled trials and 1 case-control study, yielding a total of 532 hospitalized COVID-19 positive patients. The investigators identified a statistically significant lower ICU admission rate in those who were receiving supplements compared to those who were not supplemented with vitamin D. The investigators, however, reported that vitamin D supplements had no effect on mortality as compared with placebo treatment/usual care. The investigators concluded that the meta-analysis suggests a potential role for vitamin D in reducing COVID-19 severity.

Numerous studies assessing a relationship between vitamin D and COVID-19 infection and severity have been published over the past several months. These studies, which suffered from significant limitations, yielded mixed results. As such, we evaluated meta-analyses published on this topic, as they typically provide the highest level of evidence, especially when individual studies result in conflicting findings.

However, the meta-analyses that we identified did not provide conclusive evidence, especially as it relates to an association between low vitamin D levels and the incidence of COVID-19 infection. Collectively, the meta-analyses did seem to suggest an association between vitamin D supplementation or adequate vitamin D levels and better COVID-19 outcomes. It is important to note, however, that similar to the individual studies, the meta-analyses suffered from major limitations, and as such, drawing conclusions from the data is difficult.

Considering the limited and conflicting evidence, guidelines addressing this topic have not advocated for routine supplementation with vitamin D to prevent or treat COVID-19. The National Institutes of Health’s COVID-19 Treatment Guidelines state that there is insufficient evidence either for or against vitamin D supplementation in the prevention or treatment of COVID-19.

Likewise, the United Kingdom’s National Institute for Health and Care Excellence (NICE) COVID-19 Guidelines state that vitamin D supplementation should not be recommended for the sole purpose of prevention or treatment of COVID-19, except as a part of a clinical trial.

 NICE does encourage the public to follow general advice on vitamin D supplementation to maintain adequate bone health. As of the end of January 2021, more than 70 observational and interventional studies to investigate the relationship between vitamin D and COVID-19 were registered on the ClinicalTrials.gov registry. Additional and more robust data should facilitate a better understanding of this topic.

Dr Nathan is the director at the International Drug Information Center and associate professor at Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University.

Dr Grossman is a drug information specialist at the International Drug Information Center and adjunct assistant professor at Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University.

1. National Institutes of Health. Office of Dietary Supplements. Updated October 2, 2020. 

https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

2. Hossein-nezhad A, Holick MF. Vitamin D for health: a global perspective. 

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3. Amrein K, Scherkl M, Hoffmann M, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. 

https://doi.org/10.1038/s41430-020-0558-y

4. Griffin G, Hewison M, Hopkin J, et al. Vitamin D and COVID-19: evidence and recommendations for supplementation. 

. 2020;7(12):201912. Published 2020 Dec 1. doi:10.1098/rsos.201912

5. Munshi R, Hussein MH, Toraih EA, et al. Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. 

. 2021;93(2):733-740. doi:10.1002/jmv.26360

6. Pereira M, Dantas Damascena A, Galvão Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. 

. 2020;1-9. doi:10.1080/10408398.2020.1841090

7. Liu N, Sun J, Wang X, et al. Low vitamin D status is associated with coronavirus disease 2019 outcomes: A systematic review and meta-analysis. 

. 2021;S1201-9712(20)32600-X. doi:10.1016/j.ijid.2020.12.077

8. Shah K, Saxena D, Mavalankar D. Vitamin D supplementation, COVID-19 & disease severity: a meta-analysis. 

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9. National Institutes of Health. COVID-19 Treatment Guidelines: vitamin D. Updated July 17, 2020. Accessed February 1, 2021. 

https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/vitamin-d/

10. National Institute for Health and Care Excellence (UK). COVID-19 Rapid Guideline: vitamin D. Updated December 17, 2020. Accessed February 1, 2021. 

https://www.ncbi.nlm.nih.gov/books/NBK566063/

Articles

In this article, we will review the evidence describing a possible link between vitamin D and COVID-19. 

Vitamin D and COVID-19: An Evidence-Based Review

According to the American Burn Association, about 450,000 serious burn injuries occur in the United States every year that require medical attention.

 Overall, the goals of treatment are to control pain, remove dead tissue, prevent infection, reduce scarring, and regain function.

Depending on the burn severity, appropriate management may involve initial resuscitation and stabilization, pain management, and wound care, which often involves the use of antimicrobial agents.

 One antimicrobial agent commonly used in the management of burns is silver sulfadiazine (SSD). Formulated as a 1% topical cream, SSD is FDA-approved as an adjunct for the prevention and treatment of wound sepsis in patients with second- and third-degree burns.

Anecdotally, though, SSD may have become the agent of choice for all types of burns, including minor burns.

 Despite SSD’s popularity, compelling evidence to support its use in the management of burns is lacking. The aim of this article is to provide the reader with an assessment of SSD’s utility for managing burns.

Silver sulfadiazine, which combines silver ions with a sulfonamide moiety, has broad antimicrobial activity. It is bactericidal for many gram-negative and gram-positive bacteria and also has activity against yeast.

 Silver sulfadiazine is considered to be safe, however, dermatologic, gastrointestinal, hematologic, hepatic, neurologic, and renal effects have been reported with its use. The product is contraindicated in patients with severe hypersensitivity reactions following application, pregnant women at or close to term, premature infants, and in infants during the first 2 months of life.

 Although SSD is available as a prescription medication marketed under the brand names Silvadene and Thermazene, it is available generically, as well. The average wholesale price for a 50 g jar of SSD cream is approximately $15.00 and the wholesale acquisition cost is approximately $12.00.

To assess whether clinical evidence supports the use of SSD in the management of burns, we performed a search of PubMed using the terms “silver sulfadiazine” and “burns”. In order to obtain the highest level of evidence, our search was limited to meta-analyses and systematic reviews. Although our search yielded a total of 24 articles, this review focuses on the 5 meta-analyses and systematic reviews wherein the emphasis was on the comparison of SSD with other interventions in the management of burns. The comparative interventions included aloe vera, bacitracin, collagenase, honey, petrolatum, as well as various other preparations/dressings.

A 2019 systematic review and meta-analysis by Maciel et al. evaluated the efficacy of SSD versus numerous other treatments when used for wound healing in burn patients.

 The authors analyzed 11 randomized controlled trials (RCTs) and identified wound-healing time as the primary outcome. The authors concluded that the comparator treatments were statistically superior to SSD with respect to the mean time for complete wound healing.

In a 2018 systematic review and meta-analysis, Nímia et al. examined the efficacy of SSD versus silver-containing and non-silver-containing dressings.

 The outcomes that were assessed included time to wound healing and rate of infection. After analyzing 24 RCTs, the authors concluded that dressings with and without silver showed better outcomes than SSD with respect to time to wound healing. Additionally, burns treated with non-silver-containing dressings were less likely to become infected than burns treated with SSD; there were no differences between silver-containing dressings and SSD with respect to this outcome.

A 2017 systematic review and meta-analysis by Aziz et al. examined the effects of honey as compared with SSD in the management of burns.

 The primary outcomes included time to complete wound healing and proportion of infected wounds rendered sterile (free from bacteria). The meta-analysis of 9 RCTs found that honey was more effective than SSD in the aforementioned parameters. The authors concluded that although this analysis favored honey over SSD, high quality evidence to support the use of honey in clinical practice is scarce.

A 2016 systematic review by Heyneman et al. analyzed 52 RCTs to evaluate the role of SSD as compared with a variety of burn dressings in the treatment of partial-thickness burns.

 The outcome parameters included wound healing, infection, pain, and patient satisfaction. The authors concluded that most viscous, solid, and biological dressings had better healing properties, resulted in less pain, and increased patient satisfaction compared to SSD. With respect to the infection parameter, the efficacy of SSD was comparable to the other dressings. The authors also concluded that since rapid wound closure is essential to obtain optimal functional and aesthetic outcomes, the standard use of SSD in the noninvasive treatment of burn wounds can no longer be supported. 

A 2014 systematic review and meta-analysis by Rashaan et al. assessed 7 RCTs to evaluate the efficacy of SSD as compared to non-silver treatments in the management of partial-thickness burns in children.

The outcome measures included wound healing time, number of dressing changes, pain, length of hospital stay, infection, and grafting rates. The authors concluded that non-silver treatment may be preferred over SSD with respect to wound healing time, dressing changes, pain, and length of hospital stay.

Although SSD is commonly prescribed for the management of burns, numerous systematic reviews and meta-analyses found that overall, SSD was inferior to the various agents that it was compared with. Moreover, SSD seemed to have had a negative impact on some of the outcomes related to wound healing. In view of the above, and as expressly noted in some of the aforementioned reports, the use of SSD as an agent of choice in the management of burns should be discouraged.

American Burn Association. Advanced burn life support course: Provider manual 2018 update. Published 2018. Accessed December 1, 2020. http://ameriburn.org/wp-content/uploads/2019/08/2018-abls-providermanual.pdf

Burns: Diagnosis and treatment. Mayo Clinic. July 28, 2020. Accessed December 1, 2020. https://www.mayoclinic.org/diseases-conditions/burns/diagnosis-treatment/drc-20370545

Silvadene. Package insert. Pfizer Inc; 2020. Accessed December 1, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c437213a-1cd4-445e-a39f-bbcacb9f746f

Chung JY, Herbert ME. Myth: silver sulfadiazine is the best treatment for minor burns. 

. 2001;175(3):205-206. doi:10.1136/ewjm.175.3.205

RED BOOK: IBM Micromedex. Truven Health Analytics/IBM Watson Health; 2020. Accessed December 1, 2020. https://www.ibm.com/products/micromedex-red-book

Maciel ABDS, Ortiz JF, Siqueira BS, Zanette GF. Tissue healing efficacy in burn patients treated with 1% silver sulfadiazine versus other treatments: a systematic review and meta-analysis of randomized controlled trials. 

. 2019;94(2):204-210. doi:10.1590/abd1806-4841.20198321

Nímia HH, Carvalho VF, Isaac C, Souza FÁ, Gemperli R, Paggiaro AO. Comparative study of silver sulfadiazine with other materials for healing and infection prevention in burns: A systematic review and meta-analysis. 

. 2019;45(2):282-292. doi:10.1016/j.burns.2018.05.014

Aziz Z, Abdul Rasool Hassan B. The effects of honey compared to silver sulfadiazine for the treatment of burns: A systematic review of randomized controlled trials. 

. 2017;43(1):50-57. doi:10.1016/j.burns.2016.07.004

Heyneman A, Hoeksema H, Vandekerckhove D, Pirayesh A, Monstrey S. The role of silver sulphadiazine in the conservative treatment of partial thickness burn wounds: A systematic review. 

. 2016;42(7):1377-1386. doi:10.1016/j.burns.2016.03.029

Rashaan ZM, Krijnen P, Klamer RR, Schipper IB, Dekkers OM, Breederveld RS. Nonsilver treatment vs. silver sulfadiazine in treatment of partial-thickness burn wounds in children: a systematic review and meta-analysis. 

. 2014 Jul-Aug;22(4):473-82. doi: 10.1111/wrr.12196

One antimicrobial agent commonly used in the management of burns is silver sulfadiazine.

Reevaluating the Use of Silver Sulfadiazine Cream in the Management of Burns

Cough is the most common symptom prompting patients to seek health care in the ambulatory care setting. Although a cough can be secondary to a variety of medical conditions, the most common etiology is a viral upper respiratory infection (URI).

 A nonprescription drug commonly used to manage a cough is guaifenesin which is labeled for use as an expectorant. According to a 2019 survey of pharmacists, Mucinex and Robitussin, 2 branded formulations of guaifenesin, were recommended close to 2.5 million times per month during that year.

Guaifenesin’s use as a medicinal substance dates back to as early as the 1500s when Native Americans used an extract of the guaiac tree as a natural remedy for various ailments.Today, guaifenesin is an FDA-approved drug that is sold in a variety of oral formulations, including liquid dosage forms as well as immediate- and extended-release solid dosage forms. The recommended adult dose of guaifenesin is 200 mg to 400 mg every 4 to 6 hours, as needed, for the immediate-release formulations and 600 mg to 1200 mg every 12 hours, as needed, for the extended-release formulations. Although guaifenesin’s mechanism of action is not fully understood, it is thought to act by irritating the gastric mucosa and stimulating respiratory tract secretions. This, in turn, increases the volume and decreases the viscosity of bronchial secretions.

 In addition to being an expectorant, guaifenesin has also been proposed to act as an antitussive by inhibiting cough-reflex sensitivity in patients with URI.

 Guaifenesin is generally well tolerated with the most commonly reported adverse effects being nausea, vomiting, and gastrointestinal discomfort.

Despite its popularity and its status as an FDA-approved expectorant, evidence to support guaifenesin’s efficacy is limited and conflicting. The purpose of this article is to present the reader with data from clinical trials which were designed primarily to evaluate the use of guaifenesin in the management of cough associated with URI.

In 1977, Robinson et al. described a double-blind trial that examined whether guaifenesin was superior to placebo in facilitating the coughing up of sputum and ameliorating dry cough in patients with an acute URI.

 Two hundred and thirty-nine adult patients with moderate-to-severe cough were randomly assigned to receive 200 mg of guaifenesin syrup or placebo 4 times per day for 3 days. Efficacy was evaluated subjectively through patients’ assessments of symptoms and of the quality and quantity of sputum as well as through physicians’ assessments of patients’ symptoms at different time points throughout the study. The investigators reported that, overall, in patients with dry or productive cough, guaifenesin decreased cough frequency, cough intensity, and chest discomfort, and resulted in a significantly thinner sputum. Likewise, in patients with productive cough, guaifenesin was found to facilitate raising sputum. Notably, these findings were not consistent across all the assessment parameters and time points at which they were measured.

In 1982, Kuhn et al. described a double-blind study that evaluated the effect of guaifenesin on cough frequency in young adults with a cough secondary to a cold.

 Sixty-five patients were randomly assigned to receive 400 mg of guaifenesin syrup or placebo every 6 hours for a total of 6 doses. Guaifenesin’s efficacy was evaluated subjectively through a completion of a patient self-assessment questionnaire throughout the course of the study and objectively through a cough count using an audio recording of the patients (performed on 42 of the study participants). The investigators reported that in the subjective evaluation, guaifenesin was associated with a statistically significant decrease in sputum thickness in patients who experienced a productive cough; however, guaifenesin failed to significantly reduce the number of coughs when assessed by objective cough counts. 

In 2003, Dicpinigaitis and Gayle described a randomized, double-blind trial that evaluated guaifenesin’s effect on cough reflex sensitivity in 14 healthy volunteers and 14 patients with acute viral URI.

On 2 separate days, each participant received a 400-mg guaifenesin capsule or placebo. A capsaicin cough challenge test, which involves the inhalation of capsaicin, a known tussive agent, was performed 1 to 2 hours after the ingestion of guaifenesin or placebo. Guaifenesin’s efficacy was determined by the concentration of capsaicin needed to induce 5 or more coughs (C5). The investigators reported that in the participants with URI, mean log C5 afterguaifenesin was significantly higher than after placebo; in the healthy volunteers, such a difference was notnoted. The investigators concluded that a single, 400-mg dose of guaifenesin inhibits cough reflex sensitivity to inhaled capsaicin in individuals with acute viral URI.

In 2009, Dicpinigaitis et al. described a study that assessed the antitussive effect of guaifenesin and benzonatate, alone and in combination, in 30 adult patients with acute URI.

 In this double-blind, placebo-controlled, crossover study, patients were randomized to receive capsules containing benzonatate 200 mg, guaifenesin 600 mg, benzonatate 200 mg plus guaifenesin 600 mg, or placebo. Patients received a single dose of 3 of the 4 aforementioned treatments on 3 separate days within a 7-day period. The study utilized the capsaicin cough challenge and its main efficacy measure was C5. The investigators reported that mean log C5 was significantly greater with guaifenesin as compared with placebo; mean log C5 with benzonatate plus guaifenesin was also significantly greater than with guaifenesin alone. The authors noted that guaifenesin and the combination of guaifenesin and benzonatate inhibited cough-reflex sensitivity in patients with acute URI.

In 2014, Hoffer-Schaefer et al. described a study that evaluated the impact of guaifenesin on sputum properties associated with a productive cough secondary to an acute URI.

 In this double-blind, placebo-controlled, multicenter study, 378 adolescent and adult patients were randomized to receive 1200 mg of extended-release guaifenesin or placebo every 12 hours for 7 days. No significant differences were found in the any of the sputum measures in the guaifenesin group as compared with the placebo group.

In 2015, Bennett et al. described a study assessing the effect of guaifenesin on mucociliary clearance and cough clearance as measured by the rate of removal of inhaled radioactive tracer particles; other sputum properties were also assessed.

Participants were also asked to subjectively rate the severity of the chest congestion, mucus thickness, and cough. In this double-blind, placebo-controlled study, 38 adult patients with acute URI were randomized to receive a single 1200-mg dose of extended release guaifenesin or placebo. Assessments were conducted at several time points over the course of the post-dose period. Guaifenesin use did not result in significant improvements in any of the objective outcome measures as compared with placebo. A statistically significant difference favoring guaifenesin was noted in the subjective assessment of mucus thickness at one of the evaluation time points.

Few clinical trials have been conducted to assess guaifenesin’s efficacy in the management of cough secondary to URI. The trials varied in their methodologies (eg, dosage forms, dosage regimens, outcome measures) and generally included a small number of participants. In these trials, guaifenesin was found to be effective in some, but not all, of the assessments of efficacy. Given these mixed results, drawing firm conclusions about guaifenesin’s efficacy is challenging. Nonetheless, given its overall safety profile, the use of guaifenesin may be considered on a case-by-case basis for patients who are bothered greatly by their cough.

1. Frei CR, Frei BL. Upper Respiratory Tract Infections. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. 

Pharmacotherapy: A Pathophysiologic Approach, 11e

2. Contemporary Clinic. Pharmacy Recommendations. 

https://www.contemporaryclinic.com/otcguide/coughcoldallergy/expectorants

3. Albrecht HH, Dicpinigaitis PV, Guenin EP. Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections. 

. 2017;12:31. Published 2017 Dec 11. doi:10.1186/s40248-017-0113-4.

4. Guaifenesin. In: IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Accessed August 27, 2020.

5. Robinson RE, Cummings WB, Deffenbaugh ER. Effectiveness of guaifenesin as an expectorant: a cooperative double-blind study. 

6. Kuhn JJ, Hendley O, Adams KF, Clark JW, Gwaltney JM. Antitussive effects of guaifenesin in young adults with natural colds. 

7. Dicpinigaitis PV, Gayle YE. Effect of guaifenesin on cough reflex sensitivity. 

8. Dicpinigaitis PV, Gayle YE, Solomon G, Gilbert RD. Inhibition of cough-reflex sensitivity by benzonatate and guaifenesin in acute viral cough. 

. 2009;103(6):902-906. doi:10.1016/j.rmed.2008.12.008.

9. Hoffer-Schaefer A, Rozycki HJ, Yopp MA, Rubin BK. Guaifenesin has no effect on sputum volume or sputum properties in adolescents and adults with acute respiratory tract infections. 

 2014;59(5):631-636. doi: 10.4187/respcare.02640.

10. Bennett WD, Kala A, Duckworth H, et al. Effect of a single 1200 mg dose of Mucinex on mucociliary and cough clearance during an acute respiratory tract infection. 

 2015;109(11):1476-1483. doi: 10.1016/j.rmed.2015.09.017.

Despite its popularity and its status as an FDA-approved expectorant, evidence to support guaifenesin’s efficacy is limited and conflicting. 

Reevaluating the Use of Guaifenesin in the Management of Acute Cough Associated With the Common Cold

Some patients affected by the coronavirus disease 2019 (COVID-19) may be concerned about hyposmia (reduced ability to smell) or anosmia (loss of smell) that they experience after contracting the virus. Although the exact prevalence of olfactory disturbances in patients with COVID-19 is not known, various studies reported the rates to be as low as 5% and as high as 98%.

 In a telephone survey of Italian patients diagnosed with COVID-19, the investigators found that olfactory disturbances were reported early on in the course of the disease and that severe disturbances were more likely to be reported by female patients.

 Likewise, the investigators found that patients who reported severe olfactory disturbances were significantly younger than patients with no or mild olfactory disturbances.

Reports of olfactory disturbances are not unique to the COVID-19 pandemic. Patients with other viral upper respiratory infections (URIs) may develop olfactory loss as a result of nasal inflammation, mucosal edema, and obstruction of airflow into the olfactory cleft.

 Episodes of olfactory loss secondary to URIs are usually self-limiting and generally do not persist beyond the resolution of URI symptoms. At times, however, the loss of smell may persist for an extended period of time (months to years) and is thought to result from a more direct injury to the olfactory system that is induced by the viral infection. With respect to patients with COVID-19, unpublished data and anecdotal reports suggest that the resolution of olfactory symptoms usually occurs within approximately 2 weeks. At the present time, it is unknown what proportion of patients with COVID-19 develop persistent olfactory loss.4 When these symptoms do persist for an extended period of time, they may be troubling and concerning to the affected individuals. In such cases, patients or their caregivers may turn to health care professionals for advice and guidance on management strategies.

Numerous drugs and supplements have been studied for the management of viral-associated olfactory loss.

 Oral and intranasal steroids have been used for post-infectious olfactory loss, but they are not recommended because of the risks associated with their use.

 Intranasal sodium citrate, intranasal vitamin A, or systemic omega-3 have shown some efficacy but definitive evidence to support their use in patients with COVID-19 is lacking.4 In the absence of proven pharmacotherapy, olfactory training (OT) has been recommended as a primary treatment strategy for viral-associated olfactory loss.3 Through OT, the brain is re-trained to correctly interpret the neurologic signals received from various odorants. The training consists of smelling 4 different odors twice per day, every day. Specifically, patients are advised to smell 1 odor at a time for 15 seconds while trying to recall what it previously smelled like. Patients are then advised to rest for 10 seconds and repeat the process until all 4 odors have been sampled. While specific scents have been suggested for OT (eg, rose, eucalyptus, lemon, clove), patients can select specific scents that they wish to incorporate into their training. Many individuals purchase essential oils containing the odors that are selected for inclusion in their training. The training process continues with the same 4 odors for a 3 month period, after which training begins with a new set of odors. Olfactory training has been shown to be effective in multiple clinical studies but results vary.

 The improvement in smell is often slow and occurs over many months or even years.

In summary, olfactory loss is frequently reported by patients with COVID-19. Although in some patients, the condition is self-limiting, in others it may persist for an extended period of time. In the absence of proven pharmacotherapy, OT is recommended as a primary management strategy.

1. Chung TWH, Sridhar S, Zhang AJ, et al. Olfactory dysfunction in coronavirus disease 2019 patients: observational cohort study and systematic review. 

2. Mercante G, Ferreli F, De Virgilio A, et al. Prevalence of taste and smell dysfunction in coronavirus disease 2019 [published online ahead of print, 2020 Jun 18]. 

. 2020;e201155.doi:10.1001/jamaoto.2020.1155.

3. Soler ZM, Patel ZM, Turner JH, et al. A primer on viral‐associated olfactory loss in the era of COVID‐19. 

. 2020;10.1002/alr.22578.doi:10.1002/alr.22578.

4. Whitcroft KL, Hummel T. Olfactory dysfunction in COVID-19: diagnosis and management. 

 2020;323(24):2512–2514.doi:10.1001/jama.2020.8391.

Some patients affected by COVID-19 may be concerned about hyposmia (reduced ability to smell) or anosmia (loss of smell) that they experience after contracting the virus. 