In December 2019, a novel virus of unknown etiology was detected in Wuhan, China [1]. The virus, which most often manifests as a severe respiratory syndrome, quickly spread from Wuhan, with cases appearing globally by 30 January 2020 [2]. It was quickly labeled by the World Health Organization as a public health outbreak of international concern and was later declared a pandemic ^[2][3][2,3]. This novel airborne pathogen, since named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes the disease now known as COVID-19 [2]. Despite containment efforts and the introduction of a vaccine in late 2020, by November 2021, over 5 million deaths had been attributed to the virus [4].

COVID-19 has been shown to manifest heterogeneously across different patient populations. Mild cases often result in flu-like symptoms, fever, or loss of taste and smell [5]. However, in severe cases, the effects of infection are more significant, resulting in an abnormal cytokine and chemokine response that causes systemic inflammation, affecting multiple tissues and organ systems [6]. Individuals with co-morbidities such as obesity, diabetes, cardiovascular disease, and cancer have a greater tendency to elicit this cytokine storm, making infection with COVID-19 particularly dangerous for these at-risk subgroups of the population ^{[7][8][9][10][11]}[7,8,9,10,11].

2. Nutraceuticals

Accordingly, attention has focused on protecting these vulnerable individuals, as well as the general public, from infection. However, the lack of efficacious pharmacological treatments for COVID-19 has led the public to seek alternative therapies, including nutraceuticals ^[12][13][12,13]. Nutraceuticals are foods or substances derived from food that may have a physiological effect or protect against disease. They have received heightened interest as some may affect the severity of COVID-19. For example, several observational studies have been published describing the association between specific nutrient deficiencies and COVID-19 severity and mortality ^[14][15][14,15]. A review by Vassiliou et al., which examined the role of vitamin D status in predicting outcomes in critical illness, concluded that there is an association between insufficient vitamin D status and infection, severity of illness, and mortality from COVID-19 [16]. Another review by Lordan et al. found an association between zinc deficiency and increased COVID-19 complications [17]. In vivo studies have also pointed to the role of nutraceuticals in the treatment and prevention of COVID-19, including a study by Corrao et al., which demonstrated an inverse relationship between C-reactive protein (CRP), a marker of systemic inflammation, and supplementation with vitamin C, vitamin D, and zinc [18]. Furthermore, there have been several theoretical papers discussing the potential mechanistic roles of nutraceuticals and how they might target the SARS-CoV-2 virus ^[19][20][21][19,20,21]. For example, for probiotics, one of the proposed mechanisms is by acting as angiotensin-converting enzyme (ACE) inhibitors, preventing SARS-CoV-2 from binding to ACE receptors in gastrointestinal cells [22]. For the keto-carotenoid astaxanthin (a terpene), it has been suggested that it may play a role in regulating reactive oxygen species formation, and therefore, supplementation may inhibit oxidative stress caused by SARS-CoV-2 [23]. Additionally, immunomodulatory nutraceuticals, such as glycophosphopeptide AM3, may be beneficial as either prophylactic or adjuvant therapy for SARS-CoV-2, as they improve the efficacy of action of natural killer cells and increase the production of anti-inflammatory cytokines [24]. While the use of most of these nutraceuticals is advocated on the basis of in vitro and in vivo observations for other similar viruses (e.g., SARS-CoV and MERS-CoV), there is a growing number of observational studies and randomized controlled trials (RCTs) specifically for COVID-19 that point to the potential efficacy of nutraceuticals in the fight against this novel pathogen.

The potential use of nutraceuticals for the supportive treatment of COVID-19 is particularly relevant and promising for those who are more susceptible to both infection and a severe course of the disease. Patients with cancer, in particular, may be at high risk of severe disease and mortality from COVID-19 depending on their disease stage, treatment, and type of cancer [25]. Generally speaking, there are numerous mechanisms behind the increased risk of COVID-19 infection in these patients, including immunosuppression from cancer therapy and immunosuppression from cancer itself [26]. Chemotherapy, which limits the growth of cancer cells, also impacts the production of white blood cells, leaving patients more susceptible to infection [27]. Patients with late-stage cancer are also at increased risk of infection as bone metastases can trigger an immune response that leads to bone marrow aplasia, resulting in a reduction of white blood cells, red blood cells, and platelets, which again leaves these individuals vulnerable to worse outcomes if infected with COVID-19 [28]. Additionally, patients with cancer tend to be older and have more co-morbidities, putting them at risk of a severe course of disease with COVID-19 [26].

It is therefore not surprising that the COVID-19 pandemic also resulted in increased fear and worsened anxiety and depression associated with a cancer diagnosis [29]. As such, many individuals, immunocompromised and healthy alike, have sought out ways to improve immunity [30]. Concurrently, popular media outlets have promoted the use of a variety of dietary supplements with putative immune-boosting potential that may help against COVID-19 infection ^[31][32][31,32]. This has led to a major increase in dietary supplement use during the pandemic, with a roughly 35% increase in North and South America, a 40% increase in Asia, and a 38% increase in Europe ^[30][33][30,33]. Concerningly, only 40% of these individuals consume supplements at the recommendation of a licensed medical professional [30].

Increased supplement use during the COVID-19 pandemic, especially without appropriate medical supervision, is troubling for oncologists and other oncology specialists. Specifically, one concern relates to the potential dampening of the cytotoxicity of chemotherapy by antioxidants and other supplements. The Diet, Exercise, Lifestyle, and Cancer Prognosis (DELCaP) study, a correlative study to the phase III SWOG SO221 [34], examined supplement use in patients with breast cancer and survivorship. This study found that the use of any antioxidant supplements, before or during breast cancer treatment, was associated with an increased risk of breast cancer recurrence and that vitamin B12 use during treatment was associated with poorer survival rates and poorer disease-free survival [34]. Results such as these indicate that nutraceutical use during or around chemotherapy may not be benign.

Given the rise in oral supplement use during the COVID-19 pandemic, as well as the increased interest in the efficacy of nutraceuticals in preventing or reducing the severity of COVID-19, we conducted a narrative review focusing on the safety of the most efficacious “anti-COVID-19” oral supplements for patients with cancer. As COVID-19 is still a present threat, individuals with cancer and their providers need up-to-date, evidence-based guidance for supplement use around their respective treatments.