Clinical Evaluation of Green Tea (Camellia sinensis) as a Respiratory Anti-Viral
Abstract
Green tea (Camellia sinensis) consumption originated in China and has been consumed for thousands of years due in part to its refreshing and pleasant taste and also to its purported health benefits. Over 200 compounds are synergistically present in green tea leaves including polyphenols, L-theanine, caffeine, tannins, and trace elements. Studies have found that polyphenolic compounds can constitute up to 30% of the total dry mass of green tea leaves. Catechins are the most abundant, potent, and well-studied of the polyphenolic flavonoids in green tea. Recent pandemics including influenza in 2009–2010 and the present severe acute respiratory syndrome coronavirus 2 (COVID-19) have put global pressures on the scientific, public health, and medical communities to research and develop other non-pharmaceutical preventative solutions against these infectious respiratory diseases. The aim of this review is to summarize the current clinical trials utilizing green tea as a respiratory anti-viral and bring recognition to non-pharmaceutical interventions (NPI) which hold the potential to decrease the total number of cases, spread, and severity of respiratory infections.
Introduction
Green tea (Camellia sinensis) consumption originated in China and has been consumed for thousands of years due in part to its refreshing and pleasant taste and also to its purported health benefits. The health-promoting actions of green tea are far reaching, including anti-oxidative, anti-tumor, anti-microbial, and anti-viral. Green tea has also been shown to have a beneficial impact on multiple diseases including cardiovascular disease (CVD), type-2 diabetes, obesity, and metabolic syndrome, breast, lung, esophageal, stomach, liver, and prostate cancers, psychiatric disorders, and inflammatory joint conditions (Musial et al 2020, Reygaert 2018).
Green tea has gained popularity in the Western world due to its greater concentration of naturally occurring antioxidants and polyphenols than other forms of tea. The preparation of green tea is unoxidized which preserves the polyphenolic constituents present in the leaves and buds of Camellia sinensis. Over 200 compounds are synergistically present in green tea leaves including polyphenols, L-theanine, caffeine, tannins, and trace elements. Studies have found that polyphenolic compounds can constitute up to 30% of the total dry mass of the green tea leaves. Catechins are the most abundant, potent, and well-studied of the polyphenolic flavonoids in green tea (Tallei et al 2021). Within a single cup (120 mL) of brewed green tea is an estimated 150mg of green tea catechins (GTC), of which 10 to 15% are epigallocatechin gallate (EGCG), six to 10% are epigallocatechin (EGC), two to 3% are epicatechin gallate (ECG), and 2% are epicatechin (EC) (Rawangkan et al 2021). GTCs have been shown to possess broad spectrum inhibitory viral action against many viruses such as Epstein-Barr virus (EBV), Human Immunodeficiency virus (HIV), Chikungunya virus (CHIKV), Zika virus (ZIKV), Influenza virus, and more (Xu et al 2017).
Recent pandemics including influenza in 2009–2010 and the present severe acute respiratory syndrome coronavirus 2 (COVID-19) have put global pressures on the scientific, public health, and medical communities to research and develop other non-pharmaceutical preventative solutions against these infectious respiratory diseases. Scientific evidence supports GTCs, particularly EGCG, as being an effective anti-viral agent against influenza and SARS-CoV-2 (Umeda et al 2021). In 1993, Nakayama’s research lab, was the first to discuss EGCG’s ability to inhibit influenza A (IVA) and B (IVB) as they found that the potent catechin was capable of preventing both IVA and IVB from absorbing onto the cell surface as EGCG agglutinated the viral particles while simultaneously preventing hemagglutination thereby blocking the infectivity of the virus (Xu et al 2017). EGCG also acts by inhibiting influenza viral replication by preventing the activity of viral RNA and modulating cellular oxidation-reduction reactions in vitro (Umeda et al 2021). As for SARS-CoV-2, Wang and colleagues (2021) tested EGCG’s ability to bind to COVID-19 spike protein along with 10 other plant polyphenols. The molecular docking study found EGCG to have the greatest binding affinity to the SARS-CoV-2 spike protein suggesting that it is superior at inhibiting COVID-19 infection of host cells relative to other polyphenols tested (Wang et al 2021). As green tea’s anti-viral action continues to be investigated clinically, it is important to note that even at high concentrations, polyphenols have been shown to be less toxic than other anti-viral drugs as they do not have cytotoxic effects (Tallei et al 2021).
The purpose of this review is to summarize the current clinical trials utilizing green tea as a respiratory anti-viral and bring recognition to non-pharmaceutical interventions (NPI) which hold the potential to decrease the total number of cases, spread, and severity of respiratory infections.
Human Trials of Anti-Viral Action of Green Tea
The search for studies investigating the respiratory anti-viral action of green tea in vivo identified 12 publications of interest summarized in Table 1. Of the chosen studies, three are observational trials, two are intervention trials, and the remaining seven are randomized-controlled trials (RCTs). The majority of the 12 studies are focused on influenza with publication dates ranging from 2006-2020. During the past two years however, COVID-19 has taken center stage as the pandemic disrupted human living across the globe, and research has quickly caught up producing three clinical trials on green tea and COVID-19 between 2021 and 2022.
Of the 12 publications, three RCTs (Ide et al 2014, Toyoizumi et al 2013, Yamada et al 2007) and one (Yamada et al 2006) intervention trial assessed the effects of gargling with green tea on incidence of influenza. The four studies all took place in Japan but among different populations including high school students (aged 15–17 years), healthy adults (20–65 years old), and elderly (>65 years old) residents in a nursing home. In all studies, the groups were instructed to gargle three times per day over the course of 60–90 days. In three of the four studies, a tendency towards lower incidence of infection was observed in the catechin gargling group, however it was not statistically significant. Yamada and colleagues (2006) found the incidence of influenza among elderly patients in a nursing home was statistically significantly reduced when gargling with the catechin extract over the 90-day study period. While there are many factors, including the patient’s age, exposure, and immune function, that make it challenging to compare the outcomes of the four trials. It should be noted that Yamada and colleagues (2006) used a lower total catechin concentration (200g/mL) than other groups (400
g/mL Yamada et al 2007 and 560
g/mL in Toyoizumi et al 2013), yet the percentage of EGCG was the highest at 60% compared to 18% used by Toyoizumi et al 2013. Additional clinical trials amongst different populations and using various concentrations of catechins and EGCG are needed to determine the effectiveness of gargling with green tea as a prophylaxis for influenza and other viral respiratory infections.
Three observational trials questioned participants about their green tea consumption in order to extract correlative data linking green tea consumption to change in incidence of infection. Two of the studies were performed by the same research group (Nanri et al 2021 and 2022), however the 2021 trial was a case-control study evaluating the amount of green tea consumed in individuals who were diagnosed with influenza (cases) compared to matched controls. In 2022, Nanri and colleagues switched their focus to the ever-present COVID-19, performing a serological study and questionnaire in healthcare workers to analyze the impact of drinking green tea on incidence of infection in an at-risk population. The third study, conducted by Park et al 2011 found that schoolchildren who consumed 1–5cups of green tea per day had an inverse risk of influenza infection.
While the majority of the 12 publications presented in Table 1 focused solely on GTCs or EGCG, a pair of RCTs provided participants with capsules formulated with a combination of catechins and L-theanine for the prevention of influenza and URTI. Both Rowe et al 2007 and Matsumoto et al 2011 found subjects in the intervention group had reductions in the symptom picture and clinical incidence of infection. One other trial (Bettuzzi et al 2021) used capsules as the route of administration, however their formulation only evaluated the effects of catechins. While this was a small intervention trial conducted in participants who were infected with COVID-19, all 10 participants were symptom free and fully recovered within the 15-day treatment window.
Of the remaining two studies in Table 1, one RCT conducted by Mahdavi-Roshan et al 2022 compared the effects of brewed green tea with black tea (control) on the psychological symptoms of individuals diagnosed with mild-to-moderate SARS-CoV-2. Interestingly, the subjects consuming the green tea reported reductions in fatigue, depression, and anxiety. Lastly, an intervention trial in healthcare workers randomized subjects into one of three (high catechin, low catechin, and placebo) groups. Participants receiving the high-catechin beverage had a statistically significantly lower incidence of URTI than the placebo group (Furushima et al 2019).
Table 1. Human Intervention Trials and Observational Studies of Green Tea as an Anti-Viral
| Reference | Methods | Outcomes |
| COVID-19 | ||
| Bettuzzi et al 2021 | Ten adult patients swab-positive and symptomatic (cough and fever greater than 38°C) for SARS-CoV-2 received at-home treatment with two sessions of inhalation and three capsules of ThE (total GTC: 840mg of which 595mg were EGCG) per day for 15 days. A CBC and differential along with markers of inflammation including CRP, ESR, and IL-6 were performed on recruitment day (T0) and following symptom relief (T1) – median of nine days later. | All 10 patients were symptom free and fully recovered within the treatment window, with seven out of 10 participants having a negative-COVID swab on a median of nine days from starting ThE therapy. Of the five high risk patients who were all over 52 years of age, all saw a statistically significant decrease (t-test, p-value < 0.03) in IL-6 following ThE treatment. ESR rates in seven of the 10 patients were elevated at T0 and had returned to normal by T1. |
| Mahdavi-Roshan et al 2022 | Forty adults, aged 20 and older, presenting with mild-to-moderate symptoms of COVID-19, confirmed by two positive PCR tests performed via nasopharyngeal or oropharyngeal swabs, were randomized to consume either three cups of green (intervention) or black tea (control) per day for four weeks. Patients’ fatigue, anxiety, and depression were assessed using the Chadler Fatigue Scale, Beck Depression Inventory-Fast Screen and State-Trait Anxiety Inventory questionnaires both at baseline and after completion of the intervention. | At four weeks, the green tea intervention group showed statistically significant reductions in fatigue, depression, and anxiety associated with mild-to-moderate COVID-19. |
| Nanri et al 2022 | Staff members (N=2640, 767 men and 1873 women; between the ages of 21 and 75 years old) of a referral hospital in Tokyo, Japan, participated in a serological survey and questionnaire. Investigators measured IgG and total antibodies to SARS-CoV-2 on three survey days over the one-month study period. Participants were also questioned about their green tea consumption. | Green tea consumption was not found to have a statistically significant reduction in SARS-CoV-2 infections. Participants who consumed greater than four cups of green tea per day showed a trend towards lower odds of infection, though not statistically significant. |
| Influenza | ||
| Yamada et al 2006 | One hundred twenty-four residents aged 65 and older of a nursing home in Japan participated in a three-month prospective study to evaluate the effects of gargling green tea extract on prevention of influenza infection. Seventy-six residents (24 men and 52 women) were instructed to gargle a tea catechin extract (comprising of 200 | The tea catechin group had a statistically significant lower incidence of influenza with only one resident (1.3%) infected compared to five of the control residents (10%) during the three-month study period. |
| Matsumoto et al 2011 | Healthcare workers (N=196) of three elderly care facilities in Higashimurayama, Japan, participated in a five-month study investigating the protective effects of green tea for influenza. Ninety-seven participants (21 men and 76 women; median age of 42.1 years) received capsules with GTC (378mg/day) and L-theanine (210mg/day) compared to 99 participants (23 men and 76 women; median age of 43.2 years) in the placebo group. The primary outcome of the study was the clinical incidence of influenza infection. Secondary outcomes gathered included influenza viral antigen measured by immunochromatographic assay and the period of time which the patient received the intervention prior to influenza infection. | The clinical incidence of influenza was statistically significantly lower in the GTC and theanine group (four participants) compared with the placebo group (13 participants) (adjusted OR 0.25, p-value = 0.022). The intervention group also had a lower rate of laboratory-confirmed influenza; however this was not found to be statistically significant (adjusted OR 0.17, p-value = 0.112). |
| Park et al 2011 | Schoolchildren (N=2050) between the ages of six and 13 attending one of nine elementary schools in Kikugawa City, Japan, participated in a questionnaire about their green tea consumption and personal health status including incidence of influenza infection, household exposure, preventative health measures, and influenza vaccination status. | Consumption of one to five cups of green tea on six or more days of the week supported an inverse association with incidence of influenza. Interestingly, the children who consumed greater than five cups of green tea per day saw no protective benefit against influenza infection. |
| Rowe et al 2007 | Healthy adults (N=124, 52 men and 72 women) between 21 and 70 (average age of 29) years of age were randomly assigned to the green tea extract (L-theanine and EGCG) capsule or placebo groups. Participants were told to take two capsules per day (once in the morning with breakfast and once in the evening with dinner) over a 12-week study period. A daily symptom log was used to assess cold and flu symptoms, the number of days participants experienced symptoms, and whether medical treatment was sought out. Blood samples were also taken at baseline (day zero) and at day 21 to assess the effect of the green tea capsules on the proliferation of γδ T-cells and the downstream production of interferon gamma, an antimicrobial cytokine. | Individuals in the green tea supplement group experienced 32.1% fewer cold and flu symptoms (p-value = 0.035), 22.9% fewer days with illness (p-value = 0.092), and 35.6% fewer symptoms days (p-value < 0.002) compared to participants in the placebo group. Additionally, participants in the supplement group proliferated 28% more γδ T-cells (p-value = 0.017) and secreted 26% more IFN-γ (p-value = 0.046) in response to γδ T-cell antigens than those taking the placebo. |
| Nanri et al 2021 | Japanese workers (N=4302) participated in an observational study examining the association of green tea consumption and influenza infection. To determine which subjects would represent the cases, workers were questioned about whether they had been diagnosed with influenza by a doctor between the months of November 2011 and April 2012. One hundred eighty-two subjects responded ‘yes’, however three were excluded, leaving 179 subjects to represent the influenza cases. For each influenza case, two matched controls (353 participants) were randomly selected for analysis. The 532 total participants were divided into three groups based on their green tea consumption – less than one cup per week, one to four cups per week, and five or more cups per week. | Consumption of green tea statistically reduced the rate of developing influenza (adjusted OR for the group consuming five or more cups of green tea per week was 0.61 compared to those drinking less than one cup of green tea per week, p-value = 0.028). |
| Ide et al 2014 | High school students (N=747) ages 15 to 17 years from six high schools in Schizuoka Prefecture, Japan, were randomized to the green tea or water (control) gargling groups. The green tea group (N=384) was instructed to gargle three times per day over the 90-day intervention while the water gargling group (N=363) followed the same procedure with tap water. The adherence rate was 73.7% (N=283) for the green tea group compared to 67.2% (N=244) in the water gargling group. The primary outcome of the study was laboratory-confirmed influenza determined by immunochromatographic assay for detection of influenza viral antigen. | The incidence of laboratory-confirmed influenza among high school students gargling with green tea (19 students; 4.9%) was not statistically significantly different compared to the water group (25 students; 6.9%) (adjusted OR 0.69, p-value = 0.24). |
| Yamada et al 2007 | Healthy subjects (N=404) aged 20 to 65 years where randomly assigned to either the catechin group – gargling with GTC extract containing 400 | The GTC group had half the incidence of influenza (two individuals; 1%) compared to the placebo group (four individuals, 2%), however the difference was not statistically significant. |
| Furushima et al 2019 | Healthcare workers (N=255) participated in an RCT assessing the efficacy of catechins to prevent acute URTIs. Of the 255 workers, 84 were randomized to the high-catechin group (57mg catechins and 100mg xanthan gum dosed three times per day), 85 in the low-catechin group (57mg catechins and 100mg xanthan gum dosed once per day), and 86 in the placebo group (0mg catechins and 100mg xanthan gum). The study was conducted over 12-weeks and the primary objective measurement was the incidence of URTI. | The incidence of URTI among healthcare workers in the high-catechin group (11 incidents) was significantly lower than in the placebo group (23 incidents) (OR 0.46; p-value = 0.04). There was no statistically significant difference in the incidence of URTI in the low-catechin group compared to the placebo. |
| Toyoizumi et al 2013 | Students (N=307, mean age of 15.8 years) attending high school in Kakegawa City, Japan, were asked to gargle three times per day with either green tea (total GTC content was 56mg/dL of which 18% was EGCG) or water. Of the total students who began the study, 225 participants adhered to the study protocol, including 119 students in the green tea group and 106 in the water gargling group. The incidence of infleunza infection served as the primary endpoint. | Comparison of the students adhering to the green tea and water groups, the incidence of influenza infection was lower in the green tea group (six participants) than the water group (10 participants), however the difference was not statistically significant (p-value = 0.31). |
Abbreviations
CBC = Complete blood count
CRP = C-reactive protein
CVD = Cardiovascular disease
EGCG = Epigallocatechin gallate
ESR = Erythrocyte sedimentation rate
GTC = Green tea catechin
IFN- = Interferon gamma
IL-6 = Interleukin-6
IVA = Influenza A virus
IVB = Influenza B virus
NPI = Non-pharmaceutical intervention
OR = Odds ratio
RCT = Randomized-controlled trial
SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2
ThE = Theaphenon E
URTI = Upper respiratory tract infection
Discussion
Preclinical studies of green tea have focused on polyphenols and GTCs as they have been shown to have many health-promoting actions. The objective of this review is to present several clinical studies that have been conducted to evaluate the respiratory anti-viral action of catechins, most notably EGCG, following the ingestion of green tea. As a potential NPI, the route of administration is important to consider for widespread implementation and thus the efficacy of different routes of administration for green tea consumption, i.e., drinking brewed green tea, supplementing with GTC extract, taking green tea capsules, and gargling with green tea were analyzed. None of the reviewed studies reported any safety concerns with the various interventions investigated.
Of the clinical trials reviewed in Table 1, some limitations were apparent, i.e., the size of the population, duration of the study, adherence rate and the possibility of bias due to outstanding confounding and unadjusted confounders, i.e., immune function, underlying chronic diseases, vaccination status, previous and recent viral exposure, dietary intake, etc.
Ide et al 2014 further discussed the limitations present in their study, including that the baseline consumption of green tea in both their intervention and control subjects was 70% consuming 1cup (200mL) or more of the tea per day. Expanding on this limitation, the current clinical research evaluating green tea as an anti-viral, documented in Table 1, took place in Japan, a country where 53% of adults report consuming green tea on a daily basis (Kim and Kim 2018). With the majority of the Japanese population already consuming green tea, the benefits of the intervention groups may not be as significant as in a population not taking in green tea on a daily basis. Additional large-scale randomized studies repeated in other populations where current green tea consumption is low would be welcomed.
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