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Antiviral effects
Abstract
Green tea (Camellia sinensis) and its extracts are well-recognized for their antioxidant content and associated human health benefits. In recent years, evidence from in vitro and human clinical trials has accumulated to indicate that green tea-derived antioxidants, including its chief catechin, epigallocatechin gallate (EGCG), may have potentially beneficial antimicrobial activity against various strains of pathogenic yeast, bacteria and viruses. This article aims to synthesize the available evidence concerning the use of green tea extracts in the prevention or treatment of human viral illnesses. The human viral illnesses on which the majority of the research is focused with respect to the use of green tea include viral upper respiratory tract infections (oral or buccal use), and human papilloma virus (HPV)-induced anogenital warts (topical use). Five human observational and randomized controlled trials support the use of green tea in the prophylaxis or treatment of influenza and/or the common cold. A recent systematic review and meta-analysis involving 1247 men and women found a proprietary green tea catechin formula to be effective in the topical treatment and prevention of recurrences of condylomata acuminata due to HPV.
Introduction
Besides water, tea is the most commonly consumed beverage worldwide (Mazzanti 2009). Prepared from fresh Camellia sinensis leaves, green tea is dry-heated or steamed, then rolled, dried and roasted (Mazzanti 2009). Constituents of unfermented Camellia sinensis leaves include polyphenols (20%-45% of dry weight), caffeine (2%-5%), amino acids (4%), lignin (6.5%), organic acids (1.5%), protein (15%) and chlorophyll (0.5%) (Mazzanti 2009, Meltzer 2009, Sarma 2008, Schneider 2009). EGCG ((-)-epigallocatechin gallate) is the most potent green tea antioxidant (Mazzanti 2009) and comprises 60%-80% of its catechin content (Schneider 2009).
Green Tea as an Antiviral Agent
In vitro and human evidence supports the potential antiviral prophylactic and treatment uses of green tea (Meltzer 2009, Rowe 2007, Schutz 2010). Green tea polyphenols, chiefly the catechins, are antioxidants to which a majority of the anti-microbial, anti-inflammatory, anti-tumor and immunostimulatory properties of green tea have been ascribed (Mazzanti 2009, Meltzer 2009, Schneider 2009). EGCG has direct in vitro viricidal, inhibitory and anti-infective properties against several viruses, including HIV (Hauber 2009, Nance 2009), herpes simplex virus (HSV-1) (Isaacs 2008), hepatitis A (Kuzuhara 2009) and B viruses (Xu 2008). Green tea catechin derivatives have been shown to have in vitro inhibitory effects on six influenza virus subtypes (Song 2007). EGCG is also highly anti-inflammatory and inhibits pro-inflammatory chemokines, prostaglandins and tumor necrosis factor (TNF), which contribute to symptom production during human viral infections (Rowe 2007).
Viral Upper Respiratory Tract Infections
A prospective cohort study reported influenza prophylaxis in nursing home residents who gargled with a green tea catechin solution. Seventy-six elderly nursing home residents in Japan gargled with a 200 μg/mL green tea catechin or control solution, three times daily for three months, while 48 age- and sex-matched
control participants gargled with a placebo solution. The catechin solution (60% EGCG) was approximately half the concentration of commercially available green tea beverages (Yamada 2006). All participants had received the World Health Organization (WHO)-recommended seasonal influenza vaccine prior to enrollment. Influenza A and B rapid assay was performed on nasal secretions of any resident who presented with influenza-like illness. Significantly fewer residents developed influenza B with treatment (1.3%) than control (10%), (p=0.028). None of the residents developed influenza A infection. This relatively small study was limited by the lack of dose-response determination for the treatment and non-randomization, which allowed residents to choose whether they would receive catechin or control solutions at the outset of the study (Yamada 2006).
Green tea constituents were identified to reduce incidence of influenza in health care workers in a recent, randomized, double-blind trial (Matsumoto 2011). Participants (n=197) were randomized to receive six capsules daily containing either a total of 378 mg catechin and 210 mg theanine, or placebo throughout influenza season (five months). The incidences of clinically-defined and laboratory-confirmed influenza infection and each individual’s symptom-free period were recorded. Treatment significantly decreased clinically-defined influenza (n=4, 4.1%) compared to placebo (n=13, 13%), (p=0.022). The incidence of laboratory-confirmed influenza was lower with treatment but did not significantly differ from control (p=0.112) (Matsumoto 2011). The high rate of influenza vaccination (92.9%) among all participants may have caused an underestimation of the prophylactic efficacy of catechin/theanine treatment and the need was suggested for further, large-scale randomized trials to confirm effects (Matsumoto 2011).
A large observational study reported an inverse relationship between green tea consumption and influenza infection in children (Park 2011). Elementary school students (n=2050) completed a series of two questionnaires during Japan’s endemic influenza A season. The consumption of 1-5 cups (200 mL/cup) of green tea daily compared with <1 cup per day was associated with a significantly lower risk of developing influenza. The incidence of clinically- and laboratory-confirmed influenza infection was also inversely related to consumption of green tea almost daily (i.e. ≥6 days per week) compared with <3 days per week. In contrast, no associations were observed between influenza incidence and conventional preventive measures such as hand hygiene, use of facemasks, or seasonal influenza vaccination in these children (Park 2011).
Rowe et al. (2007) conducted a randomized, double-blind, placebo-controlled study investigating whether a standardized green tea extract containing L-theanine and EGCG would prevent the development of influenza and common cold symptoms in healthy adults. Participants were randomized to receive either one treatment capsule containing a proprietary preparation of L-theanine and EGCG (ImmuneGuard; standardization not reported) (n=53), or placebo (n= 55) capsule twice daily with food. Participants were asked to log daily cold and flu symptoms, including fever, runny nose, sore throat, cough, headache, diarrhea and nausea during the 12-week study. During the 12-week study period, there was a 32.1% lower rate of symptom development in the treatment group (43.2%) versus control (63.6%), (p=0.035). There were 33.3% fewer symptomatic days in the treatment group versus placebo (p<0.022). There was a 22.9% lower incidence of illness (p=0.092) in the treatment group during the study period, but no significant differences in illness incidence from month to month (February to May). In the same study, peripheral blood mononuclear cells (PBMC) obtained from all subjects at baseline and on study day 21 were cultured for 24 hours in either media containing ethylamine (a catabolic product of L-theanine and a γδ T cell antigen) or control media.
PBMC obtained from participants after 21 days of treatment secreted 26% more IFN-γ in response to ethylamine than those from the placebo group (p=0.046), supporting the hypothesis that L-theanine could prime human γδ T cells to secrete more antimicrobial IFN-γ ex vivo (Rowe 2007). Adverse effects were mild and transient, with similar rates between treatment and control groups. A limitation of this study was the self-reporting of symptoms, which precluded both objective clinical diagnosis and the ability to rule out causation of symptoms by other illnesses such as asthma, bronchitis or allergy (Rowe 2007). Results of this study were consistent with previous work cited by the same authors, wherein PBMC obtained from subjects who had begun drinking five to six cups of green tea daily for one week secreted significantly more IFN-γ in response to γδ T cell antigens compared to baseline (Rowe 2007).
A multi-ingredient formulation containing green tea has been demonstrated to provide symptomatic benefits in the common cold (Schutz 2010). In a randomized, double-blind, placebo-controlled, multi-centre trial, participants with symptoms of a general feeling of sickness, headache and/or joint aches, sore throat and/or difficulty swallowing, hoarseness and/or cough, and stuffy nose/sniffle were randomly assigned to receive either a polyphenol-rich beverage containing green tea extract (3g/L), grape skin extract (12 g/L), grape seed extract (0.5 g/L), shiitake mushroom extract (0.05 g/L) and vitamin C (0.3 g/L) or placebo beverage containing water, sugar, citric acid and flavour, twice daily for 10 days. Participants underwent a total of three clinical examinations during the study period and logged their symptoms daily. By the third scheduled clinical examination, 19 of 49 treatment patients (38.8%) and 4 of 47 placebo patients (8.3%) who completed the study were asymptomatic (p<0.001). By their own evaluations, 41.9% of treatment patients and 5.0% of placebo patients were complaint-free by day seven of the study (p<0.001). Significant differences in sleep disorders, disturbances of daily activities and tissue use were also reported with treatment beverage (Schutz 2010). Blinded patient and physician ratings of the efficacy of the beverages received supported the superiority of the polyphenol treatment (Schutz 2010). Interestingly, the incidence of herpes labialis, a common concomitant symptom of the common cold, was significantly lower in the treatment group at the end of the study than that in the placebo group (Schutz 2010). The observed improvements in all common cold symptoms assessed suggested a general increase in defense and immunity rather than symptom-specific effects of the polyphenol beverage (Schutz 2010). This study supports the use of green tea extract in a multi-agent immunomodulatory approach to treatment of the common cold, although the presence of several antioxidant and immunomodulatory substances precludes the conclusion that the observed benefits could be solely attributed to green tea.
Human Papilloma Virus (HPV)
A recent meta-analysis demonstrated the efficacy of a Camellia sinensis leaf extract known as Polyphenon E (MediGene AG, Germany) in the topical treatment of anogenital warts (condylomata acuminata, HPV-6 and -11) (Tzellos 2011). Polyphenon E contains > 80% green tea catechins (Stockfleth 2008), which appear to inhibit HPV viral transcription and binding to cell receptors; have antiproliferative effects; and promote apoptosis when applied topically (Tzellos 2011 citing others). Three randomized, double-blind, placebo-controlled, multicentre studies enrolling a total of 660 men and 587 women met inclusion criteria for the meta-analysis; all three studies used Polyphenon E 15% or 10% (green tea catechins) ointment for HPV-induced anogenital warts. Both Polyphenon E formulations were found to be efficacious for clearance of lesions in both men and women, and compared to conventional therapies showed a low recurrence rate (Tzellos 2011). The treatment was generally well tolerated in all trials, with mild local skin reactions peaking at weeks two to four of treatment being considered essential to achieving a clinical response (Tzellos 2011).
Safety
Green tea infusion has been widely consumed throughout the world, at typical intake levels of one to three cups per day in the U.S. and up to nine cups per day in Japan, with a low incidence of adverse effects in adults (Sarma 2008 citing Imai 1997) and children (Park 2011). The most common adverse effects of green tea are gastrointestinal upset and central nervous stimulation from caffeine (Schneider 2009). As of 2009, two systematic reviews had identified 34 cases of possible or probable hepatotoxicity following intake of green tea products (Mazzanti 2009, Sarma 2008). Some of the case reports were confounded by the concomitant use, or non-reporting of other potentially hepatotoxic substances (Mazzanti 2009). The mechanism of liver damage is theoretically ascribed to paradoxical pro-oxidant activities of EGCG when present in high concentrations (Mazzanti 2009). Oral bioavailability of catechins is generally low but increases with fasting and repeated administration (Mazzanti 2009). Therefore, green tea extracts should be consumed with food (Sarma 2008). Extracts providing up to 690 mg total catechins and up to 150 mg caffeine per day are considered safe for adult use for up to 12 weeks; green tea extracts are contraindicated in individuals with liver disorders (Health Canada 2008).
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