Influenza

Influenza

1 Overview

Summary and Quick Facts

  • The flu is a common respiratory infection caused by the influenza virus. Importantly, antibiotics will not help the flu. Although the flu usually resolves on its own, it may progress to serious problems like pneumonia, especially in older people or people with suppressed immune systems.
  • In this protocol you will learn about treatments that may reduce flu symptoms. You will also learn about some novel strategies and supplements to support healthy immune system function.
  • When coupled with annual vaccination, the treatment strategies and supplements discussed in this protocol may help minimize flu risk and improve treatment outcomes.
  • Supplements such as vitamin D and zinc support a healthy immune function and have been shown in several cases to decrease risk of infections, such as colds and the flu.

What is Influenza?

The flu, which can be caused by several strains of influenza, is a highly contagious and potentially deadly viral infection of the nose, throat, and lungs. The majority of cases resolve without treatment within 2 weeks. However, if left untreated, severe complications can arise, especially in high risk groups (eg, elderly, people with existing medical conditions, immunocompromised, etc.).

Influenza viruses can be classified as type A, B, or C, with numerous subtypes. The flu virus is continually mutating, making annual vaccination essential. “Flu season” generally peaks in the autumn and winter months.

Natural interventions such as vitamin D and vitamin C may help prevent the flu and ease symptoms.

What are the Signs and Symptoms of the Flu?

  • Sudden onset of high fever
  • Fatigue
  • Head and body aches
  • Cough, congestion
  • Sore throat (not always present)

Note: The flu can be distinguished from a common cold by severity of symptoms; cold symptoms are generally mild and develop over several days, while flu symptoms are much more severe and develop within a few hours. If you suspect you have the flu, call a healthcare provider without delay.

What are Ways to Prevent the Flu?

  • Get vaccinated yearly for the flu. While this does not guarantee immunity, it is the most effective and least expensive intervention.
  • Wash or sanitize hands and surfaces frequently
  • Stay home if you are sick
  • Avoid touching your eyes, nose, and mouth
  • Cough or sneeze directly into the crook of your elbow, not into your hand or the air
  • Avoid sick people when possible or wear a mask
  • Wash all linens, eating utensils, and dishes used by sick people before others use them
  • Exercise regularly and eat a balanced diet

What are Conventional Medical Treatments for the Flu?

  • DO NOT take antibiotics for the flu. Antibiotics will not work, and can contribute to the development of drug resistant pathogens.
  • Over-the-counter drugs (eg, mild analgesics, decongestants, etc.) can provide symptomatic relief for uncomplicated cases of the flu (see the Common Cold protocol).
  • Antiviral drugs:
    • Baloxavir, a recently approved antiviral that inhibits mRNA synthesis
    • Neuraminidase inhibitors (eg, oseltamivir [Tamiflu] and zanamivir [Relenza])
    • Adamantanes (eg, amantadine [Symmetrel] and rimantadine [Flumadine])
    • Ribavirin (eg, Copegus, Rebetol, Virazole) may be prescribed for highly pathogenic or resistant forms of influenza.

What are Emerging Therapies for the Flu?

  • Cimetidine, a stomach acid medication, may boost the immune system and help fight off viral infections. However, patients at risk for cytokine storm (a potentially deadly overreaction of the immune system) should avoid cimetidine.
  • Statins, cholesterol-lowering drugs, may help regulate immune response to the flu and reduce the risk of death in patients hospitalized for the flu.

What Natural Interventions May Be Beneficial for the Flu?

  • Vitamin D. Vitamin D has a significant role in regulating the immune system. Daily or weekly supplementation and higher vitamin D levels are associated with a decreased risk of seasonal viral infection and acute respiratory infections.
  • Vitamin C. Vitamin C is required for fighting infection and has been shown to reduce the incidence and severity of colds. High doses administered before or immediately after symptom onset have been shown to lessen reported cold and flu symptoms.
  • Zinc. Zinc plays an important role in maintaining healthy immune function. Supplementation may enhance the immune system and shorten the duration of some viral infections.
  • Selenium. Selenium boosts the immune system and can provide protection against some pathogens. Deficiency promotes the spread of influenza, increases susceptibility to viral infection, and may be associated with significantly higher mortality rates from influenza than a selenium-supplemented diet.
  • Green tea. Epigallocatechin gallate (EGCG), a component of green tea, has been shown to kill the influenza virus and decrease the viral load in blood during chronic viral infection. In addition, green tea can decrease flu-like symptoms by reducing inflammation.
  • Andrographis paniculata. Andrographis has been used for its anti-viral properties in traditional Asian medicine for centuries. In a clinical trial conducted on people with the flu, andrographis sped flu recovery and reduced the risk of complications.
  • Melatonin. Melatonin helps combat many types of viral infections. Its administration is associated with increased production of antibodies and may be especially helpful in elderly populations, because its concentrations decline with age.
  • Other natural interventions that may aid with flu prevention and/or relieve symptoms include dehydroepiandrosterone (DHEA), reishi, elderberry, vitamin E, and others.

2 Introduction

Preamble

If you are reading this because you have developed flu symptoms, it is critical that you act quickly to halt the rapid replication of viruses occurring in your body at this very moment. Go to the nearest health food store or pharmacy and purchase:

  1. Zinc Lozenges: Completely dissolve in mouth one lozenge containing 18.75 mg of zinc acetate every two waking hours. Do not exceed 8 lozenges daily, and do not use for more than three consecutive days.
  2. Garlic: Take 9000-18 000 mg of a high-allicin garlic supplement each day until symptoms subside. Take with food to minimize stomach irritation.
  3. Tamiflu: 75 mg twice daily. This is a prescription drug and is only effective for certain flu viruses.
  4. Vitamin D: If you do not already maintain a blood level of 25-hydroxyvitamin D over 50 ng/mL, then take 50 000 IU of vitamin D the first day and continue for 3 more days. Slowly reduce the dose to around 5000 IU vitamin D daily. If you already take around 5000 IU of vitamin D daily, then you probably do not need to increase your intake.
  5. Cimetidine: Take 800-1200 mg daily in divided doses. Cimetidine is a heartburn drug that has potent immune enhancing properties. (It is sold in pharmacies over-the-counter.)
  6. Melatonin: 3 to 50 mg at bedtime.

Do not delay implementing the above regimen. Once a flu virus infects too many cells, it replicates out of control and strategies like zinc lozenges will not be effective. Treatment must be initiated as soon as symptoms manifest!

Introduction

The flu is a highly contagious, potentially deadly viral infection of the nose, throat, and lungs. It is caused by a number of influenza virus strains (CDC 2012b; MedlinePlus 2012; NFID 2012). The flu is responsible for over 200 000 hospitalizations and thousands of deaths annually in the United States (Ye 2012; Clark 2011; CDC 2011c; NFID 2012).

In the majority of flu cases the illness is self-limiting with recovery typically within 2 weeks (CDC 2012b; Mgbemena 2012; NIH 2008). However, some groups are at high risk for developing flu-related complications (eg, bacterial pneumonia), including people 65 or older, people with certain medical conditions (eg, asthma, COPD, diabetes), and those with weakened immune systems (CDC 2012b; CDC 2011d; Falagas 2010).

Although vaccination is the most effective and inexpensive flu prevention measure, conventional treatment strategies for severe cases of influenza are mainly limited to certain classes of antiviral drugs (eg, neuraminidase inhibitors such as oseltamivir [Tamiflu®]) (Wu 2010; Tang 2010; Cao 2011). However, among otherwise healthy individuals, these antiviral drugs are only associated with a modest 1-day decrease in flu duration (Jefferson 2006). This might be because antiviral therapy is often initiated too late after symptom onset to avert severe illness. Tamiflu® may be especially effective when initiated within 24-48 hours of contracting influenza virus.

Life Extension recommends early and aggressive action at the first sign of flu symptoms. Unfortunately, people often wait until they are very sick before seeking influenza treatment. This delay can preclude rapid eradication of the infectious agent. In some cases, treatment delay can be lethal.

This protocol will discuss the nature of the influenza virus, how it is spread, and how its transmission can be prevented. Conventional flu prevention and treatment strategies will be examined, as will novel drug strategies that may reduce severity of symptoms during influenza infection. Several scientifically studied natural therapies that may prevent or ease symptoms of the flu will also be reviewed.

3 Signs and Symptoms of the Flu

Influenza, commonly called the “flu”, is a respiratory infection that is different from the “common cold” or the “stomach flu” (NIAID 2011). Influenza is primarily characterized by inflammation of tissues that line the nasal cavity, throat, the inner surface of the eyelids (ie, conjunctiva), and the lungs (NIH 2012a; Kim 2011; Sanders 2011; Snelgrove 2011). Common clinical symptoms of influenza include a sudden onset of fever, fatigue, headache, and muscle aches (Shobugawa 2012). Although both the flu and the common cold are caused by a viral infection of the respiratory system, symptoms of the common cold rarely include severe fever, headaches, or extreme exhaustion (NIAID 2011). More information is available in the Common Cold protocol.

Common Cold vs. The Flu: Comparison of Characteristics

Feature

Colds

Flu

Etiological Agent

>200 viral strains; rhinovirus most common

3 strains of influenza virus: influenza A, B, and C

Site of Infection

Upper respiratory tract

Entire respiratory system

Symptom Onset

Gradual: 1-3 days

Sudden: within a few hours

Fever, chills

Occasional, low grade (<101° F)

Characteristic, higher (>101° F),
lasting 2-4 days

Headache

Infrequent, usually mild

Characteristic, more severe

General aches, pains

Mild, if any

Characteristic, often severe and affecting the entire body

Sore throat

Common, usually mild

Sometimes present

Cough, chest congestion

Common; mild-to-moderate, with hacking, productive cough

Common; potentially severe dry, non-productive cough

Runny, stuffy nose

Very common, accompanied by bouts of sneezing

Sometimes present

Fatigue, weakness

Mild, if any

Usual, may be severe and last 2-3 weeks

Extreme exhaustion

Rarely

Frequent, usually in early stages of illness

Season

Year around, peaks in winter months

Most cases between November and February

Antibiotics helpful?

No, unless secondary bacterial infection develops

No, unless secondary bacterial infection develops

(Roxas 2007; MD Consult 2012; Utah Dept. Health 2010; CDC 2011e; Oklahoma State Dept. of Health 2011)

4 Understanding Influenza

Influenza viruses are classified based on their protein composition. They are divided into types A, B, and C, with type A having numerous subtypes (NIAID 2011; Hayden 2011). Among the 3 types of influenza, type A viruses are the most dangerous to humans and are associated with the most severe disease (NIAID 2011). Influenza type C is less problematic because most people acquire antibodies to influenza C early in life (Gouarin 2008).

In nature, the flu virus continuously mutates (NIAID 2011). Every year or so, these mutations can create completely new viruses that are often not harmful (Hayden 2011). However, sometimes mutations can alter viral structure in such a way that the virus can suddenly jump the barrier between species and infect humans. In fact, it is the precise assortment of surface proteins that will dictate the severity of each influenza strain (NIAID 2011). This can occasionally result in the formation of a novel flu virus that is better able to evade the host’s immune system, becoming more dangerous to humans (NIAID 2011). These mutations can also allow influenza to evolve resistance to conventional antiviral drugs (Afilalo 2012).

Transmission of the influenza virus

The flu virus is mostly spread by tiny droplets (ie, aerosols) that are expelled when a person sneezes, coughs, or even speaks. These droplets contain virus-laden respiratory secretions and can transmit influenza if they land in the mouths or noses of bystanders. Also, an individual might become infected by touching their mouth, eyes, and/or nose after previously touching a surface where the virus has landed (CDC 2011a).

Once the virus has found its way to the host respiratory tract, it will attempt to invade the epithelium (ie, cells that line the tissue surface) (Afilalo 2012). Within 4 to 6 hours of invading a cell, the influenza virus will begin to replicate and the host cell will begin to release large numbers of replicated virus progeny in a process known as “virus shedding”. These released viruses are then free to invade any nearby susceptible cells, thus starting a new replication cycle in each newly infected cell. The time from initial infection to symptomatic illness (ie, incubation period) ranges from 1–4 days, with an average of 2 days (Hayden 2011). The contagious period generally begins 24 hours prior to symptom onset and can continue for up to a week after becoming sick. Young children and those with a weakened immune system may be contagious for longer periods (CDC 2012b).

Influenza among populations (epidemics and pandemics)

When disease outbreaks are confined to one geographical area, they are referred to as epidemics (Hayden 2011). An epidemic is upgraded to a pandemic once it has spread to a large number of people in other countries or continents through person-to-person contact (Hayden 2011; NIH 2012b; NIAID 2011). Out of the 3 influenza pandemics that occurred during the 20th century, the most deadly was the Spanish flu (influenza type A/H1N1) of 1918-1919, which caused approximately 50 million deaths worldwide (Gasparini 2012; Bavagnoli 2009; Taubenberger 2011). In 1997, the novel avian influenza virus (H5N1) first began infecting humans in China and has since been sporadically transmitting from birds to humans across a wide geographical area including Asia, Europe, and Africa (Gasparini 2012). The H5N1 is currently considered to be the most deadly influenza virus that has crossed the species barrier (Michaelis 2009).

The first pandemic of the 21st century was attributed to the swine-origin influenza A (H1N1) virus, which was originally identified in April 2009 in Mexico (Combes 2011; van Ierssel 2012). The H1N1 epidemic spread quickly and was confirmed worldwide in just a few weeks, forcing the World Health Organization to officially declare it a pandemic on June 11, 2009 (Combes 2011). Although most cases of H1N1 resulted in a self-limited respiratory illness, this infection also caused severe progressive pneumonia and death, even among young healthy individuals (Combes 2011; Bai 2011; van Ierssel 2012). Moreover, most of the deaths that resulted from H1N1 occurred among individuals younger than 65 years old (Hayden 2011). As of August 2010, the World Health Organization reported that H1N1 had crossed into at least 214 countries and was responsible for approximately 18 500 deaths worldwide (WHO 2010). Research suggests the true mortality rate may be 15-times higher than originally reported (Dawood 2012).

Seasonal influenza

Seasonal influenza is also a major public health threat in the United States, as it is associated with significant suffering and death each year (Seidman 2012). The seasonal flu is a term used to describe the annual outbreaks of influenza that largely occur in late fall and winter in temperate climate regions (NIAID 2011; Atmar 2010).

Annual flu outbreaks are known for having a significant impact on not only the infected individual, but also society as a whole (Pedersen 2009). For example, between 5 and 20% of the United States population is infected by the seasonal flu each year (NIAID 2011). Globally, seasonal influenza epidemics account for 3–5 million severe cases of illness (Yoo 2011) and up to 1 million deaths each year (Music 2012). In the United States, seasonal influenza is associated with more than 200 000 hospitalizations and thousands of deaths each year (Lynch 2007; CDC 2011c; NFID 2012); thus, it represents a significant economic burden with up to about 5 billion dollars annually in medical costs (Lambe 2012; Mao 2012; Afilalo 2012).

Although a majority of the suffering and death attributable to seasonal influenza is due to infections among the elderly (Afilalo 2012), seasonal influenza has been known to cause clinical illness and hospitalization in all age groups (Banzhoff 2012). Outbreaks of seasonal influenza generally begin abruptly, with a surge in clinical cases of pediatric fever and respiratory illnesses, which is followed by a similar surge in symptoms among adults. These seasonal outbreaks usually last for about 3 months, and spread within a community during a 2–3 week peak period (Afilalo 2012).

Among otherwise healthy adults, seasonal influenza is typically associated with about 6–8 days of clinical symptoms such as sudden fever, general fatigue, headache, or muscle aches (Shobugawa 2012; Pedersen 2009; CDC 2012b). Additional common symptoms can include dry/unproductive cough, sore throat, and a runny/stuffy nose (CDC 2012b; Hayden 2011). The seasonal flu can also cause more serious complications, such as secondary bacterial pneumonia, ear infections, sinus infections, dehydration, and worsening of chronic medical conditions including asthma, diabetes, and congestive heart failure (CDC 2012b). Among those in the workforce, seasonal influenza infection is associated with an average of 4–5 days of sick leave each year (Pederson 2009). In fact, taking sick leave for influenza is recommended in order to decrease the risk of transmission (Pedersen 2009).

The Role of Cytokines

Cytokines are a multifunctional group of signaling proteins that regulate immune and inflammatory responses and are released by cells in response to infection. With most infections, the release of cytokines is controlled in order to maintain a balance between killing the virus and minimizing damage to healthy cells (Tisoncik 2012; Danese 2007). However, when certain severe types of influenza A virus (such as H5N1) invade endothelial cells and begin to proliferate, the cells will occasionally flare out of control and mount an excessive host immune response (Schmolke 2009). Also called a “cytokine storm,” this clinical phenomenon involves the massive overproduction of inflammatory cytokines, such as tumor necrosis factor (TNF), interferons (IFN), colony-stimulating factors (CSFs), and interleukins (ILs) (Tisoncik 2012; Walsh 2011a; Phung 2011; Teijaro 2011).

Cytokine Storm

Cytokine storm – a massive inflammatory response mounted by a robust immune system in response to a pathogen – is a predictor of suffering and death, especially among young, otherwise healthy individuals with highly competent immune systems (Ma 2011). Although cytokine storms are associated with tissue destruction in the lungs (Us 2008), autopsy studies of H5N1 patients have shown that this dysregulation of cytokines might also be the cause of multiple organ tissue damage (Gao 2010). The initiation of a cytokine storm is not only limited to H5N1, but is also associated with a wide assortment of viral, bacterial, and immunologic diseases (Walsh 2011b).

One potential method for controlling cytokine storms is to restrict the host's immune response, in order to reduce the self-inflicted inflammatory damage (Walsh 2011a; Danese 2007). However, this has been met with little success. Other therapeutic strategies are aimed at reducing inflammation (Tisoncik 2012). Agents shown to suppress excessive cytokine production, including fish oil, green tea (Rowe 2007), black cumin seed oil (Majdalawieh 2010; Salem 2000; Salem 2011; Salem 2005), and Vitamin D (Cannell 2006), are advised.

5 Flu Prevention

Vaccination

In an effort to reduce the burden of influenza, the World Health Organization Global Influenza Surveillance Network (WHO GISN) tracks and analyzes the epidemiology and antigenic specificity (or surface protein characteristics) of circulating influenza viruses in order to figure out which strains are appropriate vaccine candidates (Russell 2008; Ravin 2012).

According to experts, vaccination is the most effective and least expensive intervention for preventing influenza (Cao 2011). The Centers for Disease Control and Prevention (CDC) recommends that all individuals over the age of 6 months be vaccinated yearly (CDC 2019). However, vaccination does not guarantee flu prevention (Lang 2012; Ornskov Pedersen 2012; Osterholm 2012). Public health agencies must correctly determine which influenza strains are likely to be most prevalent during upcoming flu seasons. Strains thought unlikely to cause an outbreak in the coming season are not included in vaccines. Sometimes one of the strains not included in the vaccine can unexpectedly cause an outbreak and the population will not be protected (Ambrose 2012; Allsup 2001).

Immunosenescence, the decline in immune function that naturally accompanies aging, along with inflammaging, the tendency toward chronic low-grade inflammation that also occurs with aging, limit the effectiveness of the influenza vaccine in the elderly (Ciabattini 2018; Andrew 2019). Taking steps to optimize immune responsiveness may improve protection against flu by strengthening antiviral immune activity and increasing the effectiveness of vaccination. Factors that regulate immune function, including physical activity, nutrition, sleep, stress, and mood, have all been reported to impact vaccine responsiveness (Ayling 2018). In addition, taking probiotics and prebiotics prior to vaccination is one strategy shown to enhance the antibody response to flu vaccine in older adults (Lei 2017; Yeh 2018).

Other considerations

Other important non-pharmaceutical interventions for preventing influenza can be recalled by using the acronym “WHACK”, as in “WHACK the Flu” (Stebbins 2011; Yardley 2011; Mayo Clinic 2011):

W ash or sanitize your hands frequently.

H ome is where you should be when you are sick.

A void touching your eyes, nose, and mouth.

C over your coughs and sneezes with a tissue or the inner crook of your elbow.

K eep your distance from sick people when possible or wear a mask.

In addition to avoiding those infected with influenza, the CDC also recommends all linens, eating utensils, and dishes used by sick individuals be thoroughly washed in a dishwasher or by hand with soap and water prior to being used by anyone else (CDC 2011a).

6 Conventional Flu Treatment

Treatment of the flu typically aims to ease symptoms and prevent complications. In many cases, over-the-counter medicines can relieve symptoms such as aches and fever. However, this approach may not be sufficient for those at high risk for flu-related complications. In high-risk cases, such as hospitalized people with severe illnesses, antiviral therapy is employed (MD Consult 2012).

The decision to initiate antiviral drug therapy for the treatment of influenza depends on a number of factors, such as individual patient characteristics, the time elapsed since symptoms began, as well as the prevalence and virulence of influenza circulating in the surrounding community (Afilalo 2012; Fiore 2008; Ebell 2005). The goal of treatment with antiviral drugs is to reduce signs and symptoms of influenza and prevent hospitalizations or death in patients with severe disease (Hsu 2012).

Antiviral drugs traditionally used to treat influenza include neuraminidase inhibitors (eg, oseltamivir [Tamiflu®] and zanamivir [Relenza®]) and adamantanes (eg, amantadine [Symmetrel®] and rimantadine [Flumadine®]).

Neuraminidase inhibitors interfere with viral enzymes called neuraminidases (ie, enzymes present on the surface of influenza viruses that are necessary for the virus to exit infected host cells). Neuraminidase inhibitors can therefore reduce the spread and release of the virus (Ghebrehewet 2016). This class of drugs can produce gastrointestinal side effects such as nausea and vomiting and some inhaled forms have rarely been reported to cause bronchospasm in asthmatics (Jefferson 2014). They should be administered within 24‒48 hours of symptom onset.

Adamantanes are thought to exert antiviral action by inhibiting early stages of viral replication via interfering with M2 protein channels (Dong 2015). These drugs can cause potentially serious side effects, such as heart rhythm irregularities, hallucinations, and respiratory distress, especially in the elderly or those with impaired kidney function (MD Consult 2007). Due to high rates of resistance among common influenza virus strains over recent years, the CDC does not currently recommend adamantanes for flu prevention or treatment (CDC 2018).

In 2018 the US Food and Drug Administration approved a new antiviral medication, a cap-dependent endonuclease inhibitor called baloxavir marboxil (Xofluza®), for use in treating uncomplicated influenza in adults and children aged 12 and older. Cap-dependent endonuclease inhibitors are a new class of antiviral drugs, of which baloxavir marboxil is the only one approved for use in the United States (Principi 2019). Baloxavir marboxil works by inhibiting an enzyme that allows influenza to interact with host cell machinery to produce viral proteins (Principi 2019; Locke 2019). It has demonstrated effectiveness against four different types of influenza virus, including types that originate in humans, other mammals (such as swine and cattle), and birds. Baloxavir marboxil has been found to be at least as effective as oseltamivir at reducing viral load and shortening duration of symptoms (Locke 2019; Mishin 2019), and because of its mechanism of action, it may be used in patients with influenza strains that are resistant to neuraminidase inhibitors (Principi 2019). Baloxavir marboxil is typically administered as a single oral dose to patients experiencing flu symptoms for 48 hours or less. Mild side effects such as nausea, headaches, diarrhea, and respiratory symptoms have been reported (Locke 2019).

Patients infected with a highly pathogenic or resistant strain of influenza (such as H5N1) may be prescribed the antiviral drug ribavirin (eg, Copegus®, Rebetol®, Virazole®) (Fediakina 2011). Ribavirin, although not directly indicated for influenza, has multiple potential clinical applications (due to its broad-spectrum antiviral activity) and has been used to treat influenza on a limited basis (Razonable 2011; Schleiss 2011; Beigel 2008). Adverse effects of ribavirin may include nausea, joint and muscle pain, bone marrow suppression, heart rhythm irregularities, and pancreatitis (MD Consult 2007).

One of the most important factors before taking antiviral drugs is how long it has been since the onset of influenza-like symptoms. In general, antiviral drug treatment should be started within 48 hours of symptom onset (MMWR 2012; CDC 2018); clinical studies have demonstrated little benefit when these agents are given later in the course of the illness (Fiore 2008).

The CDC recommends judicious use of antiviral medications because most cases of seasonal influenza are self-limiting (NIH 2008) and antiviral drugs can cause side effects and have a limited ability to decrease duration of symptoms (CDC 2018). Another important issue is the emergence of drug-resistant strains of influenza viruses. Influenza viruses are known to rapidly develop resistance to both neuraminidase inhibitors and adamantanes (Hussain 2017; Duwe 2017). Even with the newest antiviral medication, baloxavir marboxil, evidence of resistance has been seen within a few days of treatment in approximately 10% of patients (Uehara 2019). For these reasons, use of antiviral drugs for flu is generally limited to high-risk groups such as children <2 years old and adults ≥65 years old, the immunocompromised, morbidly obese, and long-term care residents. High-risk groups may also be prescribed antiviral drugs on a preventive basis. In addition, the CDC allows that treatment with a neuraminidase inhibitor or baloxavir marboxil can be considered for otherwise healthy people with confirmed or suspected flu, as long as their symptoms have not been present for more than 48 hours (CDC 2018). Since influenza is caused by a virus and not a bacterium, taking antibiotics is not recommended and could lead to unwanted side effects and/or a future antibiotic-resistant infection (CDC 2012a).

7 Novel Flu Treatment Strategies

Cimetidine

The over-the-counter drug cimetidine is a histamine receptor type 2 (H-2) blocker approved by the Food and Drug Administration (FDA) for inhibition of gastric acid secretion or gastric and duodenal ulcer disease (Kubecova 2011; Scheinfeld 2003). Cimetidine has also been shown to augment the immune system. It appears to accomplish this by mitigating the effects of specialized immune cells called T-regulatory cells, which normally suppress immunity (Shin 2012; Arae 2011; Zhang 2011; Wang 2008). Since cimetidine enhances the immune system, it may be beneficial for combating various infections and has been utilized as an immune modulator for the treatment of several diseases such as herpes simplex infections and mucocutaneous candidiasis (Stefani 2009; Kumar 1990). However, since cimetidine stimulates pro-inflammatory cytokines and inhibits regulatory T cells (Wang 2008), it may exacerbate the development of a cytokine storm and should be avoided by individuals at risk for cytokine storm.

Statin-Class Drugs

Statins (eg, simvastatin, atorvastatin, and lovastatin) reduce serum lipids (ie, cholesterol) and are used to prevent and treat vascular diseases (Goldfine 2012). Further research into the actions of statin drugs has revealed that these drugs can down-regulate inflammatory immune responses to certain influenza viruses (Vandermeer 2012; Almuti 2006). A 2007 study found that moderate-dose statin users had a dramatically reduced risk of mortality from influenza and chronic obstructive pulmonary disease (COPD) compared to non-statin users (Frost 2007). Furthermore, a 2012 study revealed that statin use may be linked with reduced mortality in patients hospitalized with influenza (Vandermeer 2012).

8 Targeted Natural Interventions

In addition to consuming a healthy, balanced diet and exercising regularly, the following natural interventions may help avoid influenza infection or ease flu symptoms (Siu 2012; Gardner 2011; Louria 2007).

Vitamin D – Vitamin D has a significant role in the regulation of the human immune system and may reduce the risk of certain viral and bacterial infections by modulating immune response to such pathogens (Beard 2011; Grant 2010). Vitamin D blood levels appear to be related to respiratory infections, in that a 4 ng/mL increase in vitamin D levels correspond to about a 7–10% decrease in infection risk (Berry 2011; Cannell 2011). Furthermore, vitamin D deficiency may be linked to an increased risk of influenza and respiratory tract infection (Beard 2011; Cannell 2008). In a comprehensive review, researchers analyzed data from 10,933 participants in 25 randomized controlled trials looking at the effect of vitamin D on risk of acute respiratory infections, such as colds and influenza. The analysis found that those receiving daily or weekly vitamin D supplements, in doses ranging from 300 IU to 4000 IU per day, had a 19% reduction in acute respiratory infection risk, and those with vitamin D deficiency (levels below 25 nmol/L or 10 ng/mL) at the beginning of the trial experienced a greater protective effect. A risk reduction was not seen in participants who received individual large doses of vitamin D (30,000 IU or more), either once or at intervals of one to three months, whether alone or in addition to daily or weekly doses (Martineau 2017). In one clinical trial, 1200 IU of vitamin D reduced influenza A incidence by 64% compared with placebo among schoolchildren who had not been taking any additional vitamin D supplements (Urashima 2010). Similarly, in a 3-year trial, postmenopausal African American women taking 2000 IU of vitamin D daily reported significantly fewer incidence of influenza compared to those taking a placebo (Aloia 2007).

Vitamin D is derived in the skin from its precursor 7-dehydrocholesterol following stimulation by ultraviolet B (UVB) light (eg, sunlight). It is then eventually converted to 1,25-dihydroxyvitamin D3, which combines with vitamin D receptors to trigger an immune response that may be effective against influenza infection (Shaman 2011). Studies suggest that vitamin D also helps prevent excessive expression of inflammatory cytokines (Cannell 2006, 2011). Because of this, it may help to prevent the occurrence of cytokine storm (Grant 2009).

Life Extension suggests an optimal 25-hydroxyvitamin D blood level of 50 – 80 ng/mL. If you do not already maintain a blood level of 25-hydroxyvitamin D over 50 ng/mL, then take 50, 000 IU of vitamin D the first day and continue for 3 more days. Slowly reduce the dose to around 5000 IU vitamin D daily. If you already take around 5000 IU of vitamin D daily, then you probably do not need to increase your intake.

Vitamin C – In order to protect against infections (particularly viral), the human immune system requires a sufficient daily intake of vitamin C. Vitamin C enhances the production and action of white blood cells; for example, it increases the ability of neutrophils (a type of white blood cell) to attack and engulf viruses (Heimer 2009; Jariwalla 1996; Anderson 1984). Daily 1-gram (g) doses of vitamin C have been shown to reduce the incidence and severity of a cold (Holt 2010). Additionally, very high doses of vitamin C administered before or after symptom onset have been shown to reduce reported cold and flu symptoms. Among asymptomatic young adults 18–30 years of age, three 1000 mg doses of vitamin C daily, or hourly doses of 1000 mg vitamin C for the first 6 hours after symptom onset followed by 1000 mg doses of vitamin C 3 times daily in symptomatic individuals, reduced reported flu and cold symptoms by 85% compared to placebo (Gorton 1999).

Zinc – Zinc is required for numerous metabolic processes and serves as a cofactor for a large number of enzymes (Eide 2011; Classen 2011). Zinc plays an important role in maintaining healthy immune function (Roxas 2007). Zinc deficiency, which is common among the elderly, can impair cell-mediated immunity. This, in turn, can increase the risk of infection. Rectifying zinc deficiency through supplementation has been shown to be efficacious for a variety of infections. This is because zinc affects the expression of interleukin-2, which helps the immune system ward off viruses (Roxas 2007). In a comprehensive analysis of the effects of zinc lozenges on viral upper respiratory tract infections, doses greater than 75 mg daily were shown to reduce symptom duration by 20 to 42%. The authors of this study emphasized that doses lower than 75 mg daily did not shorten sickness duration (Hemila 2011). Life Extension Magazine® published a comprehensive overview of the evidence suggesting that zinc acetate lozenges dissolved in the mouth every two waking hours may be an ideal approach during the early stages of upper respiratory infections.

Selenium – Selenium serves as a powerful antioxidant in nearly all human tissues (Hoffmann 2008). In addition, selenium boosts the immune system and can provide protection against some pathogens (Hoffmann 2008; Goldson 2011). Data show that selenium deficiency promotes the spread of influenza by increasing its virulence, and increases susceptibility to viral infection by interfering with human influenza-induced host defense responses (Jaspers 2007; Stỳblo 2007; Beck 2003). An animal model showed a selenium-deficient diet was associated with significantly higher mortality from influenza than a selenium-supplemented diet (Yu 2011).

Vitamin E – Vitamin E is not only a potent antioxidant, but it is also involved in a variety of physiologic processes, ranging from cognitive performance to immune function (Dror 2011). For example, vitamin E supplementation has been shown to enhance certain functions of the human immune system and decrease influenza virus titers in preclinical models of influenza (Han 2000). Animal studies have shown that vitamin E deficiency may precipitate viral genome changes that increase virulence and may contribute to greater severity of influenza (Louria 2007).

Lactoferrin – Lactoferrin is an iron-binding component of whey protein (Roxas 2007; Orsi 2004). It is known to possess some immune-modulating effects as well as an ability to exert a broad spectrum of activity against bacteria, fungi, protozoa, and viruses (Roxas 2007; Orsi 2004). Laboratory studies reveal that lactoferrin inhibits viral infection by interfering with the ability of certain viruses to bind to cell receptor sites and prevents entry of viruses into host cells (Waarts 2005; Berlutti 2011). Lactoferrin may be beneficial for alleviating symptoms or complications of viral infections, like the flu, because it suppresses free radical-mediated damage and decreases availability of essential metals to microbial cells pathogens (Roxas 2007).

Elderberry – The purplish-black fruits of the elderberry plant are a rich source of antioxidants and have long been considered a folk remedy for the treatment of influenza (Ozgen 2010). Clinical studies have revealed that the extract of elderberry appears to be a safe, effective, and cost-efficient treatment option for those infected with influenza. Laboratory research indicates this clinical effect is achieved through elderberry’s ability to interfere with the influenza virus’ replication process (Zakay-Rones 2004). A 2009 study demonstrated that elderberry extract was capable of inhibiting influenza H1N1 infection by binding to the outside of the virus and keeping it from invading host cells (Roschek 2009).

Green tea – Green tea, which contains a powerful antioxidant called epigallocatechin gallate (EGCG), has been utilized as a medicinal product for the last 4700 years (Cooper 2012; Rowe 2007). EGCG has a variety of beneficial properties with regard to influenza. For example, it has been shown to directly kill the influenza virus and decrease the number of viruses found in blood during chronic viral infection. In addition, EGCG can decrease flu-like symptoms by reducing inflammation (Rowe 2007). The antiviral effects of green tea have been demonstrated for nearly all age groups (Park 2011; Rowe 2007; Guralnik 2007).

Beta-glucans - Beta-glucans are naturally-occurring glucose polymers that constitute the cell walls of certain plants and fungi (Akramiene 2007; Medeiros 2012; Cordeiro 2012). These polysaccharides have been shown to increase host immune defense and are associated with enhanced macrophage and natural killer cell function (Pence 2012; Akramiene 2007).

Korean researchers demonstrated anti-viral properties of beta-glucans against influenza in a swine model. In this experiment, one group of piglets received beta-glucans for 3 days before being infected with swine flu, while another group received only placebo. The lungs of piglets not given beta-glucans showed significantly more damage than those that received beta-glucans. Furthermore, piglets pre-treated with beta-glucan had significantly higher concentrations of natural immune-enhancing substances, including interferon-gamma, in fluid obtained from the lungs within a week of infection. Researchers concluded that beta-glucans reduced signs of lung disease and the viral replication rate in the piglets (Jung 2004).

In another experiment, young piglets were exposed to porcine reproductive and respiratory syndrome virus. White blood cells were then removed and exposed to varying concentrations of beta-glucans. Beta-glucans increased the production of interferon-gamma in a dose-dependent manner, leading scientists to conclude that soluble beta-glucans may enhance innate viral immunity (Xiao 2004).

AndrographisAndrographis paniculata, an annual plant used as a medicinal herb among Asian cultures for centuries, has been reported to have anti-inflammatory, anti-hypertensive, anti-viral, and immune-modulating properties (Yang 2010; Akbar 2011). Chief among androgrpahis’ active constituents are andrographolides. Chinese researchers showed that an andrographolide called andrographanin enhances mobility of white blood cells in response to cytokine stimulation (Ji 2005), which may allow for more efficient immune response against pathogens. A 2009 study found that an extract of andrographis enhanced immune function, as well as reversed drug-induced immunosuppression (Naik 2009). In a clinical trial conducted on 540 people diagnosed with influenza, andrographis was shown to speed flu recovery and reduce the risk of complications (Kulichenko 2003).

Probiotics and prebiotics – Numerous animal and laboratory studies using various probiotic organisms have demonstrated their ability to enhance immune function and exert direct antiviral actions, including against influenza viruses (Arena 2018; Al Kassaa 2014). In clinical trials, probiotic supplements have been shown to reduce the incidence of flu in children (Waki 2014), reduce the duration of respiratory infections in healthy adults (Jespersen 2015; de Vrese 2006), and strengthen antiviral immune function in vulnerable elderly adults (Akatsu 2013). A growing body of evidence also suggests probiotics may improve the immune response to the flu vaccine (Vitetta 2017; Yeh 2018). The potential for certain probiotics to improve the prevention and treatment of infections has led some researchers to refer to them as “immunobiotics” (Arena 2018).

One randomized controlled trial compared a probiotic supplement to placebo in 136 adults who had contracted colds or flu at least four times in the previous year. The supplement provided a daily dose of more than 9 billion colony forming units (CFUs) composed of three Lactobacillus species. After 12 weeks, those given the probiotic experienced fewer upper respiratory tract infections and flu-like symptoms. They also had higher levels of interferon-gamma, a cytokine that activates antiviral immune activity, as well as gut secretory immunoglobulin-A, an antibody that plays a critical defensive role against infections (Zhang 2018). In another trial, 196 elderly nursing home residents were given either 20 billion CFUs of Lactobacillus rhamnosus GG or placebo daily for six months; viral respiratory infections occurred in 15% of those receiving the probiotic, but almost 23% of those receiving placebo developed a respiratory infection (Wang 2018).

Bifidobacterium species have also been found to protect against colds and flu. In a placebo-controlled trial that included 581 college students reporting academic stress, B. bifidum R0071 supplementation for six weeks was associated with more healthy days and fewer episodes of cold or flu lasting one or more days (Langkamp-Henken 2015).

Prebiotics are certain types of dietary fibers that enhance the growth of health-promoting microorganisms in the gastrointestinal tract. In stressed college students, prebiotic supplements providing 2.5 or 5 grams of galactooligosaccharides per day reduced symptoms of cold and flu during an eight-week placebo-controlled trial (Hughes 2011). In elderly subjects, prebiotics improved responsiveness to flu vaccine administered at week four of a 10-week trial (Akatsu 2016). Synbiotic supplements, which contain both probiotics and prebiotics, have been found to protect against colds and flu in healthy children and adults (Pregliasco 2008; Cazzola 2010).

Probiotics and prebiotics are increasingly being considered as therapies to enhance flu vaccine effectiveness (Vitetta 2017). Two meta-analyses of randomized controlled trials have concluded that probiotics and prebiotics can improve the response rate to vaccination against three influenza strains (Yeh 2018; Lei 2017). Recently, a trial in 98 elderly nursing home residents found taking 3 billion CFUs of L. coryniformis for six months, beginning two weeks before receiving flu vaccination, increased vaccine response rate and decreased symptoms of respiratory infection compared with placebo (Fonolla 2019). Another trial found a heat-inactivated preparation of L. paracasei, providing 10 billion non-viable organisms per day, for three weeks prior to vaccination increased flu vaccine responsiveness in those aged 85 and older (Maruyama 2016).

Reishi - Reishi mushrooms attack and reverse immunosenescence – age-related decline in immune system function – through the combined effects of three compounds: first, a group of long-chain carbohydrates called polysaccharides, second, a unique protein named LZ-8 and third, a small group of steroid-like molecules called triterpenes (Bao 2001; Xu 2011; Yeh 2010). Reishi mushrooms’ immune-stimulating effects play directly into their ability to fight off both bacterial and viral infections (Karaman 2010). Both polysaccharide and triterpene components of the mushrooms contribute to this activity (Iwatsuki 2003; Z. Li 2005). Reishi extracts have been shown to inhibit growth of a number of bacterial germs, especially infections of the urinary and digestive tracts. They also enhance the activity of standard antibiotics in treating bacterial infections. Scientists evaluated combinations of Reishi with four different antibiotics, and found an additive effect in most cases. And true synergy (the effect of both exceeds the combined effects of either alone) was demonstrated with the combination of Reishi and cefazolin, a common antibiotic for surgical infections (Yoon 1994).

But it’s in the realm of viral disease that Reishi mushrooms truly flex their muscles (Eo 1999a,b). In laboratory cell cultures, Reishi mushrooms stop or slow growth of influenza, HIV, hepatitis B, and many other viruses (Eo 1999a,b; Y. Q. Li 2006; el-Mekkawy 1998). Additional laboratory studies have shown that extracts from Reishi are especially effective against viruses in the herpes virus family, which include not only the well-known oral and genital herpes infections, but also the viruses that cause chickenpox and shingles, and the Epstein- Barr virus, a viral cause of certain lymphomas (Iwatsuki 2003; Eo 1999a,b; Eo 2000; Oh 2000). In human studies, supplementation with Reishi dramatically shortens the time until symptomatic relief by more than 50% in people with oral or genital herpes, and in people with shingles, the excruciating adult sequel to childhood chickenpox infection (Hijikata 2005; Hijikata 2007).

Enzymatically modified rice bran - Enzymatically modified rice bran is made by fermenting rice bran with enzymes extracted from the shiitake mushroom (Lentinus edodes). Through the fermentation process, immunologically active polysaccharides, including one called arabinoxylan, become more bioavailable (Choi 2014).

Animal research provides support for the immune-stimulating ability of enzymatically modified rice bran. In an experimental model of immune senescence using aged mice, treatment with enzymatically modified rice bran led to increased NK cell activity (Ghoneum, Abedi 2004). And, in a study in rats, immune cells from those fed enzymatically modified rice bran for two weeks exhibited a stronger response to an immune challenge (Giese 2008).

A number of laboratory studies performed on immune cells further demonstrate the immune-enhancing effects of enzymatically modified rice bran. Human natural killer (NK) cells treated with fermented rice bran extract increased their production of the immune-stimulating cytokines interferon-gamma and tumor necrosis factor-alpha (Ghoneum 2000). Human monocytes, macrophages, and neutrophils have been shown to increase their phagocytic activity (ie, engulfing and digestion of foreign substances) upon treatment with enzymatically modified rice bran (Ghoneum, Matsuura 2004; Ghoneum 2008). Enzymatically modified rice bran was also found to stimulate maturation and increase activity in human immature dendritic cells, which are immune cells that help activate other immune cells (Cholujova 2009; Ghoneum 2011; Ghoneum 2014).

Enzymatically modified rice bran and its arabinoxylan fraction may protect against viral infections. In healthy individuals, arabinoxylan increased levels of interferon-gamma (Choi 2014), a cytokine essential to the body’s antiviral defenses (Chesler 2002). Arabinoxylan was found in one study to protect against upper respiratory viral infections (common colds) in older people. In a double-blind, placebo-controlled, crossover trial, 36 subjects between 70 and 95 years of age received both 500 mg arabinoxylan and placebo, each for six weeks. Scores measuring total common cold symptoms were three times higher and duration of symptoms twice as long in participants during the placebo phase compared with the arabinoxylan phase. In those with low NK cell activity, the increase in NK cell activity was more than double in the arabinoxylan group compared with placebo (Maeda 2004).

Immune-Modulating Hormones

Dehydroepiandrosterone (DHEA)

  • Dehydroepiandrosterone (DHEA), a multifunctional steroid hormone derived from cholesterol, has antiviral activity and enhances host resistance to infections (Romanutti 2010; El Kihel 2012; Torres 2012; Kuehn 2011; Padgett 2000b; Prom-Wormley 2011). The enhanced immune response conferred by DHEA allows it to have activity against a wide range of viral, bacterial, and parasitic infections (Caetano 2009; Powell 2006). Low levels of DHEA have been shown to suppress the host’s antibody response by altering cytokine production (eg, TNF-α and IL-10) (Powell 2006). Higher baseline DHEA levels appear to result in better immunization against influenza (Corsini 2006; Degelau 1997). In a 20-week clinical trial, 50 mg of DHEA daily bolstered white blood cell populations among aging men. Immune cell activity was enhanced as well (Khorram 1997).

Melatonin

  • Melatonin is a hormone produced in the brain by the pineal gland. In addition to regulating the sleep-wake cycle and acting as an antioxidant, melatonin is also capable of influencing the state of the immune system both directly and indirectly. Melatonin has been shown to combat many types of viral infections (Srinivasan 2012; Arushanian 2002; Boga 2012). While the mechanism behind melatonin’s involvement with immune function is still being studied, research has shown that its binding to immune-governing cells called T-helper cells can trigger a cascade of events leading to an enhanced immune responsiveness. In addition, melatonin administration can increase the production of antibodies (Bonilla 2004). In some instances, melatonin also acts as an anti-inflammatory mediator (da Silveira Cruz-Machado 2012); thus, may be preventive or supportive for cytokine storm. Because age-related impairment of the immune system usually begins to occur around age 60 and coincides with decreased melatonin concentrations, melatonin supplementation may be beneficial among seniors (Srinivasan 2005).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

Afilalo M, Stern E, Oughton M. Evaluation and management of seasonal influenza in the emergency department. Emerg Med Clin North Am. 2012;30(2):271-305.

Akatsu H, Nagafuchi S, Kurihara R, et al. Enhanced vaccination effect against influenza by prebiotics in elderly patients receiving enteral nutrition. Geriatr Gerontol Int. 2016;16(2):205-213.

Akatsu H, Iwabuchi N, Xiao JZ, et al. Clinical effects of probiotic Bifidobacterium longum BB536 on immune function and intestinal microbiota in elderly patients receiving enteral tube feeding. JPEN J Parenter Enteral Nutr. 2013;37(5):631-640.

Akbar S. Andrographispaniculata: a review of pharmacological activities and clinical effects. Altern Med Rev. 2011;16(1):66-77.

Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E. Effects of beta-glucans on the immune system. Medicina. 2007;43(8):597-606.

Al Kassaa I, Hober D, Hamze M, Chihib NE, Drider D. Antiviral potential of lactic acid bacteria and their bacteriocins. Probiotics Antimicrob Proteins. 2014;6(3-4):177-185.

Allsup SJ, Gosney M, Regan M, Haycox A, Fear S, Johnstone FC. Side effects of influenza vaccination in healthy older people: a randomised single-blind placebo-controlled trial. Gerontology. Nov-Dec 2001;47(6):311-314.

Almuti K, Rimawi R, Spevack D, Ostfeld RJ. Effects of statins beyond lipid lowering: potential for clinical benefits. Int J Cardiol. 2006;109(1):7-15.

Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiology and infection. Oct 2007;135(7):1095-1096; author reply 1097-1098.

Ambrose CS, Levin MJ. The rationale for quadrivalent influenza vaccines. Human vaccines &immunotherapeutics. Jan 2012;8(1):81-88.

Anderson R. The Immunostimulatory, Antiinflammatory and Anti-Allergic Properties of Ascorbate. [In eng] AdvNutr Res. 1984 6(19-45.

Andrew MK, Bowles SK, Pawelec G, et al. Influenza Vaccination in Older Adults: Recent Innovations and Practical Applications. Drugs Aging. 2019;36(1):29-37.

Arae K, Oboki K, Ohno T, et al. Cimetidine enhances antigen-specific IgE and Th2 cytokine production. Allergol Int. 2011;60(3):339-344.

Arena MP, Capozzi V, Russo P, Drider D, Spano G, Fiocco D. Immunobiosis and probiosis: antimicrobial activity of lactic acid bacteria with a focus on their antiviral and antifungal properties. Appl Microbiol Biotechnol. 2018;102(23):9949-9958.

Arushanian EB, Beier EV. [Immunotropic properties of pineal melatonin]. EkspKlinFarmakol. 2002;65(5):73-80.

Atmar RL, Patel SM, Keitel WA. Intanza((R)): a new intradermal vaccine for seasonal influenza. Expert Rev Vaccines. 2010;9(12):1399-1409.

Ayling K, Fairclough L, Tighe P, et al. Positive mood on the day of influenza vaccination predicts vaccine effectiveness: A prospective observational cohort study. Brain Behav Immun. 2018;67:314-323.

Bai L, Cao B, Wang C. Influenza A pandemic (H1N1) 2009 virus infection. Chin Med J. 2011;124(20):3399-3402.

Banzhoff A, Stoddard J. Effective influenza vaccines for children: A critical unmet medical need and a public health priority. Hum VaccinImmunother. 2012;8:3.

Bao X, Liu C, Fang J, Li X. Structural and immunological studies of a major polysaccharide from spores of Ganodermalucidum (Fr.) Karst. Carbohydrate research. May 8 2001;332(1):67-74.

Bavagnoli L, Maga G. The 2009 influenza pandemic: promising lessons for antiviral therapy for future outbreaks. Curr Med Chem. 2011;18(35):5466-5475.

Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J ClinVirol. 2011;50(3):194-200.

Beck MA, Levander OA, Handy J. Selenium deficiency and viral infection. J Nutr. 2003;133(5 Suppl 1):1463S-1467S.

Beigel J, Bray M. Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008;78(1):91-102.

Berlutti F, Pantanella F, Natalizi T, Frioni A, Paesano R, Polimeni A, Valenti P. Antiviral properties of lactoferrin--a natural immunity molecule. Molecules. 2011;16(8):6992-7018.

Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr. 2011;106(9):1433-40.

Bijl D. Pandemic influenza vaccines and neuraminidase inhibitors: efficacy and side effects. Int J Risk Saf Med. 2011;23(2):65-71.

Boga JA, Coto-Montes A, Rosales-Corral SA, Tan DX, Reiter RJ. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol. 2012;18(10).

Bonilla E, Valero N, Chacin-Bonilla L, Medina-Leendertz S. Melatonin and viral infections. J Pineal Res. 2004;36(2):73-79.

Caetano LC, Santello FH, Del VecchioFilipin M, et al. Trypanosomacruzi: dehydroepiandrosterone (DHEA) and immune response during the chronic phase of the experimental Chagas' disease. Vet Parasitol. 2009;163(1-2):27-32.

Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern Med Rev. 2008;13(1):6-20.

Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-40.

Cannell JJ. The difference between a prophet and a madman. Br J Nutr. 2011;106(9):1317-8.

Cao W, Kim JH, Chirkova T, et al. Improving immunogenicity and effectiveness of influenza vaccine in older adults. Expert Rev Vaccines. 2011;10(11):1529-1537.

Cazzola M, Pham-Thi N, Kerihuel JC, Durand H, Bohbot S. Efficacy of a synbiotic supplementation in the prevention of common winter diseases in children: a randomized, double-blind, placebo-controlled pilot study. Ther Adv Respir Dis. 2010;4(5):271-278.

CDC (Centers for Disease Control and Prevention) Antibiotics Aren't Always the Answer. Last updated Feb. 27, 2012. (2012a) Accessed 7/19/12 at: http://www.cdc.gov/Features/GetSmart/

CDC (Centers for Disease Control and Prevention) How Flu Spreads. Last updated June 30, 2011 (2011a). Accessed 7/19/12 at: http://www.cdc.gov/flu/about/disease/spread.htm

CDC (Centers for Disease Control and Prevention) Key Facts about Influenza (Flu) & Flu Vaccine. Last updated March 28, 2012. (2012b) Accessed 7/16/12 at: http://www.cdc.gov/flu/keyfacts.htm

CDC. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Last updated 12/27/2018. Accessed 09/18/2019.

CDC. Centers for Disease Control and Prevention. Influenza (Flu): Preventive Steps. https://www.cdc.gov/flu/prevent/prevention.htm. 9/18/2019. Accessed 10/7/2019.

CDC (Centers for Disease Control and Prevention). Seasonal Influenza (Flu). Estimating Seasonal Influenza-Associated Deaths in the United States: CDC Study Confirms Variability of Flu. Available at: http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm?s_cid=cs_074. Last updated June 24, 2011c. Accessed October 17, 2012.

CDC (Centers for Disease Control and Prevention). Seasonal Influenza (Flu). Updated: 7/6/2011d. Accessed 10/15/2012 at http://www.cdc.gov/flu/about/qa/disease.htm.

CDC. Cold Versus Flu. 2/8/2011e. Available at: http://www.cdc.gov/flu/about/qa/coldflu.htmAccessed 8/24/2012.

Chesler DA, Reiss CS. The role of IFN-gamma in immune responses to viral infections of the central nervous system. Cytokine & growth factor reviews.Dec 2002;13(6):441-454.

Choi JY, Paik DJ, Kwon DY, Park Y. Dietary supplementation with rice bran fermented with Lentinus edodes increases interferon-gamma activity without causing adverse effects: a randomized, double-blind, placebo-controlled, parallel-group study. Nutrition journal.2014;13:35.

Cholujova D, Jakubikova J, Sedlak J. BioBran-augmented maturation of human monocyte-derived dendritic cells. Neoplasma.2009;56(2):89-95.

Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D. Vaccination in the elderly: The challenge of immune changes with aging. Semin Immunol. 2018;40:83-94.

Clark NM, Lynch JP, 3rd. Influenza: epidemiology, clinical features, therapy, and prevention. Seminars in respiratory and critical care medicine. Aug 2011;32(4):373-392.

Classen HG, Grober U, Low D, Schmidt J, Stracke H. [Zinc deficiency. Symptoms, causes, diagnosis and therapy]. Med Monatsschr Pharm. 2011;34(3):87-95.

Combes A, Pellegrino V. Extracorporeal membrane oxygenation for 2009 influenza A (H1N1)-associated acute respiratory distress syndrome. SeminRespirCrit Care Med. 2011;32(2):188-194.

Cooper R. Green tea and theanine: health benefits. Int J Food SciNutr. 2012;1:90-97.

Cordeiro LM, Reinhardt VD, Iacomini M. Glucomannan and branched (1-->3)(1-->6) beta-glucan from the aposymbiotically grown Physciakalbiimycobiont. Phytochemistry. Sep 13 2012.

Corsini E, Vismara L, Lucchi L, et al. High interleukin-10 production is associated with low antibody response to influenza vaccination in the elderly. J Leukoc Biol. 2006;80(2):376-82.

da Silveira Cruz-Machado S, Pinato L, Tamura EK, Carvalho-Sousa CE, Markus RP. Glia-Pinealocyte Network: The Paracrine Modulation of Melatonin Synthesis by Tumor Necrosis Factor (TNF). PLoS One. 2012;7(7):2.

Danese S, Dejana E, Fiocchi C. Immune Regulation by Microvascular Endothelial Cells: Directing Innate and Adaptive Immunity, Coagulation, and Inflammation. The Journal of Immunology. May 15, 2007 2007;178(10):6017-6022.

Dawood FS, Iuliano AD, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis. 2012;26:26.

Degelau J, Guay D, Hallgren H. The effect of DHEAS on influenza vaccination in aging adults. Journal of the American Geriatrics Society. Jun 1997;45(6):747-751.

de Vrese M, Winkler P, Rautenberg P, et al. Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial. Vaccine. 2006;24(44-46):6670-6674.

Dong G, Peng C, Luo J, et al. Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations. PloS one. 2015;10(3):e0119115.

Dror DK, Allen LH. Vitamin E deficiency in developing countries. Food Nutr Bull. 2011;32(2):124-143.

Duwe S. Influenza viruses - antiviral therapy and resistance. GMS Infect Dis. 2017;5:Doc04.

Ebell MH. Diagnosing and treating patients with suspected influenza. Am Fam Physician. 2005;72(9):1789-1792.

Eide DJ. The oxidative stress of zinc deficiency. Metallomics. 2011;3(11):1124-1129.

El Kihel L. Oxidative metabolism of dehydroepiandrosterone (DHEA) and biologically active oxygenated metabolites of DHEA and epiandrosterone (EpiA)--recent reports. Steroids. 2012;77(1-2):10-26.

el-Mekkawy S, Meselhy MR, Nakamura N, Tezuka Y, Hattori M, Kakiuchi N, . . . Otake T. Anti-HIV-1 and anti-HIV-1-protease substances from Ganodermalucidum. Phytochemistry. Nov 1998;49(6):1651-1657.

Eo SK, Kim YS, Lee CK, Han SS. Antiherpetic activities of various protein bound polysaccharides isolated from Ganodermalucidum. Journal of ethnopharmacology. Dec 15 1999a;68(1-3):175-181.

Eo SK, Kim YS, Lee CK, Han SS. Antiviral activities of various water and methanol soluble substances isolated from Ganodermalucidum. Journal of ethnopharmacology. Dec 15 1999b;68(1-3):129-136.

Eo SK, Kim YS, Lee CK, Han SS. Possible mode of antiviral activity of acidic protein bound polysaccharide isolated from Ganodermalucidum on herpes simplex viruses. Journal of ethnopharmacology. Oct 2000;72(3):475-481.

Falagas ME, Cholevas NV, Kapaskelis AM, Vouloumanou EK, Michalopoulos A, Rafailidis PI. Epidemiological aspects of 2009 H1N1 influenza: the accumulating experience from the Northern Hemisphere. Eur J ClinMicrobiol Infect Dis. 2010;29(11):1327-1347.

Fediakina IT, Shchelkanov M, Deriabin PG, et al. [Susceptibility of pandemic influenza virus A 2009 H1N1 and highly pathogenic avian influenza virus A H5N1 to antiinfluenza agents in cell culture]. AntibiotKhimioter. 2011;56(3-4):3-9.

Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008;57(RR-7):1-60.

Fonolla J, Gracian C, Maldonado-Lobon JA, et al. Effects of Lactobacillus coryniformis K8 CECT5711 on the immune response to influenza vaccination and the assessment of common respiratory symptoms in elderly subjects: a randomized controlled trial. Eur J Nutr. 2019;58(1):83-90.

Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;131(4):1006-1012.

Gaglia MA, Jr., Cook RL, Kraemer KL, Rothberg MB. Patient knowledge and attitudes about antiviral medication and vaccination for influenza in an internal medicine clinic. Clin Infect Dis. 2007;45(9):1182-1188.

Gao R, Dong L, Dong J, et al. A systematic molecular pathology study of a laboratory confirmed H5N1 human case. PLoS One. 2010;5(10).

Gardner EM, Beli E, Clinthorne JF, Duriancik DM. Energy intake and response to infection with influenza. Annu Rev Nutr. 2011;31:353-367.

Gasparini R, Amicizia D, Lai PL, Panatto D. Aflunov((R)): a prepandemic influenza vaccine. Expert Rev Vaccines. 2012;11(2):145-157.

Ghebrehewet S, MacPherson P, Ho A. Influenza. BMJ (Clinical research ed). 2016;355:i6258.

Ghoneum M, Abedi S. Enhancement of natural killer cell activity of aged mice by modified arabinoxylan rice bran (MGN-3/Biobran). The Journal of pharmacy and pharmacology.Dec 2004;56(12):1581-1588.

Ghoneum M, Agrawal S. Activation of human monocyte-derived dendritic cells in vitro by the biological response modifier arabinoxylan rice bran (MGN-3/Biobran). International journal of immunopathology and pharmacology.Oct-Dec 2011;24(4):941-948.

Ghoneum M, Agrawal S. Mgn-3/biobran enhances generation of cytotoxic CD8+ T cells via upregulation of dec-205 expression on dendritic cells. International journal of immunopathology and pharmacology.Oct-Dec 2014;27(4):523-530.

Ghoneum M, Jewett A. Production of tumor necrosis factor-alpha and interferon-gamma from human peripheral blood lymphocytes by MGN-3, a modified arabinoxylan from rice bran, and its synergy with interleukin-2 in vitro. Cancer detection and prevention.2000;24(4):314-324.

Ghoneum M, Matsuura M. Augmentation of macrophage phagocytosis by modified arabinoxylan rice bran (MGN-3/biobran). International journal of immunopathology and pharmacology.Sep-Dec 2004;17(3):283-292.

Ghoneum M, Matsuura M, Gollapudi S. Modified arabinoxylan rice bran (MGN3/Biobran) enhances intracellular killing of microbes by human phagocytic cells in vitro. International journal of immunopathology and pharmacology.Jan-Mar 2008;21(1):87-95.

Giese S, Sabell GR, Coussons-Read M. Impact of ingestion of rice bran and shitake mushroom extract on lymphocyte function and cytokine production in healthy rats. Journal of dietary supplements.2008;5(1):47-61.

Goldfine AB. Statins: is it really time to reassess benefits and risks? The New England journal of medicine. May 10 2012;366(19):1752-1755.

Goldson AJ, Fairweather-Tait SJ, Armah CN, et al. Effects of selenium supplementation on selenoprotein gene expression and response to influenza vaccine challenge: a randomised controlled trial. PLoS One. 2011;6(3).

Gorton HC, Jarvis K. The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections. J Manipulative PhysiolTher. 1999;22(8):530-533.

Gouarin S, Vabret A, Dina J, et al. Study of influenza C virus infection in France. J Med Virol. 2008;80(8):1441-1446.

Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918-1919 influenza pandemic in the United States. Dermato-endocrinology. Jul 2009;1(4):215-219.

Grant WB, Goldstein M, Mascitelli L. Ample evidence exists from human studies that vitamin D reduces the risk of selected bacterial and viral infections. ExpBiol Med. 2010;235(12):1395-1396.

Guralnik M, Rosenbloom RA, Petteruti MP, Lefante C. Limitations of current prophylaxis against influenza virus infection. Am J Ther. 2007;14(5):449-454.

Han SN, Meydani SN. Antioxidants, cytokines, and influenza infection in aged mice and elderly humans. J Infect Dis. 2000;182(1):S74-80.

Hayden F. (2011) Chapter 372: Influenza (pg. 2095). In: Goldman L. (Ed.), Goldman's Cecil Medicine (24th ed). Saunders, An Imprint of Elsevier.

Heimer KA, Hart AM, Martin LG, Rubio-Wallace S. Examining the evidence for the use of vitamin C in the prophylaxis and treatment of the common cold. J Am Acad Nurse Pract. 2009;21(5):295-300.

Hemila H. Zinc lozenges may shorten the duration of colds: a systematic review. The open respiratory medicine journal. 2011;5:51-58.

Hijikata Y, Yamada S, Yasuhara A. Herbal mixtures containing the mushroom Ganodermalucidum improve recovery time in patients with herpes genitalis and labialis. Journal of alternative and complementary medicine (New York, N.Y.). Nov 2007;13(9):985-987.

Hijikata Y, Yasuhara A, Sahashi Y. Effect of an herbal formula containing Ganodermalucidum on reduction of herpes zoster pain: a pilot clinical trial. The American journal of Chinese medicine. 2005;33(4):517-523.

Hoffmann PR, Berry MJ. The influence of selenium on immune responses. Molecular Nutrition & Food Research. 2008;52(11):1273-1280.

Holt S. Hype around high-dose vitamin C is unjustified: N Z Med J. 2010 Oct 15;123(1324):109-10.

Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012;156(7):512-524.

Hughes C, Davoodi-Semiromi Y, Colee JC, et al. Galactooligosaccharide supplementation reduces stress-induced gastrointestinal dysfunction and days of cold or flu: a randomized, double-blind, controlled trial in healthy university students. Am J Clin Nutr. 2011;93(6):1305-1311.

Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist. 2017;10:121-134.

Iwatsuki K, Akihisa T, Tokuda H, Ukiya M, Oshikubo M, Kimura Y, . . . Nishino H. Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganodermalucidum and their inhibitory effects on Epstein-Barr virus activation. Journal of natural products. Dec 2003;66(12):1582-1585.

Jariwalla RJ, and Harakeh S. Antiviral and Immunomodulatory Activities of Ascorbic Acid. [In eng] SubcellBiochem. 1996 25(213-31).

Jaspers I, Zhang W, Brighton LE, Carson JL, Styblo M, Beck MA. Selenium deficiency alters epithelial cell morphology and responses to influenza. Free RadicBiol Med. 2007;42(12):1826-1837.

Jefferson T, Demicheli D, di Pietrantonj C, Jones M and Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2006;3:CD001265.

Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. The Cochrane database of systematic reviews. 2014(4):Cd008965.

Jespersen L, Tarnow I, Eskesen D, et al. Effect of Lactobacillus paracasei subsp. paracasei, L. casei 431 on immune response to influenza vaccination and upper respiratory tract infections in healthy adult volunteers: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Clin Nutr. 2015;101(6):1188-1196.

Ji LL, Wang Z, Dong F, Zhang WB, Wang ZT. Andrograpanin, a compound isolated from anti-inflammatory traditional Chinese medicine Andrographispaniculata, enhances chemokine SDF-1alpha-induced leukocytes chemotaxis. Journal of cellular biochemistry. Aug 1 2005;95(5):970-978.

Jung K, Ha Y, Ha SK, et al. Antiviral effect of Saccharomyces cerevisiae beta-glucan to swine influenza virus by increased production of interferon-gamma and nitric oxide. J Vet Med B Infect Dis Vet Public Health. 2004;51(2):72-76.

Karaman M, Jovin E, Malbasa R, Matavuly M, Popovic M. Medicinal and edible lignicolous fungi as natural sources of antioxidative and antibacterial agents. Phytotherapy research : PTR. Oct 2010;24(10):1473-1481.

Khorram O, Vu L, Yen SS. Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men. The journals of gerontology. Series A, Biological sciences and medical sciences. Jan 1997;52(1):M1-7.

Kim TS, Sun J, Braciale TJ. T cell responses during influenza infection: getting and keeping control. Trends in immunology. May 2011;32(5):225-231.

Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: an anticancer drug? Eur J Pharm Sci. 2011;42(5):439-444.

Kuehn CC, Oliveira LG, Santos CD, Augusto MB, Toldo MP, do Prado JC, Jr. Prior and concomitant dehydroepiandrosterone treatment affects immunologic response of cultured macrophages infected with Trypanosomacruzi in vitro? Vet Parasitol. 2011;177(3-4):242-246.

Kulichenko LL, Kireyeva LV, Malyshkina EN, Wikman G. A randomized, controlled study of Kan Jang versus amantadine in the treatment of influenza in Volgograd. Journal of herbal pharmacotherapy. 2003;3(1):77-93.

Kumar A. Cimetidine: an immunomodulator. DICP : the annals of pharmacotherapy. Mar 1990;24(3):289-295.

Lambe T, Spencer AJ, Mullarkey CE, et al. T-Cell Responses in Children to Internal Influenza Antigens, 1 Year After Immunization With Pandemic H1N1 Influenza Vaccine, and Response to Revaccination With Seasonal Trivalent-inactivated Influenza Vaccine. Pediatr Infect Dis J. 2012;31(6):e86-91.

Lang PO, Mendes A, Socquet J, Assir N, Govind S, Aspinall R. Effectiveness of influenza vaccine in aging and older adults: comprehensive analysis of the evidence. Clinical interventions in aging. 2012;7:55-64.

Langkamp-Henken B, Rowe CC, Ford AL, et al. Bifidobacterium bifidum R0071 results in a greater proportion of healthy days and a lower percentage of academically stressed students reporting a day of cold/flu: a randomised, double-blind, placebo-controlled study. Br J Nutr. 2015;113(3):426-434.

Lei WT, Shih PC, Liu SJ, Lin CY, Yeh TL. Effect of Probiotics and Prebiotics on Immune Response to Influenza Vaccination in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2017;9(11).

Li YQ, Wang SF. Anti-hepatitis B activities of ganoderic acid from Ganodermalucidum. Biotechnology letters. Jun 2006;28(11):837-841.

Li Z, Liu J, Zhao Y. Possible mechanism underlying the antiherpetic activity of a proteoglycan isolated from the mycelia of Ganodermalucidum in vitro. Journal of biochemistry and molecular biology. Jan 31 2005;38(1):34-40.

Locke SC, Splawn LM, Cho JC. Baloxavir marboxil: a novel cap-dependent endonuclease (CEN) inhibitor for the treatment of acute uncomplicated influenza. Drugs Today (Barc). 2019;55(6):359-366.

Louria DB. Undernutrition can affect the invading microorganism. Clin Infect Dis. 2007;45(4):470-474.

Lynch JP, 3rd, Walsh EE. Influenza: evolving strategies in treatment and prevention. SeminRespirCrit Care Med. 2007;28(2):144-158.

Ma J, Dushoff J, Earn DJ. Age-specific mortality risk from pandemic influenza. J Theor Biol. 2011;288:29-34.

Maeda H, Ichihashi K, Fujii T, Omura K, Zhu X, Anazawa M, Tazawa K. Oral administration of hydrolyzed rice bran prevents the common cold syndrome in the elderly based on its immunomodulatory action. BioFactors (Oxford, England).2004;21(1-4):185-187.

Majdalawieh AF, Hmaidan R, Carr RI. Nigella sativa modulates splenocyte proliferation, Th1/Th2 cytokine profile, macrophage function and NK anti-tumor activity. Journal of ethnopharmacology. Sep 15 2010;131(2):268-275.

Mao L, Yang Y, Qiu Y. Annual economic impacts of seasonal influenza on US counties: Spatial heterogeneity and patterns. Int J Health Geogr. 2012;11(1):16.

Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017 Feb 15;356:i6583.

Maruyama M, Abe R, Shimono T, Iwabuchi N, Abe F, Xiao JZ. The effects of non-viable Lactobacillus on immune function in the elderly: a randomised, double-blind, placebo-controlled study. Int J Food Sci Nutr. 2016;67(1):67-73.

Mayo Clinic. Influenza (flu): Prevention. Last updated Aug. 20, 2011. Accessed 7/19/12 at: www.mayoclinic.com/health/influenza/ds00081/dsection=prevention

MD Consult. Chapter 53 – Antiviral Agents. In: Shannon: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th ed. Copyright 2007. Accessed 10/22/2012 at: http://www.mdconsult.com/books/page.do?eid=4-u1.0-B978-0-7216-0693-4..50058-X&isbn=978-0-7216-0693-4&sid=1370781732&uniqId=375410144-6#4-u1.0-B978-0-7216-0693-4..50058-X--cesec49

MD Consult. Influenza. Updated 10/12/2012 Accessed 10/16/2012 at: http://www.mdconsult.com/das/pdxmd/body/373143450-3/0?type=med&eid=9-u1.0-_1_mt_1014549#33988

Medeiros SD, Cordeiro SL, Cavalcanti JE, Melchuna KM, Lima AM, Filho IA, . . . Sales VS. Effects of Purified Saccharomyces cerevisiae (1-->3)-beta-Glucan on Venous Ulcer Healing. International journal of molecular sciences. 2012;13(7):8142-8158.

MedlinePlus. Flu. Available at: http://www.nlm.nih.gov/medlineplus/flu.html. Last updated October 12, 2012. Accessed October 17, 2012.

Mgbemena V, Segovia JA, Chang TH, et al. Transactivation of Inducible Nitric Oxide Synthase Gene by Kruppel-like Factor 6 Regulates Apoptosis during Influenza A Virus Infection. J Immunol. 2012;18:18.

Michaelis M, Doerr HW, Cinatl J, Jr. Of chickens and men: avian influenza in humans. CurrMol Med. 2009;9(2):131-151.

Mishin VP, Patel MC, Chesnokov A, et al. Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir(1). Emerg Infect Dis. 2019;25(10).

MMWR. Severe influenza among children and young adults with neurologic and neurodevelopmental conditions - Ohio, 2011. MMWR Morb Mortal Wkly Rep. 2012;60(51-52):1729-1733.

Music T. Protecting patients, protecting healthcare workers: a review of the role of influenza vaccination. IntNurs Rev. 2012;59(2):161-167.

Naik SR, Hule A. Evaluation of immunomodulatory activity of an extract of andrographolides from Andographispaniculata. Planta Med. 2009;75(8):785-791.

NFID (National Foundation for Infectious Diseases). Influenza. Available at: http://www.nfid.org/idinfo/influenza. Accessed October 17, 2012.

NIAID (National Institute of Allergy and Infectious Diseases). Topics: Flu: Understanding Flu: Definitions and Overview. Updated August 08, 2011. Accessed 7/1/12. Available at: http://www.niaid.nih.gov/topics/Flu/understandingFlu/Pages/definitionsOverview.aspx

NIH (National Institute of Health) MeSH Term definition: Influenza, Human. Accessed 7/6/12 (2012a). Available at: http://www.ncbi.nlm.nih.gov/mesh/68007251

NIH (National Institute of Health) MeSH Term definition: Pandemic. Accessed 7/6/12 (2012b). Available at: http://www.ncbi.nlm.nih.gov/mesh?term=pandemic

NIH (National Institute of Health). The Patient Education Institute: X-Plain: Influenza-Flu (Reference Summary). Last Reviewed 4/30/2008. Accessed 6/28/12. Available at: http://www.nlm.nih.gov/medlineplus/tutorials/ influenza/id439102.pdf

Oh KW, Lee CK, Kim YS, Eo SK, Han SS. Antiherpetic activities of acidic protein bound polysacchride isolated from Ganodermalucidum alone and in combinations with acyclovir and vidarabine. Journal of ethnopharmacology. Sep 2000;72(1-2):221-227.

Oklahoma State Dept. of Health. Cold vs. Flu: Know the difference. 09/2011. Available at: http://www.ok.gov/health/documents/Cold%20vs%20Flu%20Know%20the%20Difference.pdf Accessed: 8/27/2012.

Ornskov Pedersen L, Lund KB, Nielsen TJ, Hansen J, Tougaard NH, Andersen JH. [Unclear effect of influenza vaccination in healthy adults]. Ugeskrift for laeger. Mar 26 2012;174(13):859-861.

Orsi N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals. 2004;17(3):189-196.

Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. The Lancet infectious diseases. Jan 2012;12(1):36-44.

Ozgen M, Scheerens JC, Reese RN, Miller RA. Total phenolic, anthocyanin contents and antioxidant capacity of selected elderberry (Sambucuscanadensis L.) accessions. Pharmacogn Mag. 2010;6(23):198-203.

Padgett DA, MacCallum RC, Loria RM, Sheridan JF. Androstenediol-induced restoration of responsiveness to influenza vaccination in mice. J Gerontol A BiolSci Med Sci. 2000b;55(9):B418-424.

Park M, Yamada H, Matsushita K, et al. Green tea consumption is inversely associated with the incidence of influenza infection among schoolchildren in a tea plantation area of Japan. J Nutr. 2011;141(10):1862-1870.

Pedersen C. [Convalescence and sick leave after influenza]. UgeskrLaeger. 2009;171(40):2913-2915.

Pence BD, Hester SN, Donovan SM, Woods JA. Dietary whole glucan particles do not affect antibody or cell-mediated immune responses to influenza virus vaccination in mice. Immunol Invest. 2012;41(3):275-289.

Phung TT, Sugamata R, Uno K, et al. Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells. MicrobiolImmunol. 2011;55(12):874-884.

Powell JM, Sonnenfeld G. The effects of dehydroepiandrosterone (DHEA) on in vitro spleen cell proliferation and cytokine production. J Interferon Cytokine Res. 2006;26(1):34-39.

Pregliasco F, Anselmi G, Fonte L, Giussani F, Schieppati S, Soletti L. A new chance of preventing winter diseases by the administration of synbiotic formulations. J Clin Gastroenterol. 2008;42 Suppl 3 Pt 2:S224-233.

Principi N, Camilloni B, Alunno A, Polinori I, Argentiero A, Esposito S. Drugs for Influenza Treatment: Is There Significant News? Front Med (Lausanne). 2019;6:109.

Prom-Wormley EC, York TP, Jacobson KC, et al. Genetic and environmental effects on diurnal dehydroepiandrosterone sulfate concentrations in middle-aged men. Psychoneuroendocrinology. 2011;36(10):1441-1452.

Ravin NV, Kotlyarov RY, Mardanova ES, et al. Plant-produced recombinant influenza vaccine based on virus-like HBc particles carrying an extracellular domain of M2 protein. Biochemistry. 2012;77(1):33-40.

Razonable RR. Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clin Proc. 2011;86(10):1009-1026.

Romanutti C, Bruttomesso AC, Castilla V, Galagovsky LR, Wachsman MB. Anti-adenovirus activity of epiandrosterone and dehydroepiandrosterone derivatives. Chemotherapy. 2010;56(2):158-165.

Roschek B, Jr., Fink RC, McMichael MD, Li D, Alberte RS. Elderberry flavonoids bind to and prevent H1N1 infection in vitro. Phytochemistry. 2009;70(10):1255-1261.

Rowe CA, Nantz MP, Bukowski JF, Percival SS. Specific formulation of Camellia sinensis prevents cold and flu symptoms and enhances gamma,delta T cell function: a randomized, double-blind, placebo-controlled study. J Am CollNutr. 2007;26(5):445-452.

Roxas M, Jurenka J. Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Altern Med Rev. 2007;12(1):25-48.

Russell CA, Jones TC, Barr IG, et al. Influenza vaccine strain selection and recent studies on the global migration of seasonal influenza viruses. Vaccine. 2008;12(26):D31-34.

Salem ML, Alenzi FQ, Attia WY. Thymoquinone, the active ingredient of Nigella sativa seeds, enhances survival and activity of antigen-specific CD8-positive T cells in vitro. British journal of biomedical science. 2011;68(3):131-137.

Salem ML, Hossain MS. Protective effect of black seed oil from Nigella sativa against murine cytomegalovirus infection. International journal of immunopharmacology. Sep 2000;22(9):729-740.

Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. International immunopharmacology. Dec 2005;5(13-14):1749-1770.

Sanders CJ, Doherty PC, Thomas PG. Respiratory epithelial cells in innate immunity to influenza virus infection. Cell and tissue research. Jan 2011;343(1):13-21.

Scheinfeld N. Cimetidine: a review of the recent developments and reports in cutaneous medicine. Dermatol Online J. 2003;9(2):4.

Schleiss M. (2011) Chapter 237: Principles of Antiviral Therapy: Antivirals Used for Respiratory Viral Infections: Ribavirin (pg. 1069.e9). In: Kliegman R. (Ed.), Nelson Textbook of Pediatrics (19th ed). Saunders, An Imprint of Elsevier.

Schmolke M, Viemann D, Roth J, Ludwig S. Essential impact of NF-kappaB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol. 2009;183(8):5180-5189.

Seidman JC, Richard SA, Viboud C, Miller MA. Quantitative review of antibody response to inactivated seasonal influenza vaccines. Influenza Other Respi Viruses. 2012;6(1):52-62.

Shaman J, Jeon CY, Giovannucci E, Lipsitch M. Shortcomings of vitamin D-based model simulations of seasonal influenza. PLoS One. 2011;6(6):3.

Shin JS, Abah U. Is routine stress ulcer prophylaxis of benefit for patients undergoing cardiac surgery? Interact CardiovascThorac Surg. 2012;14(5):622-628.

Shobugawa Y, Wiafe SA, Saito R, et al. Novel measurement of spreading pattern of influenza epidemic by using weighted standard distance method: retrospective spatial statistical study of influenza, Japan, 1999-2009. Int J Health Geogr. 2012;11(1):20.

Siu E, Campitelli MA, Kwong JC. Physical activity and influenza-coded outpatient visits, a population-based cohort study. PLoS One. 2012;7(6):21.

Snelgrove RJ, Godlee A, Hussell T. Airway immune homeostasis and implications for influenza-induced inflammation. Trends in immunology. Jul 2011;32(7):328-334.

Srinivasan V, Maestroni G, Cardinali D, Esquifino A, Perumal SP, Miller S. Melatonin, immune function and aging. Immunity & Ageing. 2005;2(1):17.

Srinivasan V, Mohamed M, Kato H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat EndocrMetab Immune Drug Discov. 2012;6(1):30-39.

Stebbins S, Downs JS, Vukotich CJ, Jr. The effect of grade on compliance using nonpharmaceutical interventions to reduce influenza in an urban elementary school setting. J Public Health ManagPract. 2011;17(1):65-71.

Stefani M, Bottino G, Fontenelle E, Azulay DR. [Efficacy comparison between cimetidine and zinc sulphate in the treatment of multiple and recalcitrant warts]. An Bras Dermatol. 2009;84(1):23-29.

Stỳblo M, Walton FS, Harmon AW, Sheridan PA, Beck MA. Activation of superoxide dismutase in selenium-deficient mice infected with influenza virus. J Trace Elem Med Biol. 2007;21(1):52-62.

Tang JW, Shetty N, Lam TT, Hon KL. Emerging, novel, and known influenza virus infections in humans. Infect Dis Clin North Am. 2010;24(3):603-617.

Taubenberger JK, Kash JC. Insights on influenza pathogenesis from the grave. Virus Res. 2011;162(1-2):2-7.

Teijaro JR, Walsh KB, Cahalan S, et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell. 2011;146(6):980-991.

Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the Eye of the Cytokine Storm. Microbiology and Molecular Biology Reviews. March 1, 2012 2012;76(1):16-32.

Torres NI, Castilla V, Bruttomesso AC, Eiras J, Galagovsky LR, Wachsman MB. In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1. Antiviral Res. 2012;95(1):37-48.

Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza. J Infect Dis. 2019.

Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. The American journal of clinical nutrition. May 2010;91(5):1255-1260.

Us D. [Cytokine storm in avian influenza]. Mikrobiyol Bul. 2008;42(2):365-380.

Utah Dept. Health. Difference Between Cold and Flu Symptoms. 8/2010. Availabel at: http://health.utah.gov/epi/diseases/flu/ColdvsFlu.pdf Accessed 8/27/2012.

van Ierssel SH, Leven M, Jorens PG. Severe influenza A(H1N1)2009 infection: a single centre experience and review of the literature. ActaClin Belg. 2012;67(1):1-6.

Vandermeer ML, Thomas AR, Kamimoto L, et al. Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study. J Infect Dis. 2012;205(1):13-19.

Vitetta L, Saltzman ET, Thomsen M, Nikov T, Hall S. Adjuvant Probiotics and the Intestinal Microbiome: Enhancing Vaccines and Immunotherapy Outcomes. Vaccines (Basel). 2017;5(4).

Waarts BL, Aneke OJ, Smit JM, et al. Antiviral Activity of Human Lactoferrin: Inhibition of Alphavirus Interaction with Heparan Sulfate. [In eng] Virology. 2005 Mar 15; 333(2): 284-92.

Waki N, Matsumoto M, Fukui Y, Suganuma H. Effects of probiotic Lactobacillus brevis KB290 on incidence of influenza infection among schoolchildren: an open-label pilot study. Lett Appl Microbiol. 2014;59(6):565-571.

Walsh KB, Teijaro JR, Rosen H, Oldstone MB. Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm. Immunol Res. 2011a;51(1):15-25.

Walsh KB, Teijaro JR, Wilker PR, et al. Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus. ProcNatlAcadSci U S A. 2011b;108(29):12018-12023.

Wang B, Hylwka T, Smieja M, Surrette M, Bowdish DME, Loeb M. Probiotics to Prevent Respiratory Infections in Nursing Homes: A Pilot Randomized Controlled Trial. J Am Geriatr Soc. 2018;66(7):1346-1352.

Wang J, Su B, Ding Z, Du X, Wang B. Cimetidine enhances immune response of HBV DNA vaccination via impairment of the regulatory function of regulatory T cells. BiochemBiophys Res Commun. 2008;372(3):491-496.

WHO (World Health Organization) Pandemic (H1N1) 2009–update 112. Accessed 6/30/12. Available at: www.who.int/csr/don/2010_08_06/en/index.html

Wu JT, Lee CK, Cowling BJ, Yuen KY. Logistical feasibility and potential benefits of a population-wide passive-immunotherapy program during an influenza pandemic. ProcNatlAcadSci U S A. 2010;107(7):3269-3274.

Xiao Z, Trincado CA, Murtaugh MP. Beta-glucan enhancement of T cell IFNgamma response in swine. Vet ImmunolImmunopathol. 2004 Dec 8;102(3):315-20.

Xu Z, Chen X, Zhong Z, Chen L, Wang Y. Ganodermalucidum polysaccharides: immunomodulation and potential anti-tumor activities. The American journal of Chinese medicine. 2011;39(1):15-27.

Yang S, Evens AM, Prachand S, et al. Mitochondrial-mediated apoptosis in lymphoma cells by the diterpenoid lactone andrographolide, the active component of Andrographispaniculata. Clin Cancer Res. 2010;16(19):4755-4768.

Yardley L, Miller S, Teasdale E, Little P. Using mixed methods to design a web-based behavioural intervention to reduce transmission of colds and flu. J Health Psychol. 2011;16(2):353-364.

Ye J, Shao H, Perez DR. Passive immune neutralization strategies for prevention and control of influenza A infections. Immunotherapy. 2012;4(2):175-186.

Yeh CH, Chen HC, Yang JJ, Chuang WI, Sheu F. Polysaccharides PS-G and protein LZ-8 from Reishi (Ganodermalucidum) exhibit diverse functions in regulating murine macrophages and T lymphocytes. Journal of agricultural and food chemistry. Aug 11 2010;58(15):8535-8544.

Yeh TL, Shih PC, Liu SJ, et al. The influence of prebiotic or probiotic supplementation on antibody titers after influenza vaccination: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:217-230.

Yoo BK. How to improve influenza vaccination rates in the U.S. J Prev Med Public Health. 2011;44(4):141-148.

Yoon SY, Eo SK, Kim YS, Lee CK, Han SS. Antimicrobial activity of Ganodermalucidum extract alone and in combination with some antibiotics. Archives of pharmacal research. Dec 1994;17(6):438-442.

Yu L, Sun L, Nan Y, Zhu LY. Protection from H1N1 influenza virus infections in mice by supplementation with selenium: a comparison with selenium-deficient mice. Biol Trace Elem Res. 2011;141(1-3):254-261.

Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. J Int Med Res. 2004;32(2):132-140.

Zhang H, Yeh C, Jin Z, et al. Prospective study of probiotic supplementation results in immune stimulation and improvement of upper respiratory infection rate. Synth Syst Biotechnol. 2018;3(2):113-120.

Zhang W, Wang J, Su B, et al. Cimetidine augments Th1/Th2 dual polarized immune responses to recombinant HBV antigens. Vaccine. 2011;29(29-30):4862-4868.