What is the Flu?

The flu, which can be caused by several strains of influenza, is a highly contagious and potentially deadly viral infection that affects the upper and lower airways. Most cases resolve without treatment within two weeks. However, if left untreated, severe complications can arise, especially in high-risk groups (eg, the elderly, people with existing medical conditions, those with compromised immune function, etc.).

What are the Signs and Symptoms of the Flu?

• Sudden onset of high fever
• Fatigue
• Head and body aches
• Cough, congestion
• Sore throat

Note: The flu can be distinguished from a common cold by severity of symptoms and speed of symptom onset: cold symptoms are generally mild and develop over several days, while flu symptoms are much more severe and develop more rapidly.

How Can the Flu be Prevented?

• Get vaccinated yearly for the flu. While this does not guarantee immunity, it is the most effective and least expensive medical intervention. Influenza viruses continually mutate, making annual vaccination essential for continued protection.
• Exercise regularly and eat a balanced diet.
• Gargle with water and use saline nasal drops or nasal irrigation regularly.
• Wash or sanitize hands and surfaces frequently.
• Avoid touching your eyes, nose, and mouth with unwashed hands.
• Avoid sick people when possible or wear a face mask.
• Protect others by staying home when you are sick, coughing or sneezing into the crook of your elbow (rather than your hand or the air), and wearing a face mask when you have flu symptoms.

How is the Flu Treated?

• DO NOT take antibiotics for the flu. Antibiotics do not kill influenza viruses and can contribute to the development of drug-resistant bacteria.
• Over-the-counter drugs (eg, mild analgesics, decongestants, etc.) can provide symptomatic relief for uncomplicated cases of the flu.
• Antiviral drugs are mainly used to treat patients at high risk of developing flu complications. Currently, there are only two oral antiviral drugs being prescribed to treat the flu:
• Oseltamivir (Tamiflu)
• Baloxavir marboxil (Xofluza)

Top Nutrients for the Flu

• Probiotics. Probiotic supplements, especially those containing species of Lactobacillus and Bifidobacterium, have been found to reduce the incidence and severity of upper respiratory viral infections, including the flu.
• Ginseng. Ginseng extracts have been shown to activate the antiviral immune response while reducing the inflammatory response, and clinical trials suggest it may lower the risk of the flu and improve the immune response to the flu vaccine.
• Green tea. Green tea catechins have demonstrated antiviral actions against influenza and other respiratory viruses. Green tea may help prevent viral respiratory infections and may decrease flu-like symptoms by reducing inflammation.
• Elderberry. Clinical research indicates elderberry extract, rich in anti-inflammatory and antioxidant polyphenols, may reduce influenza symptoms and shorten duration of illness when started within 48 hours of symptom onset.
• Andrographis. Multiple randomized controlled trials and two meta-analyses have found andrographis extract, alone and in herbal combinations, reduced symptoms of upper respiratory tract infections and may be especially helpful in alleviating cough and sore throat.

Influenza (the flu), an acute viral respiratory infection caused by influenza A and B viruses, is easily transmitted from person to person.^1,2 Most people who contract influenza have upper respiratory symptoms that resolve without treatment, but influenza can also involve the lower respiratory tract causing complications like bronchitis and pneumonia, particularly in the very young, the elderly, and those with chronic diseases.³ In addition, influenza can lead to complications involving the muscles, heart, and nervous system.²

Influenza infections cause substantial illness and death every year worldwide. In places with temperate climates, such as the United States, influenza infections spike in the winter months causing seasonal epidemics.³ The virulence of influenza viruses vary from year to year due to rapid genetic mutation.⁴ In the past decade, seasonal flu in the United States has been responsible for an estimated 9.3‒454 million illnesses, 140,000‒810,000 hospitalizations, and 12,000‒61,000 deaths per year.⁵ Worldwide, influenza epidemics cause about one billion infections, 3–5 million cases of severe illness, and 300,000–500,000 deaths per year.⁴ In addition, from time to time, new influenza viruses emerge and spread rapidly around the globe causing devastating pandemics.

The flu is usually recognizable by the abrupt onset and intensity of its symptoms, but its symptoms can overlap with those of the common cold.¹ In some cases, tests may be needed to secure an accurate diagnosis and initiate appropriate isolation measures and therapies as soon as possible.⁶ Preventive measures such as hand hygiene and mask wearing, especially when adhered to by a large proportion of a population, can go a long way toward reducing the spread of influenza. Annual flu vaccines provide additional protection, with the greatest benefit in people in higher-risk groups such as the elderly, those with chronic illnesses, and those with compromised immune function.^7,8 Because uncomplicated influenza resolves without treatment, the use of antiviral medications such as oseltamivir (Tamiflu) is generally reserved for those at higher risk of severe disease and complications. Antibiotics are not effective against influenza viral infection; they are only useful if secondary bacterial infections occur.⁹

Influenza takes a disproportionate toll on people over 65 years old, largely due to an age-related deterioration in immune function known as immune senescence.¹⁰ Immune senescence, a phenomenon associated even with healthy aging, is characterized by decreased antimicrobial defenses and disordered immune signaling. Not only does immune senescence increase susceptibility to severe influenza and its most dangerous complications, but it also decreases the effectiveness of vaccination.^11,12 Integrative therapies that enhance antiviral immune activity and modulate inflammatory signaling may help reduce the incidence and severity of influenza. Some natural therapies have been found to directly inhibit viral infection. Probiotics, vitamins C, D, and E, and extracts from medicinal herbs such as ginseng, green tea, andrographis, and elderberry have shown promise for reducing the burden of influenza.

In this protocol, you will learn about influenza viruses and the immune response to influenza infection, as well as how to tell if you are likely to have the flu and what preventive and treatment options are available. The protocol also discusses evidence regarding the repurposing of well-known drugs like statins and antidiabetic medications to help fight influenza. In addition, you will learn about emerging research regarding new antiviral medications, convalescent plasma, and universal vaccines. Finally, this protocol outlines some of the nutrients that may help prevent and treat influenza.

Readers of this protocol may also find useful information in the Pneumonia and Immune Senescence protocols.

Influenza viruses are categorized into four major types: influenza A, B, C, and D viruses. Influenza A and B viruses cause substantial illness in humans, while influenza C usually causes mild or asymptomatic infections. Influenza D viruses, discovered in 2011, do not appear to cause substantial disease in humans.⁴

Influenza A viruses are the main cause of serious influenza illness and are responsible for important epidemics and pandemics throughout history.^4,13 They exist not only in humans but also domestic animals (swine and poultry) and wild birds (ducks, geese, swans, gulls, and others), which can act as reservoirs.⁴ Although cats, dogs, and horses can also contract influenza viruses, little to no transmission from these animals to humans has been reported.¹³

Two proteins on the surface of influenza A viruses, haemagglutinin (which aids viral entry into cells) and neuraminidase (which aids in the release of viral genetic material), are especially variable and are used to classify influenza A viruses into subtypes. There are 18 haemagglutinin (H) and 11 neuraminidase (N) known protein variants.^13,14 Currently, influenza A H1N1 and influenza A H3N2 are the subtypes circulating among the human population. In addition, there are two lineages of influenza B virus currently circulating in humans. Annual flu vaccines target both circulating influenza A subtypes plus one or both of the circulating influenza B lineages.⁴

Influenza A virus subtypes evolve rapidly in response to environmental, immune, and other pressures. Small adaptive mutations in viral genetic material, known as “antigenic drift,” produce new but closely related viruses. Influenza virus strains generated through antigenic drift are susceptible to varying degrees of immune cross-recognition and result in annual influenza outbreaks that vary in transmissibility and severity.^14-16 Influenza B viruses, on the other hand, have less tendency to undergo genetic mutation from year to year.¹⁴

Influenza A viruses also evolve through large changes in their genetic material known as “antigenic shift.” This can occur when a new virus is mutated enough that it transfers from another animal species, usually domesticated swine or poultry, to humans.^4,13,14 Antigenic shift involves the reassortment of segments of genetic material between distinct influenza viruses simultaneously infecting the same cell.¹⁴ This produces a new strain of influenza virus that is very different from previous strains. In rare instances when such a novel viral strain is or becomes well adapted for survival in the human host, the lack of immune memory needed to generate a swift and efficient response can pave the way for rapid spread of infection and high rates of severe illness and death.^17-19 These viruses have historically caused pandemics that severely impacted not only the very young and very old, but also young adults. However, in subsequent years seasonal outbreaks were more typical.^4,14

The following populations are at higher risk of developing severe seasonal influenza and its complications^3,21:

• Those under 5 and over 65 years of age
• Nursing home residents
• People with chronic lung or heart diseases or other chronic medical conditions
• People taking glucocorticoids or other immune-suppressive medications
• Immunocompromised individuals
• Extremely obese individuals
• Current or past smokers
• Pregnant women and those who recently gave birth
• Native Americans, Native Alaskans, and possibly other Indigenous people

Influenza pandemics, unlike seasonal influenza, have notably been associated with higher rates of severe disease, hospitalization, and death in otherwise healthy young adults.²¹ It is thought immune memory formed during previous exposure to similar virus strains may have given older individuals partial immunity against pandemic influenza virus strains.²²

Influenza is typically marked by sudden acute respiratory symptoms (eg, runny nose, sore throat, and cough) as well as systemic symptoms (eg, fever, chills, malaise, muscle pain, headache, and appetite loss), but a wide range of symptoms are possible.^2,16 These symptoms usually improve over two to five days and most people fully recover within seven to 10 days.^1,2

Influenza symptoms are usually distinguishable from those of the common cold by their sudden onset and intensity. Even severe influenza complications can appear as early as 48 hours after symptom onset.¹

Table 1: Comparison of Characteristics: Common Cold and Influenza31-36
	Common Cold	Influenza
Causative virus(es)	Rhinoviruses, influenza viruses, and others	Influenza A virus Influenza B virus Influenza C virus
Site of infection	Upper respiratory tract	Upper and lower respiratory tracts
Incubation period	1–3 days	1–4 days
Onset of illness	Gradual	Abrupt
Duration of illness	Typically 7–10 days	Typically 7–10 days
Contagious Period	Typically 7–14 days	As early as 12 hours after exposure, typically lasting 5‒10 days
Severity of illness	Mild	Mild to severe
Symptoms:
Nasal congestion and runny nose	Characteristic	Common
Sore throat	Characteristic	Common
Cough	Characteristic, usually mild to moderate	Characteristic, can be severe
Headache	Common, usually mild	Common
Fever	Rare, low-grade	Characteristic, can be high
Muscle aches	Uncommon, usually mild	Characteristic, often severe
Malaise/fatigue	Common, usually mild	Characteristic, often severe
Shortness of breath	None	Uncommon
Diarrhea and/or vomiting	None	Uncommon

Influenza Spread

Influenza viruses spread from person to person via inhalation of virus-harboring droplets or aerosols, and through direct contact³⁷:

• Droplets. Influenza viruses can spread in respiratory droplets emitted by an infected person during coughing, sneezing, singing, or talking. These droplets travel short distances (about six feet) and spread infection when they are inhaled by others in close proximity or by contaminating surfaces and contributing to contact spread.^2,37
• Aerosols. Exhaled influenza viruses can become suspended in aerosols—tiny droplets of moisture that can linger in the air for long periods of time and may be naturally carried distances as far as 12 feet. Aerosolized influenza viruses can be generated during coughing and sneezing, as well as through normal breathing.³⁷
• Contact. Hands that come in contact with the skin of an infected person or a contaminated surface can transmit influenza virus through touching the nose, eyes, or mouth. Influenza A virus may survive for 24–48 hours on metal and plastic surfaces and less than 8–12 hours on cloth and paper.

The extent of influenza spread, as well as its severity, is determined in part by factors such as degree of pre-existing immunity in the population and inherent virulence of the virus in circulation. During a typical outbreak of influenza, about 5–10% of adults and 20–30% of children are likely to become infected, but during pandemics, the infection rate may be higher than 50%.^14,38 The transmissibility of influenza viruses is also affected by environmental factors including humidity and temperature. Winters, marked by low humidity and low temperatures, favor influenza virus spread, and flu season coincides with winter in temperate regions of the Northern and Southern Hemispheres.⁴ Unlike in temperate regions, influenza patterns can vary in tropical regions and remain active throughout the year. Outbreaks related to air and cruise ship travel in non-winter months have been documented.¹⁴

Infection, Incubation, and Contagious Period

When an influenza virus makes contact with a respiratory epithelial cell, such as those lining the nose or mouth, it binds to specific receptors on the cell surface. This can trigger a process by which the virus gains entry into the cell and releases its genetic material. The cell is in this way co-opted into generating proteins needed for viral replication. Infected cells produce large amounts of virus that are shed into respiratory secretions, facilitating infection spread. In addition, they release signaling molecules that activate all types of immune cells and initiate the antiviral immune response.^2,16,39

The time between initial infection and symptomatic illness, known as the incubation period, is typically one to four days, but viral shedding may begin as early as 12 hours after influenza virus exposure.² Studies indicate viral replication and shedding likely peak about 48 hours after exposure, last for five to 10 days, and correlate with severity of illness.^1,2 In particular, longer duration of viral shedding has been observed in children, older adults, those with chronic disease, obese individuals, and those with compromised immune function.²

Illness and Recovery

The way influenza infection manifests in the body is largely determined by interactions between the virus and the immune system. These interactions are shaped by cytokines, signaling molecules released by infected cells and activated immune cells that regulate the antiviral and inflammatory immune response. A balanced immune response efficiently clears the virus but, in the process, causes the symptoms of the flu; an unbalanced immune response, however, can be the cause of severe illness and dangerous complications.^22,39 For example, excessive cytokine signaling, such as a cytokine storm, may successfully clear the virus, but causes a hyper-inflammatory response that results in tissue damage in the lungs and sometimes other body systems.^22,39,40 This is the main cause of death in influenza patients.²² Conversely, if the antiviral response is insufficient for clearing the infection, there may be few typical symptoms, but the uncontrolled infection can lead to lung damage and render one vulnerable to secondary lung infection.^22,39

For most people, the immune system effectively clears infection and symptoms abate within one to two weeks. In addition, specialized immune memory cells form that can respond immediately to control a second infection by the same virus. Some of these immune memory cells can recognize multiple influenza virus strains that share certain surface proteins. This kind of cross-recognition can facilitate a more timely and effective immune response and help limit symptom severity when similar influenza viruses are encountered in the future.^22,41

Complications

The most common complication of influenza is pneumonia, which can be caused by the influenza virus and/or a secondary bacterial infection. Influenza-related pneumonia, especially when it involves bacterial infection, is a leading cause of influenza-related hospitalizations and death.⁴⁷ Individuals who are especially vulnerable may experience other dangerous complications including widespread viral or secondary bacterial infection, severe systemic inflammation, and multi-organ failure.²¹

The flu can also lead to complications involving the muscles, heart, and nervous system, though these are less common than respiratory complications.^2,21 One study that included more than 80,000 hospitalized patients with influenza infection found 11.7% had an acute cardiovascular event such as heart failure or heart attack associated with their hospitalization.⁴⁸ Another study that included 364 heart attack patients found the risk of heart attack was six times higher during the week after a flu diagnosis than during a period extending one year before and one year after having the flu.⁴⁹ Risk factors for cardiac complications include being an older age, tobacco use, and having diabetes or cardiovascular or kidney disease. Observational research has correlated influenza vaccination with cardiovascular protection in people aged 65 years and older, further indicating the importance of vaccination for this high-risk population.⁵⁰

What Tests Are Available

Influenza virus tests used to diagnose acute illness can detect either viral proteins (antigens) or virus-specific genetic material (RNA or nucleic acids) in specimens collected from the upper or lower airways. Cultures, which have 1‒10-day turnaround times, may be helpful for public health purposes but are too slow to be clinically useful. The accuracy of diagnostic testing depends not only on the method but also on factors such as time between onset of illness and specimen collection, and specimen source, quality, handling, and processing.⁶ Ultimately, the test used depends on both test availability and how soon results are needed.

The Infectious Diseases Society of America recommends rapid molecular assays in outpatient settings and reverse transcription polymerase chain reaction (RT-PCR) and other molecular assays in hospital settings.⁶

Table 2: Influenza A and B Virus Testing Methods51
Method	Detects	Based on	Source of Specimen	Test Time
Rapid Influenza Molecular Assays	A and B	Viral genetic material	Nasal or nasopharyngeal swab	15–30 minutes
Reverse Transcription Polymerase Chain Reaction (RT-PCR) and other molecular assays	A and B; some tests distinguish between influenza A virus subtypes; some tests distinguish between influenza virus and other respiratory pathogens	Viral genetic material	Throat or nasopharyngeal swab; nasopharyngeal or bronchial wash; nasal or endotracheal aspirate; sputum	1–8 hours, depending on the exact test
Rapid Influenza Diagnostic Tests	A and B	Viral protein	Nasal or nasopharyngeal swab, aspirate, or wash; throat swab	< 15 minutes
Immunofluorescence, direct or indirect	A and B	Viral protein	Nasopharyngeal swab or wash; bronchial wash; nasal or endotracheal aspirate	1–4 hours

Who Should Be Tested?

During the flu season, people who do not require hospitalization and are not at high risk of complications can be diagnosed with influenza based on their symptoms. Influenza virus testing is only recommended if the test result will affect treatment decisions (such as whether to administer antibiotics) or guide infection control strategies (such as for nursing home residents). Diagnostic testing for influenza is therefore recommended in⁵²:

• Immunocompromised patients, both hospitalized and not hospitalized, with symptoms of acute respiratory illness
• Patients hospitalized for acute respiratory illness
• Those who develop acute respiratory illness while hospitalized for another reason
• Those hospitalized for exacerbations of chronic obstructive pulmonary disease, asthma, coronary artery disease, or congestive heart failure, since influenza can worsen these conditions

In addition, outside of the flu season, healthcare providers may consider influenza virus testing for hospitalized and non-hospitalized patients who exhibit symptoms of acute respiratory illness, including fever, especially if they have a high risk of complications or have been traveling in regions where influenza activity is unknown.⁵²

Strategies for reducing the risk of influenza and its complications include basic personal precautions and influenza vaccination.

Precautions

Basic precautions for limiting the spread of influenza include⁵³:

• Staying home when sick
• Keeping a distance from others who may be sick
• Covering your mouth and nose with a tissue (or the inner elbow) when coughing or sneezing
• Minimizing touching of eyes, nose, and mouth with unwashed hands
• Practicing good hand hygiene
• Cleaning high-touch surfaces frequently
• Using face masks when unable to avoid close contact if you or others may be sick.

Hand hygiene. Influenza viruses on skin are inactivated by washing with soap or using alcohol-based hand rubs.⁵⁴ Frequent hand washing and sanitizing have been correlated with reduced spread of influenza and other viruses.⁵⁵ Although the effectiveness of hand hygiene is more difficult to assess in the community, its value in healthcare settings has been well established.⁵⁶ Washing hands at least three and possibly five or more times per day may be needed to substantially reduce infection risk.^57-59 Effective hand washing requires rubbing soapy hands together for at least 20 seconds, then rinsing and completely drying hands. When a sink is not available, hand sanitizers with alcohol concentrations of 60% or higher are recommended for their broad antimicrobial effects and should be rubbed into hands until completely dry for best results.⁶⁰

Face masks. Medical (surgical) face masks are designed to reduce the spread of respiratory viruses by droplet, while N95 respirator masks can also reduce viral spread by aerosol. Both appear to help reduce viral respiratory infections, including influenza. Observational studies indicate wearing a medical or respirator mask is correlated with substantially reduced risks of influenza and other viral respiratory infections, and the relationship may be stronger in healthcare settings than in community settings.⁶¹ Although findings from community-based studies have been mixed, the following factors seem to increase the likelihood that masks will be effective in preventing influenza spread⁶²:

• High mask-use compliance
• Use of masks by close contacts before or soon after the appearance of symptoms
• Mask use in combination with hand hygiene measures

Importantly, face masks may be more beneficial for reducing community spread of viral infections during pandemic times, when compliance may be better and a positive impact more likely. The effectiveness of reusable cloth masks has not been well studied, but factors such as proper composition, fit, handling, and cleaning are likely to determine their usefulness.

Gargling and nasal irrigation. Regular gargling and the use of nasal irrigation and sprays may reduce the risk of influenza and other respiratory infections.⁶³ Gargling with an iodine solution or salt water have both been found to reduce respiratory infections in preliminary studies.^64,65 In a controlled clinical trial with 387 participants, gargling at least three times per day was found to lower the risk of upper respiratory tract infections and gargling with plain water was more effective than an iodine-based solution. The trial also noted that participants who gargled but got sick were less likely to develop lower respiratory symptoms.⁶⁶ Gargling with green tea may also have a preventive effect against influenza infection.⁶⁷

Clinical trials have found saline nasal sprays and drops reduced symptoms in children with upper respiratory infections. In controlled trials in adults, daily use of saline nasal spray reduced the incidence of upper respiratory infections,⁶⁸ and saline nasal irrigation reduced shedding of influenza A and other respiratory viruses, household transmission, use of over-the-counter medications, and duration of illness in patients with symptoms of respiratory infections.⁶⁹

Vaccination

Annual vaccination against seasonal flu is an important public health strategy for limiting the scope of outbreaks and epidemics and is recommended for everyone six months of age and older who does not have contraindications.^70,71 There are several types of influenza virus vaccines available⁴:

• Inactivated influenza vaccines. These vaccines contain viral proteins from a combination of two kinds of influenza A and either one or two kinds of influenza B.
• Recombinant influenza vaccines. These vaccines also contain viral proteins but are produced using non-influenza viruses that have been genetically altered to produce the desired proteins.
• Live attenuated influenza vaccine. These vaccines contain influenza A and B viruses that have been weakened through genetic manipulation.

The specific viruses used in manufacturing new vaccines each year are selected based on year-round surveillance of circulating viruses, extent to which the viruses are spreading, and effectiveness of the previous season’s vaccine against those viruses. The goal of vaccination is to elicit a minor immune response that results in sufficient immune memory to improve responsiveness should exposure to circulating viruses occur.^4,70

The choice of vaccine depends partly on the age and health status of the individual. Live attenuated influenza vaccines may be preferred for children since they are administered intranasally.^4,71 In vulnerable populations, such as those under 2 years old, the elderly, pregnant women, those with chronic illnesses, and those with weak immune function, live attenuated vaccines are not recommended.⁷¹ High-dose inactivated influenza vaccines or vaccines containing adjuvants (non-viral compounds that enhance the immune response to the vaccine) may be recommended in older individuals who have a weaker response to vaccination generally. Although inactivated influenza vaccines are commonly produced using viruses grown in an egg medium, cell-based vaccines are available for those with egg allergy.⁴

The effectiveness of the seasonal influenza vaccine varies from year to year depending in part on how well the circulating viruses match those used to develop the vaccine, and how much antigenic drift (small mutations in virus genetic code) occurs. Estimates from meta-analyses indicate that, when the influenza viruses in available vaccines are a good match with those in circulation, vaccination may reduce the risk of influenza infection by 40–60%.⁷² In addition, vaccination may reduce the risk of severe illness, adverse cardiovascular and respiratory outcomes, and death due to any cause, particularly in the elderly and those with chronic diseases.^7,8

The protective benefit of the seasonal influenza vaccine diminishes quickly relative to other types of vaccines, and it has been reported to be suboptimal after four months. This is long enough to encompass a typical flu season but may leave world travelers unprotected the rest of the year.⁷²

Inactivated influenza vaccines commonly cause temporary mild soreness at the injection site, as well as irritability, fever, malaise, muscle pain, and other systemic symptoms lasting several days in children. Live attenuated influenza vaccine can cause mild symptoms of influenza illness such as nasal congestion, sore throat, and cough, as well as systemic symptoms such as fever and decreased appetite. Rarely, serious unexpected adverse side effects have been associated with influenza vaccination.⁸¹ The most common serious adverse reaction to influenza vaccines is anaphylaxis (a life-threatening allergic reaction), which is estimated to occur at a rate of 1.6 cases per million doses of standard trivalent influenza vaccine administered.⁸² Another possible serious adverse reaction is Guillain-Barré syndrome (GBS), an autoimmune disorder affecting the nerves. An association between influenza vaccination and a small increase in risk of GBS was detected in 1976. It was estimated the occurrence of GBS increased by one case per 100,000 vaccinations administered. Since then, the risk of GBS possibly related to influenza vaccine varies from year to year but is generally 1‒2 cases per million vaccinations. It is important to note that studies suggest it is more likely for a person to get GBS after they have the flu than after the vaccine.⁸³

Influenza is usually a mild self-limited infection in people who are otherwise healthy and does not require treatment with antiviral medications.¹ Importantly, antibiotics are not appropriate in the treatment of uncomplicated influenza and should be reserved for those with secondary bacterial infections.⁹ Some over-the-counter cold medicines may reduce symptoms and provide comfort. However, parents should bear in mind aspirin and aspirin-containing products should be avoided in children due to the possibility of Reye’s syndrome, a rare and potentially fatal condition associated with aspirin use, in this age group.⁸⁶

Antiviral drugs are recommended in influenza patients with rapidly progressing infection or a high risk of complications, as well as those who are hospitalized. In these patients, antiviral drug therapy may reduce the severity and risk of complications and decrease mortality.⁹ Antiviral drugs are also used to prevent and treat influenza during outbreaks in hospitals, nursing homes, and other healthcare settings.¹ Individuals with influenza who are healthcare workers and likely to come in contact with high-risk individuals may also be treated with antiviral therapy.⁹

In otherwise healthy individuals with influenza, antiviral therapy is generally unnecessary; however, the initiation of antiviral therapy within 48 hours of symptom onset may shorten the duration of illness by about one day.⁹

There are several antiviral drugs for influenza^1,9:

• Neuraminidase inhibitors. Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab) are neuraminidase inhibitors. These drugs interfere with the release of viruses from infected cells. Oseltamivir is an oral drug, zanamivir is inhaled, and peramivir is used intravenously.
• Endonuclease inhibitor. Baloxavir marboxil (Xofluza) is an endonuclease inhibitor and disrupts viral replication. This drug is available as an oral medication.
• Adamantanes. Amantadine (Symmetrel) and rimantadine (Flumadine) belong to a class of antiviral drugs called adamantanes and are only effective against influenza A virus.

Viruses can quickly develop resistance to antiviral drugs. Influenza viruses circulating in the United States currently show little resistance to neuraminidase inhibitors and baloxavir marboxil, but resistant strains can emerge at any time, including during treatment.^1,87 Widespread resistance to adamantanes has been observed among influenza A viruses circulating in recent years in North America and Asia, and current recommendations advise against their use for influenza treatment or prevention at this time.^1,9 The use of oseltamivir is limited by its association with adverse side effects such as skin reactions, nausea and vomiting, psychiatric symptoms, and kidney problems.^1,88 Skin reactions and diarrhea have also been associated with the use of peramivir and baloxavir marboxil, and zanamivir can cause respiratory problems in those with asthma or chronic obstructive pulmonary disease (COPD).⁹

Repurposed Drugs

Drug repurposing is the process of identifying new conditions for which known medications can be used beneficially. Repurposing is faster, less expensive, and often safer than new drug development. The prospect of repurposing drugs to treat influenza is especially appealing since currently available treatment options are not highly effective.⁸⁹

Nitazoxanide. Nitazoxanide (Alinia) is a drug used to treat intestinal parasites. It has demonstrated antiviral activity against influenza A and B viruses in the laboratory⁹⁰ and early clinical trials in humans suggest it may reduce viral load and symptoms of infection. However, not all clinical trials have shown benefit.⁹¹ More clinical trials are needed to determine whether nitazoxanide or similar compounds may be effective for influenza infection.

Statins. Statins are medications used to lower high cholesterol levels. Statins have also been found to have general anti-inflammatory and immune-modulating effects that may be beneficial in patients with influenza. Some, but not all, observational studies have noted a lower mortality rate among hospitalized patients with influenza who were incidentally taking statins.⁸⁹ A randomized controlled trial found that atorvastatin (Lipitor) led to greater symptomatic improvement at 72 hours than placebo among 116 subjects with influenza. However, this endpoint was a secondary outcome and the study’s primary endpoint of change in inflammatory markers did not reach statistical significance.⁹²

Anti-diabetes drugs. Anti-diabetes drugs targeting the repair of metabolic disturbances have been found to have immune-modulating effects such as reducing inflammatory cytokine signaling and regulating antibody activity. These effects may make them useful in treating viral infections, including influenza. In newly diagnosed type 2 diabetes patients, treatment with the anti-diabetes drug metformin (Glucophage) was found to improve the function of antibody-producing immune cells as well as the antibody response to influenza vaccine.⁹³ Other research, however, has found diabetics using metformin have a suppressed immune response to influenza vaccination.^94,95 Pioglitazone (Actos), an anti-diabetes drug in the peroxisome proliferator-activated receptor (PPAR) agonist class, has also demonstrated promising anti-inflammatory and anti-influenza effects in preclinical research.⁹⁶

Cimetidine. Cimetidine(Tagamet) is an over-the-counter drug that reduces gastric acid secretion by inhibiting a type of histamine receptor (H2 receptors) found in the gastric lining. It is mainly used to treat gastroesophageal reflux disorder (GERD), but is sometimes used to treat gastric and duodenal ulcers and viral warts.⁹⁷ H2 histamine receptors are also found on all types of immune cells, and cimetidine has been shown to modulate immune cell activity. Preclinical studies indicate cimetidine can enhance antiviral immune function while diminishing the inflammatory immune response.⁹⁸ Note: cimetidine can interact with many drugs and potentially cause adverse effects. Talk with a qualified healthcare provider or pharmacist before starting cimetidine to be sure you do not take any drugs that could interact with cimetidine.

Antiviral Drugs

Development of new antiviral drugs that target aspects of viral entry and replication, as well as enhancement of host defenses, is a subject of intense research attention. Favipiravir (Fabiflu, Avigan) and fludase are among the more promising new therapeutics under investigation.^99,100

Favipiravir. Favipiravir, an antiviral drug used to treat influenza, works by interfering with viral replication in infected cells. It has demonstrated antiviral activity in the laboratory against all subtypes of influenza viruses, including those that have low or no sensitivity to other antiviral drugs, as well as a range of other viruses such as Ebola, Lassa fever, Marburg, Nipah, and Zika viruses.^100-102 In addition to having a broad spectrum of activity, favipiravir appears not to induce resistance, and may be effective even when started 72 hours after infection. Favipiravir is not approved for use in the United States, but is approved to treat influenza in Japan.^100,101 Importantly, favipiravir is contraindicated in pregnancy due to possible teratogenic effects, and its safety in children is still in question.^100,103

Fludase. Fludase is a drug with a host-based mechanism of action: rather than targeting viruses, it targets respiratory mucosal cells, reducing expression of receptors used by viruses to gain entry. Early-stage clinical research suggests it may be active against a broad array of influenza virus strains, and may safely reduce viral load and shedding in infected individuals.

Antibodies

Another approach to treating influenza is through the therapeutic use of antibodies. Studies have identified antibodies that have broad activity against influenza A virus strains. In animal research, the use of cloned antibodies, alone and in combination with antiviral drugs, has been shown to reduce viral spread and severity of illness.¹⁰⁴ Several monoclonal antibody drugs have reached phase II clinical trials in humans and have been found to reduce viral shedding and clinical symptoms after experimental exposure to influenza A virus.^100,104 However, antibody therapy has not yet been found to have clear advantages over oseltamivir.¹⁰⁰

Convalescent plasma. Convalescent plasma is obtained from donors who have recently recovered from viral illness and is rich in antibodies that support specific antiviral defense. Convalescent plasma has been used for decades in the treatment of severe respiratory viral illnesses, including influenza.^105,106 Multiple studies have reported benefits from convalescent plasma therapy in patients infected with various strains of influenza A virus, particularly when started early: lower mortality, shorter hospital stays, and less need for intensive care and emergency interventions have been noted, and there have been no reports of serious adverse effects.¹⁰⁵ However, recent randomized controlled trials and meta-analyses have not clearly demonstrated the effectiveness of convalescent plasma therapy in influenza patients.¹⁰⁶ One recent randomized controlled trial in 308 influenza A and B patients found the addition of convalescent plasma to standard antiviral therapy was only beneficial in those with influenza B infections.¹⁰⁷

Interferon-λ

Interferons (IFNs) are cytokines that are critical to initiating and sustaining antiviral immune activity. Preclinical studies suggest interferon-lambda (IFN-λ, also called type III IFN) is a critical early player in clearing influenza virus, limiting viral transmission, and producing lasting antiviral protection.¹⁰⁸ It also appears to trigger less pro-inflammatory signaling than later-acting IFN-α and IFN-β (type I IFNs).¹⁰⁹ Animal research indicates early treatment of influenza with therapeutic pegylated-IFN-λ may result in better control of viral replication, less lung tissue damage, and more rapid recovery.^109,110 One study in mice, however, found IFN-λ therapy during influenza infection impaired the immune response to bacteria, raising concern that this treatment may increase the risk of secondary bacterial infection.¹¹¹ Clinical trials in humans with the flu have not yet been undertaken, but, subcutaneous injections of IFN-λ have shown promising results in patients with another respiratory viral infection.

Universal Vaccines

Although they are currently the most effective medical tool for preventing influenza and its complications, seasonal influenza vaccines provide limited protection and require annual modification based on changes in circulating viruses. Ongoing research is focused on developing a universal influenza vaccine that would be effective against all influenza types and subtypes that infect humans regardless of antigenic drift and shift and would not need modification each year.¹¹² One systematic review identified 69 clinical trials using 27 novel influenza vaccines conducted between January 2010 and December 2019. These investigational vaccines differ in the viral proteins (antigens) they incorporate or mimic to induce an immune response, mechanism or medium for antigen delivery, and use of adjuvants to enhance the immune response. One of these vaccines demonstrated promising effects in phase III testing in children; two others are currently undergoing phase III clinical trials.¹¹³

Poor nutritional status, whether from undernutrition or overnutrition, has been recognized for centuries as a factor linked to severe influenza and complications.¹¹⁴ A healthy diet that supplies adequate amounts of vitamins A, B complex, C, D, and E, as well as zinc, selenium, magnesium, iron, copper, and omega-3 fatty acids supports normal immune function and defense against influenza and other viral respiratory infections.^115,116 Dietary fiber has been found to improve antiviral immune activity while mitigating the inflammatory response,¹¹⁷ and flavonoids from plant foods may have specific antiviral effects and may help reduce tissue-damaging oxidative stress and inflammation during the response to infection.¹¹⁸ Fermented foods that supply probiotic strains may also help by supporting a balanced immune response to influenza infection.¹¹⁹

Likewise, a sedentary lifestyle may contribute to increased severity of influenza and risk of complications. A meta-analysis of 14 randomized controlled trials found regular moderate aerobic exercise, such as walking and cycling, may reduce the severity of acute respiratory illnesses, though it does not appear to affect their incidence.¹²⁰ Moderate exercise enhances immune defenses while lowering systemic inflammation, and has been found to mitigate the effect of aging on immune function.¹²¹ Exercise may also improve the immune response to the influenza vaccine in older individuals.¹²²

Sleep is important for balanced immune function and clinical evidence suggests chronic sleep disturbance may contribute to poor influenza vaccine response and increased risk of acute respiratory illness.^123,124 During an infection, immune activation can promote increased sleep duration and intensity, which may in turn assist in recovery.¹²⁴

Chronic psychological stress is another factor that interferes with normal immune defenses and raises inflammatory signaling, increasing the risk of respiratory infections. High levels of perceived stress can weaken the response to influenza vaccination and may increase vulnerability to influenza infection.^125-128

Probiotics, Prebiotics, and Synbiotics

Beneficial microbes that colonize the intestines are integral to healthy immune function. Even in the respiratory tract, the gut microbiome helps regulate antiviral and inflammatory immune responses against viral infections including influenza. An upset in the intestinal microbial balance (dysbiosis) is associated with chronic inflammatory conditions of the airways, including allergies, asthma, and COPD, and may increase the risk of viral respiratory infections. Probiotic supplements, especially those with species of Lactobacillus and Bifidobacterium, have been found to reduce the incidence and severity of upper respiratory viral infections, including the flu.¹²⁹

Probiotics and influenza prevention. Multiple clinical trials show probiotics can reduce the risk of respiratory infections, including colds and influenza-like illnesses, but few have looked at their effects on laboratory confirmed influenza. In a placebo-controlled trial that included 96 elderly nursing home residents, eating 100 grams of yogurt fortified with L. delbrueckii ssp. bulgaricus daily for 12 weeks led to increased salivary anti-influenza antibody activity.¹³⁰ However, this same probiotic yogurt did not lower the risk of influenza infection in a 16-week placebo-controlled trial in 961 female healthcare workers.¹³¹ In a trial that included 196 elderly nursing home residents, laboratory confirmed viral respiratory infections (some of which were influenza) occurred in 15% of those given 20 billion colony forming units (CFUs) ofL. rhamnosus GG daily and 22.9% of those given placebo.¹³² An open trial that included 1,089 children also reported promising findings: in those receiving a probiotic strain of L. brevis, at a dose of 6 billion CFUs five days per week for eight weeks, 15.7% were diagnosed with influenza by a physician; in those not receiving the probiotic, 23.9% were diagnosed with influenza.¹³³

Probiotics and influenza-like illness. In one trial that included 136 participants with a history of frequent episodes of common colds and influenza-like illnesses, taking a daily supplement containing at least 63 million CFUs of L. paracasei, L. casei, and L. fermentum reduced the frequency of flu-like symptoms and upper respiratory infections compared with placebo. The probiotic combination also increased levels of IFN-γ, a cytokine that activates antiviral immune activity, and gut secretory immunoglobulin-A, an antibody that plays a critical defensive role against infections.¹³⁴ A six-week placebo-controlled trial in 581 stressed college students found those taking a daily B. bifidum supplement had more healthy days and fewer episodes of cold or flu symptoms lasting one day or longer.¹³⁵ In a meta-analysis that included data from 11 randomized controlled trials with a total of 2,417 children, probiotic use was found to decrease the risk of both upper and lower respiratory infections.¹³⁶

Synbiotics, which contain both probiotic organisms and prebiotic saccharides, have also been shown to reduce respiratory infection risk. A series of three trials in a combined total of 721 healthy participants compared the effects of four synbiotic preparations made with mixed strains of L. plantarum (LP 01 and LP 02), L. rhamnosus (LR 04 and LR 05), and B. lactis (BL 01), along with a prebiotic (either fructooligosaccharides [FOS] or galactooligosaccharides [GOS]), to placebo during three flu seasons. All of the preparations were found to reduce the incidence, severity, and duration of flu-like illnesses, as well as upper respiratory infections generally.¹³⁷ A meta-analysis that included findings from 16 randomized controlled trials with a combined total of more than 10,000 participants found supplementing with synbiotics reduced the incidence of all respiratory tract infections by 16%.¹³⁸

Probiotics and influenza vaccine response. Since certain probiotics appear to improve the immune response to influenza viruses, investigators have examined their ability to affect the response to influenza vaccination. In a placebo-controlled trial in 98 elderly subjects living in nursing homes, taking a supplement providing 3 billion CFUs per day of L. coryniformis for two weeks strengthened the response to influenza vaccination and reduced the incidence of respiratory infection symptoms and influenza-like illness during five months of monitoring.¹³⁹ A meta-analysis of 12 randomized controlled trials with a combined total of 688 participants found both probiotic and prebiotic supplements increased antibody responsiveness to influenza vaccination. In the seven probiotic trials, single probiotic strains were used, including strains of L. paracasei, L. casei, L. rhamnosus, and B. longum. The five prebiotic trials used FOS, GOS, and/or inulin.¹⁴⁰ Findings from a randomized controlled trial in which elderly participants were given a heat-treated probiotic supplement or placebo prior to influenza vaccination suggest those aged 85 years and older may benefit most from this type of intervention.¹⁴¹

Beta-Glucans

Beta-glucans (eg, beta 1,3/1,6 glucan) are a common type of prebiotic fiber, indigestible by human enzymes but fermentable via the digestive action of beneficial gut bacteria. They are found in foods such as whole grains and mushrooms, as well as yeasts and algae.^142,143 Beta-glucans have been found to stimulate antimicrobial defenses through direct action on intestinal immune cells and modulate inflammation through their ability to improve the health of the gut microbiome.^143-145 Findings from animal research suggest supplementation with beta-glucans may improve the immune response to influenza vaccination and enhance recovery from influenza infection.^146,147

In a study of 52 healthy adults, ingestion of 5 or 10 grams of shiitake mushrooms daily for four weeks resulted in increased levels of immune cells with the ability to proliferate. Additionally, levels of secretory immunoglobulin A in the saliva were increased, which implies improved gut immunity. The authors of this study attributed the beneficial effects of the mushrooms to compounds found in shiitake mushrooms, including beta-glucans and other compounds (eg, ergothioneine, linoleic acid).¹⁴⁸

In a placebo-controlled trial in 357 marathon runners, those given a yeast extract providing 250 mg beta-glucans daily for 45 days before, the day of, and 45 days after running a marathon had fewer days with upper respiratory symptoms, reduced symptom severity, and fewer workout days missed after the marathon than those given placebo.¹⁴⁹ A similar placebo-controlled trial included 182 runners and found supplementing with 250 mg of yeast-derived beta-glucans per day for 28 days after running a marathon decreased the number of post-marathon days with cold or flu symptoms by 37%. The same publication reported findings from a separate placebo-controlled trial in 60 athletes indicating supplementation with beta-glucans for 10 days before intense exercise mitigated exercise-induced immune suppression.¹⁵⁰

In 175 children with recurrent respiratory infections, those given supplements containing beta-glucan extracted from mushrooms (dosed according to body weight) had fewer flu-like illnesses and respiratory infections during 12 months of monitoring than those given placebo.¹⁵¹ Additionally, several randomized controlled trials have shown beta-glucans can help reduce the incidence and severity of common cold symptoms.^152-155

Saccharomyces cerevisiae

Saccharomyces cerevisiae (S. cerevisiae) is a probiotic yeast that is consumed in fermented foods such as beer and sourdough bread. It has been hypothesized that S. cerevisiae and other probiotic yeasts may enhance the immune system by improving the physical barrier of the gastrointestinal system and helping regulate cytokine secretion.¹⁵⁶

A yeast fermentation product partially derived from S. cerevisiae (EpiCor) has been shown to protect against cold and flu-like symptoms in two clinical trials. In a randomized controlled trial of 116 participants who had not received a recent seasonal influenza vaccine, 500 mg EpiCor daily significantly reduced the incidence of common cold or flu-like symptoms compared with placebo. When symptoms were measured individually, EpiCor significantly reduced 10 of 11 symptoms, with no effect on weakness. Although the duration of symptoms was numerically reduced from 4.25 to 3.59 symptom days with EpiCor, there was no significant difference in duration in this study.¹⁵⁷ When EpiCor was evaluated in 116 individuals recently vaccinated against influenza, similar results were reported: EpiCor significantly reduced the incidence of cold or flu-like symptoms as well as duration of symptoms (from 5.01 to 4.16 days) compared with placebo.¹⁵⁸

Ginseng

Several ginseng species, including Korean or red ginseng (Panax ginseng), American ginseng (Panax quinquefolius), and Chinese ginseng (Panax notoginseng), have been studied for their ability to modulate immune function and prevent and treat infections. Although not identical, these ginseng species have similar active constituents and overlap in therapeutic potential.¹⁵⁹ Ginseng extracts have been shown to activate the antiviral immune response while reducing the inflammatory response, possibly by lowering oxidative stress, and research in animals suggests ginseng may improve outcomes in influenza infection.^159,160

A meta-analysis of 10 randomized controlled trials found ginseng may reduce the risk of seasonal colds and flu. The analysis also showed ginseng has the potential to increase the effectiveness of the flu vaccine.¹⁶⁰ In a randomized controlled trial, 43 community-dwelling adults aged 65 years and older took either 400 mg of a standardized ginseng (Panax quinquefolius) extract per day or placebo for four months. After the first four weeks, the subjects received a standard influenza vaccine. There was no difference in rates of acute respiratory symptoms between the groups during the first two months. In the next two months, 62% of those receiving the ginseng extract, compared with 32% of those receiving placebo, experienced no acute respiratory illnesses. In addition, among those who developed infections, the average duration of symptoms was 5.6 days in the ginseng group versus 12.6 days in the placebo group.¹⁶¹ A report on two placebo-controlled trials in elderly residents of long-term care facilities (with 89 subjects in one trial and 109 in the other) found 400 mg per day of the same ginseng extract lowered the risk of acute respiratory infections due to influenza or respiratory syncytial virus by 89% compared with placebo. About 90% of subjects in these studies had received the influenza vaccine.¹⁶²

In a randomized controlled trial, 100 healthy volunteers who had not been vaccinated against influenza were given 3 grams of red ginseng per day or placebo for 12 weeks during flu season. The ginseng-treated group experienced fewer influenza-like illnesses: 24.5% versus 44.9% of those in the ginseng and placebo groups, respectively, experienced one or more influenza-like illnesses.¹⁶³ Another 12-week, randomized, placebo-controlled trial examined the effect of 100 mg per day of a standardized extract of red ginseng on the incidence of influenza and common colds in 227 healthy individuals. All participants were vaccinated against the flu in week four of the study. Ginseng-treated participants had a stronger immune response to the flu vaccine and a 64% lower number of cold and flu cases than participants given placebo.¹⁶⁴

Green Tea

Green tea (Camellia sinensis) is a rich source of polyphenols known as catechins. Green tea catechins have demonstrated antiviral action against influenza and other respiratory viruses in preclinical research.^165,166 In a randomized controlled trial in 108 healthy adults, green tea capsules providing approximately the equivalent of 10 cups of green tea per day for three months reduced the risk of flu-like illnesses and common colds lasting two days or longer by 22.9% and the number of days with cold or flu symptoms by 35.6% compared with placebo. In addition, immune cells from those receiving green tea exhibited increased antiviral activity.¹⁶⁷ In a controlled trial that included 270 healthcare workers, over 95% of whom were vaccinated against influenza, those receiving a high dose (171 mg) of green tea catechins daily for 12 weeks in the winter had a lower rate of influenza-like illness (1.2%) than those taking 57 mg of green tea catechins (5.9%) or those receiving placebo (4.7%). In addition, high-dose green tea-treated participants had fewer upper respiratory infections overall.¹⁶⁸ Another trial that included 197 healthcare workers found taking 378 mg per day of tea catechins, along with 210 mg per day of theanine (another compound from green tea), for five months resulted in fewer influenza virus infections: 4.1% of those receiving green tea compounds and 13.1% of those receiving placebo developed influenza virus infections.¹⁶⁹

Observational research also suggests drinking green tea may help protect against influenza. One study compared data from 179 influenza patients and 353 matched controls who did not contract influenza during a flu season, finding those who consumed five or more cups of green tea per week had a 39% lower risk of influenza than those who drank less than one cup per week.¹⁷⁰ Another study followed 1,121 subjects through a full flu season and noted the incidence of influenza was 61% lower in those who drank green tea two or more times per week.¹⁷¹ A study that looked at the relationship between green tea consumption and influenza virus infections in children found children who consumed green tea six or more days per week had about 40% reduced odds of developing an infection compared with those who drank green tea three or less days per week.¹⁷²

Multiple clinical trials have found the risk of influenza was reduced by regular gargling with green or black tea or tea compounds. A meta-analysis that included findings from five randomized controlled trials with a combined total of 1,890 participants found gargling with tea or tea extracts reduced the likelihood of influenza by 30%.⁶⁷

Elderberry

Black elderberry (Sambucus nigra) has a long history of traditional use in the treatment of colds and flu. Elderberry extracts are rich in polyphenols that are potent free radical scavengers and have been found to reduce inflammatory signaling.¹⁷³ In addition, elderberry extracts have demonstrated antiviral activity against influenza A and B viruses in cell culture and animal studies.^174-177

In a randomized controlled trial, 60 adults who had developed influenza-like symptoms within the previous 48 hours were given elderberry syrup, 15 mL four times daily, or placebo for five days. Those treated with elderberry recovered an average of four days sooner and were less likely to use acetaminophen (Tylenol) or a nasal decongestant compared with placebo.¹⁷⁸ In another placebo-controlled trial in 27 adults and children with viral respiratory infections, nearly 90% of those with influenza who received elderberry extract were fully recovered within three days versus six days with placebo. The elderberry extract was taken twice daily by children and four times daily by adults for only three days in this investigation.¹⁷⁹ A review of five clinical trials concluded that elderberry extract can reduce influenza symptoms and shorten duration of illness when started within 48 hours of symptom onset.¹⁸⁰ A meta-analysis of randomized controlled trials concluded elderberry reduced symptoms of viral respiratory infections including influenza.¹⁸¹ However, not all trials have had positive findings: in one randomized controlled trial that enrolled 87 adults and children seen in hospital emergency rooms for moderate-to-severe respiratory symptoms and diagnosed with influenza, treatment with elderberry extract had no effect on outcomes.¹⁸²

Andrographis

Andrographis (Andrographis paniculata) is used in Ayurvedic and traditional Chinese herbal medicine for treating common colds and flu, sore throat, and fever. Extracts of andrographis have exhibited immune-stimulating, anti-inflammatory, antiviral, and antibacterial actions in preclinical studies.^183-185 In a cellular model of influenza A H1N1 infection, andrographis was found to inhibit neuraminidase (a protein involved viral replication).¹⁸⁶ Neuraminidase-inhibiting drugs like oseltamivir are used to treat severe influenza. Andrographis extract has been found to reduce viral load, decrease lung inflammation, and increase survival in mice infected with influenza A viruses.^187,188 In 20 healthy volunteers, taking 4.2 grams per day of andrographis extract for three days increased the number of immune cells in circulation.¹⁸⁹

One research group reported on two controlled trials, one of which had 540 and the other 66 participants. Both trials found those treated with a combination of andrographis and Siberian ginseng ( Eleutherococcus senticosus), 300 mg three times daily for 4‒5 days, had faster recovery and fewer complications from influenza.¹⁹⁰ In addition, multiple randomized controlled trials and two meta-analyses found andrographis extract, alone and in herbal combinations, reduced symptoms of upper respiratory tract infections and may be especially helpful in alleviating cough and sore throat.^183,191

Vitamin C

Vitamin C is an important immune modulator, and evidence indicates it can increase production of interferons (antiviral cytokines) during the early stages of influenza virus infection.¹⁹² As an antioxidant, vitamin C also reduces tissue-damaging oxidative stress caused by viral infection and immune cell activation. Studies have shown vitamin C levels drop during infection, and vitamin C therapy may improve the antiviral immune response, suppress pro-inflammatory cytokine signaling, decrease symptom severity, and shorten duration of illness.^193,194 Vitamin C supplementation may be especially valuable in athletes since heavy physical exertion increases oxidative stress and may increase the rate of vitamin C depletion.¹⁹³

In one controlled trial, 114 patients hospitalized with influenza received 300 mg vitamin C per day and 112 similar patients received no vitamin C. Two patients in the vitamin C group and 10 in the control group developed pneumonia, and the average length of hospital stay was nine days in the vitamin C group versus 12 days in the control group.¹⁹⁵

High-dose vitamin C therapy has been found to mitigate lung damage in patients with viral pneumonia and ARDS. In critically ill patients, intravenous vitamin C is needed to achieve the high blood levels thought to be necessary to overcome infection-related oxidative stress. Promising results have been reported in cases of patients with influenza-related respiratory failure who received intravenous vitamin C as part of their treatment.¹⁹⁴

Vitamin D

Vitamin D modulates the immune response by interacting with receptors on various types of immune cells. Its complex effects on immune activation support antiviral defenses and limit inflammation.^196-198

Results from randomized controlled trials have been mixed. Moreover, differences in participant selection and dosing schedules, as well as a lack of baseline vitamin D measurement in some trials, have made it challenging to draw conclusions.^197,199 Nevertheless, the overall data leans in favor of some preventive benefit of vitamin D supplementation for influenza.

One meta-analysis found that, while daily or weekly dosing of vitamin D may reduce the risk of viral respiratory infections, bolus dosing (750 mcg [30,000 IU] or more) had no protective benefit. This finding highlights the complex nature of the role of vitamin D in regulating immune function and the importance of appropriate dosing.²⁰² 

A meta-analysis of 10 randomized controlled trials with 4,859 participants revealed a significant risk reduction with vitamin D supplementation for influenza. The clinical trials included evaluated mostly daily dosing which ranged from 500–6,800 IUs while some evaluated infrequent bolus dosages. The participants ranged from infants to the elderly. The pooled results showed that those who supplemented with vitamin D had a 22% reduced relative risk of influenza compared with controls.²⁶⁸

In a randomized controlled trial published in 2023, a total of 255 healthcare workers at a university hospital were invited to receive 125 mcg (5,000 IU) vitamin D daily for nine months, while a random group of 2,827 healthcare workers not given vitamin D served as controls. Participants who adhered to supplementation for at least two months were included in the analysis. The primary outcome was the difference in incidence rate of influenza-like illnesses over the course of 13 months from the start of the intervention. Vitamin D was associated with a reduced risk of influenza-like illnesses; three workers (1.17%) in the intervention group had at least one episode of influenza-like illness versus 165 workers (5.83%) in the control group.²⁶⁹

N-acetylcysteine

N-acetylcysteine (NAC), a form of the amino acid L-cysteine, is best known for its use as an antidote to acetaminophen toxicity; however, its ability to support antioxidant systems and reduce oxidative stress by raising glutathione production gives it multiple potential uses in conditions related to toxicity, infection, inflammation, stress, and aging.^203,204 Preclinical research suggests NAC may have beneficial effects in influenza. For instance, NAC reduced inflammation and inhibited viral replication in influenza-infected cells from the pulmonary lining. Also, in mouse models of influenza, NAC decreased lung damage and increased survival.^205,206

A randomized controlled trial that included 262 frail older adults who had not been vaccinated against influenza during the same or previous seasons found taking 1,200 mg NAC per day for six months reduced the incidence of influenza-like illness: 29% of those receiving NAC versus 51% receiving placebo developed the flu. Interestingly, viral testing revealed the infection rate was similar in both groups, but most of those treated with NAC remained asymptomatic. In addition, severity of influenza symptoms was lower in the NAC group.²⁰⁷ Clinical research has shown NAC supplementation (generally 600–1,200 mg daily) can help slow progression and inhibit exacerbation of COPD, a condition that increases the risk of severe influenza and its complications.²⁰³

Selenium

Selenium is an essential trace mineral that, when bound to the amino acid cysteine and incorporated into selenoproteins, plays a critical role in free radical quenching.^208,209 During the immune response to viral infection, free radical production increases and antioxidant systems are downregulated, raising oxidative stress and contributing to cell and tissue damage.^209,210 In a selenium deficient host, influenza infection raises oxidative stress to levels that not only exacerbate tissue damage but also cause changes in the viral genome that lead to more severe illness.^208,209 Studies in animals and humans indicate selenium status also affects antiviral immune activation and inflammatory signaling, ^208,211 and observational data suggest higher selenium intake may be linked to better outcomes in viral respiratory infections.

A two-year controlled trial in 725 elderly nursing home residents found those given a daily supplement providing 100 mcg selenium and 20 mg zinc had a better antibody response to influenza vaccination 15 to 17 months after starting the supplement than those given placebo. They also had fewer respiratory tract infections, but this difference was not statistically significant.²¹² Another trial that examined the effects of different doses and forms of selenium on immune response to the influenza vaccine in elderly individuals with borderline-low selenium levels found 100 mcg per day of yeast-derived selenium enhanced some aspects of the vaccine response, but the effects of higher and lower doses, as well as another supplement made from selenium-enriched onion, did not.²¹³

Vitamin E

Vitamin E, a fat-soluble antioxidant nutrient, is concentrated in immune cells and plays an important role in immune function, partly due to its ability to protect immune cells from oxidative damage.^214,215 Because of its important role in immune responsiveness, vitamin E (as alpha-tocopherol) is a key ingredient in a widely used influenza vaccine adjuvant called AS03. AS03 has been found to safely and effectively raise anti-influenza antibody production after vaccination, though it has been associated with more post-vaccine symptoms such as pain and fatigue.^216,217

Supplementing with vitamin E, even in the absence of deficiency, may improve immune defense against upper respiratory infections. Because vitamin E appears to reverse some aspects of immune senescence, it may be most beneficial in the elderly.^215,218,219 Clinical trials in elderly subjects have shown vitamin E, in doses of 50–800 mg (about 56–889 IU) of dl-α-tocopherol per day, can improve immune cell function.²¹⁴

A study that examined data from 717 elderly patients hospitalized for pneumonia (the most common complication of influenza) found those taking vitamin E supplements had a lower risk of re-hospitalization during 90 days of monitoring.²²⁰ Two studies in elderly nursing home residents (with 153 participants in one study and 23 in the other) found those with higher vitamin E levels had better immune responsiveness to the influenza vaccine.^221,222 However, a study in 61 healthy elderly subjects did not find a relationship between vitamin E levels and influenza vaccine response.²²³

Vitamin E supplementation may be particularly important among smokers. People who smoke cigarettes have higher levels of oxidative stress than non-smokers. Smokers also tend to have lower tissue and plasma levels of antioxidants like vitamin E.^224,225 In a cohort of nearly 22,000 male smokers, incidence of common colds was slightly reduced among participants 65 years or older who had been taking vitamin E supplements long-term. However, this reduction was not evident in the cohort overall.²²⁶ In a secondary analysis of data from a trial in Finland, taking 50 mg of alpha-tocopherol daily for five to eight years was associated with a 69% reduced incidence of pneumonia among participants who smoked 5–19 cigarettes per day and regularly exercised. However, among those who smoked 20 or more cigarettes daily, vitamin E did not reduce pneumonia incidence. Among participants who quit smoking during the trial period, vitamin E supplementation was associated with 72% lower incidence of pneumonia compared with placebo.²²⁷

Echinacea

Echinacea species (Echinacea purpurea and E. angustifolia ) are used in herbal medicine to boost immune function and prevent and treat various acute infections. Echinacea has demonstrated antiviral effects against influenza viruses (including H1N1, H3N2, H5N1, and H7N7) in the laboratory.²²⁸

In a randomized controlled trial, 473 individuals in the early stage of the flu (ie, symptoms ≤48 hours) received either an echinacea-based drink mix (which also contained elderberry) for 10 days or oseltamivir for five days followed by five days of placebo. The trial was designed to determine whether the echinacea-based drink was inferior to oseltamivir as assessed by rate of symptomatic recovery. Over the 10 days, participants’ symptoms were assessed periodically. While recovery rate was similar in both groups, the echinacea group experienced fewer adverse events and the rate of complications was lower than in the oseltamivir group.²²⁹

Zinc

Zinc is necessary for normal immune function, and increased risk of infection is a hallmark of zinc deficiency. In addition to its role in antiviral immune activity, zinc has direct antiviral actions against influenza virus and other common causes of upper respiratory tract infections, such as rhinoviruses.²³⁰ Interestingly, materials made with embedded zinc ions, which can be used to make facemasks and other personal protective equipment, have been shown to absorb and inactivate SARS-related viruses and influenza A virus H1N1 in the environment, keeping personal protective equipment virus-free and limiting viral spread.

Most research on zinc as a treatment for viral respiratory infections has focused on common colds. Multiple randomized controlled trials and several meta-analyses have found zinc lozenges, initiated within 24 hours of symptom onset and used in amounts providing 70–92 mg of elemental zinc per day, can effectively reduce the duration of common colds.^231-233 Influenza viruses are frequent causes of upper respiratory infections that fall under the category of common cold, especially when symptoms are mild.²³⁴

Melatonin

Although best known for its role in circadian system regulation, melatonin is also produced by immune cells and participates in activating antimicrobial defenses, reducing inflammatory signaling, and lowering oxidative stress.²³⁵ Melatonin production diminishes with age, contributing to higher oxidative stress, inflammation, and infection susceptibility.

Melatonin has been shown to suppress pro-inflammatory cytokine release and reduce acute lung injury in animal models of viral infection. A preclinical animal model of influenza found that melatonin increased survival of mice infected with H1N1. Intriguingly, this animal model found melatonin plus ribavirin treatment led to better survival than ribavirin alone, suggesting melatonin may act as an adjuvant to antiviral therapy.²³⁶

In light of its safety and potential to inhibit a cytokine storm and reduce the severity of viral infections, there is growing interest in the possible preventive and therapeutic use of melatonin in influenza virus and other seasonal infections. The elderly and those with chronic medical conditions, who are at higher risk for severe complications from viral respiratory infections, may benefit most from regular use of 3–10 mg of melatonin at bedtime. Furthermore, some researchers have suggested particularly high doses of melatonin, ranging from 50 to 200 mg twice daily, might be helpful as part of treatment in patients hospitalized for acute respiratory symptoms suggestive of SARS-like illness.

Lactoferrin

Lactoferrin is an iron-binding protein made by cells such as those in secretory glands and activated neutrophils (a type of immune cell). It is found in most body fluids, including tears and breast milk, and lactoferrin derived from bovine whey is frequently used in supplements. Lactoferrin possesses immune-modulating effects, is capable of enhancing antimicrobial immune activity while reducing inflammation, and has exhibited a broad spectrum of activity against bacteria, fungi, protozoa, and viruses. Laboratory studies have shown lactoferrin inhibits certain viruses, including influenza viruses, from binding to cell receptor sites and entering host cells, and even suppresses viral replication inside infected cells.²³⁷ Lactoferrin, in its iron-free state (apo-lactoferrin), can sequester pro-oxidant iron, lowering oxidative stress and suppressing the growth of pathogens.^238,239 In addition, lactoferrin decreases pro-inflammatory molecules released during the immune response to infection. Because of its immune-modulating and antiviral properties, lactoferrin has even attracted interest as a potential therapy for preventing or treating some acute infectious respiratory illnesses.²³⁷

A randomized controlled trial tested the effects of lactoferrin plus lactoperoxidase (another milk protein) in 407 healthy adults. The supplemented group used a lozenge providing 20 mg lactoferrin and 2.6 mg lactoperoxidase three times daily for eight weeks and the control group used no milk protein supplements. Although there were no significant differences in incidence of colds and flu, lactoferrin plus lactoperoxidase appeared to reduce the duration of fevers ≥38ºC (100.4ºF) in a subgroup of 190 participants who did not wear facemasks.²⁴⁰

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a steroid hormone synthesized by the adrenal gland that has a complex role in immune regulation and controlling the inflammatory process.²⁴¹ Its effects on immune function appear to be related to its ability to act as a counterbalance to cortisol.²⁴² DHEA levels decline with age, and this may be a contributing factor in immune senescence.²⁴³ In preclinical research, DHEA derivatives have been found to increase antiviral and antibacterial immune activity while suppressing inflammation, as well as protect laboratory animals from lethal influenza virus infection.^244-246

Some evidence suggests higher DHEA levels are associated with a stronger response to the flu vaccine in older adults. In a placebo-controlled trial that included 78 elderly volunteers, a subcutaneous injection of 7.5 mg DHEA at the time of influenza vaccination improved the anti-influenza antibody response in a subgroup of participants with lower baseline DHEA and antibody levels.²⁴⁷

Vitamin A

Similar to vitamin D, metabolites of vitamin A, called retinoids, function as nuclear hormones. Vitamin A plays crucial roles in vision and development as well as in maintaining the integrity of the mucus layers in the respiratory and intestinal tract. Retinoids are also critically important for healthy differentiation, maturation, and function of cells of the innate immune system. Activation of vitamin A nuclear receptors exerts considerable influence on the immune response, and vitamin A deficiency has been linked with diminished resistance to viral infections and poor vaccine responses.^248,249

In an animal model, vitamin A-deficient mice exhibited impaired immune response to influenza viral infection. The vitamin A-deficient mice displayed diminished T-cell recruitment and B-cell organization in lung lymphoid tissue and had higher viral titers than mice with sufficient levels of vitamin A. Moreover, the vitamin A-deficient mice suffered 100% mortality when exposed to a model of secondary bacterial lung infection.²⁵⁰ In diet-induced obese mice, vitamin A supplementation improved the antibody response to influenza vaccination and modulated the lung immune milieu.²⁵¹ Other preclinical evidence suggests that, in the setting of vitamin A deficiency, retinoid treatment may ameliorate the hyperactive immune response that characterizes some infectious diseases.²⁵²

In a trial that enrolled 112 pregnant women, 76% of whom had low plasma vitamin A (retinol) concentrations, supplementation with 10,000 IU vitamin A weekly improved immune responses to influenza vaccination. At six months postpartum, women who received vitamin A had 39% higher hemagglutination inhibition antibody titers than women who received placebo.²⁵³ Another small trial showed that supplementation with vitamin A plus vitamin D improved influenza vaccine response in children who were deficient in both vitamins at baseline.²⁵⁴ However, one study of older adults in Wisconsin found serum vitamin A status was unrelated to influenza vaccine antibody response.²⁵⁵ Among Indonesian preschool children, vitamin A bolus dosing (200,000 IU) plus 10 mg zinc daily was associated with reduced number of days with respiratory tract infection symptoms.²⁵⁶

Garlic

Garlic (Allium sativum) has a long history of use in preventing and treating infections, and has been shown to exert antimicrobial and immune-enhancing effects in numerous studies.^257,258 In addition to improving the antiviral immune response, sulfur compounds from garlic have demonstrated direct antiviral action.²⁵⁹ In a controlled trial in 120 healthy volunteers, 2.56 grams of aged garlic extract per day for 90 days during cold and flu season resulted in improved immune cell function compared with placebo. In addition, aged garlic extract reduced the severity of cold and flu symptoms and number of workdays missed due to illness.²⁶⁰

French Oak

French oak wood extract has been found to reduce oxidative stress and improve energy level and stamina. One controlled trial enrolled 38 patients aged 65 to 75 years old who had experienced a 7‒10-day bout of influenza and been symptom-free for three days at the beginning of the trial. They were treated with either standard care plus 300 mg per day of a French oak wood extract or standard care alone for three weeks. After 10 days, those receiving the French oak wood extract had reduced heart rate, increased oxygen saturation, less weakness, and improved recovery from exertion; after three weeks, the supplemented group maintained faster recovery from exertions and had better sleep quality and improvements in some aspects of cognitive function.²⁶¹