Herpes and shingles are clinically distinct diseases, with different symptoms and modes of transmission. However, both are caused by members of the herpesvirus (Herpesviridae) family of viruses.

Several members of this virus family can cause diseases in humans, but this protocol will focus on varicella-zoster virus, herpes simplex virus-1 (HSV-1), and herpes simplex virus-2 (HSV-2).

The varicella-zoster virus typically causes chickenpox in children and shingles later in life, whereas HSV-1 and HSV-2 can cause oral and genital herpes.^1,2

Herpes viruses are very common, with as many as 54% of U.S. adults having been exposed to HSV-1^3-5 and over 90% exposed to varicella-zoster virus.^6,7 Although incidence of chickenpox declined in the United States following introduction of a regular vaccination protocol,^8,9 the Centers for Disease Control and Prevention (CDC) estimates one of every three Americans will develop shingles at some point in their lifetime.^10-12

One of the most clinically relevant properties of herpes viruses is their ability to establish a latent infection.^1,13-15 This means the virus can remain dormant in the body, becoming “reactivated” under certain conditions and manifesting symptoms long after the initial infection. This reactivation can occur as a result of local injury or systemic factors such as stress (emotional and environmental), fever, trauma, or menstrual periods. Perhaps the most prominent risk factor, especially with regard to shingles outbreaks among older adults, is general age-related decline in immune function, known as immune senescence.^16-18

In this protocol, you will learn about the viruses that cause herpes and shingles and how these infections are treated. A number of natural ingredients that may help ease symptoms of herpes and shingles will also be discussed, and important lifestyle and dietary considerations that may help prevent outbreaks will be examined as well.

The Herpesviridae family includes viruses that infect animals and humans.¹⁹ Among these viruses, eight members are known to infect humans and are clinically important.²⁰ These viruses are herpes simplex virus types 1 and 2 (HSV-1 and HSV-2); varicella-zoster virus; cytomegalovirus; Epstein-Barr virus; and human herpesviruses 6, 7, and 8.²⁰ Members of this family of viruses may cause a variety of diseases, including genital and oral herpes (HSV-1 and HSV-2), chickenpox/shingles (varicella-zoster virus), mononucleosis (human cytomegalovirus and Epstein-Barr virus), roseola (human herpes virus 6), and even certain kinds of cancer (human herpes virus 8).^1,2,21-24 The focus of this protocol is typical manifestations of HSV-1, HSV-2, and shingles (varicella zoster).

Infection with any member of the Herpesviridae family involves multiple steps. First, the virus interacts with receptors on the external surface of human cells to gain entry into the cell.²⁵ Varicella-zoster virus interacts mainly with the myelin-associated glycoprotein (MAG; Siglec-4), while HSV receptors include many such as nectin-1, herpesvirus entry mediator (HVEM), 3-OS HS, PILRα, NMHC-IIA, and MAG.^26,27 Once attached to the appropriate receptor, the viruses enter the cell via one of two primary mechanisms. In the case of varicella-zoster virus, interaction with the cellular receptor causes a structural change in the proteins on the surface of the virus, which promotes fusion between the membranes of the virus and cell.²⁸ HSV can also utilize this mechanism of entry, but predominantly enters via endocytosis, in which the virus is taken into the cell within a membrane vacuole.²⁹ Once inside, the virus uses the cell’s own machinery to make many copies of itself (replicate).¹⁵ This stage is known as primary infection, and while it can be accompanied by a period of illness, patients may also be asymptomatic and remain unaware that they have been infected.

In addition to using the cell’s proteins to replicate, Herpesviridae viruses also make their own gene products, including latency-associated transcripts (LATs) which remain in the body during periods of viral latency (inactivity). LATs can reactivate the viral replication process up to decades later.^2,14,15

Initial replication of Herpesviridae viruses typically occurs in the skin and mucous membranes before it spreads to neurons. From there, the virus travels along the sensory nerves until it reaches large nerve clusters called ganglia, where the virus can establish a long-term latent infection.^2,8,14,15,18

Varicella-Zoster Virus

The varicella-zoster virus, which causes chickenpox in children, also causes shingles (herpes zoster), a disease that generally occurs in older adulthood as a result of the reactivation of the virus.^2,12,18,30

The primary infection manifests as chickenpox, a childhood disease that is almost always symptomatic. During symptomatic chickenpox, patients are highly contagious, and over 90% of unvaccinated individuals become infected after exposure.^2,6,31 Chickenpox presents as a characteristic rash that usually occurs 10 to 21 days after exposure, and is accompanied by many small, fluid-filled, itchy blisters over the body.^2,32 Usually chickenpox affects patients for 4 to 7 days.³³ Chickenpox is spread via direct contact with blisters, but can also be spread by aerosolized droplets from a cough or sneeze.^2,32 A runny nose often precedes the onset of the characteristic rash, and, as a result, infected individuals are typically contagious 1 to 2 days before developing blisters and remain so until all blisters crust over.^32,33 Childhood vaccination against varicella-zoster virus (Varivax or ProQuad) is over 90% effective at preventing chickenpox, and is recommended by the CDC for most children.^9,34

Once the virus enters the latent (dormant) state, patients do not experience symptoms and are no longer contagious. However, the virus may become reactivated later in life, leading to shingles.^2,8,12 The varicella-zoster virus can be spread from a person with active shingles to a person who has never had chickenpox or has not been vaccinated.¹⁰ In such cases, the person exposed to the virus may develop chickenpox, rather than shingles.¹⁰ The virus is spread through contact with fluid from the rash blisters. Shingles is less contagious than chickenpox, and the risk of a person with shingles spreading the virus is low if the rash is covered.^2,10,35

Shingles can occur at any time following primary infection but is most common in the elderly and those with weakened immune systems. This suggests that reactivation may be triggered by impaired immune function, which occurs with advancing age.³⁶

Herpes Simplex Viruses

Possible manifestations of HSV-1 or HSV-2 infection include: oral herpes (herpes labialis or “cold sores”), herpes simplex keratitis, which causes sores to appear on the corneas of the eyes, and genital herpes.^1,37 Another less common manifestation is erythema multiforme, which causes bull’s-eye shaped lesions to appear on the skin and can also cause lesions in or around the mouth.^38-40

Historically, HSV-1 has been the primary cause of oral herpes and herpes simplex keratitis, whereas HSV-2 has primarily been associated with genital herpes.⁴¹ However, more recently there has been a significant increase in the number of HSV-1 infections that cause genital herpes, with clinical trial data suggesting almost 60% of genital herpes cases are associated with HSV-1.^3,5,41-44

HSV-1 is usually spread by oral contact with an infected individual, and many people initially contract this virus at a young age.^45,46 HSV-2, on the other hand, is almost exclusively spread via sexual contact.⁴⁶ In either instance, the virus gains access to the body through mucous membranes or breaks in the skin. Initial infection with either HSV-1 or HSV-2 may be asymptomatic or manifest as small blisters or sores on the skin near the site of infection.^45,46 Once the initial infection subsides, the virus spreads to sensory nerve cells, where it stays dormant until it is reactivated.⁴⁷ Factors such as stress, fatigue, sun exposure, surgery, fever, and menstrual periods can trigger the reactivation of HSV. The frequency of these recurrent outbreaks varies from person to person.⁴⁶ The virus is most contagious during periods of active replication, but can be spread when no symptoms are present.⁴⁶

Herpes and shingles are caused by previous exposure to HSV-1 or HSV-2 (for herpes) or to varicella-zoster virus (for shingles).

Shingles

One of the most important risk factors for shingles is age; about half of all patients are older than 60 years of age.^48,49 Patients aged 60 to 79 years are over 10 times as likely to develop shingles as children younger than 10 years of age.⁵⁰ This age discrepancy is thought to be due to the gradual weakening of the immune system with age, a process called immune senescence.^16-18

In addition to increasing age, a suppressed immune system also increases the risk of developing shingles.^35,51 The incidence of shingles among individuals who have diseases that weaken the immune system, especially HIV/AIDS, is significantly higher than in the general population.^12,35,36,49 The long-term use of immunosuppressive drugs also increases the risk of developing shingles.⁶

Some studies suggest females may be more likely to develop shingles than males.^12,35,49,52 Ethnicity may also be a risk factor for shingles, with evidence suggesting that shingles occurs more frequently in Caucasian individuals.^12,52

Herpes

The main risk factor for HSV-1 infection is increasing age; the US Department of Health and Human Services estimates approximately 60% of Americans are infected with HSV-1 by 50 years of age.⁵ The incidence of HSV-1 is also higher among females, Mexican-Americans, and those living below the poverty level.^3-5 Receiving oral sex may also increase the risk of developing genital herpes caused by HSV-1.^3,46

Risk factors for HSV-2 infection are primarily related to sexual activity, as this virus is typically spread via sexual contact.⁴⁶ Engaging in sexual activity with a partner who has an active, symptomatic infection (ie, lesions on the genitals) is a very strong risk factor for transmission; however, transmission can occur even in the absence of symptoms.⁴⁶ Additional risk factors include female sex, non-Hispanic black ethnicity, and an increased number of sexual partners.^5,53-55

Shingles

The first and most common symptom of shingles is pain, which may precede development of the characteristic rash by several days.^{10,12,48,49,56} The pain is sometimes described as a burning, throbbing, or stabbing sensation localized to the area of skin that will later be affected by the rash.³⁶ During this period, which is also known as the prodromal phase, patients may also experience headache, malaise, earache, sensitivity to light, and fever.^10,12,48

The shingles rash typically begins as small, raised, reddish lesions that quickly evolve into groups of fluid-filled blisters that break and form a crust or scab after 7 to 10 days.^12,36,48 These blisters are often associated with pain and/or itchiness. Some patients will experience pain after mild contact to the affected areas, a phenomenon known as allodynia.⁵⁶

Shingles lesions have a characteristic location and distribution; they are often limited to one side of the body (unilateral) and frequently localized to a strip of skin, also known as a dermatome, which is the area served by the nerves of a single ganglion where the viral reactivation occured.^6,10,12,36 In about 20% of patients, adjacent dermatomes can be affected.⁴⁸ The most commonly affected areas are the trunk, face, and scalp.^2,6,36 Lesions typically take 2 to 4 weeks to heal, but may take longer, and permanent scarring or pigment changes may occur.^10,12,56

Some patients with shingles may have pain with no rash, known as zoster sine herpete.^12,48 Patients should be aware of this possible manifestation of herpes zoster because, in the absence of a rash, the pain may be misdiagnosed as migraine headache, dental pain, appendicitis, heart attack, or other painful conditions.^12,48

Herpes

Most herpes infections affect either the oral or genital regions. Sometimes, however, more serious infections of other organs may occur without the signs of oral or genital herpes.^41,45,57-59

The first oral infection with HSV (usually HSV-1) is known as primary herpetic gingivostomatitis.^60-62 Primary herpetic gingivostomatitis is most common in young children, but it can occur in adults as well.^61-63 While primary herpetic gingivostomatitis is often asymptomatic, infection may also cause inflammation of the gums and mouth, followed by the appearance of painful sores in or around the oral cavity.^60,61 The most common locations for these sores are the lips (“cold sores”), roof of the mouth, gums, and tongue; although, blisters can appear on any area in or around the mouth.⁴⁶

The prodromal phase of HSV-1 oral infections, which may begin a few days before sores appear, is characterized by fever, loss of appetite, irritability, swollen lymph nodes, discomfort, and muscle pain.⁶² These complications may make eating or drinking difficult.^60,61 Many recurring outbreaks are preceded by itching, tingling, or burning of the affected area. Untreated, blisters typically heal within 2 to 3 weeks, which can be significantly reduced through the use of antiviral drugs.^60-62

Genital herpes is often asymptomatic, but may cause symptoms similar to oral herpes, with the appearance of blisters on the penis, anus, buttocks, and around and inside the vagina.^55,64 These lesions may or may not cause pain and may be mistaken for other skin conditions.⁶⁴ Other symptoms may include fever, malaise, muscle aches, swollen lymph nodes in the groin, pain or burning upon urination, and vaginal discharge.^55,64 As with oral herpes, patients may experience a prodromal phase characterized by tingling, burning, or itching of the affected areas.⁵⁵

Herpes infections can also cause a variety of complications. Herpes can spread to the cornea of one or both eyes, known as herpes simplex keratitis, causing pain, sensitivity to light, a gritty feeling in the eye, blisters, and discharge. ^37,65 Without treatment, scarring may result, which can lead to cloudy vision or blindness.⁶⁵ Both HSV-1 and HSV-2 may also enter into a finger via breaks in the skin, causing a condition known as herpetic whitlow, in which the fingertip becomes swollen and painful.⁶⁶ Herpetic whitlow is most frequently seen in young children who suck their thumbs, as well as healthcare workers, such as dentists, who are exposed to body fluids while not wearing gloves.^66,67 Herpes can also infect the brain, leading to the potentially fatal condition, herpes encephalitis, which causes fever, confusion, and seizures.⁵⁹ Rarely, HSV can infect other internal organs as well, such as the lungs and trachea.^57,68

Shingles

The typical symptoms of shingles—pain, rash, and blisters extending along a limited area or strip on one side of the body—are very characteristic, so doctors are often able to diagnose shingles based on clinical presentation.^6,10 In immunocompromised individuals, more unusual presentations can sometimes be observed.⁶⁹ An example of this is abdominal zoster, in which serious abdominal pain occurs hours or days before the rash has presented.^70,71

In situations when the diagnosis is not certain, a doctor may collect material from the blisters to look for varicella-zoster virus DNA, which can confirm the diagnosis.¹⁰ Doctors can also look for antibodies to the varicella-zoster virus in the blood, but this may be difficult in immunocompromised patients.¹⁰

Herpes

Similarly, doctors can often diagnose herpes based on appearance of the characteristic sores.^55,64 However, confirmatory laboratory testing is sometimes needed. Much like shingles, herpes infections can be confirmed by taking material from the blisters and looking for the presence of either HSV-1 or HSV-2 DNA or antibodies.^55,64

Standard treatment for herpes virus infections is antiviral medication. The main antiviral medications used for both shingles and herpes are acyclovir (Sitavig), famciclovir (Famvir), and valacyclovir (Valtrex).^10,64,72 All three medications can be taken orally, reduce pain, and speed healing of the lesions; however, famciclovir and valacyclovir are often preferred because they require less frequent dosing than acyclovir.⁷²

Shingles

In patients with shingles, these medications are currently recommended for patients over age 50 years who do not present with complications, as well as for immunocompromised patients.⁷³ Treatment should be initiated within 72 hours after symptom onset. After 72 hours, treatment is only recommended if there is evidence of new lesions or disease complications.^6,73 Efficacy in patients under age 50 has not been as comprehensively studied, but clinical trials have demonstrated favorable safety profiles for famciclovir, valacyclovir, and acyclovir in children.^74,75

Another antiviral drug, brivudine, has been shown to have comparable efficacy to famciclovir and valacyclovir in the treatment of herpes zoster infection in people whose immune system is not compromised.^76,77 However, brivudine has been shown to cause serious drug-drug interactions with some cancer drugs such as 5-fluorouracil and capecitabine, so it should be used cautiously and only under physician supervision.^78-82

Pain relief is an important component of shingles management. Patients with shingles may achieve pain relief from over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen.^6,10 In cases of severe pain, clinicians might prescribe gabapentin to treat nerve pain or low-dose opioids, such as codeine, tramadol, or oxycodone.^6,83

Another treatment option is local creams that contain the compound capsaicin.⁸³ Capsaicin is extracted from hot chili peppers and stimulates receptors on sensory neurons.⁸⁴ Capsaicin causes the release of a neurotransmitter (substance P) from nerve cells, and its repeated application depletes the nerve stores of the compound, reducing pain signals.^84-86 When formulated into a cream or ointment, capsaicin can be applied to areas of intact skin to reduce pain. When applied, though, capsaicin creams generate a mild “burning” sensation which can exacerbate shingles pain.⁸⁴ For this reason, capsaicin creams are most often recommended for patients with prolonged pain after blistering has resolved, known as postherpetic neuralgia.^{48,51,73,84,86}

Herpes

Acyclovir, famciclovir, and valacyclovir reduce shedding of both HSV-1 and HSV-2 genital herpes infections, as well as outbreak frequency, and are recommended for both symptomatic and asymptomatic patients.^72,87-91 These drugs are also effective for the treatment of oral herpes.⁹² Though the efficacy of these drugs is not as well characterized in children, preliminary evidence suggests antivirals may reduce the duration of blisters and pain, and they are recommended by the National Institutes of Health and the CDC for the treatment of oral and genital herpes in children and adolescents with HIV.^61,93

In rare cases of severe or complicated manifestations of herpes that inhibit a patient’s ability to swallow or tolerate oral medication without vomiting, intravenous antivirals may be prescribed.⁷²

Vaccines

A live-attenuated vaccine against shingles (Zostavax) was licensed in 2006 by the US Food and Drug Administration.⁹⁴ When administered to individuals over age 60 years with a healthy immune system, Zostavax reduced the risk of developing shingles by 55%.⁹⁵ Among adults aged 50 to 59 years, higher antibody titers were measured after vaccination with Zostavax than placebo, suggesting the vaccine is protective against shingles in this age group as well.⁹⁶ However, the efficacy of Zostavax declines over time; a loss of protection can be seen as early as a year in some individuals and is almost completely absent after 8 years.⁹⁷ A second “booster” dose given up to 10 years after initial vaccination may help extend the duration of protection,⁹⁸ but boosters are not recommended as standard practice by current guidelines.^2,86 The efficacy of Zostavax has also been questioned in patients currently taking immunosuppressants, who may be at increased risk for developing shingles, even after administration of the vaccine.⁹⁹

In 2017, the CDC began recommending a newer shingles vaccine, Shingrix, as the preferred zoster vaccine for healthy adults over 50 years of age.⁸⁶ Shingrix is a recombinant subunit vaccine, containing only a portion of the virus (in this case, the envelope glycoprotein), rather than the whole virus.¹⁰⁰ Clinical trials of Shingrix have found over 90% efficacy at preventing the development of shingles.^101,102 Side effects of vaccination may include pain or swelling at the injection site, as well as muscle soreness, fatigue, and headache.¹⁰³ Given the efficacy, safety, tolerability, and generally lower cost of Shingrix, it is currently recommended for adults 50 years or older, including those who previously received Zostavax.^86,103 Zostavax may still be given in instances where Shingrix is not recommended, such as in the case of an allergy to a component of Shingrix.¹⁰³

Researchers have also been investigating the development of a vaccine for HSV, as this is believed to be one of the most effective ways to prevent the spread of herpes.¹⁰⁴ In the past, two recombinant subunit vaccine candidates were evaluated in clinical trials.^43,105,106 Both vaccines exhibited limited efficacy at preventing genital herpes associated with HSV-1 (<60% efficacy), and no efficacy against HSV-2 infection was reported.⁴³ A potential explanation for the limited efficacy of vaccines thus far is that HSV is very efficient at evading immune system detection once it reaches its latent stage, and its interactions with the immune system are still not entirely understood.^1,104

To overcome this obstacle, new vaccine strategies have been developed in an attempt to produce an immune response against HSV despite absence of an active infection, such as in asymptomatic or uninfected individuals. For example, GEN-003 is an investigational HSV-2 vaccine that contains viral proteins intended to produce an antibody and T-cell response.^107-110 GEN-003 is still in early stage clinical trials, but early results suggest the vaccine is safe in adults older than 18 years of age and can significantly reduce shedding of the virus and frequency of outbreaks.¹¹⁰

Topical Antimicrobial Agents

Current methods for preventing the spread of genital herpes, such as condoms, are not used consistently, highlighting the need for new preventive options. A topical antimicrobial agent, especially one that could be applied vaginally, has the potential to become a preventive measure against the spread of genital herpes.^111,112

A number of compounds are under investigation with varying mechanisms of action. Some antimicrobials directly inactivate the virus, while others enhance the body’s defense against HSV or prevent the virus from entering cells.¹¹³ One such agent is tenofovir (Viread), which was originally developed as a topical gel to prevent HIV transmission. In clinical trials, vaginal application of 1% tenofovir gel before and after sex prevented transmission of HSV-2 by as much as 51%, likely by inhibiting viral replication.^114-116 A more recent randomized controlled trial of 566 patients at risk for HSV-2 infection found that topical tenofovir gel reduced the risk for HSV-2 infection by about 40%, but this did not reach statistical significance.¹¹⁷ More research is needed in a larger population of patients, but these results suggest tenofovir may become a part of the strategy used to prevent the spread of genital herpes.

Topical antimicrobial peptides, which are naturally occurring compounds with antiviral properties, are also under investigation. Temporin B, an antimicrobial peptide isolated from frogs, was found to inhibit HSV-1 replication in cells by >99% by disrupting the outer layer of the virus (viral envelope).¹¹⁸ Importantly, temporin B was not cytotoxic at concentrations for which anti-HSV-1 activity was observed, which has been a concern with other antimicrobial agents.^118,119 A polar fish peptide (Pa-MAP) was also found to inhibit HSV-1 replication by as much as 90% in cell culture models.¹²⁰ Further testing on the safety and efficacy of these compounds in humans is needed, but these results highlight the broad potential of antimicrobial agents for use in treatment of HSV infections.

Cimetidine

Cimetidine, a medication commonly used for treating acid reflux, inhibits the production of stomach acid by blocking the signaling pathway for histamine.¹²¹ Histamine signaling also modulates a number of different types of immune cells and can affect the immune response to some viruses as well.¹²² A small prospective clinical trial done in the late 1980s found that oral cimetidine may accelerate the healing of skin lesions and provide pain relief in adults with shingles.¹²³ An in vitro study performed on cells from 22 people with shingles also found that cimetidine may help increase the proliferation of immune cells in patients with shingles who have a poor initial response.¹²⁴ Cimetidine has also been reported to decrease the duration of symptoms in individual case reports and small preliminary trials^125,126; however, large scale clinical trials have not yet been performed.

Mirogabalin

Mirogabalin is a newer drug emerging as a potential treatment for postherpetic neuralgia and is part of the same treatment family as gabapentin. In a phase 3 trial, mirogabalin reduced pain compared with placebo in Asian patients with postherpetic neuralgia.¹²⁷ Mirogabalin was approved for treatment of peripheral neuropathic nerve pain including postherpetic neuralgia in Japan in January 2019; however, development of mirogabalin was halted in the United States due to lack of efficacy.¹²⁸ As of mid-2020, research primarily out of Japan continued to suggest that mirogabalin may be efficacious in the treatment of peripheral neurological pain.¹²⁹ More prospective randomized controlled trials are needed to clarify the utility of mirogabalin in the context of postherpetic neuralgia.

Adenosine Monophosphate

The nucleotide adenosine monophosphate (AMP) is an important intermediary biochemical in cellular metabolism. For instance, it is converted through a series of reactions to adenosine triphosphate (ATP), the energy currency of cells. Nucleotides like AMP are also important to the structure and function of RNA and DNA. An early study found that intraperitoneal AMP injections, that is, injections of AMP into the abdominal body cavity, expedited the resolution of HSV-1 lesions in mice.¹³⁰ However, another early study found that AMP was not effective in preventing recurrences of HSV-2 infections in guinea pigs inoculated vaginally with the virus.¹³¹

In a randomized controlled trial that enrolled 32 adults with herpes zoster, intramuscular injections of AMP given three times per week for up to four weeks reduced pain and improved healing time compared with placebo injections. After four weeks of treatment, 88% of subjects in the AMP group reported being pain free versus only 43% of placebo subjects. The safety profile of AMP was favorable in this study, with no reported side effects of toxicity.¹³² An early, uncontrolled trial in 36 subjects with recurrent herpes labialis found that intramuscular injections of AMP led to swift healing of lesions and an overall reduction in rate of recurrences over the following two years.¹³³ These trials took place in the late 1970s and early ‘80s. Some more recent anecdotal reports have suggested efficacy, but more trials are needed.¹³⁴ The mechanism of action of AMP against herpesvirus-related diseases is not clear, and availability of AMP intramuscular injections may be somewhat limited.

Shingles

Reducing stress may help prevent shingles. Psychological stress has been linked to shingles outbreaks, and major depression was shown to decrease cellular immunity to the varicella-zoster virus and increase the risk for shingles.¹³⁵ In addition, a study reported that people who developed shingles experienced, in the six months preceding the outbreak, more frequent events that they perceived as stressful.¹³⁶

In addition to relieving stress, other techniques can help relieve symptoms associated with shingles. Cool baths and application of cool, wet compresses on the blisters can relieve itching and pain.^10,83 Good hygiene and daily washing is another important consideration; maintaining trimmed fingernails may help reduce the damage caused by scratching and can also prevent secondary bacterial infections. Moreover, eating a healthy, well-balanced diet and getting plenty of rest can strengthen the immune system. One study showed that individuals who ate less than one serving of fruit per week had a more than 3-fold higher risk of developing shingles compared with those who ate more than three servings per day.¹³⁷

Herpes

As with shingles, stress is also implicated in the occurrence of herpes outbreaks. A higher level of perceived stress was identified as a risk factor for the occurrence of oral lesions caused by HSV-1.¹³⁸ Several studies have found a link between emotional distress and herpes outbreaks.^139-142 Therefore, reducing emotional stress may help prevent flares. Getting enough sleep, eating a balanced diet, and exercising regularly can help reduce stress while simultaneously strengthening the immune system.

There is some evidence that oral herpes (HSV-1) outbreaks can be triggered by exposure to sunlight and ultraviolet (UV) radiation.^143,144 This may be due to UV-induced suppression of the immune system or direct reactivation of the virus.¹⁴⁴ Although it can be difficult to avoid sunlight entirely, minimizing exposure and using SPF 30 sunblock, particularly on the lips and surrounding skin, may help reduce outbreaks.¹⁴⁵

Using a condom correctly during sex and avoiding intercourse during an outbreak can help prevent the spread of genital herpes.⁵⁵

Although there is no effective cure for Herpesviridae infections, several natural interventions may help reduce the frequency and severity of outbreaks. Both shingles and herpes can manifest when the immune system is unable to prevent the latent viral infection from reactivating. Therefore, natural interventions that maintain the health of the immune system may help prevent outbreaks.

Vitamin C

Vitamin C, also called ascorbic acid, is a potent antioxidant with natural antiviral properties.^155,156 Laboratory studies in vitro have found that vitamin C and some of its metabolites may to some degree inhibit HSV-1 replication.^155,157 However, studies exploring the use of vitamin C in the treatment of herpes infections in humans have been limited and have largely relied on self-reported results.¹⁵⁸ A recent retrospective study of patients with herpes simplex keratitis found that ascorbic acid (2,000 mg/day) may reduce the risk of recurrence by almost 50% compared with no treatment; however, use of acyclovir (800 mg/day) was still superior.¹⁵⁹ While early results from studies exploring the use of vitamin C in reducing symptoms of HSV infection are promising, further testing is needed.

Vitamin C may also provide relief from the nerve pain that often accompanies shingles.^156,160 Vitamin C has been found to exhibit analgesic (pain-relieving) properties.¹⁶¹ Researchers have found that vitamin C supplementation at a dose of 200 mg to 1.5 g per day can help reduce pain and skin manifestations of shingles and prevent the development of postherpetic neuralgia.¹⁶¹ Vitamin C may be particularly useful in individuals who are allergic or resistant to standard pain medications.^162-164 Placebo-controlled trials in patients with shingles have found conflicting results on whether vitamin C reduces frequency or severity of spontaneous pain; however, postherpetic neuralgia may be prevented with intravenous vitamin C.^165,166 Consistent with this, vitamin C intake has been linked to a decreased risk for postherpetic neuralgia.^137,164 These results suggest vitamin C may help reduce the risk of prolonged pain associated with shingles outbreak, but further studies in humans are warranted.

Reishi Mushroom

Reishi mushroom (Ganoderma lucidum) is a fungus that has been used medicinally for centuries in China, Japan, and Korea.^167,168 Some components of reishi appear to have antiviral properties.¹⁶⁹ Researchers have identified several compounds in reishi that exhibit strong antiviral activities against both HSV-1 and HSV-2 in vitro.^170-174

Preparations of reishi mushroom have also shown promising results in early clinical studies. In a trial of five Japanese patients with shingles, a formula containing reishi and other botanicals resulted in prompt pain relief and resolution of symptoms.¹⁷⁵ Another study involving patients with herpes infections found that application of the herbal mixture also resulted in a shorter duration to symptom clearance in both oral and genital herpes compared with untreated control patients.¹⁷⁶

Much of the benefit of reishi mushroom may be due to its ability to combat immune senescence and promote a healthy immune system. A number of studies have found that compounds in the reishi mushroom have immunomodulatory activities and promote activation of immune cells, such as macrophages and T cells, and the secretion of antibodies.^177-180 Together, these activities help achieve the dual goals of promoting a healthy immune response against viral, bacterial, or fungal infections, while suppressing excessive or chronic inflammation that threatens long-term health.

Vitamin A

Vitamin A and its precursor, beta-carotene, may help modulate immune function.^181-183 Serum vitamin A levels may play a role in the shedding of HSV, as it was reported that cervical viral shedding in women who were not pregnant or taking hormonal contraceptives was associated with low or deficient levels of vitamin A.¹⁵¹ This suggests maintaining sufficient vitamin A intake may help prevent the transmission of herpes to others, but studies are needed to explore this specific relationship. Additionally, beta-carotene can provide low-level protection against UV radiation from the sun.¹⁸³ Given that minimizing sun exposure can help prevent herpes outbreaks,^144,145 sufficient beta-carotene and vitamin A intake may play a protective role against flares. Importantly, excessive intake of pre-formed vitamin A can be toxic.

Vitamin D

While in the past, vitamin D was appreciated for its role in maintaining bone health, more recent evidence suggests it may be a potent immunomodulator as well.^184-186 Vitamin D deficiency is associated with impaired immune function and increased susceptibility to infection.¹⁸⁴

Several lines of evidence suggest vitamin D may help combat herpes and shingles outbreaks.^187,188 In a cell culture model, vitamin D supplementation significantly reduced viral load of HSV-1.¹⁸⁹ Studies in patients undergoing dialysis found that serum vitamin D levels were associated with immunity to varicella-zoster virus, and vitamin D supplementation was associated with significantly lower odds of developing shingles.^190,191 Similarly, patients with recurring oral herpes outbreaks were found to have lower serum vitamin D levels than control patients.¹⁹² A study of pediatric patients with multiple sclerosis also found that higher vitamin D levels were associated with higher levels of anti-HSV-2 antibodies in the blood,¹⁹³ suggesting increased vitamin D levels may allow the immune system to better respond to the infection.

The anti-HSV activity of vitamin D may be a result of its ability to increase levels of an immunologic antimicrobial peptide called cathelicidin, which has antiviral properties against HSV-1 and other viruses.¹⁹⁴ In cell culture models, cathelicidin induced the expression of antiviral interferon response and significantly inhibited production of HSV-1.^195,196 Cathelicidin peptide LL-37 also inhibited HSV-2 replication in a mouse model, and lower levels of cathelicidin protein expression were observed in patients with disseminated HSV infections.¹⁹⁷

Vitamin E

An open-label controlled clinical trial in 89 subjects with herpes simplex genitalis or herpes zoster studied the effects of either acyclovir alone or acyclovir in combination with a 90-day course of a nutraceutical formulation (consisting of vitamin E [as alpha tocopherol acetate], coenzyme Q10, selenium, and L-methionine) on virus-related biomarkers and lesion healing rates.¹⁹⁸ The nutraceutical formulation plus acyclovir produced faster healing rates and fewer relapses compared with acyclovir alone. Moreover, these outcomes aligned with lab findings of decreased viral load and increased antiviral cytokine levels; plasma antioxidant activity was higher in the nutraceutical formulation group as well. In uncontrolled trials, topical application of vitamin E oil helped relieve pain associated with oral herpetic lesions and expedite lesion healing. Some studies of topical vitamin E have used once-daily applications, whereas others have used multiple daily applications.^134,199

A mouse model showed that vitamin E deficiency impaired the immune response to central nervous system HSV-1 infection.²⁰⁰ Another mouse study provided additional evidence that vitamin E deficiency impairs the immune response to HSV-1 infection. However, this study showed that high-dose dietary supplementation (10 times adequate intake) did not further enhance the immune response. This finding suggested that avoiding vitamin E deficiency was important for an adequate immune response in this mouse model, but large supplemental vitamin E doses beyond adequate intake did not confer further protection.²⁰¹

Zinc

Zinc plays a role in many aspects of the immune system, and deficiency has been associated with immune dysfunction and an increased risk for viral infections.²⁰² Studies reveal that zinc levels tend to decrease with age, in parallel with declining immune function.²⁰³ Low serum concentrations of zinc have been linked to increased risk for postherpetic neuralgia.¹⁶⁴

Zinc has been implicated in the disruption of almost all aspects of HSV-1 and HSV-2 replication.²⁰² In laboratory studies, zinc sulfate caused up to a 99.8% inhibition of HSV-1 replication.²⁰⁴ In addition, zinc oxide was found to effectively prevent entry of both HSV-1 and HSV-2 into cells.^205,206 Animal models have also shown that zinc solutions protect against vaginal or rectal HSV-2 infections and reduce rates of viral shedding.^207-209 Topical ointments containing zinc oxide have been used successfully to reduce the duration of outbreaks of genital and oral herpes in humans.^210-212 Coadministration of zinc and punicalagin, a component of pomegranate rind extracts, has recently been proposed as a potential topical treatment for herpes infections, with promising early results in cell and animal models.^213,214

Lysine and Arginine

Several small and generally low-quality studies published over many years provided preliminary evidence that supplementation with the amino acid L-lysine and/or dietary restriction of the amino acid L-arginine may be effective anti-HSV strategies. Arginine is required for HSV replication, and L-lysine’s potential anti-HSV effects are thought to result from blocking of arginine activity. However, taken as a whole, the clinical evidence is mixed.^270-272

A review of 12 studies of lysine supplementation in the treatment or prevention of herpes outbreaks found that doses below 1 g/day were ineffective unless combined with a low-arginine diet. One small randomized controlled trial found that a lysine dosage greater than three grams per day reduced recurrence rates and improved patients’ self-reported symptoms. Longer-duration controlled trials using lysine in doses of at least 1.2 g/day are needed in order to draw any firm conclusions about this therapy.²⁷¹

Individual results with lysine and arginine in the management of HSV may vary. Given that lysine has very little potential for side effects at typical dosages,²⁷³ and that an arginine-restricted diet can be nutritionally complete, people with HSV may wish to consider a therapeutic trial of a combination of 1–3 grams or more of supplemental L-lysine per day with a low-arginine diet.

Propolis

Propolis, a resin-like substance obtained from beehives, has a long history of medicinal use. It contains a mixture of several compounds, including flavonoids and polyphenols, many of which have anti-HSV-1 activity.^221,222 The variety of effects that it has on the immune system, together with its anti-inflammatory properties, may allow it to help the body more effectively fight infections.²²³

Propolis has been found to significantly inhibit the replication of HSV-1 and HSV-2 in cell culture.^222,224,225 Additionally, ointments and lip balms containing propolis extracts have been tested in clinical trials and found to increase the rate of healing of both oral and genital herpes lesions, and have even exhibited superiority over the standard acyclovir treatment.^226-229 The effects observed may be extended to other bee products, as a recent randomized placebo-controlled trial found that children who received 1 mL honey around four times daily in addition to acyclovir had a significantly reduced duration of oral herpes symptoms compared with those who received acyclovir alone.²³⁰ A systematic review of nine clinical trials involving bee products suggested they may be a useful complement to the treatment of herpes.²³¹

Lactoferrin

Lactoferrin, a protein found in both cow and human milk, has natural antimicrobial properties and is able to help protect the body from bacterial, fungal, parasitic, and viral infections.^232-234 In particular, many preclinical studies have shown that lactoferrin is able to inhibit the replication of HSV-1 and HSV-2 and also block the virus from entering cells through interactions with heparan sulphate on the surface of cells.^233,235-238 Although clinical trials are needed to corroborate these findings in humans, lactoferrin appears to be a promising potential therapeutic agent against HSV infections.

Curcumin

Curcumin (a compound found in the spice turmeric) is thought to help the body combat many infections, including those caused by viruses, due in part to its anti-inflammatory and antioxidant properties.²³⁹ Topical creams containing curcumin have been used in Indian traditional medicine for diseases causing blisters, such as shingles.²⁴⁰ Curcumin has also been shown to provide protection against HSV-1 and HSV-2 infection in cell culture.^241-243 Curcumin activity against HSV-1 is associated with its ability to keep the virus from expressing genes necessary for infection and replication.²⁴² Curcumin was also found to inhibit inflammatory processes that promote HSV replication in genital epithelial cells, resulting in decreased replication of HSV-2.²⁴⁴ While animal and human trials of curcumin use are still needed, these results highlight the potential for curcumin to be a useful anti-HSV agent.

Fucoidans

Fucoidans, naturally occurring sugar polymers found in edible seaweeds and some other oceanic sources, can stimulate the immune system.²⁴⁵ Many fucoidans have potent antiviral activity against several common viruses, including HSV-1 and HSV-2.^245-248 Animal models have found that fucoidans protect against HSV-1 by a combination of direct inhibition of viral replication and stimulating the body’s immune response against the virus.²⁴⁷ Fucoidan absorbs well into the skin, suggesting that topical application may be a viable mode of application.²⁴⁹ A case report study showed that a 4% fucoidan cream decreased the healing time associated with oral herpes outbreaks. In this study, case series patients treated with fucoidan cream had symptom relief from severely painful oral herpes within an average of five days.²⁵⁰

Lemon Balm

Lemon balm (Melissa officinalis) is a form of mint used traditionally to treat numerous ailments, including herpes outbreaks.²⁵¹ Several laboratory studies have shown lemon balm extracts possess a variety of antiviral activities against both HSV-1 and HSV-2.^252-257 Clinical trials have evaluated the efficacy of topical lemon balm preparations and shown positive results. In one trial, a lemon balm ointment improved symptoms of oral herpes compared with placebo when applied four times daily for five days; the lemon balm treatment also prevented the spread of the outbreak, and the authors suggested lemon balm may increase time between outbreaks.²⁵⁸ Two additional trials also found that local therapy with lemon balm extract effectively eases oral herpes symptoms.²⁵⁹

Licorice

Licorice (Glycyrrhiza spp.) has demonstrated antiviral activity against several viruses, including HSV-1.^260,261 In an animal model of herpes simplex encephalitis, licorice root extract reduced HSV-1 viral replication in the brain by 45% and significantly improved the survival rate of treated animals.²⁶² A recent study examining a herbal gel mixture containing licorice extract for the treatment of oral herpes indicated it may help reduce inflammation and shorten duration of symptoms.²⁶³ The results of this study may serve to inform the development of future trials of licorice extract’s effects on herpes in humans.

Probiotics

Prophylactic and therapeutic probiotic use has gained traction in recent years as researchers have uncovered the various ways in which they can promote not only proper gut health, but proper immune function and antiviral activity as well.²⁶⁴ Studies of probiotic strains of bacteria (Lactobacillus rhamnosus and Bifidobacterium adolescentis) have found that probiotic use can increase the activation and viability of immune cells, such as macrophages, and inhibit the spread of HSV-1 in cell culture.^265,266 In animals models, the probiotic yeast Saccharomyces boulardii improved gastrointestinal symptoms associated with HSV-1 infection.²⁶⁷ A probiotic strain of L. plantarum delayed the development of HSV-1–associated skin lesions in mice and decreased viral loads in the brain, which was likely related to increased activation of immune cell activity.²⁶⁸ In a randomized controlled trial of a multi-strain L. brevis probiotic in women with HSV-2 genital herpes, probiotic use was similar to acyclovir with regard to improvement of symptoms and duration of healing.²⁶⁹ The results of these preliminary studies support further investigation into the role of probiotics in the treatment of herpes infections.