Herpes and Shingles

Herpes and Shingles

1 Overview

Summary and Quick Facts

  • Herpes and shingles are both caused by members of the Herpesviridae family of viruses, which can establish latent infections that remain dormant before reactivating at a later time under certain conditions. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) cause oral and genital herpes, and varicella-zoster virus causes chickenpox in children and shingles later in life.
  • In this protocol, you will learn about the viruses that cause herpes and shingles, and how these infections are conventionally treated. Several natural ingredients that may help ease the symptoms of herpes and shingles will also be discussed, and important lifestyle and dietary considerations that can help prevent outbreaks will be examined as well.
  • Antiviral medication is the standard treatment for both shingles and herpes. Although there is no effective cure for herpes virus infections, several natural interventions may help reduce the frequency of outbreaks.

Herpes and shingles are both caused by members of the Herpesviridae family of viruses, which can establish latent infections that remain dormant and then reactivate under certain conditions. Herpes simplex virus-1 (HSV-1) and herpes simplex virus-2 (HSV-2) cause oral and genital herpes, and varicella-zoster virus causes chickenpox in children and shingles later in life.

Risk Factors

Shingles:

  • Age—about half of all patients are over 60 years
  • Suppressed immune system
  • Female sex
  • Caucasian ethnicity

HSV-1:

  • Age—over 60% of Americans are infected by 50 years of age
  • Receiving oral sex may increase risk of developing HSV-1 genital herpes

HSV-2:

  • Engaging in sexual activity with a partner who has an active, symptomatic infection
  • Female sex (the prevalence of HSV-2 is almost 2 times higher in women than in men)

Signs and Symptoms

Shingles:

  • First symptom is often burning or throbbing pain on one side of the body (unilateral)
  • Pain may be accompanied by headache, malaise, earache, sensitivity to light, and/or fever
  • After several days, a characteristic blistering rash may appear, which usually presents on one side of the body and is localized to a strip of skin

Oral herpes:

  • Painful sores in or around the mouth
  • The affected area may be uncomfortable or painful before sores appear
  • There may be a fever, swollen lymph nodes, and sore throat, which may make eating and drinking difficult

Genital herpes:

  • Sores on the penis, buttocks, anus, and around and inside the vagina, which may be painful
  • The affected area may itch, tingle, or burn before the sores appear
  • Fever, malaise, muscle aches, swollen lymph nodes in the groin, pain or burning upon urination, and vaginal discharge are common as well

Diagnosis

Both herpes and shingles are diagnosed mainly by physical examination. Testing for the presence of viral DNA or antibodies may be performed if symptoms are inconclusive.

Conventional Treatment

Antiviral medication (acyclovir, famciclovir, or valacyclovir) is the first line of treatment for both shingles and herpes.

Shingles:

  • Pain medication, including non-steroidal anti-inflammatory drugs, acetaminophen, or opioids, may be used for pain management
  • Topical capsaicin may be used to treat postherpetic neuralgia, or prolonged pain after blisters are gone

Herpes:

  • Intravenous antibiotics may be administered if symptoms of oral herpes (eg, blisters, swollen lymph nodes) make it difficult to swallow or take oral medication

Emerging Treatments

  • Two vaccines are now commercially available for the prevention of shingles outbreaks (Zostavax and Shingrix). An effective vaccine against HSV-1 and HSV-2 has been elusive, but early stage clinical trials suggest a new vaccine (GEN-003) may be effective against HSV-2.
  • Topical microbicides that have antiviral properties, such as tenofovir gel, may prevent the spread of herpes virus.
  • Cimetidine, commonly used for treating acid reflux, may reduce the severity and duration of shingles outbreaks, but large-scale clinical trials are still needed.

Dietary and Lifestyle Considerations

Shingles:

  • Minimize stress
  • Eat plenty of fruit and vegetables
  • Cool baths and cool, wet compresses on the blister can help relieve itching and pain

Oral herpes:

  • Minimize sun exposure and use sunscreen on lips and skin
  • Minimize stress by getting enough sleep, eating a balanced diet, exercising, and using relaxation techniques like yoga or meditation

Genital herpes:

  • Minimize stress by getting enough sleep, eating a balanced diet, exercising, and using relaxation techniques like yoga or meditation
  • Use condoms during sex and avoid intercourse during outbreaks

Targeted Natural Interventions

  • Vitamin C: Vitamin C can reduce the risk for prolonged pain (postherpetic neuralgia) after shingles outbreaks.
  • Reishi mushroom: Reishi may help with the rapid resolution of symptoms associated with shingles, oral herpes, and genital herpes outbreaks by promoting a robust immune response.
  • Vitamin A: Vitamin A may reduce the amount of HSV shed in the genital tract of infected women. Ask your healthcare provider before beginning any vitamin A supplementation.
  • Vitamin D: Higher serum vitamin D levels are associated with increased immunity to HSV, and supplementation may help lower the odds of developing herpes or shingles outbreaks.
  • Zinc: Zinc solutions can prevent HSV entry into cells and reduce shedding of the virus in the genitals. Topical solutions may also reduce the duration and severity of herpes outbreaks.
  • Lysine: Higher doses of lysine (>3 grams/day) may prevent HSV infection and reduce the duration and severity of outbreaks.
  • Propolis: Propolis and other bee products, including honey, may decrease the severity and duration of herpes symptoms. These products can be considered as an alternative or supplement to acyclovir treatment.
  • Probiotics: Probiotic strains of bacteria may improve the anti-HSV immune response and promote more rapid resolution of symptoms.

2 Introduction

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-13-5 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.

3 Biology and Pathophysiology

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

4 Causes and Risk Factors

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

5 Signs and Symptoms

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

6 Diagnosis

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

7 Conventional Treatment and Prevention

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

8 Novel and Emerging Treatments

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 trials125,126; 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.

9 Dietary and Lifestyle Considerations

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

Progesterone, Hormonal Contraception, and Herpes Infection in Women

A number of studies have shown that multiple aspects of immunity in the female genital tract are controlled by sex hormones, and hormones influence susceptibility to several sexually transmitted diseases, including HSV infection.

Evidence from animal studies has shown that treatment with female sex hormones had a significant impact on rates of HSV-2 transmission. Treatment with estradiol was found to confer some protection against vaginal HSV-2 infection in a mouse model, whereas progesterone was found to exacerbate viral infection and contributed to extensive inflammation.146-148 This may be because progesterone induces a diestrus-like state, during which mice are most susceptible to HSV-2 infection.149

Studies on the effects of hormonal contraception in women have yielded mixed results.150 Use of the injectable depo-medroxyprogesterone acetate (Depo-Provera) contraceptive has been linked to up to 4-fold higher risk of acquiring HSV-2 infection and increased rates of cervical shedding of the virus.151-153 The relationship between oral hormonal contraceptives and HSV-2 shedding is less clear, as some studies have found increased rates of occurrence,151 while others have seen no difference compared with non-users.154 More human studies are needed to determine the effects of hormonal contraception on the spread of herpes in different populations and with different types of contraceptives. Potential differences associated with the use of synthetic and natural hormones, such as progestins and progesterone, should also be explored, as this may help explain some of the differences seen in HSV-2 acquisition and shedding.154

10 Targeted Natural Interventions

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 cell culture models, 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

HSV requires large amounts of arginine, an amino acid resembling the amino acid lysin, to replicate properly.215 Because of the structural similarities of the two amino acids, lysine can antagonize the effects of arginine, making it more difficult for HSV to replicate.215

Clinical trial results exploring the use of lysine in the prevention of herpes outbreaks have been conflicting. For example, one double-blind placebo-controlled study of 65 patients with oral herpes found no effect on the recurrence rate of herpes, while a similar study observed a significant reduction in the frequency, duration, and severity of herpes outbreaks with lysine treatment.216,217 To explain the differences observed in the results of these studies, a meta-analysis of 12 studies exploring the use of lysine in the treatment of herpes infections was recently completed. 218 Based on these studies, it appears lysine supplementation is most effective at doses over 3 grams per day, or approximately 1 gram per day only when patients are on low-arginine diets.218 Diets rich in lysine and low in arginine, consisting of foods such as yogurt, cheese, fruit, fish, and poultry, and avoiding nuts, grains, refined sugar, and chocolate, may help reduce the severity of herpes outbreaks.219 The Mayo Clinic recommends individuals with a history of oral or genital herpes be careful about supplementing with arginine.220

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.

Disclaimer and Safety Information

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

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

  1. Xu X, Zhang Y, Li Q. Characteristics of herpes simplex virus infection and pathogenesis suggest a strategy for vaccine development. Reviews in medical virology. 2019;29(4):e2054.
  2. Kennedy PGE, Gershon AA. Clinical Features of Varicella-Zoster Virus Infection. Viruses. 2018;10(11).
  3. Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2--United States, 1999-2010. J Infect Dis. 2014;209(3):325-333.
  4. Looker KJ, Magaret AS, May MT, et al. Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. PLoS One. 2015;10(10):e0140765.
  5. McQuillan G, Kruszon-Moran D, Flagg EW, Paulose-Ram R. Prevalence of Herpes Simplex Virus Type 1 and Type 2 in Persons Aged 14-49: United States, 2015-2016. NCHS data brief. 2018(304):1-8.
  6. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nature reviews Disease primers. 2015;1:15016.
  7. Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans from NHANES III: implications for control through routine immunization. Journal of medical virology. 2003;70 Suppl 1:S111-118.
  8. Freer G, Pistello M. Varicella-zoster virus infection: natural history, clinical manifestations, immunity and current and future vaccination strategies. New Microbiol. 2018;41(2):95-105.
  9. Marin M, Guris D, Chaves SS, et al. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1-40.
  10. Centers for Disease Control and Prevention: Shingles (Herpes Zoster). https://www.cdc.gov/shingles/about/index.html. Updated June 26, 2019. Accessed February 27, 2020.
  11. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82(11):1341-1349.
  12. John AR, Canaday DH. Herpes Zoster in the Older Adult. Infectious disease clinics of North America. 2017;31(4):811-826.
  13. Depledge DP, Sadaoka T, Ouwendijk WJD. Molecular Aspects of Varicella-Zoster Virus Latency. Viruses. 2018;10(7).
  14. Kennedy PG, Rovnak J, Badani H, Cohrs RJ. A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. The Journal of general virology. 2015;96(Pt 7):1581-1602.
  15. Kinchington PR, Leger AJ, Guedon JM, Hendricks RL. Herpes simplex virus and varicella zoster virus, the house guests who never leave. Herpesviridae. 2012;3(1):5.
  16. Pfister G, Savino W. Can the immune system still be efficient in the elderly? An immunological and immunoendocrine therapeutic perspective. Neuroimmunomodulation. 2008;15(4-6):351-364.
  17. Oxman MN. Herpes zoster pathogenesis and cell-mediated immunity and immunosenescence. J Am Osteopath Assoc. 2009;109(6 Suppl 2):S13-17.
  18. Gershon AA, Gershon MD, Breuer J, Levin MJ, Oaklander AL, Griffiths PD. Advances in the understanding of the pathogenesis and epidemiology of herpes zoster. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2010;48 Suppl 1:S2-7.
  19. Mettenleiter TC, Ehlers B, Müller T, Yoon KJ, Teifke JP. Herpesviruses. In: Diseases of Swine.2019:548-575.
  20. Lan K, Luo MH. Herpesviruses: epidemiology, pathogenesis, and interventions. Virol Sin. 2017;32(5):347-348.
  21. Dioverti MV, Razonable RR. Cytomegalovirus. Microbiol Spectr. 2016;4(4).
  22. Balfour HH, Jr., Dunmire SK, Hogquist KA. Infectious mononucleosis. Clinical & translational immunology. 2015;4(2):e33.
  23. Agut H, Bonnafous P, Gautheret-Dejean A. Update on infections with human herpesviruses 6A, 6B, and 7. Medecine et maladies infectieuses. 2017;47(2):83-91.
  24. Goncalves PH, Ziegelbauer J, Uldrick TS, Yarchoan R. Kaposi sarcoma herpesvirus-associated cancers and related diseases. Curr Opin HIV AIDS. 2017;12(1):47-56.
  25. Azab W, Osterrieder K. Initial Contact: The First Steps in Herpesvirus Entry. Advances in anatomy, embryology, and cell biology. 2017;223:1-27.
  26. Oliver SL, Yang E, Arvin AM. Varicella-Zoster Virus Glycoproteins: Entry, Replication, and Pathogenesis. Curr Clin Microbiol Rep. 2016;3(4):204-215.
  27. Agelidis AM, Shukla D. Cell entry mechanisms of HSV: what we have learned in recent years. Future virology. 2015;10(10):1145-1154.
  28. Cole NL, Grose C. Membrane fusion mediated by herpesvirus glycoproteins: the paradigm of varicella-zoster virus. Reviews in medical virology. 2003;13(4):207-222.
  29. Weed DJ, Nicola AV. Herpes simplex virus Membrane Fusion. Advances in anatomy, embryology, and cell biology. 2017;223:29-47.
  30. Wallmann HW. A Brief Look at Shingles. Home Health Care Management & Practice. 2011;23(4):299-302.
  31. Cohen J, Breuer J. Chickenpox: treatment. BMJ Clin Evid. 2015;2015.
  32. Ayoade F, Kumar S. Varicella Zoster (Chickenpox). In: StatPearls. Treasure Island (FL)2020.
  33. Centers for Disease Control and Prevention: Chickenpox (Varicella). https://www.cdc.gov/chickenpox/about/symptoms.html. Updated December 31, 2018. Accessed February 27, 2020.
  34. Centers for Disease Control and Prevention: Vaccines and Preventable Diseases. https://www.cdc.gov/vaccines/vpd/varicella/public/index.html. Updated August 7, 2019. Accessed February 27, 2020.
  35. Koshy E, Mengting L, Kumar H, Jianbo W. Epidemiology, treatment and prevention of herpes zoster: A comprehensive review. Indian journal of dermatology, venereology and leprology. 2018;84(3):251-262.
  36. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicella-zoster virus infections. Clinical microbiology reviews. 2013;26(4):728-743.
  37. Kaye S, Choudhary A. Herpes simplex keratitis. Progress in retinal and eye research. 2006;25(4):355-380.
  38. Kamala KA, Ashok L, Annigeri RG. Herpes associated erythema multiforme. Contemporary clinical dentistry. 2011;2(4):372-375.
  39. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889-902.
  40. Magri F, Chello C, Pranteda G, Pranteda G. Erythema multiforme: Differences between HSV-1 and HSV-2 and management of the disease-A case report and mini review. Dermatologic therapy. 2019;32(3):e12847.
  41. Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future. F1000Research. 2018;7.
  42. Roberts CM, Pfister JR, Spear SJ. Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students. Sex Transm Dis. 2003;30(10):797-800.
  43. Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. The New England journal of medicine. 2012;366(1):34-43.
  44. Bernstein DI, Bellamy AR, Hook EW, 3rd, et al. Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2013;56(3):344-351.
  45. Everett RD. HSV-1 biology and life cycle. Methods in molecular biology (Clifton, NJ). 2014;1144:1-17.
  46. World Health Organization: Herpes simplex virus. https://www.who.int/news-room/fact-sheets/detail/herpes-simplex-virus. Updated January 31, 2017. Accessed February 27, 2020.
  47. Egan KP, Wu S, Wigdahl B, Jennings SR. Immunological control of herpes simplex virus infections. J Neurovirol. 2013;19(4):328-345.
  48. Sampathkumar P, Drage LA, Martin DP. Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clin Proc. 2009;84(3):274-280.
  49. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med. 2005;20(8):748-753.
  50. Kim YJ, Lee CN, Lim CY, Jeon WS, Park YM. Population-based study of the epidemiology of herpes zoster in Korea. J Korean Med Sci. 2014;29(12):1706-1710.
  51. Fashner J, Bell AL. Herpes zoster and postherpetic neuralgia: prevention and management. American family physician. 2011;83(12):1432-1437.
  52. Kawai K, Yawn BP. Risk Factors for Herpes Zoster: A Systematic Review and Meta-analysis. Mayo Clin Proc. 2017;92(12):1806-1821.
  53. Looker KJ, Magaret AS, Turner KM, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015;10(1):e114989.
  54. Huai P, Li F, Li Z, et al. Seroprevalence and associated factors of HSV-2 infection among general population in Shandong Province, China. BMC infectious diseases. 2019;19(1):382.
  55. Mayo Clinic: Genital herpes. https://www.mayoclinic.org/diseases-conditions/genital-herpes/symptoms-causes/syc-20356161. Updated October 3, 2017. Accessed March 2, 2020.
  56. Wollina U. Variations in herpes zoster manifestation. The Indian journal of medical research. 2017;145(3):294-298.
  57. Glas M, Smola S, Pfuhl T, et al. Fatal multiorgan failure associated with disseminated herpes simplex virus-1 infection: a case report. Case Rep Crit Care. 2012;2012:359360.
  58. Rabinstein AA. Herpes Virus Encephalitis in Adults: Current Knowledge and Old Myths. Neurologic clinics. 2017;35(4):695-705.
  59. Bradshaw MJ, Venkatesan A. Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2016;13(3):493-508.
  60. Mohan RP, Verma S, Singh U, Agarwal N. Acute primary herpetic gingivostomatitis. BMJ case reports. 2013;2013.
  61. Goldman RD. Acyclovir for herpetic gingivostomatitis in children. Canadian family physician Medecin de famille canadien. 2016;62(5):403-404.
  62. Aslanova M, Zito PM. Herpetic Gingivostomatitis. In: StatPearls. Treasure Island (FL)2020.
  63. Tovaru S, Parlatescu I, Tovaru M, Cionca L. Primary herpetic gingivostomatitis in children and adults. Quintessence international (Berlin, Germany : 1985). 2009;40(2):119-124.
  64. Centers for Disease Control and Prevention: Genital Herpes. https://www.cdc.gov/std/herpes/stdfact-herpes.htm. Updated August 28, 2017. Accessed March 2, 2020.
  65. Harris KD. Herpes Simplex Virus Keratitis. Home Healthc Now. 2019;37(5):281-284.
  66. Betz D, Fane K. Herpetic Whitlow. In: StatPearls. Treasure Island (FL)2020.
  67. Avitzur Y, Amir J. Herpetic whitlow infection in a general pediatrician--an occupational hazard. Infection. 2002;30(4):234-236.
  68. Prellner T, Flamholc L, Haidl S, Lindholm K, Widell A. Herpes simplex virus--the most frequently isolated pathogen in the lungs of patients with severe respiratory distress. Scand J Infect Dis. 1992;24(3):283-292.
  69. Lewis DJ, Schlichte MJ, Dao H, Jr. Atypical disseminated herpes zoster: management guidelines in immunocompromised patients. Cutis. 2017;100(5):321;324;330.
  70. Gnann JW, Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186 Suppl 1:S91-98.
  71. Shiroshita A, Nakashima K, Aoshima M. Disseminated varicella-zoster virus infection with abdominal pain possibly caused by pirfenidone: A case report. Respir Med Case Rep. 2018;25:330-332.
  72. Patel R, Kennedy OJ, Clarke E, et al. 2017 European guidelines for the management of genital herpes. International journal of STD & AIDS. 2017;28(14):1366-1379.
  73. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2007;44 Suppl 1:S1-26.
  74. Saez-Llorens X, Yogev R, Arguedas A, et al. Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection. Antimicrob Agents Chemother. 2009;53(5):1912-1920.
  75. Bomgaars L, Thompson P, Berg S, Serabe B, Aleksic A, Blaney S. Valacyclovir and acyclovir pharmacokinetics in immunocompromised children. Pediatr Blood Cancer. 2008;51(4):504-508.
  76. Wassilew S. Brivudin compared with famciclovir in the treatment of herpes zoster: effects in acute disease and chronic pain in immunocompetent patients. A randomized, double-blind, multinational study. J Eur Acad Dermatol Venereol. 2005;19(1):47-55.
  77. Yaldiz M, Solak B, Kara RO, Cosansu N, Erdem MT. Comparison of Famciclovir, Valaciclovir, and Brivudine Treatments in Adult Immunocompetent Patients With Herpes Zoster. American journal of therapeutics. 2018;25(6):e626-e634.
  78. Baena Cañada JM, Martínez-Bautista MJ, Cortés-Carmona C, González-Carrascosa Vega T. [Non-fatal drug-drug interaction between capecitabine and brivudine]. Farm Hosp. 2013;37(4):342-343.
  79. Drositis I, Kontopodis E, Saloustros E, Androulakis N. Interaction of brivudine with capecitabine: A case of serious toxicity. Journal of BUON : official journal of the Balkan Union of Oncology. 2019;24(6):2579.
  80. García Fernández V, Garrido Arévalo M, Labrada González E, Hidalgo Correas FJ. [Fatal drug-drug interaction between 5-fluorouracil and brivudine]. Farm Hosp. 2013;37(1):72-73.
  81. García Herrera AN, Moncayola Vicén JC. [Lethal interaction between 5-fluorouracil and brivudine]. An Sist Sanit Navar. 2018;41(2):277-278.
  82. Tsifi A, Papaxoinis G, Diamantopoulos P, et al. A life-threatening drug-drug interaction between capecitabine and brivudine in a patient with metastatic breast cancer. Journal of chemotherapy (Florence, Italy). 2019;31(7-8):424-427.
  83. Mayo Clinic: Shingles. https://www.mayoclinic.org/diseases-conditions/shingles/diagnosis-treatment/drc-20353060. Updated May 16, 2018. Accessed March 2, 2020.
  84. Jeon YH. Herpes Zoster and Postherpetic Neuralgia: Practical Consideration for Prevention and Treatment. Korean J Pain. 2015;28(3):177-184.
  85. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol. 2000;49(6):574-579.
  86. Saguil A, Kane S, Mercado M, Lauters R. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. American family physician. 2017;96(10):656-663.
  87. Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs. aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br J Dermatol. 2001;144(4):818-824.
  88. Wald A, Carrell D, Remington M, Kexel E, Zeh J, Corey L. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2002;34(7):944-948.
  89. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. The New England journal of medicine. 2004;350(1):11-20.
  90. Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao J, Hamed K. Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2006;42(1):8-13.
  91. Bartlett BL, Tyring SK, Fife K, et al. Famciclovir treatment options for patients with frequent outbreaks of recurrent genital herpes: the RELIEF trial. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2008;43(2):190-195.
  92. Leung AKC, Barankin B. Herpes Labialis: An Update. Recent patents on inflammation & allergy drug discovery. 2017;11(2):107-113.
  93. Siberry GK, Abzug MJ, Nachman S, et al. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. The Pediatric infectious disease journal. 2013;32 Suppl 2:i-KK4.
  94. Harpaz R, Ortega-Sanchez IR, Seward JF, Advisory Committee on Immunization Practices Centers for Disease C, Prevention. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1-30; quiz CE32-34.
  95. Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, Jacobsen SJ. Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA. 2011;305(2):160-166.
  96. Levin MJ, Schmader KE, Gnann JW, et al. Varicella-zoster virus-specific antibody responses in 50-59-year-old recipients of zoster vaccine. J Infect Dis. 2013;208(9):1386-1390.
  97. Tseng HF, Harpaz R, Luo Y, et al. Declining Effectiveness of Herpes Zoster Vaccine in Adults Aged >/=60 Years. J Infect Dis. 2016;213(12):1872-1875.
  98. Levin MJ, Schmader KE, Pang L, et al. Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults. J Infect Dis. 2016;213(1):14-22.
  99. Cheetham TC, Marcy SM, Tseng HF, et al. Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination. Mayo Clin Proc. 2015;90(7):865-873.
  100. Bharucha T, Ming D, Breuer J. A critical appraisal of 'Shingrix', a novel herpes zoster subunit vaccine (HZ/Su or GSK1437173A) for varicella zoster virus. Human vaccines & immunotherapeutics. 2017;13(8):1789-1797.
  101. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. The New England journal of medicine. 2016;375(11):1019-1032.
  102. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. The New England journal of medicine. 2015;372(22):2087-2096.
  103. Deshpande L. Recombinant Zoster Vaccine (Shingrix) for the Prevention of Shingles. American family physician. 2018;98(8):539-540.
  104. Sandgren KJ, Truong NR, Smith JB, Bertram K, Cunningham AL. Vaccines for Herpes Simplex: Recent Progress Driven by Viral and Adjuvant Immunology. Methods in molecular biology (Clifton, NJ). 2020;2060:31-56.
  105. Corey L, Langenberg AG, Ashley R, et al. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group. JAMA. 1999;282(4):331-340.
  106. Stanberry LR, Spruance SL, Cunningham AL, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. The New England journal of medicine. 2002;347(21):1652-1661.
  107. Flechtner JB, Long D, Larson S, et al. Immune responses elicited by the GEN-003 candidate HSV-2 therapeutic vaccine in a randomized controlled dose-ranging phase 1/2a trial. Vaccine. 2016;34(44):5314-5320.
  108. Bernstein DI, Wald A, Warren T, et al. Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial. J Infect Dis. 2017;215(6):856-864.
  109. Van Wagoner N, Fife K, Leone PA, et al. Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial. J Infect Dis. 2018;218(12):1890-1899.
  110. Bernstein DI, Flechtner JB, McNeil LK, et al. Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease. Vaccine. 2019;37(26):3443-3450.
  111. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature. 2002;415(6870):389-395.
  112. Frey Tirri B. Antimicrobial topical agents used in the vagina. Current problems in dermatology. 2011;40:36-47.
  113. Keller MJ, Tuyama A, Carlucci MJ, Herold BC. Topical microbicides for the prevention of genital herpes infection. The Journal of antimicrobial chemotherapy. 2005;55(4):420-423.
  114. Cates W, Jr. After CAPRISA 004: time to re-evaluate the HIV lexicon. Lancet. 2010;376(9740):495-496.
  115. Andrei G, Lisco A, Vanpouille C, et al. Topical tenofovir, a microbicide effective against HIV, inhibits herpes simplex virus-2 replication. Cell Host Microbe. 2011;10(4):379-389.
  116. Abdool Karim SS, Abdool Karim Q, Kharsany AB, et al. Tenofovir Gel for the Prevention of Herpes Simplex Virus Type 2 Infection. The New England journal of medicine. 2015;373(6):530-539.
  117. Marrazzo JM, Rabe L, Kelly C, et al. Tenofovir Gel for Prevention of Herpes Simplex Virus Type 2 Acquisition: Findings From the VOICE Trial. J Infect Dis. 2019;219(12):1940-1947.
  118. Marcocci ME, Amatore D, Villa S, et al. The Amphibian Antimicrobial Peptide Temporin B Inhibits In Vitro Herpes Simplex Virus 1 Infection. Antimicrob Agents Chemother. 2018;62(5).
  119. Fichorova RN, Tucker LD, Anderson DJ. The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission. J Infect Dis. 2001;184(4):418-428.
  120. Vilas Boas LC, de Lima LM, Migliolo L, et al. Linear antimicrobial peptides with activity against herpes simplex virus 1 and Aichi virus. Biopolymers. 2017;108(2).
  121. Pino MA, Azer SA. Cimetidine. In: StatPearls. Treasure Island (FL)2020.
  122. Jafarzadeh A, Nemati M, Khorramdelazad H, Hassan ZM. Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases. International immunopharmacology. 2019;70:156-166.
  123. Miller A, Harel D, Laor A, Lahat N. Cimetidine as an immunomodulator in the treatment of herpes zoster. J Neuroimmunol. 1989;22(1):69-76.
  124. Komlos L, Notmann J, Arieli J, et al. IN vitro cell-mediated immune reactions in herpes zoster patients treated with cimetidine. Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand. 1994;12(1):51-58.
  125. van der Spuy S, Levy DW, Levin W. Cimetidine in the treatment of herpesvirus infections. S Afr Med J. 1980;58(3):112-116.
  126. Hayne ST, Mercer JB. Herpes zoster: treatment with cimetidine. Can Med Assoc J. 1983;129(12):1284-1285.
  127. Kato J, Matsui N, Kakehi Y, Murayama E, Ohwada S, Sugihara M. Mirogabalin for the management of postherpetic neuralgia: a randomized, double-blind, placebo-controlled phase 3 study in Asian patients. Pain. 2019;160(5):1175-1185.
  128. Deeks ED. Mirogabalin: First Global Approval. Drugs. 2019;79(4):463-468.
  129. Tetsunaga T, Tetsunaga T, Nishida K, et al. Short-term outcomes of mirogabalin in patients with peripheral neuropathic pain: a retrospective study. J Orthop Surg Res. 2020;15(1):191.
  130. Blue WT, Macias EA, Sklar SH. Activity of AMP against experimental herpes simplex virus type 1 infections in mice. Antimicrob Agents Chemother. 1983;24(5):807-809.
  131. Fraser-Smith EB, Smee DF, Matthews TR. Lack of efficacy of AMP against recrudescent genital herpes infections in guinea pigs. Antimicrob Agents Chemother. 1983;24(4):611-612.
  132. Sklar SH, Blue WT, Alexander EJ, Bodian CA. Herpes zoster. The treatment and prevention of neuralgia with adenosine monophosphate. Jama. 1985;253(10):1427-1430.
  133. Sklar SH, Buimovici-Klein E. Adenosine in the treatment of recurrent herpes labialis. Oral Surg Oral Med Oral Pathol. 1979;48(5):416-417.
  134. Gaby AR. Natural remedies for Herpes simplex. Alternative medicine review : a journal of clinical therapeutic. 2006;11(2):93-101.
  135. Irwin M, Costlow C, Williams H, et al. Cellular immunity to varicella-zoster virus in patients with major depression. J Infect Dis. 1998;178 Suppl 1:S104-108.
  136. Schmader K, Studenski S, MacMillan J, Grufferman S, Cohen HJ. Are stressful life events risk factors for herpes zoster? J Am Geriatr Soc. 1990;38(11):1188-1194.
  137. Thomas SL, Wheeler JG, Hall AJ. Micronutrient intake and the risk of herpes zoster: a case-control study. Int J Epidemiol. 2006;35(2):307-314.
  138. Stock C, Guillen-Grima F, de Mendoza JH, Marin-Fernandez B, Aguinaga-Ontoso I, Kramer A. Risk factors of herpes simplex type 1 (HSV-1) infection and lifestyle factors associated with HSV-1 manifestations. European journal of epidemiology. 2001;17(9):885-890.
  139. Longo DJ, Clum GA. Psychosocial factors affecting genital herpes recurrences: linear vs mediating models. Journal of psychosomatic research. 1989;33(2):161-166.
  140. Buske-Kirschbaum A, Geiben A, Wermke C, Pirke KM, Hellhammer D. Preliminary evidence for Herpes labialis recurrence following experimentally induced disgust. Psychotherapy and psychosomatics. 2001;70(2):86-91.
  141. Chida Y, Mao X. Does psychosocial stress predict symptomatic herpes simplex virus recurrence? A meta-analytic investigation on prospective studies. Brain Behav Immun. 2009;23(7):917-925.
  142. Kushnir AS, Davido DJ, Schaffer PA. Role of nuclear factor Y in stress-induced activation of the herpes simplex virus type 1 ICP0 promoter. J Virol. 2010;84(1):188-200.
  143. Boon R, Goodman JJ, Martinez J, Marks GL, Gamble M, Welch C. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin Ther. 2000;22(1):76-90.
  144. Ichihashi M, Nagai H, Matsunaga K. Sunlight is an important causative factor of recurrent herpes simplex. Cutis. 2004;74(5 Suppl):14-18.
  145. Mazzarello V, Ferrari M, Piu G, Pomponi V, Solinas G. Do sunscreen prevent recurrent Herpes labialis in summer? The Journal of dermatological treatment. 2019;30(2):179-182.
  146. Gillgrass AE, Tang VA, Towarnicki KM, Rosenthal KL, Kaushic C. Protection against genital herpes infection in mice immunized under different hormonal conditions correlates with induction of vagina-associated lymphoid tissue. J Virol. 2005;79(5):3117-3126.
  147. Gillgrass AE, Fernandez SA, Rosenthal KL, Kaushic C. Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation. J Virol. 2005;79(5):3107-3116.
  148. Ragupathy V, Xue W, Tan J, Devadas K, Gao Y, Hewlett I. Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections. Journal of molecular endocrinology. 2016;57(3):185-199.
  149. Gallichan WS, Rosenthal KL. Effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract. Virology. 1996;224(2):487-497.
  150. McCarthy KJ, Gollub EL, Ralph L, van de Wijgert J, Jones HE. Hormonal Contraceptives and the Acquisition of Sexually Transmitted Infections: An Updated Systematic Review. Sex Transm Dis. 2019;46(5):290-296.
  151. Mostad SB, Kreiss JK, Ryncarz AJ, et al. Cervical shedding of herpes simplex virus in human immunodeficiency virus-infected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis. 2000;181(1):58-63.
  152. Grabowski MK, Gray RH, Makumbi F, et al. Use of injectable hormonal contraception and women's risk of herpes simplex virus type 2 acquisition: a prospective study of couples in Rakai, Uganda. Lancet Glob Health. 2015;3(8):e478-e486.
  153. Socias ME, Duff P, Shoveller J, et al. Use of injectable hormonal contraception and HSV-2 acquisition in a cohort of female sex workers in Vancouver, Canada. Sex Transm Infect. 2017;93(4):284-289.
  154. Micks E, Son H, Magaret A, Selke S, Johnston C, Wald A. The Effect of Hormonal Contraception and Menstrual Cycle Timing on Genital Herpes Simplex Virus-2 Shedding and Lesions. Sex Transm Dis. 2019;46(1):58-62.
  155. Brinkevich SD, Boreko EI, Savinova OV, Pavlova NI, Shadyro OI. Radical-regulating and antiviral properties of ascorbic acid and its derivatives. Bioorganic & medicinal chemistry letters. 2012;22(7):2424-2427.
  156. Wang K, Jiang H, Li W, Qiang M, Dong T, Li H. Role of Vitamin C in Skin Diseases. Front Physiol. 2018;9:819.
  157. Furuya A, Uozaki M, Yamasaki H, Arakawa T, Arita M, Koyama AH. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med. 2008;22(4):541-545.
  158. Lopez BS, Yamamoto M, Utsumi K, Aratsu C, Sakagami H. A clinical pilot study of lignin--ascorbic acid combination treatment of herpes simplex virus. In Vivo. 2009;23(6):1011-1016.
  159. Kim GN, Yoo WS, Park MH, et al. Clinical Features of Herpes Simplex Keratitis in a Korean Tertiary Referral Center: Efficacy of Oral Antiviral and Ascorbic Acid on Recurrence. Korean J Ophthalmol. 2018;32(5):353-360.
  160. Hemila H. Vitamin C and Infections. Nutrients. 2017;9(4).
  161. Carr AC, McCall C. The role of vitamin C in the treatment of pain: new insights. Journal of translational medicine. 2017;15(1):77.
  162. Schencking M, Sandholzer H, Frese T. Intravenous administration of vitamin C in the treatment of herpetic neuralgia: two case reports. Med Sci Monit. 2010;16(5):CS58-61.
  163. Byun SH, Jeon Y. Administration of Vitamin C in a Patient with Herpes Zoster - A case report. Korean J Pain. 2011;24(2):108-111.
  164. Chen JY, Chu CC, Lin YS, So EC, Shieh JP, Hu ML. Nutrient deficiencies as a risk factor in Taiwanese patients with postherpetic neuralgia. The British journal of nutrition. 2011;106(5):700-707.
  165. Chen JY, Chang CY, Feng PH, Chu CC, So EC, Hu ML. Plasma vitamin C is lower in postherpetic neuralgia patients and administration of vitamin C reduces spontaneous pain but not brush-evoked pain. Clin J Pain. 2009;25(7):562-569.
  166. Kim MS, Kim DJ, Na CH, Shin BS. A Study of Intravenous Administration of Vitamin C in the Treatment of Acute Herpetic Pain and Postherpetic Neuralgia. Annals of dermatology. 2016;28(6):677-683.
  167. Boh B, Berovic M, Zhang J, Zhi-Bin L. Ganoderma lucidum and its pharmaceutically active compounds. Biotechnol Annu Rev. 2007;13:265-301.
  168. Batra P, Sharma AK, Khajuria R. Probing Lingzhi or Reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes): a bitter mushroom with amazing health benefits. International journal of medicinal mushrooms. 2013;15(2):127-143.
  169. Paterson RR. Ganoderma - a therapeutic fungal biofactory. Phytochemistry. 2006;67(18):1985-2001.
  170. Eo SK, Kim YS, Lee CK, Han SS. Antiherpetic activities of various protein bound polysaccharides isolated from Ganoderma lucidum. Journal of ethnopharmacology. 1999;68(1-3):175-181.
  171. Eo SK, Kim YS, Lee CK, Han SS. Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum. Journal of ethnopharmacology. 1999;68(1-3):129-136.
  172. Kim YS, Eo SK, Oh KW, Lee C, Han SS. Antiherpetic activities of acidic protein bound polysacchride isolated from Ganoderma lucidum alone and in combinations with interferons. Journal of ethnopharmacology. 2000;72(3):451-458.
  173. Liu J, Yang F, Ye LB, et al. Possible mode of action of antiherpetic activities of a proteoglycan isolated from the mycelia of Ganoderma lucidum in vitro. Journal of ethnopharmacology. 2004;95(2-3):265-272.
  174. Li Z, Liu J, Zhao Y. Possible mechanism underlying the antiherpetic activity of a proteoglycan isolated from the mycelia of Ganoderma lucidum in vitro. Journal of biochemistry and molecular biology. 2005;38(1):34-40.
  175. Hijikata Y, Yasuhara A, Sahashi Y. Effect of an herbal formula containing Ganoderma lucidum on reduction of herpes zoster pain: a pilot clinical trial. The American journal of Chinese medicine. 2005;33(4):517-523.
  176. Hijikata Y, Yamada S, Yasuhara A. Herbal mixtures containing the mushroom Ganoderma lucidum improve recovery time in patients with herpes genitalis and labialis. Journal of alternative and complementary medicine (New York, NY). 2007;13(9):985-987.
  177. Yeh CH, Chen HC, Yang JJ, Chuang WI, Sheu F. Polysaccharides PS-G and protein LZ-8 from Reishi (Ganoderma lucidum) exhibit diverse functions in regulating murine macrophages and T lymphocytes. J Agric Food Chem. 2010;58(15):8535-8544.
  178. Xu Z, Chen X, Zhong Z, Chen L, Wang Y. Ganoderma lucidum polysaccharides: immunomodulation and potential anti-tumor activities. The American journal of Chinese medicine. 2011;39(1):15-27.
  179. Kubota A, Kobayashi M, Sarashina S, et al. Reishi mushroom Ganoderma lucidum Modulates IgA production and alpha-defensin expression in the rat small intestine. Journal of ethnopharmacology. 2018;214:240-243.
  180. Henao SLD, Urrego SA, Cano AM, Higuita EA. Randomized Clinical Trial for the Evaluation of Immune Modulation by Yogurt Enriched with beta-Glucans from Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), in Children from Medellin, Colombia. International journal of medicinal mushrooms. 2018;20(8):705-716.
  181. Liebler DC, McClure TD. Antioxidant reactions of beta-carotene: identification of carotenoid-radical adducts. Chemical research in toxicology. 1996;9(1):8-11.
  182. Cerezo J, Zuniga J, Bastida A, Requena A, Ceron-Carrasco JP, Eriksson LA. Antioxidant properties of beta-carotene isomers and their role in photosystems: insights from Ab initio simulations. J Phys Chem A. 2012;116(13):3498-3506.
  183. Stahl W, Sies H. beta-Carotene and other carotenoids in protection from sunlight. Am J Clin Nutr. 2012;96(5):1179S-1184S.
  184. Aranow C. Vitamin D and the immune system. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2011;59(6):881-886.
  185. Lang PO, Samaras N, Samaras D, Aspinall R. How important is vitamin D in preventing infections? Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2013;24(5):1537-1553.
  186. Trochoutsou AI, Kloukina V, Samitas K, Xanthou G. Vitamin-D in the Immune System: Genomic and Non-Genomic Actions. Mini Rev Med Chem. 2015;15(11):953-963.
  187. Lin LY, Bhate K, Forbes H, Smeeth L, Warren-Gash C, Langan S. Vitamin D deficiency or supplementation and the risk of human herpesvirus infections or reactivation: a systematic review protocol. BMJ open. 2019;9(10):e031867.
  188. Chao CT, Chiang CK, Huang JW, Hung KY. Vitamin D is closely linked to the clinical courses of herpes zoster: From pathogenesis to complications. Med Hypotheses. 2015;85(4):452-457.
  189. Kumar A, Singh MP, Kumar RS, Ratho RK. 25-Hydroxyvitamin D3 and 1,25 Dihydroxyvitamin D3 as an Antiviral and Immunomodulator Against Herpes Simplex Virus-1 Infection in HeLa Cells. Viral Immunol. 2018;31(8):589-593.
  190. Chao CT, Lee SY, Yang WS, et al. Serum vitamin D levels are positively associated with varicella zoster immunity in chronic dialysis patients. Sci Rep. 2014;4:7371.
  191. Chao CT, Lai CF, Huang JW. Risk factors for herpes zoster reactivation in maintenance hemodialysis patients. European journal of internal medicine. 2012;23(8):711-715.
  192. Oztekin A, Oztekin C. Vitamin D Levels in Patients with Recurrent Herpes Labialis. Viral Immunol. 2019;32(6):258-262.
  193. Mowry EM, James JA, Krupp LB, Waubant E. Vitamin D status and antibody levels to common viruses in pediatric-onset multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2011;17(6):666-671.
  194. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2011;50(3):194-200.
  195. Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ, McDermott AM. Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Current eye research. 2005;30(5):385-394.
  196. Takiguchi T, Morizane S, Yamamoto T, Kajita A, Ikeda K, Iwatsuki K. Cathelicidin antimicrobial peptide LL-37 augments interferon-beta expression and antiviral activity induced by double-stranded RNA in keratinocytes. Br J Dermatol. 2014;171(3):492-498.
  197. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiency predisposes to eczema herpeticum. The Journal of allergy and clinical immunology. 2006;117(4):836-841.
  198. De Luca C, Kharaeva Z, Raskovic D, Pastore P, Luci A, Korkina L. Coenzyme Q(10), vitamin E, selenium, and methionine in the treatment of chronic recurrent viral mucocutaneous infections. Nutrition (Burbank, Los Angeles County, Calif). 2012;28(5):509-514.
  199. Shah S, Devi P, Ravindra S, Tyagi K, Singh D. Primary herpetic gingivostomatitis: a case report and review of literature. TMU J Dent. 2014;1(3):119-124.
  200. Sheridan PA, Beck MA. The dendritic and T cell responses to herpes simplex virus-1 are modulated by dietary vitamin E. Free radical biology & medicine. 2009;46(12):1581-1588.
  201. Sheridan PA, Beck MA. The immune response to herpes simplex virus encephalitis in mice is modulated by dietary vitamin E. J Nutr. 2008;138(1):130-137.
  202. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The Role of Zinc in Antiviral Immunity. Adv Nutr. 2019;10(4):696-710.
  203. Haase H, Rink L. The immune system and the impact of zinc during aging. Immunity & ageing : I & A. 2009;6:9.
  204. Gordon YJ, Asher Y, Becker Y. Irreversible inhibition of herpes simplex virus replication in BSC-1 cells by zinc ions. Antimicrob Agents Chemother. 1975;8(3):377-380.
  205. Antoine TE, Mishra YK, Trigilio J, Tiwari V, Adelung R, Shukla D. Prophylactic, therapeutic and neutralizing effects of zinc oxide tetrapod structures against herpes simplex virus type-2 infection. Antiviral research. 2012;96(3):363-375.
  206. Tavakoli A, Ataei-Pirkooh A, Mm Sadeghi G, et al. Polyethylene glycol-coated zinc oxide nanoparticle: an efficient nanoweapon to fight against herpes simplex virus type 1. Nanomedicine (London, England). 2018;13(21):2675-2690.
  207. Bourne N, Stegall R, Montano R, Meador M, Stanberry LR, Milligan GN. Efficacy and toxicity of zinc salts as candidate topical microbicides against vaginal herpes simplex virus type 2 infection. Antimicrob Agents Chemother. 2005;49(3):1181-1183.
  208. Fernandez-Romero JA, Abraham CJ, Rodriguez A, et al. Zinc acetate/carrageenan gels exhibit potent activity in vivo against high-dose herpes simplex virus 2 vaginal and rectal challenge. Antimicrob Agents Chemother. 2012;56(1):358-368.
  209. Derby N, Aravantinou M, Kenney J, et al. An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques. Drug delivery and translational research. 2017;7(6):840-858.
  210. Mahajan BB, Dhawan M, Singh R. Herpes genitalis - Topical zinc sulfate: An alternative therapeutic and modality. Indian J Sex Transm Dis AIDS. 2013;34(1):32-34.
  211. Godfrey HR, Godfrey NJ, Godfrey JC, Riley D. A randomized clinical trial on the treatment of oral herpes with topical zinc oxide/glycine. Alternative therapies in health and medicine. 2001;7(3):49-56.
  212. Singh BB, Udani J, Vinjamury SP, et al. Safety and effectiveness of an L-lysine, zinc, and herbal-based product on the treatment of facial and circumoral herpes. Alternative medicine review : a journal of clinical therapeutic. 2005;10(2):123-127.
  213. Houston DMJ, Bugert JJ, Denyer SP, Heard CM. Potentiated virucidal activity of pomegranate rind extract (PRE) and punicalagin against Herpes simplex virus (HSV) when co-administered with zinc (II) ions, and antiviral activity of PRE against HSV and aciclovir-resistant HSV. PLoS One. 2017;12(6):e0179291.
  214. Houston DMJ, Robins B, Bugert JJ, Denyer SP, Heard CM. In vitro permeation and biological activity of punicalagin and zinc (II) across skin and mucous membranes prone to Herpes simplex virus infection. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2017;96:99-106.
  215. Tomblin FA, Jr., Lucas KH. Lysine for management of herpes labialis. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2001;58(4):298-300, 304.
  216. Milman N, Scheibel J, Jessen O. Lysine prophylaxis in recurrent herpes simplex labialis: a double-blind, controlled crossover study. Acta dermato-venereologica. 1980;60(1):85-87.
  217. Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica. 1987;175(4):183-190.
  218. Mailoo VJ, Rampes S. Lysine for Herpes Simplex Prophylaxis: A Review of the Evidence. Integrative medicine (Encinitas, Calif). 2017;16(3):42-46.
  219. Rossi M, Jacobs B. Herpes Simplex Virus. In: Integrative Medicine. 4th ed.2018:191-197.
  220. Mayo Clinic: L-arginine. https://www.mayoclinic.org/drugs-supplements-l-arginine/art-20364681. Published 2017. Accessed April 14, 2020.
  221. Schnitzler P, Neuner A, Nolkemper S, et al. Antiviral activity and mode of action of propolis extracts and selected compounds. Phytother Res. 2010;24 Suppl 1:S20-28.
  222. Nolkemper S, Reichling J, Sensch KH, Schnitzler P. Mechanism of herpes simplex virus type 2 suppression by propolis extracts. Phytomedicine. 2010;17(2):132-138.
  223. Sforcin JM. Propolis and the immune system: a review. Journal of ethnopharmacology. 2007;113(1):1-14.
  224. Amoros M, Lurton E, Boustie J, Girre L, Sauvager F, Cormier M. Comparison of the anti-herpes simplex virus activities of propolis and 3-methyl-but-2-enyl caffeate. J Nat Prod. 1994;57(5):644-647.
  225. Yildirim A, Duran GG, Duran N, et al. Antiviral Activity of Hatay Propolis Against Replication of Herpes Simplex Virus Type 1 and Type 2. Med Sci Monit. 2016;22:422-430.
  226. Vynograd N, Vynograd I, Sosnowski Z. A comparative multi-centre study of the efficacy of propolis, acyclovir and placebo in the treatment of genital herpes (HSV). Phytomedicine. 2000;7(1):1-6.
  227. Holcová S, Hladiková M. Efficacy and tolerability of propolis special extract gh 2002 as a lip balm against herpes labialis: a randomized, double-blind three-arm dose finding study. Health. 2011;03(01):49-55.
  228. Arenberger P, Arenbergerova M, Hladikova M, Holcova S, Ottillinger B. Comparative Study with a Lip Balm Containing 0.5% Propolis Special Extract GH 2002 versus 5% Aciclovir Cream in Patients with Herpes Labialis in the Papular/Erythematous Stage: A Single-blind, Randomized, Two-arm Study. Current therapeutic research, clinical and experimental. 2018;88:1-7.
  229. Jautova J, Zelenkova H, Drotarova K, Nejdkova A, Grunwaldova B, Hladikova M. Lip creams with propolis special extract GH 2002 0.5% versus aciclovir 5.0% for herpes labialis (vesicular stage) : Randomized, controlled double-blind study. Wien Med Wochenschr. 2019;169(7-8):193-201.
  230. Abdel-Naby Awad OG, Hamad AH. Honey can help in herpes simplex gingivostomatitis in children: Prospective randomized double blind placebo controlled clinical trial. American journal of otolaryngology. 2018;39(6):759-763.
  231. Munstedt K. Bee products and the treatment of blister-like lesions around the mouth, skin and genitalia caused by herpes viruses-A systematic review. Complementary therapies in medicine. 2019;43:81-84.
  232. Valenti P, Antonini G. Lactoferrin: an important host defence against microbial and viral attack. Cellular and molecular life sciences : CMLS. 2005;62(22):2576-2587.
  233. Jenssen H, Sandvik K, Andersen JH, Hancock RE, Gutteberg TJ. Inhibition of HSV cell-to-cell spread by lactoferrin and lactoferricin. Antiviral research. 2008;79(3):192-198.
  234. Berlutti F, Pantanella F, Natalizi T, et al. Antiviral properties of lactoferrin--a natural immunity molecule. Molecules (Basel, Switzerland). 2011;16(8):6992-7018.
  235. Fujihara T, Hayashi K. Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea. Arch Virol. 1995;140(8):1469-1472.
  236. Andersen JH, Jenssen H, Sandvik K, Gutteberg TJ. Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface. Journal of medical virology. 2004;74(2):262-271.
  237. Jenssen H, Andersen JH, Uhlin-Hansen L, Gutteberg TJ, Rekdal O. Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate. Antiviral research. 2004;61(2):101-109.
  238. Valimaa H, Tenovuo J, Waris M, Hukkanen V. Human lactoferrin but not lysozyme neutralizes HSV-1 and inhibits HSV-1 replication and cell-to-cell spread. Virol J. 2009;6:53.
  239. Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The Essential Medicinal Chemistry of Curcumin. J Med Chem. 2017;60(5):1620-1637.
  240. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). Journal of alternative and complementary medicine (New York, NY). 2003;9(1):161-168.
  241. Khan MT, Ather A, Thompson KD, Gambari R. Extracts and molecules from medicinal plants against herpes simplex viruses. Antiviral research. 2005;67(2):107-119.
  242. Kutluay SB, Doroghazi J, Roemer ME, Triezenberg SJ. Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology. 2008;373(2):239-247.
  243. Zandi K, Ramedani E, Mohammadi K, et al. Evaluation of antiviral activities of curcumin derivatives against HSV-1 in Vero cell line. Natural product communications. 2010;5(12):1935-1938.
  244. Ferreira VH, Nazli A, Dizzell SE, Mueller K, Kaushic C. The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2. PLoS One. 2015;10(4):e0124903.
  245. Oka S, Okabe M, Tsubura S, Mikami M, Imai A. Properties of fucoidans beneficial to oral healthcare. Odontology. 2020;108(1):34-42.
  246. Lee JB, Hayashi K, Hashimoto M, Nakano T, Hayashi T. Novel antiviral fucoidan from sporophyll of Undaria pinnatifida (Mekabu). Chemical & pharmaceutical bulletin. 2004;52(9):1091-1094.
  247. Hayashi K, Nakano T, Hashimoto M, Kanekiyo K, Hayashi T. Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection. International immunopharmacology. 2008;8(1):109-116.
  248. Zayed A, Muffler K, Hahn T, et al. Physicochemical and Biological Characterization of Fucoidan from Fucus vesiculosus Purified by Dye Affinity Chromatography. Mar Drugs. 2016;14(4).
  249. Pozharitskaya ON, Shikov AN, Obluchinskaya ED, Vuorela H. The Pharmacokinetics of Fucoidan after Topical Application to Rats. Mar Drugs. 2019;17(12).
  250. Tsubura S, Suzuki A. Case report using 4% fucoidan cream for recurrent oral herpes labialis: patient symptoms markedly improved in terms of time to healing and time to loss of discomfort. Dent Open J. 2017;4(2):19-23.
  251. Miraj S, Rafieian K, Kiani S. Melissa officinalis L: A Review Study With an Antioxidant Prospective. Journal of evidence-based complementary & alternative medicine. 2017;22(3):385-394.
  252. Dimitrova Z, Dimov B, Manolova N, Pancheva S, Ilieva D, Shishkov S. Antiherpes effect of Melissa officinalis L. extracts. Acta Microbiol Bulg. 1993;29:65-72.
  253. Allahverdiyev A, Duran N, Ozguven M, Koltas S. Antiviral activity of the volatile oils of Melissa officinalis L. against Herpes simplex virus type-2. Phytomedicine. 2004;11(7-8):657-661.
  254. Schnitzler P, Schuhmacher A, Astani A, Reichling J. Melissa officinalis oil affects infectivity of enveloped herpesviruses. Phytomedicine. 2008;15(9):734-740.
  255. Geuenich S, Goffinet C, Venzke S, et al. Aqueous extracts from peppermint, sage and lemon balm leaves display potent anti-HIV-1 activity by increasing the virion density. Retrovirology. 2008;5:27.
  256. Mazzanti G, Battinelli L, Pompeo C, et al. Inhibitory activity of Melissa officinalis L. extract on Herpes simplex virus type 2 replication. Natural product research. 2008;22(16):1433-1440.
  257. Astani A, Reichling J, Schnitzler P. Melissa officinalis extract inhibits attachment of herpes simplex virus in vitro. Chemotherapy. 2012;58(1):70-77.
  258. Koytchev R, Alken RG, Dundarov S. Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis. Phytomedicine. 1999;6(4):225-230.
  259. Wolbling RH, Leonhardt K. Local therapy of herpes simplex with dried extract from Melissa officinalis. Phytomedicine. 1994;1(1):25-31.
  260. Wang L, Yang R, Yuan B, Liu Y, Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta pharmaceutica Sinica B. 2015;5(4):310-315.
  261. Fukuchi K, Okudaira N, Adachi K, et al. Antiviral and Antitumor Activity of Licorice Root Extracts. In Vivo. 2016;30(6):777-785.
  262. Sekizawa T, Yanagi K, Itoyama Y. Glycyrrhizin increases survival of mice with herpes simplex encephalitis. Acta virologica. 2001;45(1):51-54.
  263. Aslani A, Zolfaghari B, Fereidani Y. Design, formulation, and evaluation of a herbal gel contains melissa, sumac, licorice, rosemary, and geranium for treatment of recurrent labial herpes infections. Dent Res J (Isfahan). 2018;15(3):191-200.
  264. Kanauchi O, Andoh A, AbuBakar S, Yamamoto N. Probiotics and Paraprobiotics in Viral Infection: Clinical Application and Effects on the Innate and Acquired Immune Systems. Curr Pharm Des. 2018;24(6):710-717.
  265. An HM, Lee DK, Kim JR, et al. Antiviral activity of Bifidobacterium adolescentis SPM 0214 against herpes simplex virus type 1. Archives of pharmacal research. 2012;35(9):1665-1671.
  266. Khani S, Motamedifar M, Golmoghaddam H, Hosseini HM, Hashemizadeh Z. In vitro study of the effect of a probiotic bacterium Lactobacillus rhamnosus against herpes simplex virus type 1. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases. 2012;16(2):129-135.
  267. Brun P, Scarpa M, Marchiori C, et al. Saccharomyces boulardii CNCM I-745 supplementation reduces gastrointestinal dysfunction in an animal model of IBS. PLoS One. 2017;12(7):e0181863.
  268. Matsusaki T, Takeda S, Takeshita M, et al. Augmentation of T helper type 1 immune response through intestinal immunity in murine cutaneous herpes simplex virus type 1 infection by probiotic Lactobacillus plantarum strain 06CC2. International immunopharmacology. 2016;39:320-327.
  269. Mohseni AH, Taghinezhad SS, Keyvani H, Ghobadi N. Comparison of Acyclovir and Multistrain Lactobacillus brevis in Women with Recurrent Genital Herpes Infections: a Double-Blind, Randomized, Controlled Study. Probiotics and antimicrobial proteins. 2018;10(4):740-747.