<h2>Practice points</h2><ul><li> L-lysine can be used in the treatment of cold sores; it has been shown to reduce healing time, severity, and the frequency of outbreaks6 </li><li> Zinc has been shown to reduce both the number of episodes of cold sores and the time to recovery, both oral and topical zinc have a role13,14,15 </li><li> A lysine-rich diet and reducing high arginine foods can be of benefit for those who experience recurrent cold sores4 </li><li> Support the immune system with a balanced, healthy diet as changes to the immune system can trigger cold sore recurrence3 </li></ul><h2>Description</h2><ul><li> The herpes virus family consists of over 100 viruses, of these only eight are known to commonly infect humans. Herpes simplex type-1 (HSV-1) and herpes simplex type-2 (HSV-2) are responsible for highly prevalent infections in humans1 </li><li> Approximately 90% of people worldwide have either HSV-1, HSV-2 or both viruses2 </li><li> HSV-1 symptomatic infection typically presents as either cold sores of the mouth (herpes labialis) and keratitis in the eyes, while HSV-2 is mostly responsible for genital lesions1 </li><li> HSV-1 is transmitted via human contact and often occurs via kissing. It is also possible to acquire lesions if medical professionals do not wear surgical gloves and come into contact with virions shed from their patients’ mouth, this is known as herpetic whitlow1 </li><li> In immunocompetent hosts, HSV-1 causes oral, labial and occasionally facial lesions. Initial infections are usually the worst and last on average 12 days, presenting as ulcerative, painful stomatitis. The most common complication of initial HSV-1 infection is dehydration, but secondary bacterial infection is also a risk2 </li><li> Reactivation of HSV-1 in the mouth usually causes the lip lesions commonly known as cold sores. The appearance of cold sores may be preceded by the prodrome phase, during which symptoms of pain, tingling and itching occur2 </li><li> The initial lesion is an erythematous papule that evolves into a fluid-filled blister. Blisters often, but not always, occur in clusters which can extend to the face and, sometimes, occur only on the face. Episodes last on average for 5-7 days and end with the vesicles drying to a crust and re-epithelialising without scarring2 </li><li> Only 30% of those with HSV-1 have recurrent cold sores, with 40% of those having more than one recurrence per year2 </li><li> Triggers for cold sore recurrence include viral infections/fever, hormonal changes, stress, fatigue, exposure to sunlight/wind and/or changes to the immune system3 </li></ul>

<h2>Management principles</h2> <ul><li> For acute presentation focus on symptom management as there is no cure for HSV-14 </li><li> Antiviral therapy significantly reduces the severity and duration of symptoms during primary infection, reduces the frequency of recurrent outbreaks when taken prophylactically, and is well tolerated. HSV-1 responds best to oral rather than topical antivirals; the latter showing only modest benefits in comparison4 </li><li> Manage pain to give short-term relief with the use of topical anaesthetic preparations e.g. lidocaine, benzocaine4 </li><li> Use complementary medicines such as lysine to treat and reduce healing time, whilst zinc will support the immune system and reduce outbreaks6,14 </li></ul>

Management

<h2>Primary recommendations</h2><h2>L-lysine Information</h2>Mechanism of Action<ul><li> L-lysine, the active stereoisomer of lysine, is an essential amino acid which plays a role in protein biosynthesis. The human body does not synthesise L-lysine so it must be obtained from the diet4 </li><li> L-lysine inhibits the multiplication of HSV in cell cultures4 </li><li> L-lysine competes with arginine, a viral growth-promoter, for inclusion into viral replicative processes. It does so by competing with arginine for intestinal absorption, transport to cells, and reabsorption at the renal tubule, and it degrades arginine by activating arginase4 </li></ul>Research<ul><li> Clinical studies have supported supplementing with oral lysine. Patients taking 1248 mg of lysine reported significantly fewer recurrences of HSV-1 symptoms than those using a placebo. The same study found that a dose of 624 mg had no effect5 </li><li> A 6-month trial using 1000 mg lysine hydrochloride or placebo three times a day found that 74% of those using lysine reported the treatment to be either effective or very effective, compared to just 28% in the placebo group. The lysine significantly reduced healing time, severity, and outbreak frequency6 </li></ul>DosageAdults: 1000 mg orally, three times daily.6Adverse effects<ul><li>Very high doses of greater than 10 g per day can cause gastrointestinal distress.6</li><li>May cause modest increases in LDL cholesterol.6</li><li>Avoid in pregnancy and lactation.7</li></ul>Key interactions<ul><li>Calcium: theoretical. Lysine intake along with calcium can increase calcium absorption and decrease urine calcium loss8</li></ul>For more information on key interactions visit: <a href="~/link.aspx?_id=4471DACF65C148EA8FD82B23FD6712D4&_z=z">https://www.blackmoresinstitute.org/interactions</a>

Primary

<h2>Secondary recommendations</h2><h2>ZINC</h2>Mechanism of action<ul><li> Zinc ions have been shown to inhibit the replication of HSV- 1 and HSV-2 in-vitro, due to selective inhibition of viral DNA polymerase8,9,10,11 </li></ul>Research<ul><li> A 2012 study found that salivary zinc levels were significantly lower in both acute and convalescent phases of HSV infection, compared to healthy control subjects12 </li><li> A small human pilot study published in 2005 investigated the effect of systemic zinc supplementation (22.5 mg twice daily) on recurrent HSV infection. The study showed that zinc sulphate appeared to reduce both the number of episodes and the time to recovery of herpes labialis13 </li><li> A 2001 clinical trial looked at the use of zinc oxide/glycine cream as a treatment for oral herpes. Subjects who began active treatment within 24 hours of onset of signs and symptoms experienced a significantly shorter duration (mean 5 days) of cold sore lesions than those treated with placebo cream (6.5 days)14 </li><li> Another double-blind randomised controlled trial conducted in 1995 showed that a zinc sulphate 1% gel applied every few hours resulted in patients with HSV-1 becoming symptom-free by day 5, compared to only 35% of subjects in the placebo group15 </li></ul>DosageOrally 22.5 mg twice daily.6Adverse effects<ul><li>Mild gastrointestinal distress has been reported at doses of 50-150 mg of supplemental zinc.15</li><li>Topically - burning and itching sensation was reported with the use of zinc/glycine cream.15</li></ul>Key interactions<ul><li>ACE inhibitors, angiotensin receptor blockers, and thiazide diuretics: urinary zinc excretion may be increased with long-term use of these drugs (decreasing zinc). Interaction is possible. Assess nutrient status and supplement if indicated17</li><li>Cefalexin: zinc may decrease the absorption of the drug by chelating with the drug. Interaction is possible. The interaction may be minimised by separating the dose of zinc at least 3 hours after taking cephalexin17</li><li>Hypoglycaemic drugs: low zinc status is common in diabetic patients. Zinc supplementation and normalisation of zinc levels have been shown to improve glycaemic control. Assess nutrient status and supplement if indicated. Monitor blood glucose level and alter drug dose if required under the supervision of a healthcare professional (HCP)17</li><li>Integrase inhibitors: may decrease the blood level of the drug by chelating with the drug. Interaction is likely. Avoid concomitant use17</li><li>Penicillamine: zinc may decrease the activity of penicillamine. Interaction is possible. The interaction may be minimised by separating the dose of medication and zinc by at least 2 hours17</li><li>Tetracycline &amp; quinolone antibiotics: zinc may decrease the absorption and blood levels of these drugs. Interaction is possible. The interaction may be minimised by taking tetracycline at least 2 hours before, or 4-6 hours after zinc supplement17
 
 </li></ul>For more information on key interactions visit: <a href="~/link.aspx?_id=4471DACF65C148EA8FD82B23FD6712D4&_z=z">https://www.blackmoresinstitute.org/interactions</a>

Secondary

<h2>Diet and lifestyle recommendations</h2><ul><li> Support your immune system with a balanced and healthy diet rich in a range of nutrients as an impaired immune system can trigger a recurrence of cold sores.3 The micronutrients zinc, selenium, iron, copper, vitamins A, C, E, B6, and folic acid have an important influence on the immune system.16 </li><li> Choose foods high in lysine and low in arginine Arginine is a viral growth-promoter which competes with L-lysine. Good food sources of lysine include fish, poultry, beef, pork, dairy products, and vegan rich sources include beans, peas, and lentils.18 </li><li> Avoid skin-to-skin contact with others while blisters are present.3 </li><li> Avoid sharing personal items such as towels, lipstick, lip balm which could spread the virus.3 </li><li> Keep your hands clean.3 </li><li> Don’t touch the lesions and touch eyes.3 </li></ul>

Diet & lifestyle

<h2>References</h2>1. Akhtar J, Shukla D. Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry. FEBS Journal. 2009;276(24):7228-7236
 2. Wald A, Corey L. Persistence in the population: epidemiology, transmission. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 36
 3. Mayo clinic. Cold sore - Symptoms and causes. <a href="https://www.mayoclinic.org/diseases-conditions/cold-sore/symptoms-causes/syc-20371017 Accessed 8 December 2018" target="_blank">https://www.mayoclinic.org/diseases-conditions/cold-sore/symptoms-causes/syc-20371017Accessed 8 December 2018</a>
 4. Rakel D. Integrative medicine. 4th ed. Philadelphia: Elsevier; 2018: 192-5
 5. McCune M, Perry H, Muller S, O’Fallan W. Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride. Cutis. 1984;34(4):366- 373
 6. Griffiths R. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica. 1987;175(4):18390
 7. Natural Medicines. Lysine rel="noopener noreferrer" Professional Monograph. <a href="https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/ professional.aspx?productid=237 Accessed 9 December 2018" target="_blank">https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=237 Accessed 9 December 2018</a>
 8. Shlomai J, Asher Y, Gordon YJ, et al. Effect of zinc ions on the synthesis of Herpes simplex virus DNA in infected BSC-1 cells. Virology 1975;66:330- 335
 9. Fridlender B, Chejanovsky N, Becker Y. Selective inhibition of Herpes simplex virus type I DNA polymerase by zinc ions. Virology 1978;84:551- 554
 10. Gupta P, Rapp F. Effect of zinc ions on synthesis of Herpes simplex virus type 2-induced polypeptides. Proc Soc Exp Biol Med 1976;152:455458
 11. Gordon YJ, Asher Y, Becker Y. Irreversible inhibition of Herpes simplex virus replication in BSC-1 cells by zinc ions. Antimicrob Agents Chemother 1975;8:377-380
 12. Khozeimeh F, Jafari N, Attar AM, et al. Comparative analysis of salivary zinc level in recurrent herpes labialis. Dent Res J (Isfahan). 2012;9(1):1923
 13. Femiano F, Gombos F, Scully C. Recurrent herpes labialis: a pilot study of the efficacy of zinc therapy. J Oral Pathol Med 2005;34(7):423-4252
 14. Godfrey HR, Godfrey NJ, Godfrey JC, Riley D. A randomized clinical trial on the treatment of oral herpes with topical zinc oxide/glycine. Altern Ther Health Med 2001;7:49-56
 15. Braun L et al. Herbs &amp; Natural Supplements. 4th ed. Chatswood NSW: Elsevier; 2015: 1207-1218
 16. Chandra R. Nutrition and the immune system: an introduction. The American Journal of Clinical Nutrition. 1997;66(2):460S-463S
 17. Blackmores Institute. Complementary Medicines Interaction Guide. 10th edition. 2019
 18. List of Foods High in Lysine &amp; Low in Arginine | Livestrong.com [Internet]. LIVESTRONG.COM. rel="noopener noreferrer" 2019 [cited 3 January 2019]. Available from: <a href="https://www.livestrong.com/article/260536-list-of-foods-high-in-lysine-low-in-arginine/" target="_blank">https://www.livestrong.com/article/260536-list-of-foods-high-in-lysine-low-in-arginine/</a>

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