Man With Painful Intraoral Ulcers

A 61-year-old man presented initially with multiple punctuate shallow intraoral ulcers localized primarily to the vestibule, cheek, and buccal gingival region of the maxilla and mandible that had been present for about 10 days. The borders were slightly erythematous (Figure 1). They began without apparent cause and were quite painful. Eating, swallowing, and talking were difficult. Ulcers had been preceded by vesicles that quickly ruptured. There were no extraoral lesions, and the patient reported no history of similar lesions.

The patient noted that he had recently had a slight weight loss and had felt somewhat fatigued. He thought he had a slight fever, but had not taken his temperature. The medical history and systems review was essentially unremarkable. Medications included occasional NSAIDs for arthritis and tamsulosin (Flomax), 0.4 mg daily.

The differential included:
• Primary herpetic gingivostomatitis
• Primary varicella-zoster 
• Herpangina
• Erythema multiforme
• Herpetiform aphthous
• Pemphigoid gestationis

A viral culture was positive for HSV-1, confirming the diagnosis of herpetic gingivostomatitis, supported by findings from the patient’s history and clinical presentation.

One year later the patient was re-examined when he complained of severe palatal pain adjacent to an upper bridge. This pain was preceded by an ‘itching’ sensation. Several small punctuate ulcers were observed on the lingual palate adjacent to a bridge replacing several teeth (Figure 2).

The differential included:
. Recurrent HSV-1
. Recurrent HSV-2

Culture of the palatal lesions was positive for HSV-1.

Questions:
 
1. If you were going to order lab tests to confirm the diagnosis in this patient, what would they be? 
2. What would constitute reasonable treatment for primary or secondary HSV-1 oral infection? 

Answers on next page...

A Closer look at HSV-1 and HSV-2
Primary HSV-1 infection is most commonly seen in children and young adults, but it can occur at any age. The condition follows primary contact with HSV-1. HSV-2, which typically causes genital lesions, may also be associated with oral disease. A recent study that assessed the variation in seroprevalences of HSV-1 and HSV-2 in Croatia found that the overall IgG seroprevalence rate for HSV-1 was 72.5% and for HSV-2, 9.9%.¹ Differences were not found between males and females. The seroprevalence of HSV-1 rose from 26% in those aged 6 months to 9 years to 90% in persons aged 40 to 49 years. There was an equivalent increase in seropositivity for those aged 20 to 30 relative to those older than 60 years.¹ These statistics appear to be similar for other world regions, including Europe and Asia.

HSV is a DNA virus and there appear to be differences in strains based on geographical region. HSV-1 and HSV-2 have different modes of transmission but in at least one study, about 12% of the population cohort was found to be coinfected by both types of the virus.² Note, however, that HSV-2 rarely occurs as a primary intraoral infection and HSV-1 as a recurrent genital lesion.

Both HSV-1 and HSV-2 infect epithelial cells and cause latent infection of neurons. The virus remains dormant until reactivated by factors such as trauma, ultraviolet light, fever, stress, menstruation, hormonal change, or immunosuppression. Recrudescent HSV-1 lesions typically involve the lip but may also affect the palatal gingival or alveolar ridge gingiva. In these locations, the lesions present as clusters of vesicles.

Herpes simplex encephalitis is a rare secondary disease, reported to follow primary infection in 2 to 4 cases per million per year.³

The clinical presentation of primary HSV infection is quite distinctive and the diagnosis can be made  on the basis of the history and examination without additional lab testing. A definitive diagnosis can be established by cytologic examination of fluid from an intact vesicle. If the specimen is taken during the prodrome, or crusted, stage, however, the possibility of detecting virus is reduced. In patients with suspected underlying immunosuppression, additional histopathologic studies, monoclonal antibodies, isolation, and nucleic acid hybridization of cultured fluid can confirm the disease. The latter test requires a substantial viral load or the sensitivity of the test is significantly reduced.⁴

Therapy
Immunocompetent patients experiencing an initial outbreak of HSV-1 infection or a subsequent recurrent HSV-1 infection do not typically require management other than supportive care. This includes maintenance of fluid intake, pain medications, and topical pain measures. Antivirals (eg, acyclovir, valacyclovir, and famciclovir) are primarily recommended for severe cases or for infection confirmed to be related to immunosuppressive disease or concomitant autoimmune disease (pemphigus vulgaris).⁵

Topical acyclovir (5% cream), penciclovir (1% cream), and docosanol (10% cream) can help shorten the duration of intraoral lesions. Antiviral prophylaxis may be necessary in cases of frequent recurrence or to prevent reactivation of the disease in immunocompromised individuals. Use caution when prescribing for pregnant women with recurrent lesions.

Other intervention strategies cited in the literature but without substantial supportive research include melatonin; supplementation with SB-73-a mixture of magnesium, phosphate, and fatty acids extracted from Aspergillus species; and use of other plant alkaloids.^6-8 Lysine supplements; Lactobacillus acidophilus and Lactobacillus delbrueckii subspecies bulgaricus; and vitamins C, E, and B12 supplementation lack adequate scientific support and are not recommended. 

References:

References
1. Vilibic-Cavlek T, Kolaric B, Ljubin-Sternak S, Mlinaric-Galinovic-G. Herpes simplex virus infection in the Croatian population. Scand J Infect Dis. 2011; June 22. Epub ahead of print. http://www.ncbi.nlm.nih.gov/pubmed/21696254. Accessed July 29, 2011.

2. Lin H, Meifang S, Feng J, Meiyang G. Herpes simplex virus infections among rural residents in eastern China. BMC Infect Dis. 2011;18:69-75. Available at: http://www.ncbi.nlm.nig.gov/pmc/articles/PMC3068093/?tool=pubmed.

3. Rozenberg F, Deback C, Agut H. Herpes simplex encephalitis: from virus to therapy. Infect Disord DrugTargets. 2011;11:235-250.

4. Shillitoe E. In: Millard HD, Mason DK, eds. 2nd World Workshop on Oral Medicine. Ann Arbor, MI: University of Michigan; 1993:16-23.

5. Brandao ML, Fernandes NC, Batista DP, Santos N. Refractory pemphigus vulgaris associated with herpes infection: case report and review. Rev Inst Med Trop Sao Paulo. 2011;53:113-117. Available at: http://www.ncbi.nlm.nih.gov/pubmed?term=hsv-1%20infection%20with%20acyclovir. Accessed July 29, 2011.

6. Nunes OS, Pereira Rde S. Regression of herpes viral infection symptoms using melatonin and SB-73: comparison with acyclovir. J Pineal Res. 2008;44:373-378.

7. Glatthaar-Saalmuller B. In vitro evaluation of the antiviral effects of the homeopathic preparation Gripp-Heel on selected respiratory viruses. Can J Physiol Pharmacol. 2007;85:1084-1090.

8. Xiong HR, Luo J, Hou W, et al. The effect of emodin, an anthraquinone derivative extracted from the roots of Rheum tanguticum, against herpes simplex virus in vitro and in vivo. J Ethnopharmacol. 2011;133:718-723.

For More Information

• Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med. 2009;361:1376-1385.

• Ficarra G, Birek C. Oral herpes simplex virus infection in pregnancy: what are the concerns? J Can Dent Assoc. 2009;75:523-526.

• James SH, Whitley RJ. Treatment of herpes simplex virus infections in pediatric patients: current status and future needs. Clin Pharmacol Ther. 2010;88:720-724.

• Laskaris G. Color Atlas of Oral Diseases. New York: Thieme Medical Publishers, Inc.

• Usatine RP, Tinitigan R. Nongenital herpes simplex virus. Am Fam Physician. 2010;82:1075-1082.