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Harrison's Internal Medicine

Herpes is best known for intermittently producing embarrassing sores on the mouth and genitals, yet representing a major public health problem in the world. It is a persistent, chronic infection with a dynamic interaction between the host and the virus. Listed below are some poorly appreciated facts about this viral infection, which are fascinating, enlightening, and helpful in clinical practice.

Besides being the #1 topic on the National STD Hotline and second greatest concern to sexually active people (the first is AIDS), ex-girlfriends of sports figures are suing for acquiring herpes from their former lovers. Four years ago, one professional basketball player, Juwan Howard, was reportedly sued for $500,000. One year ago, a different professional basketball player, Cliff Robinson, was supposedly sued for $10,000,000 for the same offense. Note that the cost of not using suppressive therapy is obviously increasing.

Quoting a noted medical textbook, with primary herpes infections, viremia occurs and the virus spreads to virtually all organs of the body (1). Viremia has been reported to frequently occur in neonatal herpes simplex infections (2), genital herpes (3), and herpes labialis (4) in otherwise healthy individuals. HSV viremia during attacks of primary and recurrent herpes infections is more frequent than previously appreciated. Moreover, numerous articles are available revealing the existence of the virus in all organs of the body by polymerase chain reaction (PCR) studies.

Any disease that causes pain for 1 to 2 weeks of any organ, which later recurs in the same location, might be herpetic in origin and may respond to anti-herpetic oral medications. Examples of diseases which may be caused at least some of the time by herpes include Bell's palsy, erythema multiforme, stomach ulcers, middle ear infections, and proctitis. Oral anti-herpetic therapy has additionally been beneficial in some cases of infertility (5). Additionally, herpetic infection of the vascular wall cellular elements has been implicated in development of several pathophysiological events including vasculitis, transplant rejection, and atherosclerosis (6,7).

PCR has been used to detect varicella-zoster virus (VZV) from the patient's hands, throat, and room environment with shingles. On day 4 of the outbreak, VZV DNA was detected on the back of a chair, doorknob, and table in the room, as well as the surfaces of hands. By day 6, VZV DNA was detected from her throat and in the air conditioner filter in her room (8). Of note, viremia was present from day 4 through day 7 of her illness. These findings confirm that rapid and widespread contamination of VZV occurs and is comparable with similar testing with varicella patients. The detection of VZV on the surface of the air conditioner filter is most significant, as there was no direct touching by the patient to the filter. This apparent aerosol transmission of VZV supports the previous determination of VZV DNA in air samples from hospital rooms (9). Strategies for managing zoster patients have to incorporate the same precautions of airborne transmission as with varicella patients to reduce the risk for transmission (10).

Although varicella provides lasting immunity and second attacks are uncommon in people with normal immune systems, clinical reinfection with mild varicella-like symptoms occasionally occurs (11). Also, recurrent herpes zoster has been proven immunologically to occur in three cases of acute, chronic, and recurrent neuropathy. The varicella zoster infections were confirmed by immunoglobulin G antibody levels to varicella zoster virus in the cerebrospinal fluid in an article entitled, "Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash." (12) As these patients were without overt cutaneous disease, they would be properly designated as zoster sine herpete. Of note, these cases exemplify that herpes viruses can not only spread distally from the dorsal root ganglion to the cutaneous surface, but also are able to disseminate from the dorsal root ganglion and spread proximally along the posterior nerve root to the meninges and spinal cord.

Besides minimum inhibitory concentration and minimum bactericidal concentration, other microbacterial parameters exist. For example, antibiotics that act by inhibiting protein or nucleic acid synthesis show concentration-dependent bactericidal activity: thus, one prefers the agent with the highest antibacterial kill in this situation. If the agent acts on bacterial cell wall synthesis, then one would prefer long bioavailability which is time dependent (13). If these principles are applicable to viral diseases, one would prefer an agent that has greater affinity for viral DNA polymerase that is also an obligate chain terminator. One could use such an agent in short burst therapy.

In terms of the serological tests for herpes, both the FDA and CDC prefer (rightfully so) the tests that detect 'viral glycoprotein G specific for HSV-1 (gG1) and HSV-2 (gG2). These proteins are located on the viral surfaces and on the surfaces of virus-infected cells. One could also probably order by stating 'glycoprotein G-based type specific herpes tests,' or 'type-specific' blood tests for herpes, or 'HerpeSelect HSV-1 and HSV-2 Elisa' or 'HerpeSelect immunoblot.' These tests are made by Focus Technologies. A website to view would be www.herpeselect.com. Remember that although 65% of patients will be seropositive in 6 weeks, about 20% do not make antibodies for 6 months.

Diagnology Inc. makes the POCkit HSV-2 test that takes 6 minutes in the office from blood obtained from a finger prick. This test only tests for HSV-2; remember that 25% of genital herpes is HSV-1 and 30% of neonatal herpes is now HSV-1.

Herpes may not be 100% villainous to humans, and God may have given us the virus for a reason. In short, herpes shows selective damage as well as initiating an immunological response to cancerous cells. Herpes viruses genetically engineered to not replicate in normal tissue have shown promise in the treatment of several cancers (14-16).

A curiosity is that some bacteria produce a resuscitation-promoting factor (Rpf) that awakens other species of dormant bacteria (17). Thus, although the medical literature continues to search for a cytokine profile that initiates reactivation of herpes (18), the initiation may be in response to a yet unidentified bacterial-made receptor.

Recent research has developed two new compounds, BILS 179 BS and BAY 57-1293, that act on two enzymes, helicase and primase, which are part of an enzyme complex that the herpes virus needs to untwist from its double-stranded DNA to form single strands and then prime the strands for replication into new viral DNA (19-21). Present therapies probably work too well, so that no drug company will pursue FDA approval because of costs in drug development.

The risk of intrauterine HSV infection in neonates acquired after rupture of membranes with disastrous sequelae again raises the question of prevention and suppressive antiviral therapy in pregnant females (22).

References:

1. Corey L. Herpes simplex viruses. In: Fauci AS, Braunwall E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, editors. Harrisons Principles of Internal Medicine, New York, McGraw-Hill. 1998: 1080-86.

2. Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes virus infections. Ped Inf Dis J 1999; 18:487-9.

3. Barinskii KF, Grebeniuk VN, Davydova AA, Malashenko LN. Viremia in genital herpes. Vestnik Kermatologii I Venerologii 1982; 11:16-8.

4. Youssef R, Shaker O, Sobeih S, Mashaly H, Mostafa WZ. Detection of herpes simplex virus DNA in serum and oral secretions during acute recurrent herpes labialis. J Dermatol 2002; 29:404-10.

5. Kundsin RB, Falk L, Hertig AT, Horne HW Jr. Acyclovir treatment of twelve unexplained infertile couples. Int J Fertility 1987; 32:200-4.

6. Scheglovitova ON, Romanox YA, Maksianina EV, Svintsitskaya VA, Pronin AG. Herpes simplex type I infected human vascular endothelial cells induce the production of anti-viral and proinflammatory factors by peripheral blood leukocytes in vitro. Russ J Immunol 2002; 7:115-22.

7. Vorobev AA. Role of viral-herpetic infection in the etiology of atherosclerosis: clinical, virological and immunological evidence. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk 2003; 4:3-10.

8. Yoshikawa T, Ihira M, Suzuli K, Suga S, Tomitaka A, Ueda H, Asano Y. Rapid contamination of the environments with varicella-zoster virus DNA from a patient with herpes zoster. J Med Virol 2001; 63:64-6.

9. Sawyer MH, Chamberlin CJ, Wu YN, Aintablian N, Wallace MR. Detection of varicella-zoster virus DNA in air samples from hospital rooms. J Infect Dis 1994; 169:91-4.

10. Burkhart CN, Barnett R. Herpes zoster; Reassessment of isolation precautions in hospitals. SkinMed: Dermatology for the Clinician 2003; 2:253-5.

11. Gershon AA, Steinberg SP, Gelb L. Clinical reinfection with varicella-zoster virus. J Infect Dis 1984; 149:137-42.

12. Fox RJ, Galetta SL, Mahalingam R, wellish M, Forghani B, Gilden DH. Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash. Neurology 2001; 57:142-7.

13 Mazzei T, Novelli A. How macrolide pharmacodynamics affect bacterial killing. Inf Med 2002; 12:22-8S.

14. Wakimoto H, Johnson PR, Knipe DM, Chiocca Ea. Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells. Gene Therapy 2003; 10:983-90.

15. Misumi M, Suzuki T, Moriuchi S, Glorioso JC, Bessho M. In vitro thymidine kinase/ganciclovir-based suicide gene therapy using replication defective herpes simplex virus-1 against leukemic B-cell malignancies Leukemia Res 2003; 27:695-99.

16. Miller CG, Fraser NW. Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model. Molecular Therapy 2003; 7:741-7.

17. ShleevaMO, Mukamolova GV, Telfox MV, Berezinskaia TL, Syroeshkin AV, Biketov SF, Kapreliatns AS. Formation of unculturable Mycobacterium tuberculosis and their regeneration. Mikrobiologiia 2003; 72:76-83.

18. Singh R, Kumar A, Creery WD, Ruben M, Giuliva A, Diaz-Mitoma F. Dysregulated expression of IFN-gamma and IL-10 and impaired IFN-gamma-mediated responses at different disease stages in patients with genital herpes simplex virus-2 infection. Clin Exp Immunol 2003; 133:97-107.

19. Crute JJ, Grygon Ca, Hargrave KD, Simoneau B, Faucher AM, Bolger G, Kibler P, Liuzzi M, Cordingley MFG. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nature Med 2002; 8:386-91.

20. Betz UA, Fischer R, Kleymann G, Hendrix M, Rubsamen-Waigmann H. Potent in vivo antiviral activity of the herpes simplex virus primase-helicase inhibitor BAY 57-1293. Antimicrob Agents Chemother 2002; 46:1766-72.

21. Kleymann G, Fischer R, Betz UA, Hendrix M, Bender W, Schneider U, Handke G. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease. Nature Med 2002; 8:392-8.

22. Vasileiadis GT, Roukema HW, Romano W, Walton JC, Gagnon R. Intrauterine herpes simplex infection. Am J Perinatol 2003; 20:55-8.

Craig G Burkhart MPH MD (1), Craig N Burkhart MSBS MD (2)

1 Clinical Professor, Medical College of Ohio, Sylvania, Ohio

2 Brown Medical School Hospitals, Providence, Rhode Island

Craig G Burkhart MPH MD

Clinical Professor, Medical College of Ohio

5600 Monroe Street, Suite 106B

Sylvania, Ohio 43560

E-mail: cgbakb@aol.com

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