A. Types

1. Three Herpesvirus Families (only human viruses listed here)
   1. Alphaherpesviruses: Herpes Simplex Virus 1, HSV-2, Varicella Zoster Virus (VZV)
   2. Betaherpesviruses: Human cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), HHV-7
   3. Gammaherpesviruses: Epstein-Barr virus (EBV), herpesvirus saimiri, HHV-8
2. Herpes Simplex Virus (HSV) [2]
   1. HSV 1
   2. HSV 2
   3. Large double-stranded DNA viruses
   4. Produce at least 84 distinct proteins
   5. Proteins produced in phases as immediate early, early, and late proteins
   6. Both infect neurons and all herpesviruses can become a latent infection
   7. Mucosal surface spreading and ~4 day incubation for both HSV-1 and -2
   8. Vaccines are being developed
3. Varicella Zoster Virus (VSV)
4. Epstein Barr Virus (EBV) - summary below
5. Cytomegalovirus (CMV) - summary below
6. Human Herpesvirus (HHV) 6
   1. Exanthum subitum in infants
   2. Febrile illness, roseola
   3. May induce exacerbations in adult multiple sclerosis
7. HHV 7
   1. Febrile illness, roseola
   2. Transmitted by contact with oral secretions or breat milk
8. HHV 8 (see below)

B. Herpes Simplex Virus 1 (HSV-1) [2]

1. Disease Entities
   1. Causes oral herpetic lesions ~80% of cases; 20% genital lesions
   2. Nearly 70% of new HSV-1 infections are symptomatic [3]
   3. Main cause of "canker" sores and probably adult idiopathic aphthous ulcers
   4. In sexually active persons, rate is 1.6 cases per 100 person-years [3]
   5. HSV-1 DNA is found in ~80% of facial nerve (CN VII) endoneural fluid in Bell's Palsy [4]
   6. Causes 95% of herpetic encephalitis [5]
   7. Also causes keratoconjunctivitis (~300,000 cases per year in USA)
   8. Infrequently found in herpes proctitis and TORCHS (see below)
   9. HSV Hepatitis - rare cause of acute hepatitis, can result in fulminant hepatitis [6]
   10. Herpetic Whitlow - unusual cause of hand pain, involves fingers (see below)
2. HSV-1 is a chronic infection with long subclinical periods
   1. Reactivation disease very common, especially in immunocompromised patients
   2. Subclinical shedding is common, particularly as precursor to recurrence
   3. Seroprevalence 62% in 1988-1994 and 57.7% 1999-2004 [52]
   4. Incidence of genital herpes caused by HSV-1 may be increasing [52]
3. Viral Characteristics
   1. Spherical virus with double stranded DNA genome
   2. Icosohedral capsule and lipoprotein envelope, 150-200 nm
   3. Replication in the cell nucleus
   4. Virus establishes latent infection within sensory nerve ganglia in spinal cord
   5. Characteristics of HSV-1 and HSV-2 are similar
   6. HSV-1 has increased tropism for oral areas, HSV-2 for anogenital areas
   7. HSV-1 seroconversion in >70% of adolescents in USA
4. Oral HSV-1 Symptoms
   1. Similar to genital lesions, with pain in oral region usually resolving by 96 hours
   2. Lesions of buccal and gingival mucosa lasting 7-10 (up to 23) days
   3. Fevers up to 40°C may occur in primary, but usually not in recurrent, infections
   4. HSV infections can trigger erythema multiforme
5. Herpetic Whitlow [7]
   1. Due to HSV 1 or 2
   2. Rare condition due to autoinoculation of virus through broken skin
   3. May occur as acomplication of primary oral or genital HSV lesions
   4. Abrupt onset of edema, erythema, localized tenderness
   5. Pain out of proportion to physical findings
   6. Fever, lymphadenitis, epitrochlear and axillary lymphadenopathy may occur
   7. Small, clear vesicles are present early on
   8. May mimic felon or paronychia
   9. Usually self limited but anti-HSV agents may be given within first 48 hours
   10. Recurrence in 30-50% of cases
6. Diagnosis
   1. Appearance and distribution of lesions
   2. History of disease
   3. Tzanck preparation (smear) - methylene blue stain of ulcer base edge showing multinucleated giant cells is essentially diagnostic
   4. Multinucleated giant cells seen with HSV-1, HSV-2, CMV, Varicella Zoster, others
   5. Serologic studies only useful for previous exposure
   6. Viral culture is standard of care; usually positive within 48 hours
   7. Polymerase chain reaction (PCR) is increasingly used and is more rapid than culture
   8. PCR is standard of care for diagnosis of herpetic encephalitis
7. Treatment Overview [8]
   1. Acyclovir (Zovirax®): 400mg po tid (acute, 5-7d) or bid (prophylaxis, to 1 year)
   2. Encephalitis Therapy: acyclovir 10-15mg/kg iv q8 hours x 14-21 days (prefer 21 days)
   3. Famciclovir (Famvir®): 500mg po tid x 7 days
   4. Immunocompromised: 5mg/kg iv acyclovir q8hr
   5. Foscarnet for acyclovir resistant: Foscarnet 40mg/kg IV q8hr
   6. Valacyclovir (Valtrex®) - 1000mg po bid x 5-10 days [9]
   7. Penciclovir Cream (1%) - good for early or late orolabial herpes (cold sores) [10]
   8. Keratoconjunctivitis is trated with trifluridine (Viroptic®) drops
   9. HSV ocular disease recurrences are reduced ~50% with 400mg po bid acyclovir [11]
   10. These recommendations are for immunocompetent patients only
   11. Immunocompromised patients usually need high dose, prolonged therapies
   12. Bell's palsy may respond to glucocorticoids
8. Specific Treatments for Oral or Genital HSV (see below) [8,12]
   1. Orolabial (immunocompetent): penciclovir 1% cream q2 hour while awake x 4 d
   2. Initial Genital HSV: Acyclovir: 400mg po tid x 10d, Severe: 5mg/kg q8hr x 5d
   3. Penciclovir or acyclovir cream can reduce symptoms of oral or labial herpes
   4. Valacyclovir very convenient for orolabial HSV: 2gm po q12 hours x 1 day (2 doses) [12]
   5. Recurrent orolabial oral: Acyclovir or famciclovir or valacyclovir
   6. Recurrent genital HSV cream: penciclovir 1% [13] or docosanol 10% [14] q2 hr during day
   7. Gential Suppression: Acyclovir 400mg bid po or valacyclovir 500mg qd
   8. Daily preventive acyclovir 400mg po bid reduces subclinical shedding >90%
   9. Keratoconjunctivitis: Trifluridine (Viroptic®) 1 drop 1% solution topically q2 hours, up to 9 drops/d
9. Severe Infection / Immunocompromise
   1. Mucocutaneous (immunocompromised): acyclovir 400mg 5x d x 10 days
   2. Severe Mucocutaneous (immunocompromised): 5mg/kg q8hr IV x 7-10 days
   3. HSV Encephalitis: 10mg/kg IV q8 10-14 days

C. Herpes Simplex Virus 2 (HSV-2) [2,15]

1. Disease Entities
   1. Mainly a sexually transmitted disease (~80% of genital herpetic lesions)
   2. HSV-2 also causes ~20% of cases of oral herpes infections
   3. In sexually active persons, rate is 5.1 cases per 100 person-years [3]
   4. About 40% of new HSV-2 infections are symptomatic [3]
   5. Primary herpetic infection - genital or oral
   6. Reactivation - genital or oral
   7. Herpes proctitis, mainly in homosexual men
   8. TORCHS Disease - severe neonatal infections
   9. Herpetic Whitlow - see above for HSV1
2. There are ~150,000 office visits per year in USA for genital herpes
   1. HSV-1 accounts for ~20% of genital herpes
   2. HSV-2 accounts for ~80% of genital herpes
   3. Condoms reduce transmission of HSV-2 by 25-85% [16,51]
   4. Chronic antiviral suppression reduces transmission by 70-90% [15]
3. Serologic Studies Show High Prevalance
   1. In 1996, ~22% of of US population has serum antibodies to HSV-2 (~15% in 1980)
   2. In 1999-2004, HSV-2 seroprevalence decreased to 15.8% [52]
   3. In sexually transmitted disease clinics, seropositive rate 40-50%
   4. Women have higher seropositive (25.6%) than men (17.8%); blacks 45%, whites 17.6%
   5. In asymptomatic seropositive patients, HSV-2 shedding occurred in 72% [18]
   6. Thus, persons seropositive for HSV-2 with no history of genital herpes can shed virus
4. Primary Infection
   1. Genital HSV-2 usually transmitted by genital-genital contact
   2. Oral HSV-2 usually transmitted by oral-genital contact
   3. Systemic symptoms are common in primary HSV-1 and -2 infections
   4. First week: fever, malaise, headaches, myalgias (decreasing over second week)
   5. Lesions develop as multiple painful vesicles in 1-2 days after infection
   6. Second wave of new lesions around day 8
   7. Lesions ulcerate with 3-4 days of appearance
   8. Ulcerated lesions then crust and epithelialize over next week
   9. Tender, nonfluctuant inguinal lymphadenopathy is common in genital herpes
   10. In women, lesions usually on labia, vagina and cervix
   11. In men, lesions usually on glans and shaft of the penis
   12. In immunocompetent persons, lesions are self-resolving
   13. Meningeal (CNS infection) signs occur in ~30% of women and 10% of men
   14. Aseptic meningitis is the most common
   15. Once resolved, virus remains dormant in sensory nerve roots and can reactivate
   16. Thus, HSV-2 is typically a chronic, lifelong disease
5. Herpes Proctitis
   1. Herpes proctitis can occur in persons who participate in receptive anal intercourse
   2. Present with fever, severe anorectal pain, tenesmus
   3. Difficulty initiating urination and sacral dermatome paresthesias also common
   4. Perianal ulcers occur in ~70% of cases
   5. Inguinal lymphadenopathy is common
   6. Mucosal friability and ulcers in distal 5-10 cm of the rectum on sigmoidoscopy
6. HSV-2 and Immunodeficiency
   1. HIV-1 is also shed in genital HSV lesions in HIV-1 infected men [19]
   2. May cause severe lymphadenitis in immunocompromised patients (HIV, marrow transplant)
7. HSV (-1/-2) Transmission During Delivery [20]
   1. HSV is one of the TORCHS Diseases with ~5% transmission risk in USA
   2. Neonatal transmission of HSV (usually HSV-2) can cause fetal morbidity and death
   3. Active HSV is indication for Cesarean Section
   4. Cesarean section associated with ~1% transmission risk in seropositive women
   5. Risk of HSV transmission in seronegative women ~2X that in seropositive women
   6. This is due to late acquisition of HSV in pregnancy
8. High rate of recurrence of genital HSV-2 infection
   1. The exact causes of reactivation (recurrence) of HSV infections are not known
   2. Both environmental and genetic components are believed to play a role
   3. >85% of patients with one symptomatic episode will have another within 1 year
   4. 38% of patients had >5 recurrences and 20% had >10 recurrences
   5. Patients with initial episode >34 days had more frequent recurrences
   6. Men have ~20% more recurrences than women
   7. ~20% of patients will have non-genital recurrence, for example, buttocks
   8. Virus is shed during subclinical phase preceeding reactivation
   9. Recurrences of HSV-2 decrease slightly in frequency after >2 years of infection [22]
   10. Recurrent genital herpes is generally milder than primary disease
9. Complications of HSV Infection
   1. Transmission to an infant is the most important HSV complication
   2. Aseptic meningitis (meningoencephalitis) occurs infrequently
   3. Sacral radiculopathy, transverse myelitis, benign recurrent lymphocytic meningitis are less common than aseptic meningitis [15]
   4. Autonomic nervous system dysfunction can also occur
   5. HSV infections may be life threatening in immunodeficient patients
10. Diagnosis
    1. Appearance and distribution of lesions (clinical suspicion is key)
    2. Demonstration of multinucleated giant cells on scraping of ulcer base
    3. This is called Tzanck preparation, and uses methylene blue staining
    4. Occasionally, a Pap smear may demonstrate these multinucleated cells
    5. Type-specific serologic antibody tests are now available
    6. Serologic testing may be useful for screening and in patients with healing lesions
    7. Consider syphilis and chancroid in the differential diagnosis
11. Treatment Considerations
    1. Primary treatment is critical in severe cases and immunocompromised persons
    2. Prophylaxis for recurrence should be considered in patients at high risk
    3. Patient initiated therapy with "prodrome" symptoms is effective
    4. Treatment for HSV-1 and HSV-2 is essentially the same
12. Specific Treatments [13]
    1. Initial Genital HSV: Acyclovir: 400mg po tid x 10d, Severe: 5mg/kg q8hr x 5d
    2. Orolabial initial or recurrent HSV effectively treated with valacyclovir 2gm q12 hours x 2 doses [12]
    3. Recurrent HSV (oral agents): Acyclovir 200mg 5X/d, famciclovir 500mg bid
    4. Recurrent HSV: topical penciclovir 1% or docosanol 10% creams (5X / day) [14]
    5. Patient initiated famciclovir 125mg po bid for recurrence is effective and safe [11]
    6. Gential Suppression: Acyclovir 400mg bid po or valacyclovir 500mg qd
    7. Women with frequent recurrences: famciclovir 250mg bid x 4 months is effective [12]
    8. Immunocompromised and encephalitis as above
    9. Acyclovir resistance usually extends to famcicolovir, but usually susceptible to foscarnet or cidofovir [5]
    10. Penciclovir or acyclovir cream can reduce symptoms of oral or labial herpes
13. Prophylaxis (Chronic Suppression) of Genital HSV Recurrence [5,6]
    1. Many specialists recommend prophylaxis for 1 year after second episode
    2. Acyclovir dose is 400mg po bid for prophylaxis
    3. Famciclovir: 250mg po bid (500mg po bid for HIV infected persons [23])
    4. Valacyclovir: 500mg po qd suppresses genital HSV transmission by >75% between heterosexual partners (where one partner is seronegative) [24]
    5. Valacyclovir is approved for suppression of genital herpes transmision [24,25]
    6. Valacyclovir 500mg qd of HSV transmission 500mg po qd (~75% effective) [26]
    7. When agents are stopped, severe flare may occur, but flare frequency usually decreases
14. Vaccination [27,28]
    1. Neutralizing antibodies to HSV-2 glycoproteins B and D may be protective
    2. New vaccines based on gB2 and gD2 proteins with various adjuvants
    3. Subunit vaccines induce high titer antibodies to HSV-2
    4. Initial trials showed no benefit of vaccine on overall rates of HSV-2 acquisition [28]
    5. HSV-2 gD2 vaccine reduced HSV-2 ~40% in women seronegative for both HSV-1 and -2 [27]
    6. Vaccine was not effective in men or in women seropositive for HSV-1 or -2 [27]

D. Cytomegalovirus (CMV)

1. Opportunistic Infection
   1. Clinically apparent in immunocompromised patients and infants:
   2. HIV Infection
   3. Organ or Bone Marrow Transplantation
   4. Prolonged (usually high dose) glucocorticoid or immunosuppressive therapy
   5. TORCHS Disease (congenital transmission)
   6. Positive CMV serology indicates exposure and latent infection
2. Organ Involvement
   1. Pneumonia - interstitial pneumonitis
   2. Ocular Disease - Retinitis (ultimately leads to blindness) and Conjunctivitis
   3. CMV Encephalitis
   4. Gastrointestinal Disturbances - usually colitis
   5. Bone Marrow Infiltration - pancytopenia, high fevers
   6. CMV commonly infects liver, particularly dangerous in setting of liver transplantation
   7. CMV positivity (donor and/or recipient) predicts poor liver transplant outcome [29]
   8. May cause high fevers - usually with liver or bone marrow disease
   9. CMV seropositivity is associated with high restenosis rates post-atherectomy
3. Anti-CMV Agents [8]
   1. Prophylaxis with high-titer anti-CMV immune globulin (high risk transplant patients)
   2. Prophylaxis with oral valganciclovir [30]
   3. Treatment: ganciclovir, valganciclovir and/or Foscarnet or Cidofovir
   4. Combination ganciclovir and foscarnet may be required in severe infections

E. Epstein Barr Virus (EBV) [31]

1. Infectious mononucleosis
   1. Classical Triad: fever, pharyngitis, severe adenopathy
   2. Most often in young persons
   3. Splenomegaly, malaise, headache occur in ~50% of patients
   4. Severe symptoms: painful splenomegaly, hemolytic anemia, thrombocytopenia [32]
   5. Presence of abnormal (CTL, NK-like) T cells in peripheral blood circulation
2. Role in Neoplasia
   1. African Burkitt's Lymphoma
   2. Nasopharyngeal carcinoma
   3. Lymphomas in immunosuppressed patients (HIV, organ transplantation)
   4. Smooth Muscle Tumors - mainly children with liver transplants, HIV
   5. Hodgkin's Lymphoma - lymphocyte depleted and mixed cellularity types
3. HIV and EBV
   1. Oral Hairy Leukoplakia - seen usually in HIV infected persons. May respond to acyclovir
   2. Leimyosarcomas associated with EBV occur in children with AIDS
   3. No apparent role of EBV in HIV-negative patients with leiomyomas / leiomyosarcomas
4. Chronic Fatigue Syndrome (CFS)
   1. High prevalence of EBV positive serology in patients with CFS
   2. However, majority of normal population has EBV antibodies
   3. There is absolutely no good evidence that EBV plays a role in CFS
5. Diagnosis
   1. Heterophile antibody test detects anti-animal RBC antibodies (nonspecific but sensitive)
   2. Antibodies to EBNA-1 (Epstein-Barr Nuclear Antigen) may olso be analyzed
   3. Variety of other antibodies are detectable and sometimes useful

F. Human Herpesvirus 6 (HHV-6) [33,34]

1. Double stranded linear DNA which encodes more than 70 proteins
   1. Includes viral polymerase, ribonucleotide reductase, and usually thymidine kinase
   2. Nucleotide ~60% similarity to CMV
   3. Two forms, A and B, have been identified
2. Over 75% of infants are infected in first 2 years of life
   1. 90% of these are symptomatic
   2. Over 10% of emergency room visits for febrile illness due to HHV-6
   3. Peak age of incidence 6-9 months
3. Symptoms in Immunocompetent Infants and Children [34]
   1. Most commonly associated with febrile illness
   2. About 20% of HHV-6 are associated with Roseola
   3. Gastrointestinal symptoms are not uncommon
   4. Neuronal tropism is prominant in infants
   5. Bulging fontanelle, meningoencephalitis and febrile seizures may occur infrequently
4. Causes 25% of heterophile negative infectious mononucleosis
5. Symptoms in immunocompromised persons
   1. Appears to be responsible for roseola (exanthum subitum) in normal children
   2. May be associated with Kaposi's Sarcoma in minority of cases
   3. Common in organ and bone marrow transplant patients
   4. Disseminated infection may occur, usually 3-4 weeks after transplant
   5. Main effect is bone marrow suppresion, particularly of leukocytes
   6. High fevers (>40°C) are not uncommon
6. Detected by PCR, serologic analysis, or culture (which requires 8-20 days)
7. Ganciclovir and Foscarnet are effective against HHV-6

G. Human Herpesvirus 7 (HHV-7) [1,34]

1. Closely related to HHV-6, but primarily infects CD4+ T cells
2. Up to 75% of healthy adults have HHV-7 in their saliva
3. 100% of adults are seropositive for HHV-7 antibodies
4. Contact with oral secretions or breast milk
5. Associated with several cases of Roseola

H. Human Herpesvirus 8 (HHV-8) [35,36]

1. Allso called Kaposi Sarcoma Associated Herpesvirus (KSHV)
   1. HHV-8 may be propagated from KS cells in vitro [37]
   2. Seropositivity for HHV-8 is strongly associated with KS [38]
2. Certain pathologies may be initiated or caused by HHV-8 [39]
   1. Kaposi's Sarcoma (KS) [21,38]
   2. AIDS-Related Lymphomas
   3. Sarcoidosis
   4. Relapsing inflammatory syndrome [50]
   5. Non-Hodgkin B cell lymphomas (mainly primary effusion lymphoma)
   6. Castleman's Disease (multicentric) [21]
   7. Mediterranean Kaposi Sarcoma (non-HIV)
   8. Bone marrow failure (after solid organ or peripheral stem cell transplantation) [11]
   9. Primary pulmonary Hypertension [41]
3. Properties [36]
   1. Genome is 165kb
   2. HHV-8 has clearly incorporated several human genes into its genome
   3. These genes include a cyclin, bcl-2 like protein, inhibitor of apoptosis, G-protein coupled receptor, immunoreceptor, IL-6 homolog, inhibitor of interferon signalling
   4. Viral cyclin inhibits the retinoblastoma protein (Rb)
   5. The major latency-associated nuclear antigen of HHV-8 binds to and blocks p53 protein
   6. Viral IL-6 induces B-cell proliferation (only expressed in infected B cells)
   7. Viral chemokines appear to activate angiogenesis and inhibit type 1 T cell responses
   8. The HHV-8 viral interferon regulatory factor blocks interferon from repressing c-myc
   9. Thus, all major cell cycle checkpoint control pathways are altered in HHV-8 infection
4. Transmission
   1. Seropositivity rates <3% in US and Europe, ~25% in Mediterranean and African countries
   2. Primarily male homosexual transmission through receptive anal intercourse [38]
   3. Infectious HHV-8 is found in mucosal (oral) secretions in HHV-8 positive homosexual men [42]
   4. Blood transfusion (HHV-8+ blood into HHV-8 negative recipient) associated with excess low risk (~2.8%) of seroconversion [17]
   5. Overall very low risk of parenteral transmission
   6. Risk factors in women include injection drug abuse, HIV, and correlates of sexual activity [43]
   7. HHV-8 antibodies are also found in sexually inactive children
   8. Mother to child and sib-sib transmission in early years is most likely cause of this [44]
5. HHV-8 and KS [21]
   1. Average levels of HHV-8 are higher in HIV+ than in HIV- persons [39]
   2. Average HIV+ patient seropositive for HHV-8 develops KS within 33 months
   3. Among men with HIV and HHV-8, 10 year probability of KS was ~50% [45]
   4. These data obtained prior to broad use of highly active antiretroviral therapy (HAART)
   5. Renal transplant donors can transmit HHV-8, eventually causing KS [46]
   6. HHV-8 levels have not declined over past 20 years but KS rates have declined [47]
   7. Therefore, KS development requires HHV-8 infection in setting of immunosuppression
6. Relapsing Inflammatory Syndrome [50]
   1. Immunocompetent adult
   2. Fever, lymphadenopathy, splenomegaly, edema, arthrosynovitis, rash
   3. Kaposi's sarcoma developed after 10 months
   4. Antiviral treatment with foscarnet or cidofovir suppressed HHV-8 and KS lesions
7. Multicentric Castleman Disease (MCD) [21,35]
   1. Angiofollicular lymphoid hyperplasia
   2. Nonmalignant, usually polyclonal lymphomadenopathy
   3. MCD is systemic with aggressive course, usually fatal
   4. HHV-8 sequences found in all HIV+ and ~50% HIV- cases of MCD
   5. HHV-8 viral load in peripheral blood correlates with disease progression
8. HHV-8 and Sarcoid [36]
   1. Sarcoid is a non-caseating granulomatous disease
   2. HHV-8 DNA has been in essentially all tested sarcoid biopsy samples in one study [48]
   3. HHV-8 was not found in the vast majority of control tissue samples tested
9. AIDS Related Atypical Lymphomas [35]
   1. HHV-8 related sequences are also found in unusual lymphomas from AIDS patients
   2. Usually body cavity based lymphomas with effusions (primary effusion lymphoma)
   3. Most are large B cell lymphomas in persons age 25-45 years
   4. Most are also positive for EBV DNA in tumor genomes
   5. Clinical outcome is typically fatal
10. Primary HHV-8 Infection in Immunocompetent Children [26]
    1. Well documented infection in normal children
    2. Maculopapular skin rash with fever
    3. HHV-8 DNA found in saliva
    4. Patients are seropositive
11. HHV-8 DNA sequences in Healthy Adults
    1. Mainly found in healthy men's prostate tissue (44%) and ejaculate (91%)
    2. Isolated from <10% of peripheral blood, and in <10% of female genital tracts
12. Drugs with Anti-HHV-8 Activity
    1. Ganciclovir, foscarnet and cidofovir all have in vitro activity against HHV-8
    2. Oral or IV ganciclovir reduces risk of Kaposi's sarcoma in HIV+ persons >75% [49]

References

1. Prober C. 2005. NEJM. 352(8):
2. Whitley RJ and Roizman B. 2001. Lancet. 357(9267):1513
3. Langenberg AGM, Corey L, Ashley R, et al. 1999. NEJM. 341(19):1432
4. Gilden DH. 2004. NEJM. 351(13):1323
5. Crumpacker CS, Gonzalez RG, Makar RS. 2003. NEJM. 349(8):789 (Case Record)
6. Bliss SJ, Moseley RH, Del Valle J, Saint S. 2003. NEJM. 349(19):1848 (Case Discussion)
7. Clark DC. 2003. Am Fam Phys. 68(11):2167
8. Drugs for Non-HIV Viral Infections. 2002. Med Let. 44(1123):9
9. Valacyclovir. 1996. Med Let. 38(965):3
10. Spruance SL, Rea TL, Thoming C, et al. 1997. JAMA. 277(17):1374
11. Herpetic Eye Disease Study Group. 1998. NEJM. 339(5):300
12. Valacyclovir for Herpes Labialis. 2002. Med Let. 44(1143):95
13. Topical Penciclovir for Herpes Labialis. 1997. Med Let. 39(1003):57
14. Docosanol Cream. 2000. Med Let. 42(1092):108
15. Kimberlin DW and Rouse DJ. 2004. NEJM. 350(19):1970
16. Wald A, Langenberg AGM, Link K, et al. 2001. JAMA. 285(24):3100
17. Hladik W, Dollard SC, Mermin J, et al. 2006. NEJM. 355(13):1331
18. Wald A, Zeh J, Selke S, et al. 2000. NEJM. 342(12):844
19. Schacker T, Ryncarz AJ, Goddard J, et al. 1998. JAMA. 280(1):61
20. Brown ZA. Morrow RA, Selke S, et al. 2003. JAMA. 289(2):203
21. Scadden DT, Muse VV, Hasserjian RP. 2006. NEJM. 355(13):1358 (Case Record)
22. Benedetti JK, Zeh J, Corey L. 1999. Ann Intern Med. 131(1):14
23. Schacker T, Hu H, Koelle DM, et al. 1998. Ann Intern Med. 128(1):21
24. Corey L, Wald A, Patel R, et al. 2004. NEJM. 350(1):11
25. Crumpacker CS. 2004. NEJM. 350(1):67
26. Andreoni M, Sarmati L, Nicastri E, et al. 2002. JAMA. 287(10):1295
27. Stanberry LR, Spruance SL, Cunningham AL, et al. 2002. NEJM. 347(21):1652
28. Corey L, Langenberg AGM, Ashley R, et al. 1999. JAMA. 282(4):331
29. Falagas ME, Snydman DR, Griffith J, et al. 1997. Ann Intern Med. 126(4):275
30. Martin DF, Sierra-Madero J, Walmsley S, et al. 2002. NEJM. 346(15):1119
31. Cohen JI. 1997. JAMA. 278(6):510
32. Greene WL and Craft J. 1997. Lancet. 349:696 (Case Report)
33. Zerr DM, Meier AS, Selke SS, et al. 2005. NEJM. 352(8):768
34. Hall CB. 1997. Ann Intern Med. 127(6):481
35. Sarid R, Klepfish A, Schattner A. 2002. Mayo Clin Proc. 77:941
36. Antman K and Chang Y. 2000. NEJM. 342(14):1027
37. Foreman KE, Friborg J, Kong WP, et al. 1997. NEJM. 336(3):163
38. Sitas F, Carrara H, Beral V, et al. 1999. NEJM. 340(24):1863
39. Cesarman E. 2003. NEJM. 349(12):1107
40. Luppi M, Barozzi P, Schulz TF, et al. 2000. NEJM. 343(19):1380
41. Cool CD, Rai PR, Yeager M, et al. 2003. NEJM. 349(12):1113
42. Pauk J, Huang ML, Brodie SJ, et al. 2000. NEJM. 343(19):1369
43. Cannon MJ, Dollard SC, Smith DK, et al. 2001. NEJM. 344(9):637
44. Plancoulaine S, Ab el L, van Beveren M, et al. 2000. Lancet. 356(9235):1062
45. Martin JN, Ganem DE, Osmond DH, et al. 1998. NEJM. 338(14):948
46. Regamey N, Tamm M, Wernli M, et al. 1998. NEJM. 339(19):1358
47. Osmond DH, Buehbinder S, Cheng A, et al. 2002. JAMA. 287(2):221
48. Di Alberti, Piatelli A, Artese L, et al. 1997. Lancet. 350(9091):1655
49. Martin DF, Kuppermann BD, Wolitz RA, et al. 1999. NEJM. 340(14):1063
50. Dagna L, Broccolo F, Paties CT, et al. 2005. NEJM. 353(2):156
51. Wald A, Langenberg AGM, Krantz E, et al. 2005. Ann Intern Med. 145(10):707
52. Xu F, Sternberg MR, Kottiri BJ, et al. 2006. JAMA. 296(8):964