Infectious Diseases & Dermatology & Neurology & Family Medicine
Herpes PCR (HSV-1 and HSV-2)
Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are double-stranded DNA viruses of the Herpesviridae family, characterized by their ability to establish a lifelong latent infection in sensory ganglia after primary infection, with periodic symptomatic or asymptomatic reactivations. PCR (polymerase chain reaction) has become the reference test for the diagnosis of all forms of HSV infection - definitively supplanting viral culture, Tzanck cytology and serology in most clinical contexts - due to its far superior sensitivity (90-100 %), near-absolute specificity (99-100 %), rapidity (results in 2-6 hours for multiplex panels) and ability to differentiate HSV-1 from HSV-2. HSV PCR on cerebrospinal fluid (CSF) is indispensable in the diagnosis of herpes encephalitis - the most frequent cause of fatal sporadic viral encephalitis in developed countries - where one hour's delay in IV aciclovir can definitively compromise the neurological prognosis. PCR on genital, urethral, cervical or anal swabs is the method of choice for diagnosing genital herpes, replacing Vero cell culture, whose sensitivity fell to 30-50 % in the healing phase. Type-specific serology (gG-based serology) has a distinct place in partner screening and management, but should not be used as a replacement for PCR for the diagnosis of an active clinical episode.
Virology, epidemiology, and pathophysiology
- Viral biology and mechanisms of latency and reactivation: structure and biology : HSV-1 and HSV-2 = enveloped viruses with 152 kb linear double-stranded DNA → family Herpesviridae (subfamily Alphaherpesvirinae) → 11 envelope glycoproteins (gB + gC + gD + gE + gG + gH + gI + gJ + gK + gL + gM) → gD = main fusion protein and target of neutralizing antibodies → gG = glycoprotein type-specificity → gG-1 vs gG-2 → basis for type-specific serological tests → replication cycle : attachment via gB/gC to heparan sulfates + binding of gD to entry receptors (nectin-1 + nectin-2 + HVEM + 3-O-sulfate HS) → envelope fusion → internalization of nucleocapsid → transport to nucleus → viral DNA replication → budding release + retrograde axonal transport to sensory ganglia → latency; latency mechanisms in sensory ganglia: retrograde axonal transport of virion along axons → trigeminal ganglion (HSV-1) or sacral ganglion S2-S4 (HSV-2) → circularization of viral DNA → formation of episomes in neuronal nuclei → limited transcription of LATs (Latency-Associated Transcripts) → non-coding RNAs → inhibit neuronal apoptosis → maintain latency → reactivation mechanisms: triggering stimuli: psychological stress + immunosuppression + UV (herpes labialis) + fever + microtrauma (sexual intercourse → genital herpes) + menstruation + trigeminal ganglion surgery → anterograde axonal transport → replication in skin or mucosal epithelia → symptomatic or asymptomatic viral shedding → Spruance 1977 - Lancet: pathophysiological model of the HSV latency-reactivation cycle → Bloom 2010 - Journal of Neurovirology: molecular mechanisms of HSV latency + role of LATs; global and Canadian epidemiology: HSV-1 seroprevalence: 67 % of world population (Looker 2015 - PLOS ONE: WHO meta-analysis → 3.7 billion people under 50 years of age HSV-1 carriers) → genital HSV-1: 30-50 % of genital primary infections in high-income countries → increase in young adults (decrease in oral exposure in childhood) → HSV-2 seroprevalence: 11 % worldwide (Looker 2015 - PLOS ONE) → 491 million carriers aged 15-49 → Canada: HSV-2 seroprevalence ≈ 14-16 % adults → HSV-1 seroprevalence ≈ 60-67 % adults → asymptomatic viral shedding (AVE): key mechanism of transmission → Tronstein 2011 - JAMA: 9 % of days → HSV-2 excreted asymptomatically → 76 % of excretion is asymptomatic → up to 5 daily micro-short (<6h) episodes → responsible for the majority of transmissions because the source partner is asymptomatic → Schiffer 2010 - PLOS Medicine: modeling asymptomatic excretion → fountain model (fountain model) → multiple daily reactivations of short duration → biological differences HSV-1 vs HSV-2: HSV-2 → frequency of genital recurrences 5.1 recurrences/year vs genital HSV-1 1.3 recurrences/year (Langenberg 1999 - Annals of Internal Medicine) → HSV-2 → more frequent asymptomatic excretion → HSV-1 → more frequent in encephalitis + recurrent herpes labialis → different neurotropism + different antiviral resistances (TK-mutations for aciclovir - more frequent under immunosuppression)
- Clinical manifestations by type and location: orofacial herpes (HSV-1 predominant): primary infection (herpetic gingivostomatitis): children 1-5 years + young adults → vesicles + painful erosions on gingiva + oral mucosa + palate + lips + cervical adenopathies + fever + dysphagia + duration: 7-14 days + 10-15 % of symptomatic primary infections → recurrent herpes labialis (cold sore): vesicles clustered at labial mucocutaneous junction → 5 phases: prodrome (1-2d) + vesicular (2-3d) + pustular + ulcerative + healing → total duration: 8-10 days + recurrences: 1-6/year on average → triggers: UV + stress + fever + menstruation + local trauma → ocular herpes: dendritic keratitis (fern-leaf corneal ulcer) + conjunctivitis + uveitis → HSV-1 = leading cause of infectious corneal blindness in developed countries (Wilhelmus 2008 - Cochrane) → herpetic panariasis (herpetic whitlow): finger ± in caregivers or nail-drinkers; genital herpes (HSV-2 predominant but HSV-1 increasing): genital primary infection: often asymptomatic (60-80 %) or not very typical → if symptomatic: vesicles + painful erosions on penis + vulva + vagina + cervix + perineal + anorectal region + aseptic meningitis (15-30 % of HSV-2 primary infections) → urinary retention syndrome + 20-40 days resolution → prolonged viral excretion + recurrences : HSV-2 genital → 5-7 recurrences/year on average in the first few years → HSV-1 genital → 1-3 recurrences/year + prodromes (burning + tingling) 12-24h before → prevalence of atypical manifestations (fissure + erythematous papule + pain without visible lesion) → frequent underdiagnosis; severe forms and complications: herpetic encephalitis: HSV-1 involved in 90 % of cases + life-threatening neurological emergency → fever + behavioral disorders + olfacto-gustatory hallucinations + headaches + disorientation → temporal localization (temporal gyrus + insula + cingulate) → Whitley 1982 - NEJM: IV aciclovir vs vidarabine in herpetic encephalitis → mortality reduced by 70 % → 28 % (aciclovir) vs 54 % (vidarabine) → time to treatment = major prognostic factor → if treatment within first 4 days: mortality 1 month = AIDS criterion)
Diagnostic by PCR, serology, and treatment
| Domain | Data, modalities, and criteria | Key studies and recommendations |
|---|---|---|
| PCR HSV — methods, sample collection, and diagnostic performance Real-time PCR — multiplex — LCR — genital sample — swabbing — HSV-1/HSV-2 differentiation — false negatives — sensitivity/specificity |
HSV PCR methods available: quantitative or qualitative real-time PCR (qPCR): reference method → amplification of a conserved region of the HSV genome (glycoprotein B genes or DNA polymerase - UL30) → TaqMan or SYBR Green probes → results in 2-4h → sensitivity: 95-100 % → specificity: 99-100 % → HSV-1/HSV-2 differentiation by type-specific probes → viral load quantification possible (useful in encephalitis and monitoring of the immunocompromised) → multiplex PCR on CSF (example: BioFire FilmArray Meningitis/Encephalitis Panel): simultaneous detection of 14 agents (HSV-1 + HSV-2 + CMV + HHV-6 + EBV + VZV + enterovirus + parechovirus + meningeal bacteria) → results in 1h → very useful in emergencies → but: sensitivity slightly lower than conventional PCR for some rare agents → high cost → viral culture (historical method): Vero cells or human diploid cells → EPC (cytopathogenic effect) visible in 2-7d → sensitivity: 70-85 % in vesicular phase → 30-50 % in healed ulcer phase → abandoned in practice in favor of PCR → useful if antiviral resistance suspected (viral antibiogram) → Tzanck cytology: multinucleated giant cells (Cowdry type A intranuclear inclusion) → sensitivity: 50-70 % → very unspecific (does not differentiate HSV from VZV) → only in limited resources → direct immunofluorescence (DIF): fluorescent monoclonal antibodies + sensitivity: 70-85 % + gradual abandonment in favor of PCR; types of samples and preanalytical conditions: lesion sampling (mucocutaneous herpes) : dacron or nylon swab (no cotton - PCR inhibitors) → rub the base of the lesion vigorously (ruptured blister or active ulcer) → place in Universal Transport Medium (UTM) or PBS → store at +4°C → analyze within 48-72h → sensitivity decreases sharply if lesion is healing → frequent false negatives if : crusty lesion + delay between sampling and analysis + poor technique (insufficient superficial sampling) + insufficient volume → CSF sampling (meningitis + herpetic encephalitis): lumbar puncture → CSF in a sterile tube → HSV PCR on CSF: reference method → sensitivity: 96-98 % + specificity: 99 % → Aurelius 1993 - Lancet: PCR on CSF → diagnostic revolution in herpetic encephalitis → replaces brain biopsy as gold standard → do not delay aciclovir while waiting for PCR → result may be falsely negative if: sampling <72h after onset of symptoms + rare but documented early false negative → repeat LP at 48-72h if strong clinical suspicion and first negative result → genital sampling: urethral swab (male) + cervical or vaginal swab (female) + swab of visible lesions → PCR on desquamated cells → do not use lubricating gel (PCR inhibitor) + rectal or anal swab if anal herpes suspected → PCR on oral or pharyngeal lesions → direct swabbing; comparative sensitivity of methods according to lesion stage: vesicular phase: PCR = 100 % + culture = 85 % + Tzanck = 70 % → ulcerative phase: PCR = 95 % + culture = 60 % → scabby phase: PCR = 70 % + culture = 30 % → healed lesion: PCR = 40 % (residual DNA) + culture = 0 % → PCR is 3-5× more sensitive than culture on lesions in regression phase → saliva sample / genital secretion without visible lesion: EVA (asymptomatic viral excretion) → PCR detects EVA → does not immediately predict contagiousness as quantities are small → epidemiological value + useful in serodiscordant couple workup + Wald 2001 - JAMA: asymptomatic HSV-2 excretion → detected in 28 % of specimens in HSV-2 seropositive women without symptoms → antiviral resistance workup: culture + antibiogram (IC50 aciclovir) → mutations in the TK gene (UL23) or DNA polymerase (UL30) → indication: clinical resistance (persistent lesions on aciclovir after 14-21d in the immunocompromised) → alternative treatment: foscarnet + cidofovir | Fundamental data on diagnostic performance: Aurelius 1993 - Lancet: CSF PCR in herpetic encephalitis → sensitivity 96 % + specificity 99 % → diagnostic revolution → abandons brain biopsy as gold standard → Corey 1992 - Sexually Transmitted Diseases: PCR vs culture for diagnosis of genital herpes → PCR 3-5× more sensitive on lesions in regression phase → Wald 1995 - Annals of Internal Medicine: lesion PCR = reference method for genital herpes → sensitivity 98 % in active phase → Wald 2001 - JAMA: asymptomatic HSV-2 shedding → 28 % of PCR-positive specimens in symptomless HIV-positive women → serodiscordant couple workup → Tronstein 2011 - JAMA (prospective cohort): 9 % of HSV-2 days excreted + 76 % asymptomatic excretion → PCR is the essential tool for VAS measurement + IDSA 2015: PCR = test of choice for all HSV syndromes → replaces culture + CDC 2021 STI Guidelines: PCR on genital lesion or swab → reference test for genital herpes → type-specific (gG) serology reserved for asymptomatic screening + STI national guidelines Canada 2022 (PHAC): HSV PCR = test of choice in Canada |
| HSV Type-Specific Serology (gG-based) — Role and Limitations IgG HSV-1 — IgG HSV-2 — reactivity index — serological window — false positives — asymptomatic screening — serodiscordant couple |
Type-specific gG-based serology - principles: detects IgG against the glycoprotein G of HSV-1 (gG-1) and HSV-2 (gG-2) → the two antigens are sufficiently different to allow reliable distinction between serotypes → methods: ELISA (HerpeSelect 2 Focus Diagnostics + Captia Herpes Select + Trinity Biotech) → immunoblot (Kalon HSV-2) → results expressed as index of reactivity (IR): for HerpeSelect ELISA → IR ≥1,10 = positive → IR 1,10-3,49 = gray area → IR ≥3,50 = strong positive → problem of false positives in the gray area (IR 1,10-3,49) → confirmations recommended by Western blot or immunoblot (Johnston 2016 - Sexually Transmitted Infections: false positive in 50-80 % of IRs between 1.10 and 3.49 if low prevalence) → HSV-2 serology does not provide information on site of infection or active nature → serological window: anti-HSV IgG appear 2-12 weeks after primary infection → a negative result within the first 12 weeks does not exclude infection → do not use serology to diagnose an acute episode + current role of type-specific serology: asymptomatic screening in high-risk individuals (MSM + UDIV + multiple partners + history of STI) → assessment of serodiscordant couple: identify source partner + adapt prevention measures → pregnant woman with HSV-2 seropositive partner: screening to assess risk of periconceptional acquisition → patients with atypical picture whose diagnosis of genital herpes is suspicious but without active lesion → decision on suppressive therapy → USPSTF 2023: routine screening for HSV-2 by serology is not recommended in the asymptomatic general population without risk factors → serology is recommended in the clinical contexts listed above → HSV IgM: not recommended → does not reliably distinguish primary infection and reactivation → often false positive by cross-reactivity + not type-specific → to be avoided; interpretation of common serological profiles: HSV-1 IgG + / HSV-2 IgG - : HSV-1 seropositivity only → oral infection in childhood in most cases → an episode of genital herpes in this context → genital HSV-1 primary infection possible + HSV-2 IgG + : HSV-2 infection (most often genital) → suppressive therapy to be considered + preventive measures → both positive : double seropositivity → very frequent (50-60 % of sexually active adults in certain populations) + HSV-1 IgG - / HSV-2 IgG - : uninfected → susceptible → preventive counseling + HSV-2 IgG in the gray area (IR 1.10-3.49) → confirm by Western immunoblot before concluding | Fundamental data on serology: Johnston 2016 - Sexually Transmitted Infections: HerpeSelect ELISA in IR 1.10-3.49 → false positives 50-80 % if low prevalence → confirmation by immunoblot recommended → Looker 2015 - PLOS ONE (WHO meta-analysis): worldwide HSV-1 seroprevalence: 67 % + HSV-2: 11 % → 3.7 billion and 491 million carriers respectively → Wald 2005 - NEJM: suppressive treatment with valaciclovir → reduction of HSV-2 transmission to serodiscordant partners by 48 % → demonstration that serology + suppression are a prevention strategy + Tronstein 2011 - JAMA: HSV-2 VAS → 9 % days + 76 % asymptomatic → serology identifies asymptomatic carriers → preventive measures → USPSTF 2023: no routine HSV-2 screening by serology in general population → but in high-risk settings + Langenberg 1999 - Annals of Internal Medicine: HSV-2 genital recurrences 5.1/year vs HSV-1 genital 1.3/year → basis for suppressive therapy decision according to type → CDC 2021 STI Guidelines + STI Canada 2022 (PHAC): serology algorithm in STI → validated contexts of use |
| Antiviral Treatment — Acyclovir, Valacyclovir, Famciclovir, and Special Situations Acyclovir — Valacyclovir — Famciclovir — Encephalitis — Neonatal — Genital — Suppressive — Pregnancy — Immunocompromised — Resistance — Foscarnet |
Mechanism of action of anti-HSV antivirals: aciclovir (aciclovir = ACV + valaciclovir = aciclovir prodrug × 3-5 best oral bioavailability + famciclovir = penciclovir prodrug) : viral TK (thymidine kinase) phosphorylates aciclovir to aciclovir monophosphate → cellular kinases add 2nd and 3rd phosphates → aciclovir triphosphate → guanosine triphosphate (GTP) competitor → incorporation into growing viral DNA by viral DNA polymerase (UL30) → DNA chain termination (absence of the 3'-OH group) → viral DNA polymerase is 10-30× more sensitive to inhibition by aciclovir triphosphate than cellular DNA polymerase → very good therapeutic index → no toxicity on uninfected cells + resistance : TK gene mutation (UL23) → non-functional TK → no phosphorylation → resistance → or DNA polymerase mutation (UL30) → less frequent → treatment of resistance : foscarnet (direct inhibitor of viral DNA polymerase - no need for TK phosphorylation) + or cidofovir (nephrotoxic); treatment of herpetic encephalitis - absolute emergency: aciclovir IV 10 mg/kg × 3/d × 14-21 days (in immunocompetent adults) → adjustment according to renal function (longer interval if CKD) → Whitley 1986 - NEJM : IV aciclovir vs vidarabine → mortality 28 % vs 54 % → aciclovir = standard of care since 1986 → Raschilas 2002 - Annals of Neurology: prognostic factors in herpetic encephalitis → time to treatment + age + Glasgow score on admission → treatment before D4 = major protective factor → if strong clinical suspicion + inflammatory CSF → start IV aciclovir WITHOUT waiting for PCR result (early treatment takes priority over confirmation) → assess response at D7 by control CSF PCR → duration 21 days if severe or immunocompromised → oral relay (valaciclovir 2 g × 3/d × 3 months in some postencephalitis protocols); treatment of genital herpes: primary infection: aciclovir 400 mg × 3/d × 7-10d OR valaciclovir 1 g × 2/d × 7-10d OR famciclovir 250 mg × 3/d × 7-10d → Mertz 1984 - NEJM: aciclovir in primary genital infection → reduction in duration of symptoms from 5 to 8 days + reduction in duration of viral excretion → standard of care since the 1980s → symptomatic recurrence (episodic treatment): valaciclovir 500 mg × 2/d × 3-5d OR aciclovir 800 mg × 3/d × 2d (short regimen) OR famciclovir 1,000 mg × 2/d × 1d (single dose) → to be initiated within 24 h of prodrome or appearance of lesions → continuous suppressive therapy: valaciclovir 500 mg/d × 12 months (or indefinite) → indicated if: ≥6 recurrences/year + or reduction in transmission to HIV-negative partner + or anxiety related to recurrences + or pregnancy → Reitano 1998 - Journal of Infectious Diseases: valaciclovir 500 mg/d → reduction in recurrences by 80 % + reduction in VAS → Wald 2005 - NEJM (PARTNERS study): valaciclovir 500 mg/d in serodiscordant couple → reduced transmission by 48 % + reduced recurrences by 79 % → dual role (suppressive + transmission preventive) → Strauss 1984 - NEJM: first trial suppressive aciclovir in genital → reduction in recurrences + feasibility; recurrent herpes labialis (topical + oral aciclovir): topical aciclovir (Zovirax cream): reduces duration from ½ to 1 day → modest efficacy + Spruance 2003 - Antimicrobial Agents and Chemotherapy: valaciclovir 2 g × 2 taken 12h apart → single dose → reduction in lesion duration by 1.5 days + abortive effect of the episode in 40 % of cases → taken as soon as prodrome → famciclovir 1,500 mg single dose (Spruance 2006 - JAMA) → penciclovir cream (Denavir): Spruance 1997 - JAMA → reduced duration; neonatal herpes (Kimberlin 2001 - NEJM CASG 103): aciclovir IV 60 mg/kg/d divided into 3 doses × 14-21 days → depending on form → disseminated or CNS form: 21 days → after IV: suppressive oral aciclovir 300 mg/m²/dose × 3/d × 6 months → significant improvement in survival + neurological development; pregnancy and herpes → prevention of neonatal transmission: woman with primary HSV infection in late pregnancy (3rd trimester): aciclovir 400 mg × 3/d from 36 SA → reduction of viral excretion at the time of delivery → or Caesarean section if active lesions in labor + woman with recurrence of genital HSV herpes in late pregnancy: aciclovir 400 mg × 3/d from 36 SA → ACOG 2020 + SOGC 2008 → recommendation to reduce the risk of neonatal transmission + woman with active lesions at the time of labor → cesarean section recommended → no contraindication to breastfeeding if no lesions in the breast; immunocompromised (HIV + transplant patients + chemotherapy): high-dose IV or oral aciclovir → valaciclovir 1 g × 2/d → antiviral prophylaxis indicated if CD4 <200 or profound immunosuppression → Gnann 2012 - NEJM: aciclovir IV + immunosuppressed with disseminated herpes → reduced mortality + Kimberlin 1996 - Journal of Infectious Diseases: resistance to aciclovir in immunosuppressed patients → foscarnet 40-60 mg/kg × 3/d IV → cidofovir 5 mg/kg IV qwk × 2 with hydration and probenecid | Fundamental data on treatment: Whitley 1982 - NEJM: aciclovir IV vs vidarabine in herpetic encephalitis → mortality 28 % vs 54 % → aciclovir = absolute standard + Whitley 1986 - NEJM: confirmation of superiority → therapeutic revolution → Raschilas 2002 - Annals of Neurology (n=93 encephalitis): treatment delay <4d → major prognostic factor → treatment without waiting for PCR if strong suspicion + Mertz 1984 - NEJM: aciclovir in genital primary infection → reduction in duration from 5-8 days → founder + Reitano 1998 - JID: valaciclovir 500 mg/d suppressive → -80 % recurrences + Wald 2005 - NEJM (PARTNERS trial): valaciclovir 500 mg/d + serodiscordant couple → -48 % transmission → demonstration of preventive role + Spruance 2003 - AAC: valaciclovir 2 g × 2 doses → abortion 40 % labial episode → Kimberlin 2001 - NEJM (CASG 103): aciclovir IV 60 mg/kg/d neonatal → reduced disseminated mortality + better neurological development + 6-month suppression → ACOG 2020 + SOGC 2008: suppressive aciclovir from 36 SA if history of genital herpes + CDC 2021 STI Guidelines + STI Canada 2022 ASPC: recommendations for episodic + suppressive + pregnancy prophylaxis treatment |
| Prevention, partner screening, and special situations Condom — HSV PrEP — Transmission — Serodiscordant Couple — HIV + HSV — Mollaret's Meningitis — Ocular Herpes — Informed Consent |
Prevention of HSV transmission: condom: reduces transmission risk by 50 % (Wald 2001 - JAMA) → but protection is incomplete as lesions or asymptomatic excretion may be present in areas not covered by the condom (perineum + pubis + buttock + periscrotal skin) → suppressive treatment with valaciclovir: additional 48 % reduction in transmission (Wald 2005 - NEJM PARTNERS trial) → combination condom + valaciclovir → estimated >90 % reduction in transmission by modeling → abstinence during active episodes (symptoms + visible lesions) + counseling on asymptomatic shedding → asymptomatic patient may transmit unknowingly → Tronstein 2011 - JAMA: asymptomatic transmission in the majority of cases → patient education essential → HSV vaccine: Simplirix (GSK - adjuvanted gD-2 vaccine) : HERPEVAC Trial (Stanberry 2002 - NEJM): efficacy 73 % in doubly seronegative women (HSV-1- and HSV-2-) → no protection in HSV-1+ men or women → partial and short-lived efficacy → not marketed → 2nd and 3rd generation vaccines in trials (DNA + recombinant proteins + mRNA) → no vaccine available in Canada in 2026 + management of serodiscordant couple: identify source partner → type-specific serology of both partners → if seronegative receiving partner → counseling + suppressive treatment of source partner + condom + avoid intercourse during outbreaks → discuss voluntary reporting (no legal requirement to report genital herpes in Canada); HSV-2 and HIV - major bidirectional interaction: HSV-2 → increases the risk of HIV acquisition by 2-3× (Wald 2009 - Current Opinion in Infectious Diseases) → mechanism: genital erosions and ulcerations → HIV entry doors + reactivation of HIV replication at HSV foci of inflammation → HIV patient + HSV-2 → increased HIV viral load in genital secretions during HSV episodes → HSV-2 suppressive therapy in HIV+ patients: reduces HSV shedding + slightly lowers HIV viral load + Celum 2010 - NEJM (HPTN 039): aciclovir 400 mg × 2/d in HSV-2/HIV-positive patients → reduced HIV acquisition by 7 % (not significant) → aciclovir alone is insufficient to prevent HIV acquisition → HIV PrEP remains the strategy of choice + Barnabas 2016 - NEJM: valaciclovir + HIV positive + HSV-2 → reduction of HSV episodes + modest lowering of HIV viral load → but no effect on HIV transmission; Mollaret meningitis (recurrent HSV-2 meningitis): recurrent episodes of lymphocytic aseptic meningitis + fever + meningismus + headache → duration 3-5d per episode + several episodes over years → pathognomonic: Mollaret cells (large endothelial cells in CSF - historical observation not pathognomonic in reality) → diagnosis: HSV-2 PCR on CSF during an acute episode → treatment: aciclovir IV or oral × 5-7d per episode + valaciclovir prophylaxis 500-1,000 mg/d if frequent episodes → favorable prognosis → ocular herpes - herpetic keratitis: HSV-1 as main cause → dendritic keratitis (fern-leaf epithelial ulcer) → treatment: ophthalmic aciclovir 3 % ointment × 5/d × 10-14d + or ganciclovir ophthalmic gel 0.15 % × 5/d + or trifluridine eye drops (Viroptic) → CONTRAINDICATION of ocular topical corticoids in the absence of antiviral (aggravation of corneal herpes) → Wilhelmus 2008 - Cochrane: trifluridine + IDU + aciclovir → comparable efficiencies for epithelial keratitis → stromal ocular herpes (stromal keratitis - immune lesion) → corticoids + oral antiviral → ophthalmic opinion + suppressive therapy: aciclovir 400 mg × 2/d → prevention of recurrences + HEDS Trial (Herpetic Eye Disease Study - Wilhelmus 1994 - Archives of Ophthalmology): oral aciclovir → 41 % reduction in ocular recurrences → recommended if frequent recurrences | Fundamental data on prevention and special situations: Wald 2001 - JAMA: condom → transmission reduction 50 % + EVA 28 % of HSV-2 seropositive female samples → educational role + Wald 2005 - NEJM (PARTNERS trial): valaciclovir 500 mg/d + serodiscordant couple → -48 % HSV-2 transmission → rigorous demonstration of preventive role of suppressive therapy + Stanberry 2002 - NEJM (HERPEVAC): gD-2 vaccine → 73 % efficacy doubly seronegative women → not marketed → 2nd-generation vaccine expected + Wald 2009 - Current Opinion in Infectious Diseases: HSV-2 → increased risk of HIV acquisition × 2-3 → bidirectional interaction + Celum 2010 - NEJM (HPTN 039): aciclovir + HSV-2/HIV- → reduced HIV acquisition 7 % (not significant) → HIV PrEP remains the primary strategy + Tronstein 2011 - JAMA: EVA → mostly asymptomatic transmission → mandatory counseling + Wilhelmus 2008 - Cochrane: comparable ocular treatments → HEDS Trial Wilhelmus 1994 - Archives of Ophthalmology: oral aciclovir → reduced ocular recurrences 41 % + CDC 2021 STI + STI Canada 2022 ASPC + ACOG 2020 + SOGC 2008: recommendations for prevention and management of herpes during pregnancy |
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In case of suspected herpes encephalitis, start IV acyclovir immediately without waiting for PCR results. Herpes simplex encephalitis is the most common cause of fatal viral encephalitis. Every hour of delay in acyclovir treatment increases the risk of irreversible neurological sequelae and death. HSV PCR on CSF (sensitivity 96-98 %) is the gold standard test, but it should never delay treatment. If clinical suspicion is high (fever + behavioral changes + seizures + temporal lobe involvement on MRI), IV acyclovir 10 mg/kg × 3/day should be started as soon as lumbar puncture is performed, even before results are available.
Situations Requiring a 911 Call or Urgent Medical Attention
Fever + intense headaches + behavioral or memory disturbances + olfactory-gustatory hallucinations + confusion + seizures + MRI showing abnormal temporal signal Herpes encephalitis → Call 911 → Emergency hospitalization → Lumbar puncture + CSF PCR + Start IV acyclovir 10 mg/kg × 3/day WITHOUT waiting for results → Every hour of delay worsens the neurological prognosis.
Newborn with fever + irritability + skin vesicles + seizures + jaundice + hemodynamic instability whose mother had a primary herpes infection late in pregnancy or active lesions at delivery neonatal herpes → pediatric emergencies → acyclovir IV 60 mg/kg/day × 3 doses → HSV PCR blood + CSF + skin swab + funduscopy → NICU if available.
Immunocompromised patient (HIV + transplant + chemotherapy) with persistent or spreading cutaneous or mucosal herpes lesions despite oral acyclovir for >14 days → Possible acyclovir resistance → Lesional PCR + culture + viral antibiogram → Infectious disease consultation → IV foscarnet if TK resistance confirmed → do not increase acyclovir alone.
Eye pain + photophobia + corneal ulcer visible with a slit lamp or decreased visual acuity + history of ocular herpes. Recurrent herpetic keratitis → urgent ophthalmological consultation → acyclovir ophthalmic ointment or ganciclovir gel → never use ocular corticosteroids alone without antivirals (possible worsening of herpetic keratitis).
Consult at Clinique Omicron
Clinique Omicron physicians prescribe PCR HSV on lesion or genital samples for the diagnosis of herpes simplex, initiate episodic or suppressive antiviral treatment as appropriate, prescribe type-specific serology for validated indications (serodiscordant couple + STI workup + pregnancy), refer to the emergency department in cases of suspected herpes encephalitis or neonatal herpes, and provide transmission prevention counseling. Consultations are available at several service points in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for the advice of a physician or infectious disease specialist. Herpes encephalitis and neonatal herpes are medical emergencies requiring immediate IV treatment without diagnostic delay.
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