Overview
Herpesvirus, humans contract eight different types of herpesviruses ( see Table: Herpesviruses That Infect Humans). All herpesviruses are capable of reactivation after becoming latent in some host cells following initial infection. Clinical symptoms brought on by an original infection can differ greatly from those brought on by a virus’s reactivation. Herpesviruses cannot survive for very long without a host, therefore close contact is typically necessary for transmission. People who have latent infections are susceptible to the virus reactivating asymptomatically, leading to asymptomatic shedding and the spread of infection.
The herpesviruses are genetically and physically identical, yet they also induce a wide range of clinical symptoms that are often non-overlapping.
Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), can lead to some malignancies, in contrast to other herpesviruses which are not known to induce malignancy.
Herpesvirus 6 is the culprit behind the childhood illness roseola infantum (and sometimes 7).
Types
The herpesvirus family presently consists of eight known members. They are exceptionally well adapted pathogens that are present everywhere. The word “herpes” means “to creep” in Greek, and it describes the persistent, latent, or recurrent nature of illnesses.
Herpesviruses That Infect Humans
| Common Name | Other Name | Typical Manifestations |
|---|---|---|
| Herpes simplex virus type 1 | Human herpesvirus 1 | Gingivostomatitis, keratoconjunctivitis, cutaneous herpes, genital herpes, encephalitis, herpes labialis, viral meningitis, esophagitis*, pneumonia*, disseminated infection*, hepatitis*† |
| Herpes simplex virus type 2 | Human herpesvirus 2 | Genital herpes, cutaneous herpes, gingivostomatitis, neonatal herpes, viral meningitis, disseminated infection*, hepatitis*† |
| Varicella-zoster virus | Human herpesvirus 3 | Chickenpox, herpes zoster, disseminated herpes zoster* |
| Epstein-Barr virus | Human herpesvirus 4 | Infectious mononucleosis, hepatitis, encephalitis, nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, lymphoproliferative syndromes*, oral hairy leukoplakia*, gastric cancer |
| Cytomegalovirus | Human herpesvirus 5 | Cytomegalovirus (CMV) mononucleosis, hepatitis, congenital cytomegalic inclusion disease, hepatitis*, retinitis*, pneumonia*, colitis* |
| Human herpesvirus 6 | — | Roseola infantum, otitis media with fever, encephalitis* |
| Human herpesvirus 7 | — | Roseola infantum |
| Kaposi sarcoma–associated herpesvirus | Human herpesvirus 8 | Not a known cause of acute illness but has a causative role in Kaposi sarcoma* and AIDS-related non-Hodgkin lymphomas that grow primarily in the pleural, pericardial, or abdominal cavities as lymphomatous effusions (primary effusion lymphoma)Also linked with multicentric Castleman disease |
Herpes simplex virus types I and II (HSV-1 and HSV-2)
- Primary infection occurs through a break in the mucous membranes of the mouth or throat, via the eye or genitals or directly via minor abrasions in the skin.
- Many individuals are infected with HSV-1 by 1-2 years of age; HSV-2 infection tends to be with the onset of sexual activity.
- Initial infection is usually asymptomatic, although there may be minor local vesicular lesions. Local multiplication is followed by viraemia and systemic infection and subsequent lifelong latent infection with periodic reactivation.
- During primary infection, the virus enters peripheral sensory nerves and migrates along axons to sensory nerve ganglia in the CNS – hence managing to escape the host’s immune response.
- Between reactivations, the virus is truly latent – viral DNA is maintained as an episome (not integrated) with limited expression of specific virus genes required for the maintenance of latency. The delicate balance of latency may be upset by various disturbances – physical (eg, injury, ultraviolet light, hormones, menstruation) or psychological (eg, stress, emotional upset).
- Reactivation of latent virus leads to recurrent disease – virus travels back down sensory nerves to surface of body and replicates, causing tissue damage:
Manifestations of primary HSV infection
- Systemic infection: eg, fever, sore throat, and lymphadenopathy. It often passes unnoticed. If immunocompromised, it may be life-threatening with fever, lymphadenopathy, pneumonitis, and hepatitis.
- Gingivostomatitis: ulcers filled with yellow slough appear in the mouth.
- Herpetic whitlow: a breach in the skin allows the virus to enter the finger, causing a vesicle to form. .
- Traumatic herpes (herpes gladiatorum): vesicles develop at any site where HSV is ground into the skin by brute force.
- Eczema herpeticum: HSV infection of eczematous skin; usually seen in children.
- Herpes simplex meningitis: this is uncommon and usually self-limiting; typically, HSV-2 in women during a primary attack – see the separate Meningitis article.
- Genital herpes: usually HSV-2, although either virus can appear in the mouth or the genitals if there has been cross-transmission through orogenital sex. See the separate Genital Herpes Simplex article.
- HSV keratitis: manifests with corneal dendritic ulcers. Avoid steroids.
- Herpes simplex encephalitis: usually HSV-1. It spreads centripetally – eg, from cranial nerve ganglia, to frontal and temporal lobes. Suspect if the patient has a fever, fits, headaches, odd behaviour, dysphasia, hemiparesis, or coma or subacute brain stem encephalitis, meningitis, or myelitis. See also the separate Encephalitis and Meningoencephalitis article.
Transmission
HSV-1 is mainly transmitted via contact with the virus in sores, saliva or surfaces in or around the mouth. Less commonly, HSV-1 can be transmitted to the genital area through oral-genital contact to cause genital herpes. It can be transmitted from oral or skin surfaces that appear normal; however, the greatest risk of transmission is when there are active sores. People who already have HSV-1 are not at risk of reinfection, but they are still at risk of acquiring HSV-2.
HSV-2 is mainly transmitted during sex through contact with genital or anal surfaces, skin, sores or fluids of someone infected with the virus. HSV-2 can be transmitted even if the skin looks normal and is often transmitted in the absence of symptoms.
In rare circumstances, herpes (HSV-1 and HSV-2) can be transmitted from mother to child during delivery, causing neonatal herpes.
Diagnosis
- Rising antibody titres in 1° infection.
- Viral culture.
- PCR for fast diagnosis.
Treatment
Drugs Used to Treat Herpesvirus Infections
| Drug | Activity | Uses | Adverse Effects |
|---|---|---|---|
| Acyclovir | Active against (in order of potency) HSV type 1 (HSV-1), HSV-2, VZV, and EBVMinimal activity against CMV | Oral or IV: IV indicated when a higher serum drug level is required, as for herpes simplex encephalitis | Oral: InfrequentIV: Rarely, renal toxicity due to precipitation of acyclovir crystals; in immunocompromised patients, TTP/HUS |
| Cidofovir | In vitro inhibition of a broad spectrum of viruses, including HSV-1, HSV-2, VZV, CMV, EBV, KSHV, adenovirus, HPV, poxviruses, and human polyomavirus (JC and BK viruses) | IV: Generally used for CMV, but use limited by renal toxicityIntravitreal injection: For CMV retinitis | Significant renal toxicity |
| Famciclovir (prodrug of penciclovir) | Antiviral spectrum similar to acyclovir (strains resistant to acyclovir also resistant to famciclovir) | Oral: As effective as acyclovir for genital herpes and herpes zoster and more bioavailable than acyclovir after oral administration (which is theoretically important for VZV infection) | Infrequent |
| Fomivirsen | Potent activity against CMV (antisense oligonucleotide inhibits CMV protein synthesis) | Intravitreal injection: For patients with HIV infection and CMV retinitis that is resistant to other therapies | Increased intraocular pressure, corticosteroid-responsive uveitis |
| Foscarnet | Active against EBV, KSHV, human herpesvirus 6, acyclovir-resistant (and acyclovir-susceptible) HSV and VZV, and ganciclovir-resistant (and ganciclovir-susceptible) CMVSome anti-HIV activity | IV or intravitreal injection: Efficacy similar to that of ganciclovir for treating and delaying progression of CMV retinitis | Renal toxicity in up to one third of patients if foscarnet is given without adequate hydration, electrolyte imbalances |
| Ganciclovir | In vitro activity against all herpesviruses, including CMV, but HSV strains that are resistant to acyclovir also cross-resistant to ganciclovirTypically drug of choice for CMVUsed in HIV patients with CMV retinitis | IV form: Most commonIntravitreal injection: For CMV retinitisOral: Only 6 to 9% bioavailable; requires 12 capsules/day for a standard dose (1 g tid), limiting its usefulness | Primarily, bone marrow suppression, particularly neutropenia, which sometimes requires treatment* |
| Idoxuridine | Active against HSV-1, HSV-2, VZV, vaccinia, and CMV | Topical: Because of its high systemic toxicity, limited to topical ophthalmic treatment of herpes simplex keratoconjunctivitis | Irritation, pain, photophobia, pruritus, inflammation or edema of the eyelidsRarely, allergic reactions |
| Letermovir | Active against CMV | IV or oral: CMV prophylaxis in bone marrow transplant patients | Nausea, vomiting, diarrhea, peripheral edema, cough, headache, fatigue, abdominal pain |
| Penciclovir | Active against HSV-1, HSV-2, VZV, and EBV | Topical (cream): Used to treat recurrent herpes labialis in adults | Erythema |
| Trifluridine (trifluorothymidine) | Active against HSV-1 and HSV-2 | Topical: Ophthalmic treatment of primary keratoconjunctivitis and recurrent keratitis or ulceration caused by HSV-1 and HSV-2(Systemic use precluded by bone marrow suppression) | Ocular stinging, palpebral edemaLess commonly, punctate keratitis, allergic reactions |
| Valacyclovir (prodrug of acyclovir) | Antiviral spectrum similar to that of acyclovir | Oral: 3–5 times more bioavailable than acyclovir | Similar to those of acyclovirTTP/HUS in some patients with advanced HIV and in transplant recipients who received valacyclovir in higher doses than currently recommended† |
| Valganciclovir (prodrug of ganciclovir) | Similar to ganciclovir | Oral: More bioavailable than oral ganciclovir | Similar to ganciclovir |
| Vidarabine (adenine arabinoside, ara-A) | For HSV infections | IV form not used anymore because of neurotoxicityOphthalmic preparations: Effective for acute keratoconjunctivitis and recurrent superficial keratitis caused by HSV-1 and HSV-2 | Superficial punctate keratitis with tearing, irritation, pain, and photophobia |