Herpesviruses: HSV, VZV, EBV, CMV & HHV-6/7/8

The herpesvirus family: structure and latency

Structure. Herpesviruses are large, enveloped viruses with a linear double-stranded DNA genome inside an icosahedral capsid. They replicate in the nucleus and bud through the nuclear membrane to acquire their envelope.

Latency. After primary infection each virus persists for life in a characteristic cell type and reactivates when cell-mediated immunity wanes with age, stress, or immunosuppression.

Herpes simplex viruses

HSV-1. Spread by contact with lesions or asymptomatic shedding in saliva. Primary infection in young children causes gingivostomatitis — fever with painful ulcers of the gums and mouth. Reactivation from the trigeminal ganglion produces herpes labialis (cold sores). Inoculation of a finger causes herpetic whitlow. Keratitis shows branching dendritic ulcers on fluorescein staining; HSV is a leading infectious cause of corneal blindness, and topical steroids alone can worsen it.

HSV encephalitis. HSV-1 is the most common cause of sporadic viral encephalitis. It produces hemorrhagic necrosis of the medial temporal and inferior frontal lobes, often asymmetrically, so patients have fever, confusion, personality change, aphasia, olfactory hallucinations, and focal seizures. Untreated mortality is about 70%.

Erythema multiforme. Fixed, symmetric target lesions — a dusky center, a pale ring, and a red outer halo — mainly on the hands and limbs, appearing days after a cold-sore recurrence. HSV is the most common trigger, Mycoplasma pneumoniae the next. It is distinct from drug-induced Stevens-Johnson syndrome, and suppressive antivirals prevent HSV-associated recurrences.

HSV-2. Genital herpes starts as grouped, painful vesicles on a red base that erode into shallow ulcers with tender inguinal lymphadenopathy. The primary episode is the most severe, with fever and sometimes aseptic meningitis; recurrences are milder. HSV-2 establishes latency in the sacral ganglia and is the main cause of recurrent benign lymphocytic (Mollaret) meningitis. HSV-1 now causes a large share of new genital infections. In immunocompromised patients HSV also causes esophagitis with small, punched-out ulcers.

Neonatal herpes. Most cases are acquired in the birth canal from maternal genital shedding (HSV-2 or HSV-1). Risk is roughly 30–50% when the mother acquires a primary infection near term, versus under 1% with recurrent disease. Infants present in the first weeks with skin-eye-mouth disease, encephalitis, or disseminated infection, and receive IV acyclovir. Cesarean delivery is indicated if genital lesions or prodromal symptoms are present at labor, and suppressive acyclovir from 36 weeks reduces recurrences at term in women with known genital herpes.

Laboratory diagnosis. A Tzanck smear of a scraped vesicle base shows multinucleated giant cells, and tissue shows Cowdry A inclusions (eosinophilic intranuclear bodies with a clear halo). Both occur in HSV-1, HSV-2, and VZV, so they cannot identify the virus. PCR of lesion fluid or CSF is the preferred test: the most sensitive, and it names the virus.

Acyclovir needs viral thymidine kinase for activation, so it covers HSV and VZV but not CMV (details in the antivirals lesson).

Varicella-zoster virus

Varicella (chickenpox). Highly contagious by airborne droplets and direct contact, with an incubation of 10–21 days. After a mild prodrome, itchy clear vesicles on red bases erupt in crops, beginning on the trunk and face, so macules, papules, vesicles, and crusts coexist — unlike smallpox, whose lesions share one stage. Patients are contagious from 1–2 days before the rash until every lesion has crusted.

Complications.

• Children — bacterial superinfection of lesions (S. pyogenes, S. aureus) and acute cerebellar ataxia.
• Adults, pregnant women, smokers — severe varicella pneumonia; acyclovir is given to adolescents, adults, and high-risk patients.
• Reye syndrome — aspirin during varicella or influenza injures mitochondria, causing microvesicular fatty liver and encephalopathy.

Varicella-zoster immune globulin protects exposed susceptible high-risk people: pregnant women, the immunocompromised, and newborns whose mothers develop varicella from 5 days before to 2 days after delivery.

Zoster (shingles). As cell-mediated immunity wanes with age or immunosuppression, VZV reactivates from a dorsal root or cranial nerve ganglion. Burning pain precedes unilateral grouped vesicles confined to one dermatome that stop at the midline, most often thoracic; immunocompromised patients may develop disseminated zoster. Antivirals (valacyclovir, famciclovir, acyclovir) work best within 72 hours of rash onset. Postherpetic neuralgia — pain lasting beyond 90 days — is the commonest complication, rises with age, and is treated with gabapentin or pregabalin, tricyclics, or topical lidocaine.

Cranial nerve zoster. Herpes zoster ophthalmicus involves V1. Vesicles on the tip of the nose (Hutchinson sign) indicate nasociliary branch involvement, which also supplies the eye, so keratitis and uveitis are likely and urgent ophthalmology is needed. Ramsay Hunt syndrome is reactivation in the geniculate ganglion: ipsilateral facial palsy, ear pain, and vesicles in the ear canal or auricle, often with hearing loss, tinnitus, or vertigo.

Epstein-Barr virus and cytomegalovirus

EBV entry and mononucleosis. EBV spreads in saliva; its gp350 glycoprotein binds CD21 (complement receptor 2) on B cells, and it also infects oropharyngeal epithelium. Mono in teens and young adults brings fever, marked fatigue, exudative pharyngitis, posterior cervical lymphadenopathy, splenomegaly, and mild hepatitis. Because the enlarged spleen can rupture, contact sports are avoided for at least 3–4 weeks.

Diagnosis. The atypical lymphocytes on the smear are reactive CD8+ cytotoxic T cells attacking infected B cells. Heterophile antibodies — IgM that agglutinates horse or sheep RBCs, detected by the Monospot — confirm the diagnosis but may be negative in the first week and in young children; then EBV-specific serology helps (VCA IgM for acute infection; EBNA antibodies appear later). Amoxicillin or ampicillin given for presumed strep throat triggers a diffuse maculopapular rash.

EBV-associated tumors and lesions. Burkitt lymphoma (t(8;14) juxtaposing MYC with the IgH locus; endemic African jaw tumors), nasopharyngeal carcinoma (southern China, Southeast Asia), Hodgkin lymphoma, post-transplant lymphoproliferative disorder, and primary CNS lymphoma in AIDS (usually a single ring-enhancing lesion with EBV DNA in CSF). Oral hairy leukoplakia — white, corrugated plaques on the lateral tongue that do not scrape off, unlike thrush — is a benign EBV lesion of HIV.

CMV. Infected cells enlarge ("cytomegalic") and carry owl's-eye intranuclear inclusions. CMV is latent in monocytes and myeloid progenitors and spreads by saliva, sex, breast milk, transfusion, transplanted organs, and across the placenta. Healthy hosts are usually asymptomatic or develop heterophile-negative mononucleosis. Congenital CMV, the most common congenital infection, causes sensorineural hearing loss and periventricular calcifications (see the TORCH lesson).

CMV in the immunocompromised. In AIDS with CD4 counts below 50/μL, CMV causes retinitis (painless floaters and vision loss; hemorrhages with yellow-white necrosis along vessels), esophagitis with large, shallow, linear ulcers, and colitis. In transplant recipients, where it is the most important viral pathogen, it causes pneumonitis, hepatitis, and colitis, with the highest risk when a seropositive donor organ goes to a seronegative recipient. Treatment is IV ganciclovir or oral valganciclovir (myelosuppression), with foscarnet for resistant virus.

HHV-6, HHV-7, and HHV-8

Roseola (exanthem subitum). HHV-6, less often HHV-7, infects infants from 6 months to 2 years. Three to five days of high fever (often ≥40 °C) in a well-appearing child — a common cause of febrile seizures — ends abruptly, and a pink, blanching maculopapular rash erupts on the trunk, spreads to the neck and face, and fades within 1–2 days. Parvovirus B19, by contrast, causes slapped cheeks and a lacy rash.

HHV-8. Spread sexually and in saliva, HHV-8 causes Kaposi sarcoma: purple patches, plaques, and nodules on skin, oral mucosa, gut, and lung. Biopsy shows spindle cells lining slit-like vascular spaces with extravasated red cells. Classic groups are people with AIDS, transplant recipients, older men of Mediterranean or Eastern European descent, and an endemic African form. HHV-8 also causes primary effusion lymphoma and multicentric Castleman disease.

AIDS-associated Kaposi sarcoma is treated first with antiretroviral therapy, which often shrinks lesions. Its look-alike, bacillary angiomatosis (Bartonella), shows neutrophils rather than spindle cells and responds to macrolides or doxycycline.