Herpesviruses Notes

NOTES NOTES HERPESVIRUSES MICROBE OVERVIEW ▪ Large family of DNA viruses Species known to infect humans ▪ Herpes simplex virus (HSV) ▫ HSV-1, HSV-2 ▪ Varicella-zoster virus (VZV) ▪ Epstein-Barr virus (EBV) ▪ Human cytomegalovirus ▪ Human herpesvirus 6 (roseola) ▪ Human herpesvirus 8 (Kaposi’s sarcoma) Genetic material ▪ Double-stranded, linear DNA genome encoding 84 proteins Morphology ▪ Icosahedral capsid; enveloped virus Life cycle ▪ Obligate intracellular parasites ▪ Can perpetuate in latent phase ▪ Expression of lytic genes → lytic phase→ host cell death → shedding CYTOMEGALOVIRUS osms.it/cytomegalovirus PATHOLOGY & CAUSES ▪ Primary infection of immunocompetent individuals usually asymptomatic; lifelong latency ▪ Infects mononuclear leukocytes, endothelial cells CAUSES ▪ Person-to-person transmission ▫ Kissing; intimate, sexual contact ▪ Vertical transmission ▫ Congenital infection ▪ Blood products/transfusion ▪ Organ/stem cell transplant RISK FACTORS ▪ Immunocompromised ▫ HIV/AIDS; organ transplant; medications (e.g. steroids, chemotherapy) 422 OSMOSIS.ORG COMPLICATIONS ▪ Congenital CMV infection ▫ Cognitive, sensorineural deficits SIGNS & SYMPTOMS ▪ Usually asymptomatic ▪ Fever, malaise, sore throat, splenomegaly ▪ Individuals with AIDS ▫ Retinitis, colitis, encephalitis, pneumonitis ▪ Individuals with congenital CMV infection ▫ Positive CMV-IgG (if pregnant); intrauterine fetal growth restriction (IUGR), hydrocephalus, microcephaly, intracranial calcification, poly/ oligohydramnios, hepatosplenomegaly

Chapter 79 Herpesviruses DIAGNOSIS LAB RESULTS ▫ Highly active antiretroviral therapy (HAART) ▫ CMV immunoglobulin G (CMV-IGIV) ▪ Complete blood count ▫ Atypical lymphocytosis, anemia, leukopenia, thrombocytopenia ▪ ↑ serum creatinine, AST, ALT ▪ Serology tests ▫ ↑ CMV-IgM titre; acute infection ▫ ↑ CMV-IgG titre; past infection TREATMENT ▪ Usually self-limiting MEDICATIONS ▪ At-risk individuals ▫ Antiviral prophylaxis; IV ganciclovir; oral valganciclovir Figure 79.1 A colonic biopsy taken from an individual with CMV colitis. The large nuclei that give the virus its name can be clearly seen. EPSTEIN–BARR VIRUS (INFECTIOUS MONONUCLEOSIS) osms.it/epstein-barr_virus PATHOLOGY & CAUSES ▪ EBV (human herpesvirus 4) ▪ Causes Infectious mononucleosis (glandular fever) ▪ Infection in children ▫ Asymptomatic/mild flu-like symptoms ▪ Infection in adolescents, young adults ▫ Fever, sore throat, enlarged lymph nodes ▪ Lytic, latent life cycle ▫ Lytic in oropharyngeal B cells; latent in lymphocytes CAUSES ▪ Transmitted through saliva (“kissing” disease), sexual transmission RISK FACTORS ▪ Multiple sexual partners COMPLICATIONS ▪ Splenic rupture ▪ EBV infection associated with Hodgkin’s, Burkitt’s lymphoma ▪ Neurologic syndromes (2–4 weeks after initial symptoms) ▫ Guillain-Barré syndrome, cranial nerve palsies (e.g. facial nerve palsy); meningoencephalitis (e.g. aseptic meningitis), transverse myelitis, peripheral neuritis, optic neuritis ▪ EBV can affect, manifest in any organ system ▫ Hepatitis, pneumonia, myocarditis, pancreatitis, acute renal failure, gastric pseudolymphoma OSMOSIS.ORG 423

▪ Classic triad ▫ Fever; cervical/generalized lymphadenopathy; tonsillar pharyngitis (exudative/non-exudative) ▪ Malaise, hepatosplenomegaly, rash, jaundice, myalgia morphology (large, irregular nuclei) ▪ ↑ hepatic transaminase (50% of infected individuals) ▪ Monospot test ▫ Positive heterophile antibodies (IgM) ▪ Identification of EBV ▫ EBV-specific antibodies, real-time PCR, EBV DNA detection DIAGNOSIS TREATMENT SIGNS & SYMPTOMS MEDICATIONS LAB RESULTS ▪ Complete blood count (CBC) ▫ Lymphocytosis (50%) with atypical ▪ Antipyretics, analgesics ▫ Avoid aspirin; may lead to Reye’s syndrome ▪ Corticosteroid for upper airway obstruction (e.g. prednisolone) ▪ Intravenous immunoglobulin (IVIG) for thrombocytopenia Figure 79.2 Atypical lymphocytes with bizarre nuclear forms in a peripheral blood film from an individual infected with infectious mononucleosis. HERPES SIMPLEX VIRUS osms.it/herpes-simplex-virus PATHOLOGY & CAUSES ▪ HSV-1, HSV-2 ▫ Members of herpesviridae family ▪ Causes oral, genital, ocular ulcers ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth 424 OSMOSIS.ORG ▪ Primary infection often symptomatic; replicates in epidermis of skin → travels down nerve endings, axon→ sensory ganglia ▪ Periodic reactivation, subsequent episodes ▫ Virus becomes active in ganglia → transported via axon to skin → replicates in epidermis → sheds → new sores ▫ Often asymptomatic shedding; may feel tingling, burning sensation

Chapter 79 Herpesviruses TYPES ▪ Infection types ▫ Primary: first infections; seronegative; symptoms more extensive, systemic; greater viral shedding loads ▫ Non-primary: previously infected individuals; serum antibody, humoral immunity (e.g. genital HSV-2 infection in adulthood after oral mucosa HSV-1 infection in childhood) ▫ Recurrent: previously infected individuals; reactivation episodes (e.g. genital HSV-2 infection in adulthood after genital HSV-2 infection in adolescence) ▪ Herpes labialis (AKA oral herpes) ▫ HSV-1 infection of oral mucosa, lips ▪ Genital herpes ▫ HSV-2, HSV-1 infection of genital area ▫ Healing takes 2–4 weeks SIGNS & SYMPTOMS ▪ Herpes labialis ▫ Painful ulcers around mouth; high fever; sore throat; pharyngeal oedema; myalgia, cervical lymphadenopathy ▫ Recurrent infection: pain, burning, tingling, vesicle formation ▪ Genital herpes ▫ Genital ulceration, vesicles: vulva, cervix, vagina, penis shaft/glans, perineum, buttocks ▫ Genital pain, dysuria, fever, neuralgia ▫ Constipation, rectal pain, tenesmus, proctitis CAUSES ▪ Portal of entry ▫ Mucosal surfaces/skin breaks; vertical transmission during pregnancy/ childbirth ▪ Spread person to person; sexual transmission RISK FACTORS ▪ Genital herpes ▫ Contact with infected individual (producing, shedding virus) ▫ Immunosuppression (e.g. medications, HIV/AIDS) ▫ High-risk sexual behavior (e.g multiple sexual partners, unprotected intercourse, first sexual activity at early age) COMPLICATIONS ▪ Neonatal HSV infection, meningitis, encephalitis, acute retinal necrosis, uveitis, keratitis, esophagitis Figure 79.3 Blisters on the lips caused by infection with herpes simplex virus. DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Viral culture HSV polymerase chain reaction (PCR) Direct fluorescent antibody (DFA) test Serological HSV-1/HSV-2 specific IgG assay OSMOSIS.ORG 425

TREATMENT MEDICATIONS Herpes labialis ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Topical antivirals Genital herpes ▪ Antivirals (e.g. oral aciclovir, valaciclovir, famciclovir) ▪ Pregnant: antiviral prophylaxis OTHER INTERVENTIONS Genital herpes ▪ Pregnant: possible cesarean delivery Figure 79.4 Blisters on the dorsum of the penis of an individual infected with genital herpes simplex. HUMAN HERPESVIRUS 6 (ROSEOLA) osms.it/human-herpesvirus-6 PATHOLOGY & CAUSES ▪ Causes roseola (infantum) ▪ Common cause of fever, followed by rash in early childhood, associated with febrile seizures ▪ Incubation period ▫ 1–2 weeks CAUSES ▪ Asymptomatic contacts ▫ Person-to-person spread by respiratory secretions ▪ Trophic for CD4+ T lymphocytes 426 OSMOSIS.ORG ▪ Following acute infection, remains latent in various tissues RISK FACTORS ▪ More common in young children (six months–two years) ▪ Immunosuppressed ▫ Bone marrow/organ transplant ▫ Reactivation of latent virus COMPLICATIONS ▪ Afebrile seizures ▪ Associated with chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus

Chapter 79 Herpesviruses SIGNS & SYMPTOMS ▪ 3–5 days of high fever; peak in early evening ▪ Exanthem; morbilliform rash appears with defervescence; 3–5mm pink/red macules, papules along trunk, extremities ▪ Diarrhea, tympanic membrane inflammation, upper respiratory symptoms ▪ Nagayama’s spots: enanthem of red papules on soft palate, uvula ▪ Rare ▫ Seizures, periorbital oedema, bulging anterior fontanelle, cervical/occipital/ postauricular lymphadenopathy TREATMENT ▪ Usually self-limiting MEDICATIONS ▪ Immunocompromised ▫ Antiviral compounds (e.g. acyclovir, ganciclovir, cidofovir, foscarnet) ▪ Oral hydration, antipyretics (e.g. paracetamol, ibuprofen) ▪ Avoid aspirin; may lead to Reye’s syndrome DIAGNOSIS LAB RESULTS ▪ Complete blood count ▫ ↓ white blood cells ▪ Detection of HHV-6B/HHV-7 ▫ Viral culture, specific IgG detection Figure 79.5 A child with roseola infantum, also known as sixth disease. The most common causative agent is human herpes virus six. HUMAN HERPESVIRUS 8 (KAPOSI'S SARCOMA) osms.it/human-herpesvirus-8 PATHOLOGY & CAUSES ▪ Causes Kaposi’s sarcoma ▫ Low-grade vasoformative neoplasm associated with human herpesvirus-8 (HHV-8) infection/Kaposi’s sarcoma herpesvirus (KSHV) infection ▪ Lesions on mucocutaneous areas; may involve lymph nodes, viscera ▪ Skin lesions ▫ Patch → plaque → ulcerating tumor nodules ▪ Morphology ▫ spindle-shape, vasoformative cells with vascular proliferation, inflammatory cells OSMOSIS.ORG 427

▪ Spontaneous regression may occur after HAART/immunosuppressive treatment TYPES ▪ Epidemic AIDS-associated Kaposi’s sarcoma ▫ HIV-positive individuals ▪ Classic sporadic Kaposi’s sarcoma ▫ More common in individuals who are male, older, with Mediterranean/Jewish background ▪ Iatrogenic, transplant-associated Kaposi’s sarcoma ▫ Solid organ transplant individuals ▪ African endemic Kaposi’s sarcoma ▫ More common in central Africa, unrelated to HIV RISK FACTORS ▪ More common in individuals who are biologically male, > 50 years ▪ Immunosuppression, HIV (co-infection synergistic → aggressive, widespread); drug abuse; immunosuppression therapy COMPLICATIONS ▪ Secondary skin lesion infection SIGNS & SYMPTOMS ▪ Skin lesions ▫ Multifocal; asymmetrically distributed; size, colour variation; non-pruritic; papular; nodular; plaque-, bullous-like; indurated; hyperkeratotic ▪ Oral lesions ▫ Hard palate, gingiva, dorsum of tongue ▫ Macules, papules, nodules, exophytic masses ▪ Lymphadenopathy, lymphoedema ▪ Fever, weight loss, night sweats 428 OSMOSIS.ORG Figure 79.6 The skin of an individual with Kaposi’s sarcoma. DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray ▪ Nodular/interstitial/alveolar infiltrates; hilar/ mediastinal lymphadenopathy; nodules LAB RESULTS ▪ HIV test ▪ Positive in AIDS-associated Kaposi’s sarcoma ▪ Fecal occult blood ▫ Positive may indicate intestinal lesions OTHER DIAGNOSTICS ▪ Lesion, lymph node biopsy of vascular lesion TREATMENT MEDICATIONS ▪ Delay disease progression ▫ HAART; in HIV infected individuals, HIV suppression may shrink Kaposi’s sarcoma lesions; systemic chemotherapy ▪ Cosmetic ▫ Topical retinoids; intralesional vinblastine

Chapter 79 Herpesviruses SURGERY ▪ Cosmetic ▫ Surgical excision; cryotherapy; laser therapy (external beam radiation) Figure 79.7 The histological appearance of a Kaposi sarcoma. The tumor is composed of spindle cells and numerous branching vascular spaces. The occasional spindle cell contains hyaline globules. VARICELLA ZOSTER VIRUS osms.it/varicella-zoster-virus PATHOLOGY & CAUSES ▪ Double-stranded, linear DNA virus ▫ Causes chickenpox, shingles ▫ Chickenpox: generally benign, selflimited disease in immunocompetent children ▫ Shingles: painful skin rash, can occur in individuals who have recovered from primary VZV infection Primary infection (chickenpox) ▪ Transmission: airborne spread through aerosolized droplets, direct lesion contact ▪ VZV enters respiratory system → lymph node spread → targets skin, mucous membranes → small blood vessel vasculitis → epithelial cell degeneration → fluid-filled vesicles ▫ Incubation period: 14 days ▫ Most infectious: 1–2 days before rash; infectious 3–4 days, until lesions crusted ▫ After symptoms resolve, VZV dormant in nervous system; latent in trigeminal, dorsal root ganglia Figure 79.8 A child with chickenpox. OSMOSIS.ORG 429

Secondary infection (shingles) ▪ Occurs when dormant VZV reactivates ▫ Reactivation in dorsal root, cranial nerve ganglia → travels down axons → local skin inflammation innervated by ganglion ▫ Prodromal 2–4 day tingling/localized pain before rash onset RISK FACTORS Chickenpox ▪ More common in children ▫ 1–9 years old (highest risk) ▪ Non-immunized status ▪ Immunocompromised status Shingles ▪ Primary varicella infection history ▪ More common in adults ▫ > 50 years old (highest risk) ▪ Immunocompromised status ▪ Stress SIGNS & SYMPTOMS Chickenpox ▪ Fever, headache, malaise, sore throat, tachycardia ▪ Rash characteristics ▫ Generalized pruritic, vesicular rash ▫ “Dew drop on rose petal” appearance ▫ Formation: macules → vesicles → rupture → scab ▫ Vesicles on mucous membranes (e.g. nasopharynx, conjunctiva, mouth, vulva) Shingles ▪ Erythematous, maculopapular lesions evolve into painful vesicular rash ▫ Rash follows dermatomal distribution of cranial nerve/dorsal root ganglion ▫ Thoracic, lumbar dermatomes most commonly affected COMPLICATIONS Chickenpox ▪ Secondary bacterial infection, cutaneous scarring, encephalopathy, varicella pneumonitis/pneumonia ▪ Central nervous system (CNS) complications ▫ Meningitis, encephalitis, intracranial vasculitis ▪ Congenital varicella syndrome ▫ Limb hypoplasia, paresis, microcephaly, ophthalmic lesions Shingles ▪ Ramsay Hunt syndrome ▫ VZV of geniculate ganglion affects facial nerve; hearing loss, facial weakness ▪ Postherpetic neuralgia, superinfection of skin lesions, encephalitis, Mollaret’s meningitis, zoster multiplex/sine herpete, stroke, myelitis ▪ Herpes zoster ophthalmicus (sightthreatening) 430 OSMOSIS.ORG Figure 79.9 Herpes zoster, or shingles, affecting the ophthalmic branch of the trigeminal nerve.

Chapter 79 Herpesviruses TREATMENT MEDICATIONS Chickenpox ▪ Low risk: usually self-limiting ▪ Moderate risk: oral antiviral therapy ▪ High risk: intravenous antiviral therapy; zoster-immune globulin (ZIG) Figure 79.10 Herpes zoster in a dermatomal distribution on the chest. DIAGNOSIS LAB RESULTS ▪ Microbe identification ▫ PCR: VZV DNA ▫ Viral culture: positive VZV ▫ DFA: VZV antigen Shingles ▪ Oral/intravenous antiviral therapy ▪ Analgesics ▫ E.g. paracetamol, ibuprofen; topical; opioid ▪ Calamine lotion ▪ Varicella-zoster immune globulin OTHER INTERVENTIONS ▪ Prevention ▫ Live attenuated VZV vaccine OSMOSIS.ORG 431