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Human Herpesvirus Infections Asmita Gupte, M.D. Division of Infectious Diseases University of Florida


Characteristics of herpes viruses •Persistence •Latency •Reactivation •Tissue

tropism


Human Herpes Viruses •

Alphaherpesviruses • •

Betaherpesviruses • •

HSV-1 and HSV-2 Varicella-zoster virus (VZV) Cytomegalovirus (CMV) HHV-6 and HHV-7

Gammaherpesviruses • •

Epstein-Barr Virus (EBV) Kaposi’s sarcoma-associated herpesvirus (KSHV,HHV-8)


Cell types infected by different herpesviruses • VZV and HSV • Epithelial cells and neurons

CMV • Ductal epithelium, leukocytes

EBV •Oropharyngeal

epithelium, B lymphocytes

KSHV •Endothelium,

B cells


Herpes simplex virus Ubiquitous virus that infects greater than 75% of the adult population (HSV-1) and to varying degrees in the case of HSV-2, depending on the population studied. There are many manifestations of HSV infection in addition to the common cold sore or fever blister. Manifestations depend on anatomic site involved, age, immune status of the host Herpes labialis Genital herpes Herpes gladiatorum Herpetic whitlow Eczema herpeticum Congenital HSV infection Herpetic gingivostomatitis Disseminated infections Pneumonia Esophagitis Hepatitis Encephalitis Chronic and resistant infections


Oral-Facial Herpes Gingivostomatitis and pharyngitis most common manifestation of primary HSV−1 infection. Systemic s/s may be present 

Recurrent herpes labialisreactivation from trigeminal ganglia-lesions at vermilion border 

Rx:

Acyclovir, Famciclovir, Valacyclovir. Symptom directed or suppression


Antivirals-HSV Require TK phosphorylation for activity  ACV binds to replicating viral DNA causing premature chain termination  ACV and Famciclovir both inhibit viral DNA polymerase  Resistance mediated by reduction in viral TK  Valacyclovir rapidly converted to ACV and higher levels achieved  Excellent activity against HSV  Moderate activity against VZV 


Genital Herpes Primary episode: Fever, headache, myalgias, dysuria, vag/urethral discharge lymphadenopathy Lesions: vesicles, pustules, erythematous ulcers Can be caused by HSV-1 & 2 Recurrence rate higher with HSV-2 infection HSV proctitis (ulcerative lesions on sigmoidoscopy) and perianal lesions: HIV, rectal intercourse Trigeminal ganglia & sacral ganglia- most common sites of HSV-1 and HSV-2 latency Rx: Acyclovir, Famciclovir, Valacyclovir


Neonatal Herpes <

6 weeks of age Without therapy mortality is approx 65% Skin lesions most commonly recognized feature - may not appear or may be delayed Acquired perinatally from contact with genital secretions or close contact with family member  30% due to HSV-1 and 70% HSV-2 Rx- IV Acyclovir


 Infection of the finger  Occurs as complication of primary oral or genital herpes, direct innoculation, occupational exposure Vesicular or pustular lesion Abrupt onset erythema, localized tenderness Fever, lymphadenitis, lymphadenopathy are common Prompt diagnosis


Herpes Gladiatorum Any skin area may be infected Transmission facilitated by trauma Prompt diagnosis to contain the spread


Eczema Herpeticum

 Potentially life-threatening viral infection that arises in pre-existing skin conditions like atopic dermatitis  In some cases may lead to fulminant life threatening disseminated infection  Acyclovir, Valacyclovir. Antibiotics may be needed as well


Rare entity

Skin lesions, chorioretinitis, microcephaly 

H in TORCH infections


Herpes Encephalitis Accounts for 10-20% of viral encephalitis 2.3 cases per 1 million HSV-1 >95% cases Biphasic- 5-30, >50yrs Primary infection or reactivation Fever, altered mental status, bizarre behavior, seizures Temporal lobe involved


 Diagnosis: LP: Increased CSF protein, leucocytes with lymphocytic

predominance and increased CSF RBCs due to hemorrhagic necrosis  CSF HSV PCR: High sensitivity and specificity  Treatment: IV Acyclovir, reduces mortality. Despite treatment mortality upto 15% with survivors with longterm cognitive impairments


Eryrthema Multiforme EM is a acute self limiting, sometimes recurring skin condition considered to be a Type IV hypersensitivity reaction associated with certain infections, medications. Cell mediated immune reaction associated with HSV antigens Antigens may be detected in keratinocytes by IF or HSV DNA detected by PCR Typical â&#x20AC;&#x153;Target Lesionsâ&#x20AC;? Suppression of HSV may prevent EM. Once EM erupts antivirals not effective


“B” virus, Herpesvirus simiae • • • •

Endemic HSV homolog of nonhuman primates Risk for those handling animals Causes a fulminant neurologic syndrome in humans May be treatable with acyclovir


Varicella-Zoster Virus Infections Varicella (Chickenpox) Bacterial superinfection CNS: aseptic meningitis, transverse myelitis, GBS, encephalitis, Reyeâ&#x20AC;&#x2122;s syndrome Varicella pneumonia Myocarditis, nephritis, hepatitis Perinatal varicella: high mortality

Herpes Zoster (Shingles) T3-L3 dermatomes most frequently involved Zoster opthalmicus: Opthalmic branch of Trigeminal Nerve involved Ramsay Hunt syndrome: vesicles in EAC, loss of sense of taste in ant 2/3rds of tongue, ipsilateral facial palsy: geniculate ganglia of sensory branch of Facial Nerve involved.


Chickenpox Childhood disease Highly contagious: pt infectious 48hrs prior to rash. IP: 10-21 days Fever, malaise, skin lesions: maculopapules, vesicles, pustules, scabs in various stages of evolution Early lesions â&#x20AC;&#x153;dew drop on rose petalâ&#x20AC;? Diagnosis: clinical, VZV DNA PCR, Tzanck smear demonstrating multinucleate giant cells, Direct immunofluorescence Acyclovir therapy efficacious if used <24hrs Immunocompromised: IV Acyclovir


Herpes Zoster Opthalmic division of Trigeminal Nerve

Adapted from: gb.udn.com


HZ: Involvement of tip of nose is classic indicator of ocular involvement (Hutchinsonâ&#x20AC;&#x2122;s sign)


Herpes Zoster treatment Treatment with acyclovir, Famciclovir or valacyclovir is beneficial with accelerated healing of lesions and resolution of neuralgia Immunocompromised should receive initial reaction with IV Acyclovir


CMV disease β Herpes virus dsDNA Spread by repeated prolonged exposure CMV present in breast milk, saliva, feces, urine, semen, cervical secretions Daycare centers Once infected person carries CMV for life. Reactivation syndromes: T cell mediated immunity compromised

     

Pneumonitis  Bone marrow transplant Colitis  AIDS, solid organ transplantation Retinitis  AIDS Hepatitis  SOT Nephritis  Kidney transplantation Mononucleosis: F/C, malaise, fatigue, splenomegaly, atypical lymphocytosis, leucopenia, LFT abnl Congenital infection: IUGR, microcephaly, chorioretinitis


When GCV enters cells, it must undergo a series of phosphorylations until it is active to be able to inhibit viral DNA polymerase. The initial phosphorylation step is done by a viral protein kinase that's encoded by UL97. 

Mutations in UL97 or in the viral DNA polymerase are the 2 major mechanisms that underlie ganciclovir resistance and antiviral resistance in general 

Activity: CMV, HSV, varicella

Adapted from: medscape.com


Cidofovir Analog of deoxycytidine monophosphate causes premature chain termination of viral DNA and inhibits DNA polymerase Does not require TK ACV resistant strains usually not resistant to cidofovir HSV, CMV, HHV6 & 8, VZV Nephrotoxic and BM toxicity

Foscarnet Blocks binding of deoxynucleotidyl triphosphate to viral DNA polymerase CMV, HSV, VZV CMV retinitis and ACV resistant HSV, GCV resistant CMV Nephrotoxicity and electrolyte abnormalities


CMV Retinitis

Normal Fundoscopic exam

www.kellogg.umich.edu/.../cmv-retinitis.html

Hemorrhages, vessel sheathing, retinal edema AIDS with CD4<50 IV Ganciclovir then oral Valganciclovir until CD4>100-150


CMV Pneumonitis   

Highest risk in Lung transplant and BMT patients High mortality Diagnosis with BAL with cells showing viral CPE and inclusions, viral cx and PCR. Lung biopsy-gold std Treatment with IV Ganciclovir CMV inclusions in lung http://library.med.utah.edu/WebPath/TUT ORIAL/AIDS/AIDS021.html


CMV colitis The transplanted organ is particularly vulnerable as a target for CMV infection Patients may present with diarrhea, heartburn, odynophagia Diagnosis made with biopsies obtained on endoscopy CMV immunostain positive IV Ganciclovir


Properties of transforming herpesviruses • •

• •

Drive infected cell proliferation Prevent apoptosis of infected cells Avoid immune attack Infect new cells


Epstein Barr virus (EBV)-associated diseases •Infectious Mononucleosis •Burkitt lymphoma •Nasopharyngeal carcinoma •Lymphoproliferative Disease •Hodgkin’s Disease, EBV-assoc. NHL •Gastric carcinoma


Infectious mononucleosis: Kissing disease


Oral Hairy Leukoplakia White plaques on lateral surface of tongue Seen in HIV/AIDS, immunocompromised individuals


Burkitt’s Lymphoma  

Rapidly growing NHL 15% of cases in US and 90% cases in Africa associated with EBV Extremely responsive to chemotherapy and recurrence is rare

from thacher’s.org


NPC and EBV

Figure 135-4 Nasopharyngeal carcinoma. A, Nests of metastatic undifferentiated nasopharyngeal carcinoma in a fibrous stroma in a lymph node (hematoxylin and eosin). Metastases often lack infiltrating lymphocytes. B, In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) (brown) demonstrates EBV infection in most cells in the same area of the tissue. (Magnification &#215;100.) (Courtesy of Dr. Miguel Rivera.) Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 03:59 PM) Š 2005 Elsevier


Hodgkinâ&#x20AC;&#x2122;s lymphoma and EBV

Figure 135-3 Mixed cellularity classic Hodgkin's lymphoma. A, Lymph node architecture is effaced by an infiltrate comprised of small lymphocytes, epithelioid histiocytes, plasma cells, eosinophils, and Hodgkin and Reed-Sternberg cells (arrow) (hematoxylin and eosin). B, In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) (brown) demonstrates EBV infection in the malignant Hodgkin and Reed-Sternberg cells. (Original magnification x400.) (Courtesy of Dr. Jeffery Kutok.) Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 04:00 PM) Š 2005 Elsevier


PTLD and EBV

Figure 135-2 Post-transplantation lymphoproliferative disease involving the colon. A, The tumor is composed of large, atypical lymphoid cells (hematoxylin and eosin). Scattered macrophages (arrow) are seen, producing a "starry-sky" appearance. B, In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) (brown) shows variably intense nuclear staining in the majority of tumor cells, indicating EBV infection. (Original magnification x400.) (Courtesy of Dr. Jeffery Kutok.) Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 04:00 PM) Š 2005 Elsevier


Kaposi’s sarcoma-associated virus (KSHV, HHV8) •Kaposi’s sarcoma (KS) •Multicentric Castleman’s disease •Primary Effusion Lymphoma (PEL)


Kaposiâ&#x20AC;&#x2122;s sarcoma Classic Kaposi's sarcoma (CKS) is a neoplasm characterized by abnormal angiogenesis that requires infection with a human herpes virus, HHV-8, along with other cofactors. purplish, reddish blue, or dark brown/black macules, plaques, and nodules on the skin. mucous membranes of mouth and gastrointestinal (GI) tract and regional lymph nodes may be affected later in the course. Biopsy for definitive diagnosis radiation therapy, excision, cryotherapy, laser ablation, chemotherapy

emedicine.medscape.com/article/279734-overview


Kaposiâ&#x20AC;&#x2122;s sarcoma: Seen in AIDS patients

Figure 137-2 Kaposi's Sarcoma Involving a Lymph Node. Left panel, Spindle cell proliferation (white arrows) containing poorly formed vascular spaces with entrapped red blood cells (black arrows). Areas of uninvolved lymph node (LN) are seen at the top (H&E). Right panel, Immunohistochemical detection of Kaposi's sarcoma-associated human herpesvirus (KSHV) latency-associated nuclear antigen 1 (LANA1) (brown) in the nuclei of many spindle cells indicates KSHV infection (&#215;200). (Courtesy of Dan Jones, MD, PhD.) Downloaded from: Principles and Practice of Infectious Diseases (on 28 February 2006 03:59 PM) Š 2005 Elsevier


ď ą Fever, LAN, hepatosplenomegaly, night sweats ď ą Most patients with MCD die due to fulminant infection, progressive disease or related malignancy


Human Herpes Viruses •

Alphaherpesviruses • •

Betaherpesviruses • •

HSV-1 and HSV-2 Varicella-zoster virus (VZV) Cytomegalovirus (CMV) HHV-6 and HHV-7

Gammaherpesviruses • •

Epstein-Barr Virus (EBV) Kaposi’s sarcoma-associated herpesvirus (KSHV,HHV-8)


Cell types infected by different herpesviruses • VZV and HSV • Epithelial cells and neurons

CMV • Ductal epithelium, leukocytes

EBV •Oropharyngeal

epithelium, B lymphocytes

KSHV •Endothelium,

B cells


Take Home points Latency and potential for reactivation Immunocompromised with defective cell mediated immunity at risk of severe disease HSV- Acyclovir HSV encephalitis: IV ACV improves mortality Chickenpox: lesions in various stages of development Zoster Opthalmicus: opthalmic division of Trigeminal Nerve VZV diagnosis: Tzanck smear- mulinucleate giant cells, PCR CMV : Mononucleosis without exudative pharyngitis CMV retinitis, colitis, pneumonia CMV dx: PCR, cells with classic inclusions on biopsy EBV: IM, Heterophile antibody positive Transforming virus: EBV, KSHV, HHV-8

Herpes 2010 gupte مهم