Viral Infections that Affect the Oral Cavity

Dr. Monica Helcer Oral Medicine Department

Viral Infections
DNA viruses Herpes family Herpes Simplex V Varicella Zoster V Epstein Barr V CytoMegalo V Human Papilloma V. Measles (Paramyxovirus) German Measles- Rubella (Paramyxovirus) Mumps (Paramyxovirus) RNA viruses Coxsackie's (Enterovirus) Herpangina Hand foot and mouth Acute Lymphonodular Pharyngitis
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PART I

PART II

Herpes Simplex Virus - HSV

HSV-1 : Primary Herpetic Gingivostomatitis (PHGS) Secondary (=Recurrent) Herpes Labial Intra-oral Herpetic Withlow (finger) HSV-2 : genital herpes
Enveloped virus
glycoprotein

envelop

Viral DNA Viral capsid

HSV : Distribution
1. HSV-1 : 70-90% above the waist Mouth Skin Ocular, nasal region (usually self inoculation) Transmitted by saliva or direct contact 2. HSV-2 : 70-90% below the waist genital area Transmitted by sexual contact
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Statistics
Frequency : USA: evidence of serological infection with HSV-1 approaches 80% in the general adult population Only about 30% of these individuals have clinically apparent outbreaks Mortality/ Morbidity : usually none Severe complications may be associated with HSV infection in : pregnant females & immunosuppressed patients May develop disseminated disease and encephalitis
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Primary Herpetic Gingivostomatitis (PHGS)

Most cases are asymptomatic, sub-clinical Symptomatic : + early childhood Adults : immunocompromised Infection during pregnancy : congenital defects Lesions may be accompanied by : lymphadenopathy, low grade fever, fatigue, dysphagia, sore throat

Clinical Features of PHGS

Painful vesicles in erythematous & edematous base ulcers crusts Skin and mouth Spontaneous healing (7-14 days)

PHGS : Intra-oral

PHGS : Labial, Gingival

PHGS : Palatal Lesions

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PHGS: tongue

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Primary HSV and Superinfection: opportunistic bacteria and/or fungal

More frequent in immunosuppressed patients

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Secondary Lymphadenitis

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Latency Period : Trigeminal Ganglia

After primary infection the virus may be latent for a variable amount of time (months to years) until a recurrence is triggered
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Recurrent disease : Clinical considerations

Recurrent outbreaks usually less severe than primary infection Age of onset : older than PHGS (young adults, adults) Triggers for recurrent disease: Sun exposure Stress Pregnancy Menstruation Trauma Allergy Resp. illness Immunosuppression Malignancy
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Secondary Infection (reactivation of virus)

HSV lesions tend to recur at or near the same location within the distribution of a sensory nerve Podromal symptoms : Itching Burning sensation Paresthesia Pain Location of lesions : Most common site : vermillion Intra-oral : less common
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border of lips

Recurrent Infection : Labial

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Recurrent Infection : Intra-oral

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Recurrent : Healing (7-10 days)

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Herpetic Withlow : secondary infection affecting fingers - self-inoculation

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Diagnosis of HSV :
Clinical Presentation : history signs symptoms Direct Microscopic examination of cells from base of lesion (smear or biopsy) Viral Culture and Ag detection from vesicular fluid Serology
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Diagnostic Considerations :
Microscopic Examination: Acantholysis (Tzanck Cells) Intercellular edema (vesicle) Balloning degeneration (clear cells) Inclusion bodies Multinucleated cells Inflammatory infiltrate Same as for VZV : Not Diagnostic

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Diagnostic Considerations
Best diagnosis made by:
isolation of virus in tissue cultures (cytophatic effect on cells)

confirmation by demonstration of HSV-Ag in scraping from lesion or vesicular fluid Most specimens can be identify within 48h after inoculation, spin amplified cultures (shell vial assays) within 24h Sensitivity varies with : Stage of lesion (vesicular lesion > ulcerative lesions) Whether is first or recurrent disease ( in first episodes) Whether the sample is from immunocompromised or immunocompetent (immunocompromised patient Ag level)

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Viral culture

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Serology :
Only 5% positive for demonstration of seroconversion Should be used to identify asymptomatic carriers of infection (epidemiologic studies)

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Treatment of HSV Infection

Usually palliative treatment : analgesic, antipyretic, anesthetic mouth rinses, hydration For recurrent cases : Acyclovir (Zovirax, Supravir, Viroxy), Valacyclovir (Valtrex) topical 5%, 5X/day, from beginning of podromal signs/symptoms For severe cases or immunosuppressed patients : Acyclovir PO/ IV, 400mgX5/day For resistant cases : Foscarnet or Famcyclovir may be needed

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Varicella Zoster Virus (VZV)

Primary infection : Varicella (=Chickenpox) 90% children disease <10y.old Rare in adults : immunosuppressed Asymptomatic or symptomatic Highly contagious ( HSV) Contamination : inhalation of airborne resp. droplets from an infected host or direct contact The typical patient is infectious for 1-2 days prior to the development of rash and for 4-5 days afterwards which is usually the time at which the last crop of vesicles has crusted
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Clinical Features
Frequency : chickenpox is a common disease that affects mostly pediatric population Affect mucosa and skin (scalp, face, trunk, proximal limbs) First symptoms : malaise, fever, pharyngitis, pruritus, nausea, headaches, rash The lesions are characterized by : erythematous macules papules (1214h) vesicles pustules crust scarring (sometimes) Recovery : 2-3 weeks
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Mortality/Morbidity & Complications

Mortality/Morbidity: Affecting healthy children : usually self-limited Mortality : + immunosuppressed Complications : Secondary bacterial infection of skin lesions is a common complication (staph., strept.) scarring Congenital infection due to maternal chickenpox :

congenital defects
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Varicella: Primary Infection- skin

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Varicella: Intraoral

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Treatment of Varicella
1. Usually palliative: analgesic, antipyretic, anesthetic mouth rinses 2. Anti-pruritic agents (e.g. Benadryl) 3. Hydration 4. Passive immunization with Varicella Zoster Immunoglobulin G (VZIG) or acyclovir PO/IV may be needed for an immunosuppressed or pregnant patient 5. VZV active vaccine : approved in 1995 in USA, live attenuated vaccine (OKA strain) for prophylactic use in healthy children and adults. Studies in Japan showed seroconversion rates and long term immunity
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Latency
After primary infection VZV spreads from mucosa/ skin to local sensory nerves where it stays latent for a variable period of time at the Dorsal Spinal Ganglia or Trigeminal Ganglia

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Secondary Infection : Herpes Zoster (Shingles)

Reactivation of primary infection + elderly adults, immunosuppressed patients Unilateral involvement !! Usually in cellular immunity is believed to trigger the reactivation of the virus Zoster infection in patients < 40y. : may be the earliest sign of AIDS therefore these patients should be assessed for HIV risk factors Herpes Zoster presents as a vesicular rash in a dermatome distribution that usually is associated with pain Affected dermatomes : thoracic (56%), cervical (17%), trigeminal nerve (12%), lumbar (10%), sacral (5%) Inflammation of peripheral nerves can persist for months and lead to demyelization and sclerosis

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Frequency
USA : cumulative incidence is 20%, or an annual rate of 3 -5 cases/ 1000 persons Incidence with age and impaired immune status Immunosuppressed adults (HIV, malignancy) : risk, 3040%, can be life threatening 45% of BMT patients have reactivation of VZV, including localized and disseminated cutaneous disease and visceral involvement, 10% mortality Internationally : no accurate data is available, but incidence is to that in USA
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Clinical features of Zoster Infection

The clinical manifestation of Zoster infection can be divided into : 1. Pre- eruptive phase (pre-herpetic neuralgia) 2. Acute eruptive phase 3. Chronic phase (post-herpetic neuralgia)
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Pre- eruptive phase

Characterized by unusual skin sensation and lymphadenopathy 80%: burning, itching or paresthesia that typically is localized to a dermatome distribution These symptoms usually last for several days/ weeks before cutaneous eruption appears The burning pain prior to the characteristic eruptions may present a diagnostic dilemma because it can simulate migraine headaches, tooth pain During this time also : malaise, myalgia, fever
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Acute eruption phase

Marked by the emerge of vesicular eruptions Almost all adult patients experience pain (acute neuritis) Crust formation and drying occur over 7-10 days and are followed by resolution at 14-21 days Patients are infectious until lesions are dried

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Zoster: Oral & Intra-oral

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Chronic Phase : Post-herpetic Neuralgia

Pain persists for 1-2 months after resolution of lesions Frequency of occurrence : 70% of cases that affect elderly Most patients report deep, burning or aching pain, paresthesia, dysesthesia, hyperesthesia or electric shock-like pain The pain can be very extreme and incapacitating Treatment : Zostrix cream (Capsaicin), Elatrolet P.O. (TCA-Amitryptilin)
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Complications
Ramsey- Hunt syndrome:
1. Cutaneous lesions along the auditory canal, ipsilateral side 2. Auditory nerve involvement -hearing deficits 3. Facial nerve paralysis ( Bells palsy), ipsilateral side

Herpes Zoster Ophthalmicus :

Lesions may occur in any of the 3 branches of the ophthalmic nerve(frontal, lacrimal, nasociliary nerves) 7-10% of VZV cases develop eye problems 28% develop long term sequela that may result in blindness
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Diagnosis of VZV Infection

Clinical presentation (unilaterality)
Cytology Viral isolation (culture) Antigen detection (culture) DNA detection (culture) Serology

HPV HSV VZV

= HSV not diag. Difficult to isolate (only 40% positive)

Ab titers later Only for primary infect.

EBV CMV COXS

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Treatment
Supportive therapy : antipyretic, antipruritic, analgesics/capsaicin for neuralgia Immunosuppressed patients and severe cases : PO/ IV Acyclovir, Valacyclovir, Famcyclovir

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Epstein Barr Virus (EBV)

Primary disease : Infectious Mononucleosis (= Kissing Disease, Glandular Fever) Contamination : saliva (kissing), sharing objects Children : usually asymptomatic Young adults & adults (+ 15-24y old) : symptomatic Frequency : about 90% worlds population is infected with EBV Incubation period : 30-50 days Podromal symptoms (1-2 weeks): fever, fatigue, malaise, anorexia
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Signs & Symptoms

Oral signs & symptoms : Pharyngitis Tonsilitis Petechia in hard/soft palate (25% of cases) Exudates in the fauces ANUG like symptoms Systemic signs & symptoms : Bilateral lymphadenopathy Fever Hepatosplenomegaly + abnormal liver functions Maculopapular rash Eyelid edema Symptoms of upper resp. tract inf. Symptoms persist for 2-3 weeks, but fatigue is often more prolonged
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Clinical Features
After initial inoculation the virus replicates in nasopharyngeal epithelial cells and spreads to contiguous structures such as salivary glands and oropharyngeal lymphoid tissues Primary infection is followed by a latency period (characteristic of herpesviruses) in lymphocytes and epithelial cells EBV is also associated with other conditions (mostly in immunosuppressed): Burkitts Lymphoma Nasopharyngeal carcinoma Hairy leucoplakia Sialadenitis
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Diagnosis & Treatment of EBV

Diagnosis : Clinical presentation WBC count : 70-90% of cases lymphocytosis Atypical lymphocytes Serology : Paul - Bunnel Heterophil Ab + 90% of cases

Treatment : Bed rest Palliative (analgesics, antipyretic, hydration) Sometimes antiviral therapy (Gancyclovir) Short duration steroids for immunosuppressed patients (against pharyngeal edema)

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Cytomegalovirus (CMV)
Primary infection : children, asymptomatic Secondary infection : old adults, immunosuppressed patients Contamination : all physical secretions : saliva, blood, sexual contact, breastfeeding, placenta Infection during pregnancy : congenital defects Signs & symptoms EBV Immunosuppressed : Variety of clinical syndromes and multiple organ-system involvement (pneumonitis, GI disease, renitis,..) Disease severity depends on degree of host immunosuppression Infection may occur because of reactivation of latent viral infection or may be newly acquired via organ transplant or BMT from a sero - positive donor
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Histopathology of CMV
CMV usually infects epithelial cells. The infected cells are larger than uninfected Have both nuclear (owl's eye) and cytoplasmic blue inclusion bodies (arrow shows one infected cell).

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CMV Diagnosis & Treatment

Cytology Viral isolation (culture) Antigen detection (culture) DNA detection (culture) Serology

HPV HSV VZV EBV CMV COXS

Treatment : Gancyclovir, Foscarnet, Acyclovir, Cidovir, CMV- Ig

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References

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Oral Pathology : Clinical & Pathologic Correlations Regezi, Sciuba Oral & Maxillofacial Pathology Neville Principals of Internal Medicine Harrisons Medical Microbiology PR Murray, KS Rosenthal, GS Kobayashi, MA Pfaller Interpretation of Diagnostic Tests Wallace eMedicine : Herpes Simplex, article by Gisela Torres, MD, May 20, 2003 eMedicine : Herpes Zoster, article by Tomazs M Ziedalsky, MD, April 8, 2002 eMedicine : Mononucleosis and Epstein Barr Virus, article by Glenma B Winnie, MD, July 8, 2003 eMedicine : Cytomegalovirus, article by Mark R Schleiss, MD, Dec. 18, 2003