VIRAL INFECTIONS

IHAB YOUNIS, MD

Part II

Herpes simplex

Etiology• HSV(types 1&2) is a double-stranded DNA virus• Characterized by: 1-Neurovirulence:the capacity to invade and replicate in nerves 2-Latency: latent infection in sensory nerve ganglia 3-Reactivation:induced by a variety of stimuli

(eg, fever, trauma, emotional stress, sunlight, menstruation)

Clinically1- Acute herpetic gingivostomatitis

• Occurs in children aged 6 months to 5 years

• Mode of infection: Infected saliva from an adult or another child

• The incubation period : 3-6 days

• Abrupt onset ,high temperature, anorexia and listlessness

• Gingivitis: swollen, erythematous, friable gums

• Vesicular lesions: on the oral mucosa, tongue, lips and later rupture and coalesce, leaving ulcerated plaques

• Tender regional lymphadenopathy • Perioral skin also may be involved because

of contamination with infected saliva

Course

• Acute disease lasts 5-7 days

• Symptoms subside in 2 weeks

• Viral shedding from the saliva may continue for 3 weeks or more

2-Acute herpetic pharyngotonsillitis• In adults, oropharyngeal HSV-1 causes pharyngitis and

tonsillitis more often than gingivostomatitis

• Fever, malaise, headache and sore throat

• Vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils& posterior pharynx

• Less than10% have associated oral & labial lesions

• HSV-2 can cause similar symptoms and is associated with orogenital contact or can occur concurrently with genital herpes

3-Recurrent Herpes labialis• A prodrome of pain, burning & tingling• Followed by the development of erythematous

papules that rapidly develop into tiny, thin-walled, intraepidermal vesicles that become pustular and ulcerate

• In most patients, fewer than 2 recurrences each year, but some individuals have monthly recurrences

• Maximum viral shedding is in the first 24 hours of the acute illness but may last 5 days.

4-Primary genital herpes• Primary genital herpes can be caused by both HSV-1

and HSV-2• Recurrences are more common with HSV-2• Asymptomatic in most patients• Primary genital herpes is characterized by severe

and prolonged systemic and local symptoms. The symptoms of persons with a first episode of nonprimary HSV-2 infection are less severe and of shorter duration

• Preexisting antibodies to HSV-1 have an ameliorating effect on disease severity caused by HSV-2

• Prior orolabial HSV-1 protects against genital HSV-1 but not HSV-2

• Women's symptoms are more severe and women have a higher rate of complications than men

Clinical features in men• Herpetic vesicles appear in the glans penis, the

prepuce, the shaft of the penis, and sometimes on the scrotum, thighs, and buttocks

• In dry areas, the lesions progress to pustules and then crust

• Herpetic urethritis occurs in 30-40% of patients and is characterized by severe dysuria and mucoid discharge

• The perianal area and rectum can be involved in persons who engage in anal intercourse, resulting in herpetic proctitis.

Clinical features in women• Herpetic vesicles appear on the external genitalia, labia majora, labia minora, vaginal

vestibule, and introitus• In moist areas, the vesicles rupture, leaving exquisitely tender ulcers• The vaginal mucosa is inflamed and

edematous. The cervix may be involved in 70-90% of patients

• Dysuria may be very severe and may cause urinary retention

• In men and women, the ulcerative lesions persist from 4-15 days until crusting and reepithelialization occur

• The median duration of viral shedding is about 12 days.

5-Recurrent genital herpes• 60% of patients with 1ry genital HSV-2 have recurrences in the 1st

year• 38% had 6 recurrences/year and 20% had more than 10

recurrences • Both subclinical and symptomatic reactivation are more common

with HSV-2 compared to HSV-1• Recurrent genital herpes is preceded by a prodrome of tenderness,

pain, and burning at the site of eruption that may last from 2 hours to 2 days

• Pain is mild, and lesions heal in 7-10 days and constitutional symptoms are uncommon. The lesions heal in 8-10 days and viral shedding lasts an average 5 days

• The symptoms are more severe in women than men

Subclinical genital herpes• The majority of primary genital HSV infections

are asymptomatic and 70%-80% of seropositive individuals have no history of symptomatic genital herpes Nevertheless, they experience periodic subclinical reactivation with virus shedding, thus making them a source of infection

• The rate of viral shedding may be 1-2% . This fact is important in neonatal herpes because most mothers have no signs and symptoms of genital herpes during pregnancy

Histopathology

•Epidermal spongiosis

•Intraepidermal vesicle formation

• Dermal inflammatory infilt

Investigations• HSV infection is best confirmed by isolation of

virus in tissue culture

• Immunofluorescent staining of the tissue culture cells can quickly identify HSV and can distinguish between types 1 and 2

• Rapid detection of HSV DNA in clinical specimens is now possible with polymerase chain reaction (PCR)

• Antibody testing can demonstrate a primary seroconversion, particularly with HSV-1 in childhood– Because of sero–cross-reactivity, HSV-1 and

HSV-2 are not generally distinguishable unless a glycoprotein G antibody assay is available

– Antibody titer increases generally do not occur during recurrences of HSV.Therefore, the test generally is not used for the diagnosis of mucocutaneous HSV relapse

• Tzanck smear is a time-honored procedure to assist in the diagnosis of cutaneous herpesvirusinfections

• Typically, an intact vesicle is used from which the vesicular fluid is aspirated

• After aspiration, the vesicle should be unroofed aseptically.Using a sterile instrument, the floor of the newly produced ulcer can then be scraped. The obtained material can be spread on a glass microscope slide and then dried and fixed for staining

• Staining can be performed with a Papanicolaou stain,Gram or Giemsa• A positive result is the finding of

multinucleate giant cells.• Using appropriate immunofluorescent

antibody reagents, the smear can distinguish different herpesviruses and nonherpesviruses that may be present (eg, vaccinia, smallpox)

Treatment• 1-Acyclovir (Acyclovir cream, zovirax,

Lovir 400 mg tab))

• Inhibits the thymidine kinase of herpes viruses

• Evidence from multiple clinical trials shows that topical acyclovir has little or no therapeutic effect

• Oral Dose:

-First episode mucocutaneous herpes simplex:

400 mg tid for 7-10 d or until clinical resolution - Recurrent genital herpes: 200 mg PO five

times daily for 5 d

-Chronic suppressive therapy: 400 mg bid or 200 mg 3-5 times daily; reevaluate after 1 y

2-Valacyclovir (Valtrex):• Prodrug rapidly converted to the active drug

acyclovir. More expensive but has a more convenient dosing regimen

• Dose:

-First episode: 1 g bid for 10 d

-Recurrent episode : 500 mg bid for 5 d

beginning within 24 h of onset -Suppressive dosing for HSV: 500 mg to 1 g/d

3-Famciclovir (Famvir)

• Prodrug that when biotransformed into active metabolite, penciclovir

• Inhibits viral DNA synthesis/replication

• Dose:

-Recurrent genital HSV: 125 mg bid for 5 d-Suppression of frequent recurrence of genital HSV: 250 mg bid up to 12 mo

Eczema herpeticum

Etiology• It is caused by a disseminated HSV

infection in patients with atopic dermatitis

• Patients have cell-mediated and humoral defects

• A disorder of infants& children of any age

• Occurs occasionally in adults

• Umbilicated vesiculopustules that progress to punched-out erosions

• The eruption is most commonly disseminated in the areas of dermatitis, with a predilection for the head& trunk. Localized forms also exist

• The vesicles often become hemorrhagic and crusted and can evolve into extremely painful erosions with a punched-out appearance

• These erosions may coalesce to form large, denuded areas that frequently bleed and can become secondarily infected with bacteria

• The eruption continues to spread over 7-10 days and may be associated with a high temperature, malaise, and lymphadenopathy

• Recurrent episodes may also occur but are milder and not usually associated with systemic symptoms

Eczema herpeticum

Treatment• Acyclovir IV or orally

• Eczema treated as usual but steroids are used cautiously

• Patients with atopic dermatitis should be aware of herpetic infection

Herpes zoster

(Shingles)

Zoster=girdle

Etiology• VZV is a double-stranded DNA virus • Infection initially produces chickenpox. Following

resolution of the chickenpox, the virus lies dormant in the dorsal root ganglia until focal reactivation along a ganglion's distribution results in herpes zoster

• Although the exact precipitants that result in viral reactivation are not known certainly, decreased cellular immunity appears to increase the risk of reactivation.

• Regarding primary infection, more than 90% of the population is infected by adolescence, and approximately 100% are infected by 60 years of age

• Herpes zoster affects about 10-20% of the population

Clinically• A prodrome (pain,fever, malaise, headache, and

dysesthesia) occurs 1-4 days before the development of the cutaneous lesions

• Grouped vesicles, usually involving 1, but

occasionally up to 3, adjacent dermatomes• Vesicles become pustular, and occasionally

hemorrhagic, with evolution to crusts in 7-10 days

• Pain may subside in 2-3 w in young patients but may last for 1 m in the elderly

• Pain lasting longer than 1-3 months is referred to as postherpetic neuralgia. It affects 10-15%

• Its incidence & severity increase with age• Types:

-Continuous burnning with allodynia

-Spasmodic shooting

-Crawling pruritus

• Herpes zoster ophthalmicus– Vesicular rashes involving the ophthalmic division of the

trigeminal nerve. Crusting begins on the fifth to sixth day– Hutchinson sign: severe ocular complications can occur with a

vesicular rash anywhere on the forehead

• Herpes zoster oticus– Vesicles involve the external auditory canal, concha, and pinna,

postauricular skin, lateral nasal wall, soft palate, and anterolateral tongue

– Vertigo and sensorineural hearing loss and/or paralysis of the facial nerve may be noted

– Clinically, total loss of the ability to wrinkle the ipsilateral brow differentiates a peripheral seventh nerve lesion from a central seventh nerve lesion, which spares the forehead

Treatment 1-Antivirals:should start within 1-2 d

-Acyclovir 800 mg orally 5 times/d. for 7-10 d -Valacyclovir 1gm orally q8h for 7 d

- Famciclovir (Famvir) 500 mg PO q8h for 7 d

2-Analgesics

3-?Prednisolone 60 mg/d orally tapered over 3 wk

• For postherpetic neuralgia:

I- For stabing pain : Anticonvulsants:

1-Gabapentin (Neurontine,Gaptin,Conventine)

400-1200 mg orally 3 tds

2-Phenytoin (Dilantin)100 to 300 mg orally at bedtime; increase dosage until response is adequate

3-Carbamazepine (Tegretol)100-200 mg orally

1-3 times/day

II- For burning pain :Tricyclic antidepressants:

1-Amitriptyline (Tryptizol 10mg Tab ) 25 mg

orally tds

2-Imipramine (Tofranil 25 mg tab)25 mg orally

1-6 times/d

Investigations

• Tzanck smear

• Biopsy is required for definitive diagnosis

• PCR

• Immunologic tests for viral antigen– Direct immunofluorescence or

immunoperoxidase stains– Radioimmunoassay– Enzyme-linked immunosorbent assay– Agar gel immunodiffusion– Immunoelectrophoresis

• Serology for VZV antibodies– Neutralizing or complement-fixing antibody

tests– Enzyme-linked immunosorbent assay– Radioimmunoassay– Membrane antigen immunofluorescence– Immune adherence hemagglutination

Chickenpox

(Varicella)

Etiology• The varicella-zoster virus enters through the

respiratory system &by direct contact• The virus replicates in regional lymph nodes• After a week, a secondary viremia disseminates

the virus to the viscera and skin • Varicella is highly contagious; secondary attack

rates range from 80-90% for household contacts• Varicella's infectious period begins 2 days

before skin lesions appear and ends when the lesions crust, usually 5 days later

Clinically• Incubation period: 10-21 days

• Prodrome : Low-grade fever, abdominal pain, cough and coryza preced skin manifestations by 1-2 days

• Fever usually is low-grade and subsides within 4 days

• Rash– The characteristic rash appears in crops– There are 250-500 lesions but can be as few as

10 – Lesion starts as a red macule, rapidly develops

into papule, vesicle, pustule and crust– Varicella's hallmark is the simultaneous

presence of different stages of the rash– Rash is centripetal starting on the back– New lesions continue to erupt for 3-5 days, crust

by 6 days and heal completely by 16 days

Investigations• Laboratory studies are unnecessary for

diagnosis because varicella is obvious clinically• Serology is used to confirm past infection to

assess a patient's susceptibility status. This helps determine preventive treatment requirements for an adolescent or adult who has been exposed to varicella

• The most sensitive test is the indirect fluorescent antibody (IFA)

In-Utero Infections1-Congenital varicella syndrome • Occurs in 2% of children born to women who

develop varicella during the first or second trimester

• Manifests as intrauterine growth retardation, microcephaly, cortical atrophy, limb hypoplasia, eye abnormalities and cutaneous scarring

• Fetal injury risk is unrelated to the severity of disease in the mother

• Zoster exposure during pregnancy has not been associated with fetal injury

2-Infantile zoster:

• Manifests within the first year

• The cause is maternal varicella infection after the 20th week of gestation

• Commonly involves the thoracic dermatomes

3-Neonatal varicella • If the mother develops varicella within 5 days before

delivery,the baby acquires the virus transplacentally but acquires no protective antibodies because of insufficient time for antibodies to develop in the mother

• In these circumstances, neonatal varicella is likely to be severe and disseminated

• Prophylaxis or treatment is required with varicella-zoster immune globulin (VZIG) and acyclovir. Without these drugs, mortality rates may be as high as 30%. The primary causes of death are severe pneumonia and fulminant hepatitis

Treatment• Pruritus is managed with cool compresses

and regular bathing

• Scratching is discourage to avoid scarring

• Antivirals in adults

Varicella vaccination• Vaccine was licensed for use in Japan and

Korea in 1988 and in the USA in 1995• It is a live attenuated vaccine• It is given to all infants and to older

children&adultss who have never had chickenpox

• one dose until age 13• Later two doses of vaccine are needed,

given 4-8 weeks apart

• 99% develop immunity after the recommended two doses

• It is still 70-100% effective if given within 72 hours of infection

• The special "zoster vaccine" may be available in 2006 to prevent herpes zoster

• In the USA chickenpox cases and complications of chickenpox have declined by more than 80% compared to 1995

Rubella

(German Measles)

“little red”

Etiology• Rubella virus:a single-stranded RNA

• Portal of entry: respiratory epithelium of

the nasopharynx

• This is followed by a viremia that occurs 6-20 days after infection

ClinicallyPostnatal rubella :• Incubation period: 14-21 days• Prodromal symptoms are unusual in young

children but are common in adolescents and adults

• The exanthem of rubella consists of a discrete rose-pink maculopapular rash ranging from 1-4 mm.

• Rash in adults may be quite pruritic

• The synonym “3-day measles” derives from the typical course of rubella exanthem that starts initially on the face and neck and spreads centrifugally to the trunk and extremities within 24 hours. It then begins to fade on the face on the second day and disappears throughout the body by the end of the third day

• Temperature: Fever usually is not higher than 38.5°C

• Lymph nodes: Enlarged posterior auricular and suboccipital lymph nodes are usually found on physical examination

• The Forchheimer sign(pinpoint or larger petechiae that usually occur on the soft palate) may still be present on the soft palate

Congenital rubella: The classic triad presentation of congenital rubella

syndrome consists of the following: • Sensorineural hearing loss is the most common

manifestation • Ocular abnormalities including cataract, infantile

glaucoma, and pigmentary retinopathy occur in approximately 43%

• Congenital heart disease including PDA and pulmonary artery stenosis is present in 50%

Investigations1-Isolation of rubella-specific IgM antibodies in

serum using ELISA2-Culture using African green monkey kidney cells• It is expensive, time consuming & not readily available• It is the preferred technique in congenital rubella syndrome because rubella serology may be difficult to interpret in view of transplacental passage of rubella-specific maternal IgG antibody

Immunization• A single dose confers long-term immunity,

probably lifelong immunity, against clinical and asymptomatic infection in more than 90% of immunized persons.

• It is given as the MMR immunization:

-The first dose is received at age 12-15 months

-The second dose is received at age 4-6 years

Measles(rubeola)

• Measles was the first exanthem described historically• Measles has been called the greatest killer of children in

history• Despite the availability of an effective vaccine for more

than 30 years , the measles virus still affects 50 million people annually and causes more than 1 million deaths

• Measles was the first exanthem described historically• Measles has been called the greatest killer of children in

history• Despite the availability of an effective vaccine for more

than 30 years , the measles virus still affects 50 million people annually and causes more than 1 million deaths

Etiology• The measles virus is a single stranded RNA

virus • Initially infects the respiratory epithelium and is

transmitted via respiratory droplets• Replication in regional lymph nodes eventually

leads to viremia • Infection with the measles virus leads to a

prolonged immunosuppression, which accounts for much of the morbidity and mortality associated with this disease

Clinically• incubation period of 7-14 days

• The prodrome:– The 3 C's of measles: cough, coryza &

conjunctivitis– Fever and photophobia– These symptoms increase in severity up to

3-4 days prior to the onset of the morbilliform rash

• The enanthem (Koplik spots) predates the exanthem by 24-48 hours and last approximately 2-4 days– These blue-white spots, surrounded by a red

halo– They appear on the buccal mucosa opposite

the premolar teeth and are pathognomonic for measles

• The exanthem itself begins on the fourth or fifth day following the onset of symptoms.– The rash appears as slightly elevated papules

0.1-1 cm in diameter that begin on the face and behind the ear. It spreads to the entire trunk and the extremities

– Initially, the color is dark red and reaches its maximum intensity in approximately 3 days. It slowly fades to a purplish hue and then to yellow-brown lesions with a fine scale over the following 5-10 days

Koplic spotsExanthem

Investigations

• IgM antibody testing by ELISA

Treatment• Treatment for measles generally consists of only

supportive care, with particular attention to maintaining good hydration, especially in the developing world

• Recently, WHO has recommended that vitamin A supplementation be given with measles vaccination in the developing world as measles causes a decrease in vitamin A levels, which may already be low in children who are malnourished

Erythema infectiosum

(Fifth disease)

Etiology• Human parvovirus (HPV) B19• A single-stranded DNA virus • Transmission occurs through respiratory

secretions, possibly through fomites, and parenterally via vertical transmission from mother to fetus and by transfusion of blood or blood products

• The incidence peaks in winter and early spring. HPV B19 epidemics appear to occur in cyclical fashion every 4-7 years and are estimated to affect 30-50% of US households

• Approximately 70% of total cases occur in children aged 5-15 years. Infants and adults are affected infrequently

• Mild prodromal symptoms begin approximately 1 week after exposure and last 2-3 days

• These symptoms precede a symptom-free period of about 7-10 days, followed by a typical exanthem

• Exanthem occurs in 3 phases: -Phase 1: A bright red, raised, slapped-cheek

rash with circumoral pallor -Phase 2 : Occurs 1-4 days later and is

characterized by an erythematous maculopapular rash on proximal extremities and trunk, which fades into a classic lace-like reticular pattern as confluent areas clear

-Phase 3: Frequent clearing and recurrences for weeks, and occasionally months, may be due to stimuli such as exercise, irritation, or overheating of skin from bathing or sunlight

• The rash is often pruritic, especially in adults• Enanthems are virtually never observed• The rash is observed in approximately 75% of

infected pediatric patients.• The patient is no longer infectious when the rash

appears• Arthropathy is observed most commonly in adult

women and occurs in fewer than 10% of children

Slapped faceLace-like rash

Investigations

• IgM Ab is usually detectable within 3 days of onset of symptoms by ELISA

Gianotti-Crosti Syndrome

(Papular Acrodermatitis of Childhood)

Etiology• Gianotti-Crosti syndrome likely represents

a localized cutaneous inflammatory response to deposition of viral particles or bacteria within the dermis as a result of transient viremia or bacteremia. Deposition of immune complexes in the skin may also play a role

• Although the original reports of this syndrome were attributed to acute infection with the hepatitis B virus, more recent studies have demonstrated that it is more commonly associated with a number of other infectious agents

• The agents reported include Epstein-Barr virus, cytomegalovirus, coxsackievirus and other enteroviruses, parainfluenza virus, parvovirus B19, poxvirus, human herpesvirus v 6 (HHV-6), rotavirus, human immunodeficiency virus, and group A beta-hemolytic streptococci

Clinically• Monomorphous pale, pink-to-flesh–colored

or erythematous 1- to 10-mm papules or papulovesicles

• Localized symmetrically and acrally over the extensor surfaces of the extremities, the buttocks, and the face

• Extensive involvement of the trunk is not consistent with a diagnosis of Gianotti-Crosti syndrome

• The eruption typically lasts at least 10

• Pruritus accompanies the eruption in 23% of patients

• Other findings upon physical examination include the following:

-Fever (27%(

-Lymphadenopathy (31%)

-Hepatosplenomegaly (4%)

Pityriasis rosea

EtiologyPR has often been considered to be a viral

exanthem• Its clinical presentation supports this concept• PR has been linked to upper respiratory infections• It can cluster within families and close contacts• It has an increased incidence in immunocompromised

individuals• Incidence may increase in fall and spring• A single outbreak tends to elicit lifelong immunity • Increased amounts of CD4 T cells and Langhans cells

are present in the dermis; this observation may indicate viral antigen processing and presentation

• A recent work demonstrated human herpesvirus (HHV)–7in both the lesions and the plasma in patients with PR

• However, follow-up studies have not confirmed a herpes etiology, and because HHV-7 is frequently found in healthy individuals, its etiologic role is controversial

• One study found it to be twice as common in women as in men

Clinically• The herald patch is usually a single pink

patch, 2-10 cm in diameter, on the neck or the trunk with a fine collarette scale

• It is observed in more than 50% of patients and it may be multiple

• Generalized eruption appears within hours to 3 months later

• It consists of salmon-colored macules or patches(medallions), 0.5-1.5 cm in

diameter, with a collarette scale• The long axes of the lesions are oriented

in a parallel fashion along cleavage lines, giving the classic Christmas tree pattern

• These secondary lesions most commonly occur on the trunk, the abdomen, the back and the proximal upper extremities

• Pruritus occurs in 75% of patients and is severe in 25%

• Lesions disappear im1-8 W

• Second attacks occur in 2% of patients

Variations• Atypical PR occurs in 20% of patients

I-Variations in distribution

1-Localized:Lesions may be localized to single areas, such as the abdomen

2-Inverse:Lesions occur on the face & distal extremities&it is more common inchildren

3-Burnt out: The herald patch may be the only manifestation of the disease

4-Unilateral:Lesions do not cross the midline5-Drug-induced:Frequently observed without the

herald patch. Reported with captopril, metronidazole, isotretinoin, penicillamine, levamisole, bismuth, gold, barbiturates, ketotifen, clonidine

II-Variation in morphology1- Pityriasis circinata et marginata of Vidal: Large

patches,few in number& may coalesce2-Papular:Scaling papules in the normal

distribution

3-Vesicles, pustules or urticarial or purpuric plaques

4-Erythema multiforme–like plaques

5-Oral involvement may occur as punctate hemorrhages, ulcers, papulovesicles, bullae, or erythematous plaques. Most studies find the incidence to be less than 10%

Differential diagnosis

Pityriasis Lichenoides

Erythema Dyschromicum Perstans

Secondary syphilis

Guttate psoriasis Tinea corp.

Pityriasis

versicolor

Histopathology

Parakeratosis,

spongiosis,dermal

vasodilatation

&superficial dermal

infilterate

Treatment• Most cases require no treatment

• Topical steroids can be given if itching is severe