1. VIRAL INFECTIONS
Part II
IHAB YOUNIS, MD

2. Herpes simplex

3. 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)

4. 1- Acute herpetic gingivostomatitis
Clinically
1- 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

5. 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

6. Course Acute disease lasts 5-7 days Symptoms subside in 2 weeks
Viral shedding from the saliva may continue for 3 weeks or more

7. 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

8. 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.

9. 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

10. 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.

11. 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

12. 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.

13. 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

14. 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

17. Histopathology Epidermal spongiosis Intraepidermal vesicle formation
Dermal inflammatory infilt

19. 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)

20. 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

21. 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

22. 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)

23. 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

24. 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

25. 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

26. 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

27. Eczema herpeticum

28. 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

29. 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

30. 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

31. Eczema herpeticum

32. Treatment Acyclovir IV or orally
Eczema treated as usual but steroids are used cautiously
Patients with atopic dermatitis should be aware of herpetic infection

33. Herpes zoster
(Shingles)
Zoster=girdle

34. 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.

35. 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

36. 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

37. 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

39. 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

40. Treatment -Acyclovir 800 mg orally 5 times/d. for 7-10 d
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

41. For postherpetic neuralgia:
I- For stabing pain : Anticonvulsants:
1-Gabapentin (Neurontine,Gaptin,Conventine)
mg orally 3 tds
2-Phenytoin (Dilantin)100 to 300 mg orally at bedtime; increase dosage until response is adequate
3-Carbamazepine (Tegretol) mg orally
1-3 times/day

42. 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

43. Investigations Tzanck smear
Biopsy is required for definitive diagnosis
PCR

44. Immunologic tests for viral antigen
Direct immunofluorescence or immunoperoxidase stains
Radioimmunoassay
Enzyme-linked immunosorbent assay
Agar gel immunodiffusion
Immunoelectrophoresis

45. Serology for VZV antibodies
Neutralizing or complement-fixing antibody tests
Enzyme-linked immunosorbent assay
Radioimmunoassay
Membrane antigen immunofluorescence
Immune adherence hemagglutination

46. Chickenpox
(Varicella)

47. 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

48. 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

49. Rash
The characteristic rash appears in crops
There are 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

51. 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)

52. In-Utero Infections 1-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

53. 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

54. 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

55. Treatment Pruritus is managed with cool compresses and regular bathing
Scratching is discourage to avoid scarring
Antivirals in adults

56. 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

57. 99% develop immunity after the recommended two doses
It is still % 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

58. Rubella
(German Measles)
“little red”

59. 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

60. Clinically Postnatal 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

61. 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

62. 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

64. 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%

65. Investigations
1-Isolation of rubella-specific IgM antibodies in serum using ELISA
2-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

66. 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 months
-The second dose is received at age 4-6 years

67. Measles(rubeola)

68. 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

69. 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

70. 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

71. 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

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

73. Exanthem
Koplic spots

74. Investigations
IgM antibody testing by ELISA

75. 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

76. Erythema infectiosum
(Fifth disease)

77. 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

78. Approximately 70% of total cases occur in children aged 5-15 years
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

79. 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

80. 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

81. Lace-like rash
Slapped face

82. Investigations
IgM Ab is usually detectable within 3 days of onset of symptoms by ELISA

83. (Papular Acrodermatitis of Childhood)
Gianotti-Crosti Syndrome
(Papular Acrodermatitis of Childhood)

84. 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

85. 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

86. 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

87. 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%)

89. Pityriasis rosea

90. Etiology PR 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

91. 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

92. 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

93. Generalized eruption appears within hours to 3 months later
It consists of salmon-colored macules or
patches(medallions), 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

94. 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

96. I-Variations in distribution
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

97. II-Variation in morphology
4-Unilateral:Lesions do not cross the midline
5-Drug-induced:Frequently observed without the herald patch. Reported with captopril, metronidazole, isotretinoin, penicillamine, levamisole, bismuth, gold, barbiturates, ketotifen, clonidine
II-Variation in morphology
1- Pityriasis circinata et marginata of Vidal: Large patches,few in number& may coalesce
2-Papular:Scaling papules in the normal distribution

98. 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%

99. Differential diagnosis
Erythema Dyschromicum Perstans
Pityriasis Lichenoides

100. Secondary
syphilis

101. Guttate psoriasis
Pityriasis
versicolor
Tinea corp.

102. Histopathology Parakeratosis, spongiosis,dermal vasodilatation
&superficial dermal
infilterate

103. Treatment Most cases require no treatment
Topical steroids can be given if itching is severe