Viral infections of the face Oktay Avci MD, Ilgen Ertam MD PII: DOI: Reference:

S0738-081X(14)00044-3 doi: 10.1016/j.clindermatol.2014.02.010 CID 6827

To appear in:

Clinics in Dermatology

Please cite this article as: Avci Oktay, Ertam Ilgen, Viral infections of the face, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.010

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ACCEPTED MANUSCRIPT Viral infections of the face

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Oktay Avci, M.D.1, Ilgen Ertam, M.D.2

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1: From the Department of Dermatology, Dokuz Eylul University, Izmir, Turkey

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2: From the Department of Dermatology, Ege University, Izmir, Turkey

Correspondence: Oktay Avci, M.D., Department of Dermatology, Dokuz Eylul University, 35340 Narlidere, Izmir, Turkey

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Phone: 90 232 4123851

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E-mail: [email protected]

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Facsimile: 90 232 4646308

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Abstract Viral infections affecting the face may cause significant morbidity, cosmetic disfigurement

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and psychological distress. The success of therapy needs whole and correct evaluation of the clinical signs and symptoms. Some viruses such as Papillomaviridae, Herpesviridae and

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Polyomaviridae primarily infect the facial skin while others affect the face infrequently as in parapox virus infections. Sometimes, involvement of the face can be a part of more

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generalized eruption and systemic symptoms in viral infections caused by Todaviridae, Flaviviridae, Arenaviridiae and Flaviviridae . Clinical diagnosis can be challenging in various viral diseases when they occur in non-endemic geographic areas. The objective of this review was to concentrate on epidemiological and clinical characteristics of the viral illnesses with

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facial skin involvement.

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and face

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Key words: viral skin disease, viral facial diseases, diseases of face, viruses and skin, viruses

Conflict of interest: None

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Introduction Viruses are obligate intracellular pathogens . A virus particle (Virion) has a length of nucleic

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acid, either RNA or DNA. While enveloped viruses are surrounded by a lipid bilayer, nonenveloped viruses are surrounded by a proteinaceous capsid. Viral entry into the host cell is a

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critical step in the viral life cycle and the genetic information of the virus encodes proteins involved in viral replication. The entry of both enveloped and non-enveloped viruses requires

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interactions between host cell molecules, or receptor to produce systemic infection and they enter the body via mucous membranes after inhalation, ingestion or contact. Viruses evade or inhibit important elements of the innate immune system, namely the type I interferon

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response1.

Due to the defects of the barrier function of the integument such as a fissure or a scratch or by

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direct inoculation , the skin can serve as a portal of viral entry. Viruses differ in the type of cells which they can infect, and tissue tropism and host specificity are the main features of

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viral infections. For instance, hepatitis B virus can infect liver cells while human

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papillomaviruses infect keratinocytes of skin and mucosa. After viral entry via different mechanisms, genetic information of the virus requires host cell ribosomes for translation. In acute infections, the time required for viral replication is measured in hours. Newly produced virions can invade adjacent cells or can disseminate via the bloodstream. Due to the development of an immune response against the virus particles, containment and clearance of the infection occur2, 3. The involvement of the facial skin during a viral infection may be associated with significant morbidity, inconvenience, pain, cosmetic disfigurement and psychological distress. An overall evaluation of the clinical symptoms and general health of the patient is essential to the success of the therapeutic interventions for viral infection with the involvement of facial skin.

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We want to give here an overview about the symptoms and signs of viral diseases affecting the face.

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A classification of viruses that cause diseases in humans with facial skin involvement is given in Table 1.

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Papillomaviridae

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Warts

Warts are the cutaneous manifestations of human papillomavirus (HPV) infection. They may exist in different clinical forms. Common warts (Verruca vulgaris), plantar warts (Verruca plantaris), flat warts (Verruca plana), and genital warts (Verruca genitalis) are main clinical

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manifestations of HPV infection. They may occur in up to 10% of children and adolescents

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with greater frequency in girls than in boys. The greatest incidence is between 12 and 16 years of age with a peak of 13 years of age in females and 14,5 years of age in males 4,5. Viral warts

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may spontaneously disappear after two years without treatment in 40 percent of children6

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while those children without wart treatment potentially may be reservoirs for virus transmission. In case of their location in visible areas, warts may be viewed as socially unacceptable.

HPVs are small DNA viruses that have a double-stranded DNA genome of nearly 8,000 base pairs and are strictly epitheliotropic .More than 120 different types of HPV have been identified to date7. After entry, viruses adapt their life cycle to the differentiation of the host cells. HPVs are classified into mucosal/genital and cutaneous types based on clinical features and sequence analyses. L1 gene sequences of HPVs caused identification a series of taxonomic units such as alpha-, beta-, and gamma- PV8. Cutaneous HPVs are phylogenetically heterogeneous and cutaneous warts –associated types are species 2 and 4 of

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alpha-PV, mu-PV, and nu-PV. These can be distinguished from the Epidermodysplasia verruciformis-associated or EV/cutaneous types of beta-PV and gamma-PV8,9. The incubation

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period for cutaneous warts is long and variable, and has been estimated to range between a

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few weeks and months10,11. Warts are spread by direct or indirect contact, and impairment of the skin barrier function by trauma or maceration predisposes to inoculation of HPV. For

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example, common hand warts may spread to the lips and perioral area, and especially round

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the nails in children who bite their nails or cuticle or suck fingers habitually. It is also known that shaving may cause new inoculations over the beard area10. It has been suggested that for lesion maintenance, infection of an epithelial stem cell is necessary12. Since stem cells are abundant within the hair follicle, hair follicles may be an

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important portal of entry for HPVs such as HPV 5 that cause inapparent or latent infections

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in the general population, but may cause a problem in immuno-suppressed people13-15.

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Common warts

are rare.

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HPV 2 , 4 and 28 cause cutaneous wart in the general population while types of 27, 29 and 48

Filiform warts occur on the face and neck, commonly in the male. Eyelids, beard region, and nostrils are preferential sites. Typically they are a long, fleshy-based stalks with a papilliferous frond-like appearance. In children, filiform warts mostly occur around the mouth or lips, often coexisting with hand warts presumably serving as the source of facial infection. Filiform warts may be confused with fibromas. HPV types of 3, 10 or 28 cause plane warts. These are epidermal flat-topped papules, 1-5 mm or more in diameter. They are round or polygonal in shape and are flesh-colored or lightly pigmented with little hyperkeratosis. The face and dorsa of the hands are the sites of

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predilection. The number of plane warts varies from a few to hundreds, and may spread due to scratching in a linear arrangement. Plane warts on the face, due mainly to HPV 3 and HPV

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10, have sometimes been associated with laryngeal papillomas. After months or years,

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regression of plane warts may occur and is usually heralded by itch, erythema and edema due to an inflammatory reaction within warts. During this phase, previously unnoticed warts may

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become evident, and depigmented haloes may appear around the warts16, 17.

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Lichen planus may cause some difficulties in differential diagnosis. It is itchy and unusual in the face. Flat lichen papules are lilac-pink in color, shiny, and may show Wickham‟s striae. Seborrheic warts of old individuals may also be confused with plane warts.

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Epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare heritable disorder, first described by

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Lewandowski and Lutz in 1922. The susceptibility to EV is due to a defect in cellular

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immunity and the cases are linked to chromosome X. The disease is characterized by a predisposition to infection with disease-specific HPVs, named EV-HPV types (now termed β-

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HPV types) including HPV types 5, 8, 9, 12, 14, 15, 17, and 19-25 that are harmless for the general population. The disease is lifelong and originally described as a genodermatosis8,10,19,20. The disease is characterized by parental consanguinity and sibling involvement and mental retardation can be observed in some cases18. Sporadic cases were also reported21. The cutaneous lesions generally manifest in childhood or at puberty and are polymorphic. EV exhibits flat wart-like lesions and erythematous macules on the face and neck initially. Slightly scaly macules, brown, red or white in color, coalesce into large patches resembling pityriasis versicolor and develop on the trunk, neck, arms and face a few years after. The lesions may affect entire skin and perineum. Actinic keratosis-like lesions are observed after middle age and occur mainly on the sun-exposed regions and trunk18. Isolated

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seborrheic keratosis-like lesions can be observed mainly on the forehead, neck and trunk22,23. Polymorphous lesions on sun-exposed areas proceed into cutaneous squamous cell carcinoma

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(SCC) in about 30% of the patients24,25. HPV types of 5 and 8 have been found in 90% of

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SCC in these patients26. In benign EV clinical form, lesions are more monomorphous and consists of plane warts due to the infection with HPV 3 and/or 10. EV cases in which

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malignant transformation occurs, present with polymorphic, pityriasis versicolor-like lesions,

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plane wart-like lesions and erythematous macules27-29. In some patients, malignant transformation occurs predominantly on the face, mainly on the forehead, and is rarely observed in non-exposed skin areas28,30,31.

In biopsy specimens, features of the cytopathic effect have been described histologically,

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including clarification of cytoplasm, small nuclei and pyknotic and small basophilic granules

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mostly in the upper epidermal layers. In specimens that were taken from the lesions with

observed29,32.

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Polyomaviridae

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malignant transformations, findings of Bowenoid cancer in situ and SCC have been

Polyomaviruses are small non-enveloped double-stranded DNA viruses that can infect mammals and birds. In humans, polyomaviruses can infect the central nervous system, skin, urinary tract and possibly the respiratory tract. Skin diseases that have been reported to have a causal relationship with polyomaviruses include Merkel cell carcinoma and viral-associated trichodysplasia Merkel Cell Carcinoma Merkel cell carcinoma is frequently seen in head and neck region. It is most commonly seen in the elderly and in patients with immunosuppression. It is a rare, aggressive skin tumor

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exhibiting neuroendocrine differentiation. The recently discovered human polyomavirus species, the Merkel cell polyomavirus (MCPyV or MCV), has been detected in 80% of

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Merkel cell carcinomas but only in 8% of controls33. Viral DNA has been found to be

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integrated within the tumor genome in a clonal pattern, suggesting that viral integration is an

etiological factor in this carcinoma33,34.

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early event in Merkel cell carcinogenesis and that Merkel cell polyoma virus may be an

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The primary lesion is asymptomatic. Patients with generalized lesions or metastasis may have constitutional symptoms such as fatigue. Most lesions are located on sun-exposed areas, particularly perioral and periorbital region. The appearance is a pink-red or violaceous, firm, dome-shaped solitary nodule with a smooth, shiny surface, sometimes with telangiectasia.

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The nodule grows rapidly. After excision, recurrences occur frequently33,34 (Figure 1).

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Viral-associated trichodysplasia (Trichodyplasia spinulosa)

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Trichodysplasia spinulosa (TS) is a rare skin disease exclusively appears in immunocompromized patients and is characterized by follicular papules and keratin spines

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that become widespread on the central portion of the face. The disease is also known as pilomatrix dysplasia, virus-associated trichodysplasia or cyclosporine-induced folliculodystrophy. The lesions involve particularly the nose, eyebrows and auricles; however, other skin areas can be affected as well. Thickening of the facial skin, loss of eyebrows, sometimes also the eyelashes and scalp hair may cause distortion of facial features and a leonine appearance. Keratin spicules, 1-3 mm in length, originate from the abnormal maturation of hair follicles with increased inner root sheath cells containing excessive amounts of trichohyaline35-37. Herpesviridae

ACCEPTED MANUSCRIPT The herpesvirus group includes relatively large DNA viruses. They replicate in the cell nucleus and produce typical intranuclear inclusions. They are divided on the basis of their

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genome into the α, β and γ herpesviruses. Herpes simplex virus (HSV) type 1 and 2 (α),

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varicella-zoster virus (β), human cytomegalovirus (β), human herpes virus 6 (β), human herpes virus 7 (β), Epstein-Barr virus (γ) and human herpes virus 8 (γ) are eight members of

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the group that cause human diseases.

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Herpesviruses do not eliminate following clinical recovery and persist their existence throughout the individual‟s life as a latent infection in the strain-specific cells of the host. Under certain circumstances, particularly immune suppression, the virus may show

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reactivation and causes acute infective disease. Herpes Simplex

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HSVs are common human DNA viruses that intermittently re-activate. Herpes simplex virus

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infections are caused by two closely related types of HSV. HSV-1 is mostly associated with orofacial disease, whereas HSV-2 is usually associated with perigenital infection though both

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HSV types can infect oral and genital areas and cause acute and recurrent infections. Both HSV-1 and HSV-2 persist in sensory nerve ganglia after primary infection and remain undetected since they produce no viral proteins while latent. However the virus may travel along the nerve fiber and, if it replicates in keratinocytes or in mucosal epithelia, can cause recurrent illness38, 39. HSV infections can be divided into three stages: acute infection, establishment and maintenance of the latency, and re-activation of virus. The clinical findings of HSV infection depend on the site of infection. Primary infection with HSV is usually more severe, frequently with systemic signs and symptoms and they have a higher rate of complications than recurrent episodes. Herpetic gingivostomatitis and

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pharyngitis are most commonly associated with HSV-1 infection. The symptoms of primary oral herpes may include ulcerative lesions involving the hard and soft palate, tongue, buccal

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mucosa, and neighboring facial areas. Systemic symptoms related to herpes infection are

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fever, malaise, myalgias, irritability, and cervical adenopathy. Re-activation of herpes infections involves the perioral facial area, lips, with the outer one-third of the lower lip.

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Other facial locations include the nose, chin, and cheek. Two-thirds of labial lesions involve

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the vermillion border. In patients with frequent recurrence, lesions may differ in location with each episode. Patients experience pain, burning, or itching at the site of the subsequent eruption. Trigger factors for herpes recurrences include emotional stress, illness, exposure to sun, trauma and menses. Other triggers are trigeminal nerve surgery, ablative lasers, and

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chemical peeling for facial rejuvenation38,39.

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HSV-2 causes a primary orofacial infection in adolescents and young adults following

1 disease.

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genital-oral contact. The reactivation of HSV-2 orofacial infection is less common than HSV-

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Kaposi’s varicelliform eruption and eczema herpeticum Kaposi‟s varicelliform eruption (KVE) is a widespread skin infection with a virus that normally causes localized vesicular eruptions, appearing in an individual with pre-existing skin disorder. Mostly the causative virus is HSV-1. The term eczema herpeticum is now used for more localized infections (Figure 2). Dissemination of other viruses including coxsackie A16 and vaccinia is now rarely seen40,41. Atopic dermatitis is the commonest pre-existing skin disease. Darrier‟s disease42, various bullous disorders43,44, congenital ichthyosiform erythroderma45, ichthyosis vulgaris46, Sézary syndrome and mycosis fungoides47 can also complicated by dissemination of HSV. Extensive spread of herpetic infection on the face following burns48, laser therapy49 or dermabrasion50 has been reported.

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Mostly, eczema herpeticum arises as primary infection though it may result from a recurrent infection. Cases can be at all ages, mostly in the second and third decades 51. Patients with

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eczema herpeticum usually have an intact cell-mediated immunity to HSV52. Systemic steroid

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treatment51 and topical tacrolimus53 may predispose patients to HSV infection and eczema

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herpeticum.

The incubation period may range from 5 to 19 days. A vesicular eruption, quickly becoming

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pustular, appears in crops covering large skin areas. They often generalize beyond the preexisting diseased skin, simulating smallpox41. New crops of vesicles may continue to develop during the next 5-7 days and vesicles may become hemorrhagic. The face may become severely edematous. Fever develops 2-3 days after the appearance of the eruption and

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subsides in 4 or 5 days after the pustules become crusted. The regional lymph nodes are

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enlarged. Rarely a fatal outcome may occur. The lesions heal slowly, leaving slight scarring51,54-57.

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HSV infections are the most common precipitating factor in recurrent erythema multiforme.

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A history of herpes labialis preceding the erythema multiforme can be obtained in 65% of patients. HSV antigen gB and HSV DNA have been demonstrated in erythema multiforme lesions58,59. HSV-associated erythema multiforme is usually an acute, self-limited, recurrent disease. The lesions are usually symmetric, especially on acral extremities and face, and over the elbow and knees39. Herpes simplex folliculitis is characterized by recurrent folliculitis mostly on the cheek associated with pain. Follicular papules and vesicles are seen on the face. Typical clinical appearance can not be seen in all cases and differential diagnosis from other types of folliculitis may be challenging. Polimerase chain reaction (PCR) has been reported to be more sensitive to diagnose herpes simplex folliculitis60.

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Varicella and Herpes Zoster

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Varicella (Chickenpox)

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Varicella zoster virus (VZV) is a member of the herpesvirus family. Varicella is an acute, highly contagious exanthem that occurs most often in childhood. The rash usually begins on

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the face and scalp and spreads rapidly to the trunk. Lesions are scattered and progress from rose-colored macules to papules, vesicles, pustules, and crusts. Lesions at all stages are

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usually present in the body at the same time. Entry of VZV is through the mucosa of the upper respiratory tract and oropharynx. The major site of virus replication is reticuloendothelial system. After the primary viremia, the virus is cleared by cells of the

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reticuloendothelial system. Approximately 2 weeks after infection, a much larger (secondary) viremia and associated symptoms and lesions occur. Effective host immune responses

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terminate viremia and limit progression of varicella lesions in the skin and other organs.

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Humoral immunity to VZV protects against varicella61,62. The rash is often preceded by 2 to 3 days of fever, chills, malaise, headache, anorexia, sore

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throat and dry cough. The rash is located on the face and scalp and spreads rapidly down to the trunk. The rash begins as small red dots. Progressing to small bumps in 10-12 hours occurs and blisters and pustules are followed by umblication and formation of crusts. On examination, lesions are at various stages. At the blister stage intense itch is present. A few vesicles can be seen on the palms and soles, and mucous membranes. The typical vesicle is 2 to 3mm in diameter and elliptical, with its long axis parallel to the folds of the skin. An individual with varicella is contagious one to two days before the rash appears and remain contagious until all lesions have crusted over. Adults may have a more widespread rash and longer fever. Varicella pneumonia is more frequently seen complication in adults. In patients

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with varicella vaccine, the usual breakthrough rash is predominantly maculopapular with fewer lesions and fewer vesicles than the rash of natural varicella 61,62.

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Herpes Zoster

During varicella infection, VZV passes from lesions in the skin and mucosal surfaces into the

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contiguous endings of sensory nerves and its transported centripetally up the sensory fibers to the sensory ganglia. The virus establishes a latent infection in the ganglia that persists for life.

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The mechanisms of re-activation of latent VZV are unclear, but re-activation has been associated with immunosuppression, emotional stress, irradiation of the spinal column, local trauma, surgery of the spine, and frontal sinusitis63,64.

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Prodromal pain precedes the eruption by several days and vary from itching, burning, tingling, to lancinating pain. The pain may be constant or intermittent and it is often

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accompanied by tenderness. The prodromal pain may simulate myocardial infection, duodenal

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ulcer and renal colic. The localization and distribution of the rash are distinctive for herpes zoster which is usually unilateral. The area supplied by the trigeminal nerve, and the trunk

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from T3 to L2 are most frequently affected. Between 10 percent and 15 percent of reported cases of herpes zoster involve the ophthalmic division of the trigeminal nerve. The classical lesions of herpes zoster consist of closely grouped red papules or vesicles on an erythematous base. Vesicles form within 12 to 24 hours and evolve into pustules by the third day. These pustules dry and crust in 7 to 10 days. The crusts persist for 2 to 3 weeks. The regional lymph nodes are enlarged and tender. The rash is most severe and lasts longest in older people. The rash of ophthalmic zoster may extend from the level of the eye to the vertex, but it terminates sharply at the midline of the forehead. When lesions localize on the tip and the side of the nose, careful attention must be given to the condition of the eye. Corneal lesions may lead to neurotrophic keratitis and chronic ulceration. Ramsay Hunt syndrome is characterized by

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facial palsy, in combination with herpes zoster of the external ear or tympanic membrane, with or without tinnitus, vertigo, and deafness63-65.

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Human Cytomegalovirus (HCMV) Infection

CMV is a member of the Herpesviridae family which, on infection, produces a systemic

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infection and may result in significant morbidity and mortality if acquired in utero. It infects 40-60% of the population and the infection increases with age66. Humans are the only known

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reservoir for HCMV. Transmission occurs from person to person. Transmission can also occur via saliva, fomites, sexual activity, organ transplantation, breast milk, blood transfusions67. Intrauterine transfer occurs 0.1-1% of births. Perinatal and neonatal infections

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are due to infectious cervical secretions in the birth canal or from infected breast milk. In preschool children, CMV is acquired from urine or oral secretions of other infected children

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while sexual transmission is important at an older age. Blood transfusions and organ

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transplantations are other sources of infection. Congenital human cytomegalovirus infection is characterized by petechial rash secondary to

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thrombocytopenia, jaundice due to hepatitis and blueberry muffin lesions from dermal erythropoiesis. Purpuric lesions are present at birth and evolve during 24 to 48 hours of life. They regress during the first 6 weeks of life. Hepatosplenomegaly, microcephaly, periventricular calcifications, chorioretinitis, hearing loss, intrauterine growth retardation are related findings of infection. Most infants die within months. Neurological damage is severe in survivors67,68. An infant with acute hemorrhagic edema, a cutaneous leukocytoclastic vasculitis characterized by the acute development of peripheral edema and targetoid purpuric lesions on the face and extremities, associated with CMV infection has been reported 69. In immunocompromised patients, perianal and rectal ulcerations are most common. Hyperpigmented nodules, papular and purpuric eruptions, vesiculobullous lesions, purpura,

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petechia can also be seen67,68. In healthy children and adults, there are usually no clinical symptoms. In symptomatic cases, the clinical picture may resemble infectious mononucleosis.

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In up to one-third of patients, a follicular rubeoliform or maculopapular rash fading in 2 days

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can be observed. Ampicillin can trigger a widespread rash is in Epstein-Barr virus infection. Urticaria can be observed in some cases70,71. CMV may precipitate scleredema of infancy72,

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papular-purpuric gloves-and-socks syndrome73, and Gianotti-Crosti syndrome74.

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Epstein-Barr Virus (Human Herpes Virus-4, Infectious mononucleosis) Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that causes infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma and post-transplant lymphoproliferative

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disorder. Antibodies against EBV can be detected in 90-95% of the population by childhood. The virus is excreted in saliva and transmission occurs via close contact 66. EBV infects B

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lymphocytes directly within oral mucosa or infects mucosal epithelial cells and then infects the B lymphocytes. B lymphocytes allow dissemination of the virus throughout the

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lymphoreticular system. A clonal expansion of cytotoxic T lymphocytes allows recovery from

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primary infection75,76. Primary infection most often occurs during adolescence or early adulthood however can be observed in early childhood as well.. Acute EBV infection can cause a diffuse macular or maculopapular rash in about 10% of cases. It commonly involves the trunk and upper arms, and in some cases, face and forearms. The eruption may accompanied by fever, lymphadenopathy, pharyngitis, the classic triad of the disease, in more than 50% of patients. Use of ampicillin during the course of the illness causes an extensive maculopapular or morbilliform exanthem in more than 90% of cases, 710 days after the start of treatment. Vesicular, petechial, purpuric eruptions 77 and urticaria78 have been reported. Periorbital and eyelid edema can be seen in up to 50% of cases with EBV infection. Lymphocytosis with more than 10% atypical cells, liver function test abnormalities,

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splenomegalia, jaundice and petechia at the junction of soft and hard palate can also be observed76,79. Other cutaneous manifestations of EBV are oral hairy leukoplakia in

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immunosuppressed or HIV (+) patients80, Gianotti-Crosti syndrome81, Lipschütz ulcers82,

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erythema multiforme83, erythema nodosum84, facial inflammatory granuloma annulare85, pityriasis lichenoides86, erythema annulare centrifugum87 and hydroa vacciniforme-like

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lesions88.

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Exanthema Subitum (Roseola infantum, Sixth disease)

Human Herpes Virus-6 (HHV-6) has been identified as a causative agent for exanthema subitum (ES). HHV-6 is a member of the β-Herpesviridae subfamily. The incubation period

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for HHV-6 infection is 5-15 days, with an average of 10 days. Primary infection with HHV-6 results in an acute febrile illness typically in children 6 months to 1 year of age. The fever

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lasts 3-7 days. The exanthem is seen from 1 day before to 1 to 2 days after fever fades and lasts 3-5 days. HHV-6 infection is a frequently seen in transplant recipients (especially bone

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marrow transplantation)89.

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Palpebral edema can be seen from the first to third day of fever. Due to edema, the patient has a “sleepy” appearance and it resolves after a day of the exanthem. Erythematous papules on the soft palate (Nagayama spots) may precede the viral exanthem. The exanthem is characterized by rose red macules or papules 2-5 mm in diameter, surrounded by a white halo. Lesions are localized mainly on the neck and trunk; it may spread to face, arms and legs89, 90. After 1 or 2 days the eruption fades, leaving scaling and pigmentation. Cervical and occipital lymph nodes are usually enlarged91. Patients may have high fever and febrile convulsion, conjunctival infection, gastrointestinal and respiratory tract symptoms, and malaise89,90. Fatal encephalitides, fatal hepatitis and hemophagocytic syndrome have been

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reported92. In adults, primary HHV-6 infection may cause an infectious mononucleosis-like disease93.

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Human Herpes Virus 7 (HHV-7)

HHV-7 is responsible for the 10 percent of ES cases. HHV-7 is a member of the β-

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Herpesviridae family. It has significant homology to HHV-6; however, it is serologically and biologically distinct. It was isolated from human CD4+ T lymphocytes in 1990 94. The virus

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has been isolated from the peripheral blood of healthy people and an individual with chronic fatigue syndrome95. HHV-7 causes a small subset of ES cases. When HHV-7 is associated, ES occurs later in life than when HHV-6 is associated. HHV-7 has been isolated from the patients

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with pityriasis rosea and lichen planus; however, further studies are needed to establish a causal relationship90. HHV-7 has been very common, infecting children at a similar age to

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HHV-695.

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Pityriasis rosea is a common skin disorder affecting people 20 to 29 years of age, with no gender predilection. It is characterized by a herald patch and the subsequent appearance of

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oval-shaped erythematous lesions arrayed along Langer‟s lines96-98. The etiology pityriasis rosea is unclear but several factors indicate an infectious agent 99. In a study, electron microscopy investigations and polymerase chain reaction in mononuclear cells, plasma and skin in patients with pityriasis rosea showed elevated levels of HHV-7100. However, subsequent studies showed no consistent increase of HHV-7 levels in patients compared with control individuals101-103. The skin eruption can be preceded by prodromal symptoms such as malaise, nausea, fatigue, headache and arthralgy90,104,105. A herald patch then appears, typically on the trunk, 2-10 cm in diameter. It is an ovoid, erythematous and raised lesion with a collarette of scale at the

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margin. It is followed by a secondary eruption a few days to a few weeks after. The lesions are smaller and follow Langer‟s lines that may cause a typical “Christmas tree” or “fir tree”

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appearance on the back. A mild to severe pruritus may accompany in 25% of cases. The

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illness can occur in an inverse form in which the limbs are involved but the trunk is spared. In some cases, a herald patch may not be observed and the diagnosis may be difficult 98.

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Gigantean, purpuric, vesicular and pustular forms of the disease have been described106. Face,

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scalp, palms and soles are usually spared, however they can be affected during the course of disease (Figure 3). Kaposi’s Sarcoma

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Kaposi‟s sarcoma (KS) is a multifocal systemic disease with four principal clinical variants: chronic or classic KS, African endemic KS, iatrogenic KS, AIDS-related epidemic KS.

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Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi‟s sarcoma107 has been strengthened by further studies. Kaposi‟s sarcoma-associated herpesvirus DNA has

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been determined in 95% of Kaposi‟s sarcoma cases including immunocompetent patients 108.

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Most AIDS patients with Kaposi‟s sarcoma develop antibodies against HHV-8 related nuclear antigens 6-75 months prior to the appearance of sarcoma109. Blue-red to violet macules occur on the skin that may coalesce to form large plaques. Sometimes, nodules and polypoid tumors can be seen. KS commonly arises on the extremities. It rarely occurs in the mucosa or skin of the head and neck. In these patients, cutaneous tumors most commonly appear on the eyelids, nose, ears or other parts of the face. The commonest mucosal sites are conjunctiva, palate, tongue, gums and tonsils 110. Immunsuppressive drug-induced, African-endemic, and AIDS-related epidemic KS may behave more aggressive fashion than classic KS. KS may involve viscera, including the gastrointestinal tract, lymph nodes and lungs111,112.

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Poxviridae The poxviruses are double-stranded DNA viruses. They replicate in the cytoplasm and

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produce eosinophilic inclusion bodies, known as Guanieri bodies. Poxviruses are resistant to physical conditions such as dryness and variola can remain viable for months in crusts. Four

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genera can cause disease in humans: Orthopoxvirus, Parapoxvirus, Molluscipoxvirus and Yatapoxvirus.

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Smallpox (Variola)

The disease has not been seen since 1978 and routine vaccination against it has been abandoned. But the recent global terrorism has reawakened concerns that the aerolized variola

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virus could be used as a biological weapon113. Smallpox is caused by the variola virus, a double-stranded DNA virus which is a member of orthopoxviruses. Humans are the only

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known natural reservoir of variola virus. The infection is transmitted mainly by the

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respiratory route. After entry, the virus involves regional lymph nodes and replicates at these

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sites, and then a viremia leads to cutaneous and visceral involvement. A prodrome of high fever, chills, myalgia and severe headache develops within 7 to 17 days of infection. The eruptive phase is characterized by an oropharyngeal enanthem followed by the rash. Skin rash starts two to several days after the onset of fever. The variola major virus is more common than variola minor. Variola major is classified into five clinical types (ordinary smallpox, modified smallpox, flat smallpox, fulminant type, variola sine eruption). Ordinary smallpox is the most common type. Skin lesions begin as macules on the face and upper extremities. The macules become raised papules within 1 day and then form tense and pustules that frequently show central umbilication. Swelling of the eyelids can be seen during the course of illness. The eruption usually affects extremities more than the trunk and palms

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and soles are frequently involved. One week after, the lesions dry and a crusting develops. After resolution, pitted scars often develop. Scarring is most common on the face. Variola

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virus can lead to arthritis, encephalopathy, hematuria, corneal ulcer and keratitis 114. Monkeypox

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Monkeypox is caused by the monkeypox virus, a zoonotic virus. The animal reservoir is not thought to be a monkey. African rodents, particularly squirrels, are found to harbor the virus.

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It is the other member of orthopoxviruses115. It is endemic in the countries of Central and West Africa, mainly in Congo. Monkeypox is transmitted through abraded skin after a bite or scratch from an infected animal or by contact with their body fluids. Human-to-human spread

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is also possible. The illness in humans is similar to that of in monkeys. It occurs mostly in children under 10 years old. Death may occur in 17% of African children.

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The infection is very similar to smallpox. It starts with fever, malaise and upper respiratory

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tract symptoms. The eruption begins on the face and/or trunk. The lesions spread in a centrifugal pattern and become generalized quickly. They then progress to vesicles and

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pustules that umblicate, crust, and desquamate. Between rash lesions, uninvolved intact skin areas can be onserved on the face. This period lasts 14 to 21 days. After healing, pitted scars occur. Mucosal lesions, submandibular, cervical, or inguinal lymphadenopathy can be seen in monkeypox. The major sequelae in disease survivors are scars and blindness 116. Cowpox The disease caused by an orthopoxvirus mainly in cats and humans, not in cows. The natural host of the virus is a vole or wood mouse, and humans usually acquire the cowpox virus from infected cats by transferring it into scratched or fissured skin117. Cowpox occurs in Europe, Russia and East Mediterranean.

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The incubation period is 2-14 days. The lesions are usually on exposed skin of the hands, arms or face. They are often multiple and spread centrally from the periphery118. Typically a

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papule appears and quickly becomes vesicular, and then hemorrhagic and pustular. The

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pustule is often umblicated and is surrounded by an erythematous and edematous zone. Ulceration and a hard black eschar develop in the second week. Healing occurs in 3 or 4

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weeks119,120. Dissemination in an atopic patient mimicking eczema herpeticum121 and

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extensive anogenital involvement in a patient with Darier‟s disease 122 have been reported. Milker‟s nodule and orf should be excluded in differential diagnosis. A history of contact with cats may suggest cowpox but nearly half the patients do not have such a history119.

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Vaccinia and Eczema Vaccinatum

The vaccinia virus is a member of the genus Orthopoxvirusvirus, a distinc virus named

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poxvirus officinalis. It does not occur naturally. The virus closely resembles variola antigenically and cowpox culturally. It could be a mutant of either that might have been

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resulted from the human activity in the serial propagation of viruses for human inoculation.

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The virus shows significant homology with other poxviruses123. Smallpox vaccination involves the introduction of vaccinia virus into the outer layers of the intact skin. After injection of vaccine, the virus rapidly multiplies locally and in regional lymph nodes. The local reaction to vaccination begins within 3 to 5 days. The appearance of the papules is followed by the vesicle and then, pustule formation. After the development of crusts and scabs, healing occurs with residual scars at day 17 to 21 124. In generalized vaccinia which occurs 6-9 days after the vaccination, as a result of a brief viremia, a generalized rash may develop. Recovery is the rule. The involvement of the face may result from the autoinoculation from the site of vaccination125.

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Eczema vaccinatum is the localized or generalized spread of vaccinia virus in a patient with atopic dermatitis or other chronic dermatoses. Papules and pustules, or vesicles can occur on

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the body. The lesions usually occur in areas with prior lesions of atopic dermatitis. It is

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associated with high fever, lymphadenopathy and about 5% mortality rate 124.

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Parapoxvirus Infections

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Orf

Orf virus is a parapoxvirus and has a characteristic woven appearance. It is an endemic disease in sheep and goats that usually affects the area around the lips and nostrils of the animal. It is transmitted to humans through contact with infected tissue and fomites. The virus

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has also been found in camels, mountain goats, gazelles, and musk oxen. The virus is resistant

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to heating, drying, and to certain solvents such as ether and chlorophorm126-128. Facial lesions are quite rare and it is only occasionally reported 129,130. The first lesion of orf

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appear 5 to 6 days after inoculation. Red papule folllowed by vesiculation. After 10-14 days,

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targetoid nodule with a red center, white ring, and red halo is seen. Acute weeping stage followed by regenerative dry stages at the 21 to 28 days. Finally, a dry crust and scab occur. The lesions can be solitary or few in number and are more common on the fingers, hands or forearms, but rarely on the face (Figure 4). Lymphangitis, regional adenitis and mild fever may accompany in some cases. Spontaneous recovery occurs in 3-6 weeks with no scarring. Orf is common among sheep handlers and is readily recognized by their local physicians. The diagnosis is easy if orf is suspected126,130. Milker’s Nodule (paravaccinia, pseudocowpox) Milker‟s nodule is caused by a parapoxvirus with the same morphology as orf virus. It has a worldwide distribution but is prevalent in milkers, veterinarians, and workers in the meat

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industry. The virus typically is found at the teats and mouth of cattle but may also be on the trunk and legs. The virus is transferred by direct inoculation into the skin. It is closely related

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to orf131. The incubation period is 4 to 7 days. Lesions are characterized by a red and occasionally

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pruritic macules that become raised papules. After these lesions, papulovesicles with a targetlike appearance develop. The lesions then become bluish or violaceous tender nodules. The

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epidermis becomes opaque and grey and forms a crust over the depressed centre of the nodule. Lymphangitis is common though lymphadenopathy is rare. The number of the nodules is 2 to 5, but they may be solitary or more numerous. The nodules commonly occur on the fingers, however, are occasionally seen on the face. In some patients, a papular or

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papulovesicular eruption on the hands, forearms and arms may develop one or two weeks

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after the appearance of the nodules. It fades in 1-2 weeks. The nodules heal without scarring in 4-6 weeks. The illness produces lifelong immunity. The differential diagnosis includes

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pyogenic granuloma if the nodule is very vascular. The nodule is very similar to that of orf

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and differential diagnosis from orf may not be possible clinically132,133. Molluscipoxviridae

Molluscum Contagiosum Molluscum contagiosum virus (MCV) is a large, brick-shaped poxvirus. Two types of MCV have been identified, MCV-1 and MCV-2. But there is no relationship between the virus type and anatomical location of the lesions134. The disease occurs in worldwide distribution. Contact with infected individuals or contaminated stuff causes the transfer of virus. Transmission may occur via direct skin or mucous membrane contact. The incubation period

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may vary from 14 days to 6 months. Molluscum contagiosum generally affects young children. Autoinoculation and koebnerization also play a role in the spread of lesions135,136.

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Clinical lesions are small pink or flesh-colored hemispherical papules with central pore or umblication. Erythema and eczematous changes may occur around lesions; this is termed

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molluscum dermatitis. Large and extensive lesions may develop in patients with immunodeficiency syndrome135. Although many patients are asymptomatic, pruritus can be a

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problem in patients with atopic dermatitis. Secondary bacterial infection can occur. The localization of the lesions is affected by the mode of infection and by the climate. In temperate areas lesions more frequently appear on the neck or the trunk, especially around the

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axillae. In children living in hot climate, lesions are more common on the extremities. Face is involved particularly in patients with HIV infection and disseminated refractory lesions are

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observed137. In healthy individuals, facial lesions are seen occasionally, particularly on the

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Hepadnaviridae

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eyelids.

Gianotti-Crosti Syndrome (Infantile papular acrodermatitis) It is a common, self-limited dermatosis. It affects infants and children between the ages of 6 months and 12 years. In children, there is neither an ethnic nor sexual predilection. The disease is rarely seen in adults138. The exact pathogenesis of GCS is not known but may be due to a viral antigenemia or circulating immune complexes. GCS is a cutaneous reaction pattern associated with viruses, bacteria, and vaccines. Virus-like particles have been seen in cytoplasmic vacuoles and lysosomes in lesional skin. Associated triggers include hepatitis B and Epstein-Barr virus (EBV) most commonly; however, other associated viruses including cytomegalovirus,

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enterovirus, respiratory syncytial virus, rotavirus, adenovirus, echovirus, poxvirus, poliovirus, coxsackie virus, parvovirus, HIV, hepatitis A, hepatitis C, and parainfluenza virus can be

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detected. Bacterial pathogens that may cause GCS are Mycoplasma pneumonia, Borrelia

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burgdorferi, Bartonella henselae, and group A β-hemolytic streptococcus. Vaccines that have

Haemophilus influenza type b, and oral polio 138, 139.

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been reported as GCS triggers include tetanus, pertussis, influenza, diphtheria, BCG,

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The disease characterized by multiple coalescing, monomorphous, flat-topped or domeshaped, red-brown papules and papulovesicules located on the cheeks, extensor surfaces of the extremities, and the buttocks. The trunk, palms, and soles are usually spared. Lesions can be pruritic, and rarely hemorrhagic. A non-specific prodrome of upper respiratory tract

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infection with fever and pharyngitis may be present. Cutaneous lesions evolve over a few

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days and last for 2-8 weeks. Patients can develop lymphadenopathy, especially of the cervical, axillary and inguinal region138,139.

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The diagnosis of GCS is based on clinical findings. Diseases that may cause difficulties in the

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differential diagnosis include papular urticaria, pityriasis rosea, erythema multiforme, lichenoid drug eruption, lichen planus, pityriasia lichenoides et varioliformis acute, scabies, infectious mononucleosis and Henoch-Schönlein purpura138,139. Parvoviridae Parvoviruses are small viruses with a single stranded genome that lack of lipid envelope. Human parvovirus B 19 was discovered in 1974, and before the descriptions of human bocavirus and human parvovirus 4, it was the only member of the family parvoviridae known to be pathogenic in humans140-143. Human Parvovirus B 19 Infection

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The human parvovirus B 19 is the most common virus in school-aged children. Viral transmission can occur via the respiratory tract, hand-to-mouth contact, blood products, and

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vertically from mother to the fetus.The virus replicates mainly in erythroblast precursors.

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Parvorvirus B 19 infects more than 50% of all individuals by adulthood though it is often asymptomatic. However, it can cause a wide range of self-limiting clinical diseases including

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erythema infectiosum (fifth disease), ‟gloves and socks‟ syndrome, oligoarthritis, acute

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anemia by aplastic crisis in patients with other types of anemia, any disorder with hemoglobin gene expression or red cell membrane constitution, and hydrops fetalis 143-145. Other conditions suggested to have a link to parvovirus B 19 infection include myocarditis, cardiomyopathy, hepatitis, encephalopathy, aseptic meningitis, and glomerulonephritis142,146.

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Erythema infectiosum presents with mild symptoms approximately1 week after infection

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such as mild fever, malaise, nausea, arthralgia, myalgia and headache. After 2 to 5 days, initial stage of the rash presents as erythema of the cheeks („slapped-cheek‟) with perioral

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pallor. After 1 to 4 days, the second stage rush appears as pink maculopapular lesions on the trunk and the limbs. Due to central clearing of the lesions, a reticular pattern can be observed

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in this stage that lasts 1 to 6 weeks. In the third stage, the rash persists but may show some changes due to exposure to heat or sunlight and resolves without permanent sequlea 142,146,147. The course of the disease is controlled by neutralizing antibodies. A transient viremia occurs after infection lasting less than 1 week and then declines depending on the occurrence of specific IgM antibodies that persist for 8-10 weeks. After the appearance of specific IgG antibodies, immunity persists lifelong148. However, in immunocompromised patients unable to produce neutralizing antibodies persistent infections can be observed. Persistent infection in the bone marrow has also been reported in immunocompetent individuals with or without clinical symptoms149-152.

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Maternal exposure to the virus has the potential risk of adverse fetal outcome. The risk is high if infection occurs in the first or second trimester. Fetal anemia and hydrops fetalis may

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develop144. Gloves and Socks Syndrome

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Parvovirus B 19 has been associated with papular, purpuric gloves and socks syndrome that typically occurs in young adults although a causative relationship has yet to be proven. Gloves

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and socks syndrome also has been associated with Epstein-Barr virus, cytomegalovirus, hepatitis B, human herpes virus 6, coxsackievirus B, and measles153. The disease presents as painful, symmetric erythema and edema of the hands and feet. Progression to purpuric lesions

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and then into vesicles and bullae can be observed. Sharp demarcation of the rash on the wrists and ankles is the hallmark of the syndrome. Other areas including cheeks may be

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involved146,155. The rash disappears within one to three weeks with no scarring. Arthalgia

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Retroviridae

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and/or fever can be observed in some patients146.

Adult T-Cell Leukemia/Lymphoma Adult T-Cell Leukemia/Lymphoma (ATLL) is a mature T-lymphoid malignancy and is unique in its pathogenesis because it is a rare presentation of human T-Cell lymphotrophic virus type 1 (HTLV-1)156,157. It is endemic in south-western Japan and Caribbean basin158. HTLV-1 is a single-stranded RNA virus from the retroviridae family first isolated from the Tcells of a patient with cutaneous lymphoma159. Another similar HTLV virus, HTLV-2, was identified in cells from a patient with hairy cell leukemia. together with HTLV-1. Both viruses are similar in 66% of their genome sequences and HTLV-2 has not been related to any

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given disorder so far although there are few reports that linked it to neurological diseases160. HTLV-1 acts slowly within the organisms, hence even if the infection occurred in the early

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years of life, the majority of the disorders caused by this virus emerge after several decades.

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The majority of HTLV-1 carriers remains asymptomatic. In some individuals, HTLV-1 can cause serious disorders such as ATLL and HTLV-1-associated myelopathy/tropical spastic

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paraparesis in adults and infective dermatitis (IDH) associated with HTLV-1 in children160, . ATLL has a wide clinical spectrum and five clinical subtypes have been described 162.

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161

Acute ATLL has a rapid progressive course and is characterized by fever, cough, lymphadenopathy, hepatosplenomegaly, leukocytosis, hypercalcemia, increased serum levels of LDH and skin lesions. Atypical lymphocytes with convoluted or lobulated nuclei and

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basophilic cytoplasm(flower cells) are typical for this ATLL subtype.

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Lymphoma type: lymphadenopathy with or without extranodal lesions are observed. There are

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no lymphocytosis and hypercalcemia and circulating leukemia cells can be observed (

Viral infections of the face.

Viral infections affecting the face may cause significant morbidity, cosmetic disfigurement, and psychological distress. The success of therapy needs ...
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