Introduction

The term virus comes from Latin, meaning poison or toxin. Most modern medical practitioners think of viruses as micro-organisms rather than toxins, but some experts argue that viruses are not living organisms as they do not fulfil all the necessary criteria. Viruses do not have cell structures and they require host cells to replicate and synthesise new products. This spontaneous self-assembly within the host cells has been likened to the autonomous growth of crystals. Viral self-assembly has also been used to strengthen the hypothesis that the 'origins of life' started from self-assembling organic molecules. Nonetheless, viruses do possess genes, cause disease, trigger immune responses, and evolve through natural selection; so, from a practitioner's point of view, living or otherwise, they have an enormous impact on human health.

The inability of viruses to grow or replicate outside the host cell means that they have become masters at persistence within the host. Viruses persist within the host cell because they are often able to replicate without killing the host cells, their gene expression can be restricted, they can mimic host molecules, down-regulate host immunity, and directly infect the host's immune cells. Viruses continuously change, either gradually (called 'drift') where they accumulate minor mutations, or suddenly (called 'shift') following major changes during recombination of the viral genome.

RNA viruses such as measles and human immunodeficiency virus (HIV) are unstable, undergoing immense drift and shift, with up to 2% of their genome altered each year through multiple mutations. These viruses tend to cause systemic disease in humans, leading to generalised cutaneous eruptions such as a 'viral exanthem'. In contrast, DNA viruses such as human papillomavirus (HPV), molluscum contagiosum, herpes simplex virus (HSV), and varicella zoster virus (VZV) are more stable. They are frequently inoculated directly into the skin and replicate in epidermal cells.

Viruses can be transmitted by direct contact from skin to skin, through aerosols, transplacental spread, blood products, contaminated needles, and via the faecal-oral route. Once inside the host, viruses can spread directly from cell to cell, via the blood, or central nervous system by axonal transport. Many viruses demonstrate tropism (in other words a predilection for a certain host cell) via virus attachment to protein-specific cell surface receptors. HPV, for example, has tropism for keratinocytes.

The behaviour of different viruses therefore determines the type of disease they cause with resultant localised or widespread reactive skin disorders. Common viral infections of the skin are usually easily identified by pattern recognition through the characteristic skin or mucous membrane site affected and/or typical lesions.

Herpes viruses

Herpes simplex

HSV is spread by direct contact - 'shedding' from one host to another. Two viral subtypes exist: type I is associated mainly with facial lesions although the fingers (Figure 14-1) and genitals may be affected. Type II is associated almost entirely with genital infections. HSV remains within the host for life, remaining latent in the sensory nerve ganglia, leading to recurrent reactivation.

Primary herpes simplex (type I) infection usually occurs in or around the mouth/nose, with variable involvement of the face (Figure 14-2). Lesions consist of small vesicles (Figure 14-3) which crust over and are associated with regional lymphadenopathy. HSV type II infects the external genitalia; the initial vesicle or vesicles rapidly break down into painful ulcers (Box 14-1).

Episodes of reactivation of HSV may be triggered by the cold ('cold sore'), bright sunlight, trauma, immunosuppression, or intercurrent illnesses. There is frequently a prodrome of tingling or itching before the appearance of the vesicles, which occur in the distribution of a sensory nerve. Topical aciclovir/penciclovir/idoxuridine cream can be used to treat mild labial herpes. Severe infections should be treated with oral aciclovir 200 mg five times daily or 400 mg three times a day for five days.

Secondary prophylaxis (suppressive therapy) for frequent reactivation can be given as 400 mg once or twice daily. Higher doses are needed in immunocompromised patients. Valaciclovir (HSV 500 mg twice daily for five days, VZV 1 g three times daily for seven days) and famciclovir (genital HSV 250 mg three times daily for seven days, VZV 750 mg daily for seven days) are alternatives that are taken less frequently. Brisk inflammatory responses to genital HSV can be seen in patients with HIV whose immune system is reconstituting once they start their HAART (highly active antiretroviral therapy) - the so-called immune reconstitution inflammatory syndrome (IRIS). Clinically, this is seen as deteriorating signs and symptoms of HSV disease and may look like a hyperkeratotic nodule (pseudoepithelial hyperplasia) and may warrant aggressive treatment of the HSV with oral high-dose valaciclovir (with additional imiquimod 5% cream) and occasionally a reduction in the HAART medication.

Varicella zoster virus

VZV is a herpes virus that causes chickenpox (the primary illness), which is characterised by a prodromal illness for about two days followed by crops of papular-vesicular lesions (Figure 14-5) that eventually crust over and heal. Primary chickenpox in adults can lead to a severe pneumonitis. Subsequently shingles (reactivation) may occur as the virus remains latent in the sensory nerve ganglia (Box 14-2). The thoracic nerves are most commonly affected. In shingles, pain, fever, and malaise may precede the rash, which is characterised usually by its dermatomal distribution (Figure 14-6); however, adjacent dermatomes may be affected (Figure 14-7). Erythematous papules usually precede vesicles which develop over several days, crusting as they resolve, often with secondary bacterial colonisation. Occasionally, peripheral motor neuropathy can result, and a proportion of patients develop severe chronic post-herpetic neuralgia. Skin lesions of shingles and nasopharyngeal secretions can transmit chickenpox to susceptible individuals.

Patients ideally should receive high-dose aciclovir (800 mg five times daily for seven days) within 72 hours of the onset of the eruption. If the eye is affected or there is nerve compression, then intravenous aciclovir (5 mg/kg every eight hours for five days) should be considered and patients may require systemic steroids (prednisolone 40-60 mg daily) to prevent nerve paralysis in severe cases. Greasy emollient should be applied to the affected skin regularly to prevent cracking and reduce pain as lesions heal. Topical antibiotic ointments can be used to treat secondary bacterial infections (mupirocin, fusidic acid, and polymyxin). Post-herpetic neuralgia may respond to gabapentin or carbamazepine. Preliminary studies using a topical 8% capsaicin patch applied for one hour reduced pain by >30% in 40% of shingles patients for up to eight weeks. For one month following herpes zoster (shingles) there is an increased risk of cerebrovascular accident (stroke), particularly following herpes zoster ophthalmicus (HZO). Ischaemic stroke was more common than haemorrhagic stroke after herpes zoster infection, and this appears to be more common in those under the age of 40 years and those who had not received antiviral treatment for their zoster infection.

Varicella zoster virus vaccination is given in some countries to prevent primary chickenpox infections, a single dose of vaccine is 80% successful in preventing disease and two doses 95% effective. Any breakthrough disease is likely to be milder following primary vaccination. Shingles (reactivation of VZV) is thought to occur as the specific cell-mediated immunity against the virus wanes with time. Vaccination to try to prevent shingles is currently given to individuals in their seventh decade in the UK using non-live recombinant zoster vaccine (two doses); this has been shown to give a boost to zoster immunity. Studies showed a 90% reduction in shingles and 98% reduction in post-herpetic neuralgia at 3.7 years in patients vaccinated over the age of 70 years. Shingrix® a recombinant (non-live) shingles vaccine is also available and will be the preferred vaccination for the immunosuppressed.

Pityriasis rosea (PR) has been thought recently to be triggered by an upper respiratory tract infection with human herpes virus type 6 or 7. The evidence for this is not conclusive but for the ease of categorisation PR is described here. PR classically presents with an initial single annular erythematous patch with a collarette of scale - the 'herald patch' (Figure 14-9a), so called because it heralds the onset of the rest of the rash within five to eight days, which consists of multiple smaller scaly patches on the trunk (Figure 14-9b) and upper arms and thighs (old-fashioned bathing suit distribution). On the back, the lesions may follow the angle of the ribs in a 'Christmas tree pattern'. Patients may have experienced corysal symptoms before the onset of the rash as part of the viral illness. Patients mainly present in spring and autumn and there may be clustering of cases. The rash settles spontaneously over about four to six weeks, but a mild topical steroid and emollient can be given if the rash is pruritic or inflammatory. Some practitioners advocate the use of high-dose acyclovir to shorten the course of the rash.

Poxviruses

The poxviruses are large DNA viruses, with a predilection for the epidermis. Variola (smallpox), once a disease with high mortality, has been eliminated (last reported case of smallpox occurred in Somalia in 1977) by vaccination with modified vaccinia (cowpox) virus. Vaccination of the general population is no longer required due to the eradication of the virus, but some military and front-line medical personnel are being vaccinated due to the theoretical threat of biological attack with smallpox.

Molluscum contagiosum

The commonest poxvirus skin infection is usually acquired in childhood. It is highly contagious and is spread by direct contact often within families or schools. The incubation period is variable, between 14 days and 6 months. In adults florid molluscum may be an indication of underlying immunodeficiency such as HIV. Flesh-coloured, umbilicated papules are characteristic (Figures 14-10 and 14-11). Large solitary lesions (giant molluscus) and infected lesions may look atypical. Resolving lesions may be surrounded by a small patch of inflammation; this is usually a sign that the lesions may soon resolve because of activation of the immune system.

Parents may be keen for their children with molluscum to be treated. However, most lesions will resolve spontaneously, leaving no marks on the skin. Therefore, painful and potentially scarring treatments should be avoided if possible. Topical hydrogen peroxide 10-15% and cryotherapy can be used to cause local inflammation and speed up resolution in non-cosmetically vulnerable sites. 5% imiquimod cream is not beneficial in the treatment of molluscum.

Orf is usually recognised in rural areas. It is seen mainly in early spring as a result of contact with infected lambs. A single papule or group of lesions develops on the fingers or hands with purple papules developing into bullae (Figure 14-12). These rupture to leave annular lesions 1-3 cm in diameter with a necrotic centre and surrounding inflammation. The incubation period is a few days and the lesions last two to three weeks with spontaneous healing. Associated erythema multiforme and widespread rashes are occasionally seen. Lifelong immunity does not result from infections.

Wart viruses

More than 100 different subtypes of HPV have currently been identified. HPV subtypes 6 and 11 are responsible for the majority of genital warts and subtypes 16/18 with the development of cervical/anal/vulval/vaginal/oral carcinomas. This discovery led to the production of two vaccines against HPV (Cervarix against 16, 18 and Gardasil against 6, 11, 16, 18), which are administered in three doses, mainly to teenage girls/boys. It is thought, however, that HPV infection alone does not cause malignant transformation and identified cofactors include smoking, UV light, folate deficiency, and immunosuppression. Vaccinated women should still have regular cervical smears.

Warts are classified as ano-genital/mucosal, non-genital cutaneous, and epidermodysplasia verruciformis (EV). The latter is a rare condition associated with a defect of specific immunity to wart virus. Genital HPV infections are also described as symptomatic (latent, i.e. viral DNA detected), subclinical (detected with acetic acid under magnification), or clinical (warts easily seen).

HPV only infects humans and is spread by direct contact, usually through a small break in the skin/mucous membrane. Viral warts can have a varied clinical appearance from filiform (Figure 14-13) to hyperkeratotic periungual (Figure 14-14). HPV can remain viable in the environment at low temperatures for prolonged periods and therefore be contracted from contact with inanimate objects (changing room floors). The basal keratinocytes become infected, causing epidermal hyperplasia seen clinically as an exophytic warty lesion. Plantar warts (verruca) form painful plaques (mosaic) containing black 'dots' (Figure 14-15) that represent thrombosed capillaries.

Cutaneous HPV lesions can undergo malignant transformation, particularly in individuals who are immunosuppressed by HIV or medication. If skin lesions suddenly increase in size or are painful, then transformation to squamous cell carcinoma should be suspected. Acitretin is given to some transplant recipients to try to reduce the rate of cutaneous malignant transformation.

Treatment

Warts commonly occur in childhood and usually resolve spontaneously. There are, however numerous treatment options available (indicating that not all warts respond to a particular treatment). Warts are generally slow to clear but studies show 70% will resolve following four months of salicylic acid applied once daily. Salicylic, lactic acids, and glutaraldehyde in various formulations can be purchased over the counter and online. Gels/ointments/paints/lotions should be applied daily after paring down the wart surface with a file or pumice stone to remove dead skin cells. Occlusion with a plaster can help drive the treatment into the wart surface.

Duct tape (used by builders) has been shown in some studies to be beneficial; however, other studies showed no benefit over placebo.

Glutaraldehyde 10% solution has been shown to have some antiviral properties and is useful in clinical practice at drying out vascular warts which are then easier to pare down.

For large/painful/recalcitrant warts other measures may be considered.

Liquid nitrogen is effective but has to be stored in special containers and replaced frequently. It can be applied with cotton wool or discharged from a special spray with a focused nozzle. Freezing is continued until a rim of frozen tissue forms around the wart, this is then repeated three times with thawing in-between cycles. Cryotherapy is accompanied by a burning sensation or pain and is not usually tolerated in young children. Subsequent pigment changes, blistering, and even scarring may occur. Carbon dioxide is more readily available and can be transported in cylinders that produce solid carbon dioxide 'snow'. The temperature (about –64 °C) is not as low as that of liquid nitrogen (–196 °C).

Diathermy loop cautery under local anaesthetic is effective for perianal warts. Curettage and cautery for very large warts under local anaesthetic is often used to debulk the lesions prior to other measures.

Podophyllin derived from Mayapple is available in various formulations including ointment (Posalfilin^®) for plantar warts (daily) and solution/cream (weekly) for genital warts (Warticon^® and Condyline^®). Podophyllin 15% paint should only be applied to warts by a trained practitioner as it can cause chemical burns. It should not be used on large numbers of warts simultaneously because of toxicity and must never be used in pregnancy.

Immune response modifier imiquimod 5% cream is licensed for the treatment of genital warts. It stimulates cytokine production at the site of application, which is carried out three times per week. Treatment should continue until the warts resolve or up to a maximum of 16 weeks. Local irritation and inflammation can be severe, especially on mucosal surfaces. Imiquimod 5% can also be used to treat cutaneous warts but daily application is usually required under occlusion to aid penetration and efficacy.

Immunotherapy with the contact sensitiser diphencyprone (DPC) can also be effective. Following sensitisation to DPC increasing concentrations are painted onto the warts to cause a local inflammatory response. At six months, 60% complete cure rates are reported in patients with previously highly recalcitrant warts.

Other treatments include carbon dioxide laser vapourisation, 5-fluorouracil, intralesional bleomycin and interferon alpha, oral cimetidine, and oral isotretinoin.

Viral diseases with rashes

Many childhood viral illnesses have become less common because of increased availability of effective vaccines (Box 14-3). However, these vaccines are not universally available or accepted by parents, leading to regional outbreaks among susceptible populations. Approximately 880 000 deaths from measles occur worldwide each year. Recently, there has been a marked resurgence of measles in parts of the UK following a decline in take-up of MMR (measles/mumps/rubella) vaccinations. Measles is probably the best-known example of a viral exanthema - a widespread reactive cutaneous eruption that usually results from RNA viruses.

Measles usually affects children under the age of five years and is highly contagious. The incubation period is 7-14 days. Prodromal symptoms include fever, malaise, upper respiratory symptoms, conjunctivitis, and photophobia. Children are miserable and look unwell. Initially, Koplik's spots (white spots with surrounding erythema) (Figure 14-16) appear on the oral mucosa and then within two days a macular rash appears, initially behind the ears and on the face and trunk, and then on the limbs (Figure 14-17). Papules form and coalesce and may be haemorrhagic or vesicular, which fade to leave brown patches. Rarely encephalitis, otitis media, and bronchopneumonia may complicate the infection. Reliable rapid diagnostic testing can be undertaken using oral fluid samples to detect measles virus RNA using real-time RT-PCR. Urine and serology tests are also available. There is no specific treatment for measles except supportive care; however, some studies have shown that vitamin A supplementation during the acute illness can reduce morbidity/mortality. Parents should be encouraged to get their children vaccinated with two doses of live-attenuated MMR.

Rubella affects children and young adults who may display prodromal fever, malaise, and upper respiratory tract symptoms. The incubation period is 14-21 days. First signs of the disease include erythema of the soft palate and lymphadenopathy. Later, pink macules appear on the face, spreading to trunk and limbs over one to two days (Figure 14-18). The rash clears over one to two days (occasionally no rash develops). Infection during pregnancy can cause congenital defects. The risk is highest in the first trimester. The acute diagnosis is usually clinical with confirmation from convalescent serum antibody titres. Prevention through immunisation of school-aged girls is highly effective.

Erythema infectiosum (fifth disease) is caused by parvovirus B19, which mainly affects children aged 2-10 years. The incubation period is 5-20 days. The disease manifests as a prodrome of mild fever before the onset of a hot erythematous eruption on the cheeks - hence the 'slapped cheek syndrome'. Over two to four days a maculopapular eruption develops on the limbs and trunk (Figure 14-19), which can extend to the hands, feet and mucous membranes, and then fades over one to two weeks. The diagnosis can be confirmed by serology for parvovirus B19-specific IgM antibody. Complications include thrombocytopenia, arthropathy, and foetal abnormalities if acquired in utero.

Roseola infantum (sixth disease) is caused by human herpesvirus type 6 (HHV6). This mainly affects infants below two years of age. The incubation period is 10-15 days. The onset of a rose-pink maculopapular rash appearing on the neck and trunk usually follows a few days of fever. The rash can spread to the limbs before clearing over one to two days. The diagnosis is made on clinical ground; however, HHV6 virus can be isolated from the blood or serology to detect antibody responses if necessary. Young infants may develop febrile convulsions. Care is supportive.

Gianotti-Crosti syndrome is the term given to a papular viral exanthem caused by infections due to Epstein-Barr virus (EBV) and hepatitis B. Children under the age of 14 years are most commonly affected. The incubation period is unknown; however, children generally present with malaise, lymphadenopathy, and an acral eruption. Initially the rash consists of erythematous papules on the face, neck, limbs, buttocks, palms, and soles (Figure 14-20). The rash is usually itchy and may become purpuric before it slowly settles over two to six weeks. Viral-specific serology can be requested. Rarely lymphadenopathy and hepatomegaly can persist for many months. The symptoms from the exanthem can be relieved with a topical steroid.

Hand, foot, and mouth disease (HFMD), as the name suggests, is an infection causing lesions on the hands/feet and in the mouth. It is most commonly associated with Coxsackievirus A16 and Enterovirus 71 (the later can be associated with severe illness, flaccid paralysis) and affects mainly children. The virus is highly contagious with a short incubation period of three to six days. Young children in particular present with fever, headache, and malaise alongside the rash. The characteristic rash consists of intense erythema surrounding yellow-grey vesicles 1-1.5 mm in diameter on palms/soles and lips (Figure 14-21). A global upsurge of Coxsackie A6 has led to atypical presentations of HFMD in children and adults with a more severe and generalised eruption (Figure 14-22a,b). Onychomadesis (nail shedding) is seen in 20% of these Coxsackie A6 cases two months after the infection (Figure 14-23). Treatment is supportive care. The rash and symptoms usually settle rapidly over four to six days (two to three weeks for A6). The virus can be rapidly isolated from lesions using viral swabs or be identified in the stools. Serology for viral-specific antibody can also be requested. Rarely, erythema multiforme can also occur.