Herpes labialis generally refers to HSV infection on the lips and is the most common form of recurrent herpes infection. Primary infection may be subclinical or appear as gingivostomatitis (refer to above section “Herpetic Gingivostomatisis”). Symptoms typically begin with a prodrome of tingling, burning, or itching. Around 1–2 days later, a localized cluster of small vesicles on an erythematous base appear. As the vesicles rupture, they form painful erosions, which crust over in about 8 days. Other areas of the face may be involved (Fig. 18.1). Immunosuppressed children can develop severe, chronic disease, which may become resistant to antivirals. The diagnosis is generally determined clinically, but can be confirmed by laboratory investigations. The sensitivity of these tests is generally regarded as lower with recurrent episodes since viral shedding is intermittent and declines rapidly as lesions heal.

Herpes labialis may self-resolve and require no intervention. Symptomatic treatment includes oral analgesics, petroleum jelly, and topical antibiotics to decrease risk of bacterial superinfection. As with herpes gingivostomatitis, other topical treatments such as “magic mouthwash” or topical anesthetics are not routinely recommended in children. Zilactin, a nonprescription topical medication containing lidocaine and hydroxypropyl cellulose, can protect lesions from trauma and irritants, but studies regarding its efficacy and safety in young children are lacking. Topical benzocaine may cause methemoglobinemia and should not be used in children younger than 2 years.

For recurrent herpes labialis, episodic therapy with antivirals may be beneficial if initiated at first sign of symptoms. Topical antivirals, such as acyclovir, penciclovir, and docosanol can modestly decrease the time to lesion healing, although are not approved in children <12 years (Table 18.3) [8–10]. Oral acyclovir may provide greater benefit than topical antivirals if treatment is initiated during the prodromal stage; benefits include decreased duration of symptoms and time to healing (Table 18.1) [11, 12]. For those ≥18 years with recurrent disease, valacyclovir or famiciclovir can be considered [13, 14]. There are no clinical trials directly comparing antiviral medications. For immunocompromised children, oral acyclovir can be considered; however, those with spreading or persistent infection should be treated with intravenous acyclovir (Table 18.2) [15–17].

Although there are no studies for prophylactic therapy in children, antivirals should be considered for frequent recurrences, immunosupression, and serious systemic complications such as erythema multiforme and eczema herpeticum (Table 18.1 and 18.2) [18, 19]. To reduce frequency and severity, antiviral treatment should be continuous for several weeks to months. After approximately 6 months to 1 year of treatment, acyclovir should be discontinued and the recurrence rate re-evaluated. UV protection may also help reduce viral reactivation [20].

Genital herpes is a widespread sexually transmitted disease primarily caused by HSV-2, but HSV-1 is increasing in prevalence, especially amongst young adults. Primary genital herpes demonstrates painful vesicles on an erythematous base 2–20 days after exposure. Distribution includes the vulva, labia, vagina, perineum, penile shaft, glans penis, urethra, and less often the scrotum; extragenital involvement may also be seen. Painful erosions or ulcers occur following rupture of vesicles and can be associated with burning, pruritus, vaginal or urethral discharge, and regional lymphadenopathy. Influenza-like systemic symptoms are also common and include fever, malaise, myalgias, and headache. Symptoms generally improve over 5–7 days, and cutaneous lesions heal over 2–4 weeks. Aseptic meningitis and sacral radiculomyelitis are potential complications.

The diagnosis is generally determined clinically, but can be confirmed by laboratory investigations. Viral culture, direct fluorescent antibody (DFA) and Polymerase chain reaction (PCR) have varying sensitivities and specificities. PCR is currently regarded as both a rapid, sensitive, and specific method and is increasingly used when available. The diagnosis of genital HSV in a child should prompt question of sexual abuse.

Recurrent genital herpes can be trigged by menstruation, febrile illness, or stress. Outbreaks are typically preceded by a prodrome of pain, itching, and paresthesia. Compared to primary genital herpes, recurrent lesions are less severe, with fewer vesicles. Shedding of the virus can occur even without active lesions (subclinical shedding) and increases with frequency of symptomatic recurrences.

The treatment of genital herpes includes supportive care and antivirals to promote rapid healing, decrease recurrences, decrease viral shedding, and minimize complications [21, 22]. There is no curative therapy.

For primary genital infections, supportive care includes analgesics and Sitz baths. Systemic antiviral therapy should be initiated promptly, even before laboratory confirmation. Antiviral dosing for immunocompotent patients is provided in Table 18.1. Oral acyclovir initiated within 6 days of onset of disease shortens the duration of illness and viral shedding by 3–5 days [23]. Acyclovir is the only antiviral approved for genital herpes in children, but famciclovir and valacyclovir are well studied in adults; they do not seem to be more effective than acyclovir, but allow for less frequent dosing [24, 25]. Topical acyclovir should not be used, as it is less effective than oral acyclovir.

Antivirals can also be used for recurrent episodes (Table 18.1) and have been shown to decrease duration of lesions and viral shedding and increase proportion of aborted episodes [26–29]. The prescription should instruct patients to initiate treatment immediately when symptoms begin.

Prophylactic therapy has not been studied in children, but in adults, daily oral antiviral suppressive therapy is effective in decreasing the frequency of symptomatic recurrences and improving quality of life [30–32]. Thus, children with frequent recurrences may benefit from continuous oral acyclovir, and a reasonable starting dose in provided in Table 18.1. After approximately 6 months to 1 year of treatment, acyclovir should be discontinued and the recurrence rate re-evaluated.

Immunocompromised patients have more frequent recurrences, develop more severe lesions, and require longer treatment periods (Table 18.2). Intravenous acyclovir should be administered for severe or disseminated cases. Long-term suppressive therapy has been used, although may lead to selection of resistant strains of the virus. In acyclovir-resistant cases, intravenous foscarnet may be required [33].

Evaluation for other sexually transmitted diseases should be considered, and potential sexual abuse cases must be referred to the appropriate investigative agencies. The recurrent nature of the disease can have significant psychological effects on patients; education about the risk of transmitting genital herpes and safe sex practices should be provided [34].

Ocular herpes infection can result in numerous complications including blepharitis, conjunctivitis, keratitis, uveitis, and acute retinal necrosis. HSV keratitis typically appears as an infection of the superficial layer of the cornea (epithelial keratitis) while deeper involvement of the cornea (stromal keratitis), uvea, and retina are associated with a greater risk of visual loss.

HSV keratitis has an acute onset with pain, photophobia, blurred vision, and watery discharge. Physical exam is notable for conjunctival injection, decreased corneal sensation, and characteristic dendritic lesions of the cornea. The eyelid may also be involved, leading to blepharitis (Figs. 18.2 and 18.3). Infections may be unilateral or bilateral, and bacterial superinfection is not uncommon. The diagnosis is generally determined clinically, but can be confirmed by laboratory investigations. Ocular samples should be taken from scrapings of epithelial lesions.

Children typically have more severe cases then adults, with higher levels of inflammation, risk of amblyobia, and estimated recurrence rates of 50 %. Recurrent HSV keratitis continues to be a leading cause of corneal blindness in the United States.

Management depends upon whether the infection is primary or recurrent and the location of the infection within the eye [35]. From a dermatologist’s perspective, the most important action is to promptly consult an ophthalmologist, especially if there is facial involvement in a child with disseminated mucocutaneous herpes.

For primary infection involving the superficial layer of the cornea (epithelial keratitis), topical antiviral therapy was previously the standard of care, but randomized trials in adults have also shown oral antivirals to be equally effective [36, 37]. Oral antivirals may be superior, given difficulty of topical antiviral application with small children. Topical ganciclovir 0.15 % gel and trifluridine 1 % drops are potential antiviral treatments (Table 18.3). Oral acyclovir has been reported to be effective in children with ocular herpes, although the study did not evaluate if oral acyclovir should be used in lieu of topical antiviral medications [36]. Topical glucocorticoids should be avoided as they can exacerbate epithelial lesions.

For deeper involvement of the cornea (stromal keratitis), a combination of topical corticosteroids and antivirals is currently the standard of care [38]. The addition of oral acyclovir to these two treatments has not been shown to provide additional benefit. Topical cyclosporine may be considered for those non-responsive to topical prednisolone, although this has only been studied in adults [39].

The most important management issue in HSV ocular infection is prevention of recurrences, as these can lead to corneal scarring and blindness. Suppressive acyclovir has been successful and well tolerated in children and should be considered, given the high rate of recurrence.

Eczema herpeticum or Kaposi’s varicelliform eruption is a severe, disseminated HSV infection in patients with atopic dermatitis or other chronic skin conditions such as pemphigus, Darier disease, or burns. Patients typically have abrupt onset of fever, malaise, lymphadenopathy, and widespread monomorphic vesicles and erosions. Often “punched-out” erosions with hemorrhagic crust are more evident than intact vesicles (Fig. 18.4). Lesions are most prominent in areas of chronic skin disease, but also favor the head, neck, and trunk. If eczema herpeticum is suspected, treatment should be initiated while awaiting diagnostic results such as viral culture, DFA, and PCR. Complications include ocular involvement, secondary bacterial super infections (Staphylococcus aureus and/or group A streptococci), fluid loss, and viremia.

The mainstay of treatment is systemic antiviral therapy (Table 18.1) [40, 41]. For most pediatric patients, hospital admission and intravenous acyclovir is the standard of care [42]. There are limited studies available evaluating acyclovir therapy, but one large multicenter retrospective cohort study showed that delayed acyclovir initiation was associated with increased hospital length of stay [43].

Other treatment considerations include intravenous hydration with attention to electrolyte balance, pain control, and antibiotic therapy for secondary bacterial infection [44]. Empiric antibiotic therapy has not been associated with shorter hospital length of stay, but it is critical to recognize systemic bacterial illness early [44]. Topical therapy includes bland emollients and topical corticosteroids as needed [45]. Facial involvement necessitates an ophthalmologic evaluation to monitor for ocular involvement.

Herpetic whitlow is a deep, painful, vesicular or bullous eruption with surrounding erythema involving the pulp of the distal fingertip(s) (Fig. 18.5). It can be a complication of primary oral or genital herpes. The prodrome includes a tingling and burning sensation of the finger(s) and influenza-like symptoms including fever and localized lymphadenopathy. Blister fluid is initially clear, but then appears purulent, mimicking a bacterial infection. Diagnostic studies such as viral culture, PCR, DFA, and Tzanck should be considered to confirm diagnosis. If untreated, symptoms generally spontaneously resolve in 1–3 weeks, but can recur.

Treatment is typically supportive including anti-inflammatory agents, immobilization, and dry dressings to prevent transmission [46].

Oral antiviral therapy has been accepted as an effective means of reducing the duration of symptoms in primary infection and recurrent episodes (Table 18.1) [47]. Intravenous acyclovir is recommended for immunocompromised patients or those with severe infections (Table 18.2). Topical acyclovir is not believed to be helpful, and surgical intervention should be avoided. Prophylactic oral acyclovir may be effective in suppressing recurrent infections.

Herpes gladiatorum is the term used when herpes simplex virus is transmitted during contact sports such as wrestling and rugby. It is characterized by widespread grouped vesicles on an erythematous base, and typically occurs on the head, neck, and upper extremities. Because lesions may become abraded during competition, they may have an atypical appearance. Systemic symptoms include fever, malaise, headache, and regional lymphadenopathy. Diagnosis may be made clinically, but when possible, laboratory confirmation should be performed. There is a general consensus in the literature that herpes gladiatorum is misdiagnosed, and diagnostic tests are underutilized.

Herpes gladiatorum can be treated with oral antivirals. Depending upon the age of the patient and immunosupression status, antivirals include acyclovir, valacyclovir, and famiciclovir (Tables 18.1 and 18.2). No clinical studies have been performed on patients with primary herpes gladiatorum. Return-to-play criteria has been published by the National Collegiate Athletic Association and National Federation of State High School Associations Sports Medicine Advisory Committee and is summarized in Table 18.20 [48–50].

Recurrent infections should also be treated with antivirals (Tables 15.​1 and 15.​2). In a double-blind, placebo-controlled prospective study of 20 wrestlers and coaches with confirmed recurrent HSV, a 7-day regimen of valacyclovir 500 mg twice daily reduced the length of time until clinical clearance [51].

Suppressive antiviral therapy should be limited to athletes with a history of recurrent herpes to reduce the risk of reactivation during the sport season (Table 18.1). Valacyclovir 500 mg to 1 g daily has also been studied in wrestlers ages 13–31 and appears to suppress recurrent outbreaks [52].

Varicella or chickenpox is caused by varicella zoster virus (VZV), a member of the herpesvirus family. It is a highly communicable disease transmitted by aerosolized droplets or direct person-to-person contact. The typical incubation period is 10–14 days and it is infectious from 48 h prior to the onset of rash until skin lesions have crusted over.

Clinical features include a prodrome of fever, chills, malaise, headache, and arthralgias, with subsequent development of a generalized vesicular exanthem within 24–48 h. These pruritic vesicles initially appear on the scalp, face, and trunk, and then spread to the extremities (Figs. 18.6 and 18.7). New vesicle formation generally stops within 4 days, and most lesions have fully crusted by day 6. “Breakthrough varicella” can occur after a single dose of the varicella vaccine and subsequent exposure to VZV. Clinical features include absent to low fever, <50 macules and papules, and a shorter duration of illness.

Varicella tends to be more severe in infants, adolescents, and the immunocompromised. Potential complications include secondary bacterial superinfection of skin lesions, pneumonia, nervous system involvement (encephalitis, cerebellar ataxia, aseptic meningitis), thrombocytopenia, glomerulonephritis, and hepatitis. Reye syndrome was a common complication before the association with salicylates was understood. Herpes zoster (shingles) represents delayed sequelae of varicella and will be discussed in a subsequent section.

In the United States, a two-dose live, attenuated vaccine program is recommended for all healthy individuals 12 months of age or older without evidence of immunity [53]. For children 12 months to 12 years, a first dose is recommended at age 12–15 months and a second dose at age 4–6 years. The second dose may be administered at an earlier age, provided the time interval between the first and second dose is >3 months. For adolescents >13 years without evidence of varicella immunity, two doses of the vaccine should be administered at least 4–8 weeks apart.

In healthy children below the age of 12 years, treatment is usually symptomatic for itch, pain, and prevention of secondary superinfection. This includes antihistamines, acetaminophen, and topical care including cool compresses, oatmeal baths, calamine lotion, menthol-camphor (Sarna) lotion, and mupirocin. Fingernails should be clipped to avoid excoriation and bacterial superinfection. Salicylates should be avoided given the risk of Reye syndrome. Antiviral therapy is not recommended for routine use in otherwise healthy children [54].

According to the American Academy of Pediatrics, oral acyclovir or valacyclovir should be considered in (1) children older than 12 years without evidence of immunity, and in children of any age with (2) chronic cutaneous or cardiopulmonary disorders, (3) on long-term salicylate therapy, (4) on short, intermittent systemic, or aerosolized courses of corticosteroids, and (5) secondary infections by a household member, as the disease is usually more severe than the index case [55, 56]. Table 18.22 contains antiviral dosing recommendations [57]. Antivirals have a limited window of opportunity to affect clinical course, and should be started within 24 h of the rash developing.

Intravenous acyclovir is recommended for immunocompromised children, including those treated with chronic steroids [58, 59]. Therapy initiated within 24 h of rash onset maximizes efficacy, but individuals should be treated even if this time window has passed. Some experts have used valacyclovir in selected immunocompromised patients believed to be at lower risk of developing severe varicella, but this should be reviewed on a case-by-case basis. Foscarnet should be used to treat infections caused by acyclovir-resistant VZV strains, which are typically limited to immunocompromised hosts (Table 18.22) [60].

In the setting of VZV exposure, immunization may prevent or modify disease if given to otherwise healthy children within 72–120 h after varicella exposure [61]. Acyclovir is not recommended for prophylactic use in either the immunocompetent or immunocompromised. Varicella-Zoster Immune Globulin (VZIG; 125 units/10 kg, maximum 625 units) is recommended in immunocompromised children with no history of varicella and/or negative serologic testing as soon as possible within 10 days of exposure [62]. If VZIG is not available, IVIG (400 mg/kg administered once) is a potential alternative [63]. Immune globulin preparations are not effective once symptoms are present. Potential varicella exposures include an infected member of the household, playmate (face-to-face indoor contact), hospital roommate, or healthcare worker. Varicella can be contracted from those with zoster, but requires intimate contact (touch or hugging) before the lesions are crusted [55].

In neonates, varicella infection has a higher case-fatality rate when the mother develops varicella from 5 days before to 2 days after delivery. This is secondary to immature neonatal cellular immunity and insufficient development and transplacental transfer of VZV-specific maternal immunoglobulin G antibodies. VZIG is recommended in this population and is also recommended in a hospitalized preterm infant (28 weeks or more gestation) whose mother lacks evidence of immunity against varicella, and a hospitalized preterm infant (less than 28 weeks gestation or birth weight of 1000 g or less) regardless of maternal immunity [55, 62].

VZIG is not indicated for healthy term infants exposed postnatally to varicella, even in those whose mother develops a rash more than 2 days after delivery. However, some would advise VZIG for exposed newborns within the first 2 weeks of life whose mothers do not have evidence of VZV immunity.

Herpes zoster or shingles is caused by reactivation of varicella zoster virus (VZV) in the dorsal root ganglia. VZV establishes latency during primary varicella infection or following varicella vaccine. Although pediatric zoster is most common among immunocompromised children and those exposed in utero or within the first year of life, it can occur in children without these risk factors. Childhood zoster tends to be milder and less associated with postherpetic neuralgia. The classic presentation is an acute, unilateral vesicular eruption in a dermatomal distribution along one or more sensory nerves (Figs. 18.8 and 18.9). Patients may complain of pain, hyperesthesia, and tenderness before cutaneous findings. Crusting of the vesicles and healing occurs within a few days to 1 week. Zoster may become disseminated in immunocompromised children, with visceral complications including encephalitis, pneumonia, and hepatitis.

Treatment includes symptomatic therapy and antivirals [64]. Symptomatic care includes cool compresses, calamine lotion, antihistamines, and analgesics. Fingernails should be kept short to avoid superinfection and excoriation.

Acyclovir is the only antiviral agent for zoster with specific pediatric dosing guidelines; famciclovir and valacyclovir do not have sufficient clinical data for pediatric zoster (Table 18.26). Ideally, antiviral therapy should be given within 72 h of exanthem onset to decrease acute neuritis, vesicle formation, and time to crusting [65]. Immuncompromised patients as well as those with serious complications or disseminated disease should be treated with intravenous acyclovir [66].

Infectious mononucleosis (IM) is one of the most recognized syndromes of Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV4). IM is caused by primary EBV infection in older children or adolescents, and consists of fever, pharyngitis, lymphadenopathy, and fatigue. Cutaneous manifestations are nonspecific and usually appear as a morbilliform copper-colored eruption on the trunk and extremities (Figs. 18.10 and 18.11). Administration of antibiotics, particularly penicillins such as ampicillin and amoxicillin, will lead to development of a morbilliform, scarlatiniform, or petechial eruption in the majority of patients with IM. This is thought to represent an enhanced reaction to drugs or their metabolites rather than a true allergy. Systemic complications include encephalitis, upper airway obstruction (due to tonsillar hypertrophy), mild acute hepatitis, lymphocytosis with atypical lymphocytes, thrombocytopenia, hemolytic anemia, splenomegaly and, rarely, splenic rupture.

Another dermatologic manifestation of EBV involves large, painful, symmetric genital ulcers, particularly in adolescent females, on the labia minora and majora. Most patients then develop symptoms of infectious mononucleosis.

Initial laboratory evaluation should include a complete blood count with differential, hepatic function panel, and heterophile antibody test (or Monospot test). Monospot may be negative in the early stages and in children less than 4 years of age. Further serologic testing including EBV IgM, and IgG antibodies against viral capsid antigens, early antigens, and nuclear antigen proteins may be pursued in those who are Monospot-negative.

Management is mainly supportive. Rest, hydration, antipyretics, and analgesics are recommended. Patients should avoid exertion and participation in sports for a minimum of 3 weeks. Amoxicillin and ampicillin should not be prescribed. Systemic corticosteroids may be helpful in managing more severe complications including upper airway obstruction, hemolytic anemia, and thrombocytopenia [68–70].

Warts or verrucae are a common dermatologic condition in children and adults, with a variety of presentations. They may be cobblestoned or filiform as in the common wart (verruca vulgaris) (Fig. 18.12); flesh-colored, flat-topped plane warts (verruca plana); or hyperkeratotic warts on soles (verruca plantaris) or palms (verruca palmaris). A study of wart incidence by age range showed warts were most common among 9- and 10-year-olds, with 8.61 % having warts [71]. In children, verrucae are typically benign and more of a cosmetic concern. Pain and functional impairment may occur if warts proliferate on soles, hands, or periorificially.

Verrucae are caused by the human papillomavirus (HPV), with different strains of HPV being more common in different types of warts. Verruca vulgaris is most commonly associated with HPV strains 1, 4, 27, and 57 while palmoplantar warts are thought to be caused by HPV 2 [72].

Warts are benign, and immunocompetent children will eventually clear the infection [73]. Treatment strategies for warts in children should focus on minimizing discomfort and progression of lesions, while avoiding painful treatment modalities. Verruca plantaris should be treated to minimize functional impairment and discomfort. Management is similar to verruca vulgaris, with possible need to move to second- and third-line therapies sooner, given the potential symptomatic nature of plantar warts. With any painful treatment modality, encouraging the patient’s family to pretreat with acetaminophen or ibuprofen can help lessen the patient’s pain and make him or her a more willing treatment partner.

HPV is ubiquitous in the environment, and children with warts do not represent a significant infectious risk to others. Children are more likely to auto-inoculate and spread the virus to other parts of their skin. Families should be counseled on this potential for auto-inoculation. Children should be dissuaded from their natural tendencies to touch, bite, pick, or otherwise manipulate warts.

First-line therapies to treat warts include observation, salicylic acid, and occlusion with duct tape [73–75]. While requiring patience on the part of the patient and family, these options are typically well-tolerated by children and are a good initial choice for asymptomatic verrucae that are not cosmetically disturbing to the patient.

More advanced wart therapies involve various degrees of local irritation and immunomodulation to the wart. Topical prescription creams such as 5-fluorouracil and imiquimod and in-office application of a combination of tricholoroacetic acid, podophyllin, and Cantharidin 0.7 %, are well-tolerated [76, 77]. Liquid nitrogen cryotherapy can be effective, and is better tolerated in older children and teenagers [75] (Fig. 18.13). Isolated case reports have described clearance of recalcitrant verrucae after patients received the HPV vaccination, despite the fact the serotypes covered in the vaccine are not those typically associated with common warts [72]. Squaric acid, diphenylcyclopropenone, intralesional bleomycin, intralesional candida antigen, and laser treatments are other advanced wart therapies that may require additional cooperation and pain tolerance on the part of the patient [78–87].

Condyloma or anogenital warts are pink-gray, polypoid verrucous-surfaced papules along vulvar, penile, perineum, or peri-rectal skin. Condyloma result from infection with human papillomavirus (HPV) on genital skin, primarily with HPV strains 6 and 11 with the incubation period ranging from a few weeks to several months [88]. Adjacent skin folds may have “kissing” lesions representing spread of the virus through skin-on-skin contact. Multiple studies have suggested peri-rectal is the most common location for condyloma. Lesions may be asymptomatic or associated with pruritus, discomfort, or bleeding.

A child may acquire condyloma through several modes of transmission: vertically from mother to child perinatally, auto-inoculation by the child from a non-genital verruca, direct transmission from a caregiver during diapering or bathing, or inoculation from fomites [89]. Suspicion for transmission via sexual abuse is higher in older children (3 years and above) who do not have non-genital verruca in themselves, relatives, or other caregivers. When sexual abuse is a concern, careful history-taking by trained providers and the involvement of child protection agencies are the crucial first steps. A detailed physical exam for any other signs of abuse is key, but many patients who have experienced sexual abuse have no pertinent findings on exam.

The location and persistence of lesions can make treating condyloma a prolonged and potentially uncomfortable process. Condyloma may be treated with topical preparations applied in-office or at home. Destructive modalities, such as cryotherapy, excision, or laser treatments, are alternative treatment strategies that may be more painful and require more cooperation [90, 91].

With the growing use of HPV vaccines, condyloma management now starts with prevention [92–94]. The quadrivalent HPV vaccine available in the US (Gardasil™) covers HPV strains 6, 11, 16, and 18 [92, 95]. Gardasil-9 is a new expanded version of the original vaccine and covers HPV strains 6, 11, 16, 18, 31, 33, 45, 52, and 58. Both are FDA-approved for females and males aged 9–26 years. A bivalent vaccine (Cervarix™) covers HPV strains 16 and 18 and is FDA-approved for girls aged 9–26 years [92, 95]. The vaccines are given as a series of three intramuscular injections into the deltoid muscle.

Cryotherapy has a clearance rate that varies from 27 % to 88 % depending on technique [88]. Two applications of liquid nitrogen—delivered from cryo-canister, cold forceps, or cotton-tipped application—for at least 15 s or until a rim of frost covers the entire lesion with a 1 mm border, should be separated by sufficient time to allow the lesion to thaw without external re-warming. Cryotherapy should be repeated every 2–4 weeks. Podofilox (Condylox) and podophyllotoxin are plant-derived anti-mitotic medications that may be used topically on condyloma [90, 91, 96, 97].

For second-line therapies, imiquimod applied three to five nights a week is usually well-tolerated by patients [90–98]. Symptomatic smaller condyloma may be excised under local or general anesthesia. Initial clearance rates for excision range from 35 % to 70 %, with recurrence rates around 20 % [88].

Numerous additional destructive and immunomodulatory treatments have been tried for condyloma [99–102]. Cimetidine is an H₂ receptor antagonist whose efficacy against condyloma and verruca vulgaris as demonstrated in open-label studies and case series has not been duplicated in randomized controlled trials [103, 104]. In adults, the application of 5-aminolevulinic acid (ALA) following by photodynamic therapy has produced clearance of condyloma, and could be considered for older children able to tolerate the procedure and discomfort [105]. Sinecatechins (VEREGEN or Polyphenon E) are green tea-based polyphenols with immunomodulatory properties, and may appeal to families who prefer a more plant-derived, less medicalized approach [106]. Cidofovir and interferon are treatments used for extensive condyloma in immunosuppressed patients [107].