Skin manifestations of HIV-1 infection in children

Candidosis is the most common mucocutaneous manifestation of HIV infection in children, and its incidence has been estimated to range between 20% and 72%., , , Although thrush can occur without severe CD4+ cell depletion,, it is more common in children with low CD4+ cell counts or symptomatic HIV disease., , It has been suggested in several studies that thrush is a marker of rapid HIV disease progression and death., , Esophageal candidosis, which manifests as loss of appetite or dysphagia, may coexist with oropharyngeal candidosis or occur independently, with an estimated incidence of 15.4%. Disseminated candidosis is uncommon in AIDS patients but may occur particularly in neutropenic patients and patients with central venous catheters.

Thrush is a common and benign disorder in children under the age of 6 months and in infants receiving antibiotic therapy or who were born to drug-abusing mothers. The difference in the HIV positive child is the persistence beyond the age of 6 months, the presence of severe or recurrent episodes, and the coexistence of lymphadenopathy, splenomegaly, or wasting syndrome., There are six typical modes of presentation of oral candidosis: (1) pseudomembranous, (2) erythematous (atrophic), (3) papillary hyperplasia, (4) chronic hyperplastic, (5) angular cheilitis, and (6) median rhomboid glossitis. Pseudomembranous candidosis is characterized by removable white plaques that may occur at any mucosal surface. Erythematous candidosis appears as a red thumbprint-like patch on the palate and/or the dorsum of the tongue, often causing a metallic taste or a local burning sensation. The buccal mucosa is involved less frequently. Papillary hyperplasia, which represents a chronic infection, is noted more commonly on the anterior hard palate and gives the impression of a clustering of small, ovoid nodules on an erythematous mucosa. The chronic hyperplastic form may be seen as a thickened hyperkeratotic mucosa on the tongue or the retrocommissural region, resembling an area of leukoplakia. Angular cheilitis presents as cracking or fissuring at the corners of the mouth, alone or in combination with the other forms. Median rhomboid glossitis has a nodular or fissured appearance on the tongue and is asymptomatic. The manifestations of oral candidosis may fluctuate over time (from pseudomembranous to erythematous and back to pseudomembranous)., In a recent study, erythematous candidosis was found to occur more commonly than pseudomembranous, particularly in children with advanced disease, but this has not been confirmed by others. Candida albicans is the usual pathogen causing oral candidosis, but other strains can occasionally be isolated (C. parapsilosis, C. pseudotropicalis, C. guillermondii, C. krausei, C. tuloropsis, C. tropicalis, C. rugosa)., ,

Children with HIV infection may also develop severe or persistent candidal diaper dermatitis, with widespread papules and pustules, and may also have involvement of the intertriginous areas such as the neck folds and the axillae., Occasionally, granulomatous lesions may occur. Chronic candidal paronychia seems to present more commonly between the ages of 2 and 6 years and is sometimes associated with severe nail dystrophy.

Oral candidosis is often difficult to eradicate, as recurrences are high once treatment is discontinued., The goal of therapy is not only the cure but also the prevention of the dissemination of disease to the esophagus. Maintenance of good oral hygiene and prevention of xerostomia are important. Nystatin oral pastilles and clotrimazole oral troches clear the infection effectively., , , , , The usual duration of treatment is 14 days. For refractory cases or those with severe involvement, treatment with ketoconazole or fluconazole in a single daily dose of 3–6 mg/kg is effective., A higher dosage is significantly more effective in eradicating the organism. The cure rate of fluconazole is reported to be about 90%,, , but the rate of eradication of the organism ranges between 76% and 82%., Itraconazole offers an alternative option. Another concern is the emergence of resistant organisms, which largely involves non-albicans species., , , Spreading of the disease to the esophagus requires systemic treatment with fluconazole, ketoconazole, or amphotericin B. Prophylactic or maintenance therapy may be indicated in children who have had esophageal candidosis and two or more episodes of oral candidosis. Nystatin oral suspension given twice daily and fluconazole given daily or weekly seem effective., , Hepatotoxicity can be a concern with the azole group, especially with ketoconazole.

Infection by dermatophytes occurs with an increased frequency and aggressiveness in HIV-infected patients, and many children with HIV infection may develop atypical forms of dermatophytoses. Don et al studied the mucocutaneous fungal colonization in HIV-infected children and concluded that the rates of yeast and mold colonization were the same for 13 HIV and 12 control children. Interestingly a case of widespread mucocutaneous colonization of T. beigelii, the cause of white piedra, was observed in an HIV-infected child in their series of patients.

Tinea corporis, tinea capitis, tinea faciale, and onychomycosis are particularly common., , Tinea corporis lesions usually are erythematous, scaly, and pruritic plaques, but atypical presentations like flat-topped, discrete papules may also occur. T. rubrum is a particularly common isolate, and T. tonsurans can give rise to unusual clinical features. Cases of severe and recurrent tinea capitis have been observed. Onychomycosis in HIV-infected patients has some unusual features, which are rare in immunocompetent individuals. Proximal white subungual onychomycosis of fingernails, periungual involvement, and rapid spreading of the infection to involve all 10 finger and toenails are common findings in HIV-infected individuals with low CD4+ cell counts.

Dermatophytic infections are particularly resistant to topical agents, and recurrences after topical and systemic therapy are common. Oral griseofulvin may prove to be effective,, and other antifungals such as fluconazole, itraconazole, or terbinafine may be useful. Onychomycosis responds poorly to treatment. Fluconazole and itraconazole are reasonable therapeutic options, but for severely ill patients, keeping the nails short and using topical broad-spectrum antifungal solutions may be more appropriate.

In patients with profound immunodeficiency, a myriad possible opportunistic fungal infections are possible. Histoplasma capsulatum, Coccidiodes immitis, Aspergillus fumigatus, Malassezia furfur, Sporothrix schenckii, and others can cause opportunistic infections in HIV-infected adults but are rarely observed in HIV-infected children. Cryptococcosis, sporotrichosis, and histoplasmosis may occur in either localized or disseminated forms. Papules, nodules, plaques, ulcers, or abscesses may occur. Disseminated sporotrichosis with painful ulcers has been described in children.

Cutaneous lesions indicate systemic involvement, so administration of a single agent or multidrug systemic chemotherapy with amphotericin B, flucytosine, fluconazole, or itraconazole is the appropriate treatment.

Penicillium marneffei is a dimorphic fungus that is endemic in southeast Asian countries and China. It has been suggested that P. marneffei infection should be regarded as another AIDS-defining illness. Sirisanthana et al reported a series of 21 HIV-infected children with disseminated P. marneffei infection. Papular skin lesions with central umbilication on the face and extremities appeared in 67% of patients and provided the most significant clue to the diagnosis, which is made by isolation of the organism from blood and skin specimens. Other findings included generalized lymphadenopathy, fever, hepatosplenomegaly, severe anemia, and thrombocytopenia. The disease occurs late in the course of HIV infection and is fatal unless treated with antifungals (amphotericin B, fluconazole, or ketoconazole).

Bacillary angiomatosis (BA), a cutaneous infection caused by Bartonella henselae and B. quintana, was originally described in adults with HIV infection. The lesions of BA begin as small, erythematous, vascular papules that may enlarge to form exophytic, friable nodules surrounded by a collarette of scale with or without erythema. Subcutaneous and eruptive lesions of BA may also occur. The disease can affect virtually every organ system, including the liver and spleen, and may be accompanied by fever and weight loss. Although the disease has been described in immunocompetent children,, it is rarely seen in HIV-infected children. BA presenting with abdominal visceral granulomas in a child with HIV infection has been reported. The case of an HIV-infected child has been reported, with a vascular nodule on the scalp and red papules on the right arm and back, who eventually proved to suffer from BA and was successfully treated with erythromycin. The reason for the rarity of BA in children is not known. Previous exposure to the bacillus might be necessary to initiate the reaction. Pediatric HIV-positive patients are unlikely to have past exposure to the bacillus and may also have a different susceptibility profile.

The disease needs to be differentiated from Kaposi sarcoma, and the diagnosis is made histologically. Electron microscopy, culture, polymerase chain reaction, and serological testing may prove helpful to the diagnosis. In general, patients with cutaneous disease without visceral involvement or bacteremia respond well to 8–12 days of therapy with erythromycin or doxycycline. BA is resistant to penicillin and cephalosporins.

HIV-infected children are at increased risk of tuberculosis (TB), not only because of their failing immunity but also because many of them are living with HIV-infected adults, who are infected with Mycobacterium tuberculosis. A study of the impact of HIV infection on the development of tuberculosis revealed that children with TB were significantly more likely to be HIV-seropositive, but none of the children in the study had cutaneous involvement.

Nontuberculous mycobacterial infection, particularly with M. avium intracellulare complex (MAC), is less common in children than in adults, occurs in 6–14% of infected children overall, and more commonly affects transfusion-associated AIDS cases. Children with late-stage disease and CD4+ counts <100 mm³ are particularly affected. MAC can involve any organ system; however, the skin is rarely the site of extrapulmonary mycobacterial infection., Cutaneous abscesses, macular lesions, and perianal ulcerations have been reported in HIV-infected adults but may also occur in pediatric cases. Chemoprophylaxis may be warranted for MAC.

In the United States and in areas with a low prevalence of TB, BCG is not recommended. In developing countries, however, where the prevalence is high, the WHO recommends that BCG should be given to all asymptomatic infants at birth, regardless of maternal HIV infection. Severe complications appear to be rare, justifying continued vaccine use.

VZV infection, which is usually self-limited in immunocompetent children, can be very problematic for HIV-infected children. Typical varicella may occur at any stage of HIV disease. The typical vesicular eruption may be observed, but more profuse or atypical ulcerative forms, hemorrhagic, poxlike, or disseminated ecthymatous are also possible., Varicella runs a milder course in HIV-infected children with relatively normal CD4+ counts than that observed in leukemic children. and does not seem to precede any clinical deterioration. Nevertheless, complications may occur, like hepatitis, pulmonary involvement, disseminated intravascular coagulation, superinfection of the skin, or thrombocytopenia. Kelley et al did not observe any complicated VZV infections among 13 HIV-infected children, but this can be attributed to their almost-normal CD4+ counts and the early administration of VZV immune globulin and acyclovir. Varicella may run a prolonged course (>10 days) in HIV-infected children, and persistent and recurrent infections are particularly problematic. In a retrospective study of 421 HIV-infected patients (including adults and children), 15 had varicella and one patient experienced three relapses of atypical varicella. Von Seidlein et al documented an association between increasing numbers of episodes of VZV infection and a low CD4+ count at the time of primary infection. It is of note that 53% of 73 HIV-infected children enrolled in the study had one or more recurrences of VZV infection (either zoster or recurrent varicella), 45% had a recurrence in 24 months, and 10 of 73 children had a persistent infection for 2–24 months.

Chronic VZV infection is a well-documented condition seen almost exclusively in HIV-infected individuals. Patients develop disseminated ulcerative and hyperkeratotic nodular lesions that persist., , , , , Deaths from central nervous system involvement have been reported with this form of infection., Except for chronic infection, inadequate acyclovir therapy or coinfection may result in hyperkeratotic VZV lesions. The failure of the lesions to heal may signal the development of a strain of VZV that is resistant to acyclovir.

Herpes zoster (HZ) is rare in immunocompetent children but occurs with increased frequency in HIV-infected children. In addition to classic papulovesicular HZ, persistent ulcerative and disseminated forms may be observed. The skin lesions tend to be deeper, more extensive, and more painful than in the immunocompetent child. There is a significant incidence of scarring, and there may be a very brief interval between an episode of chickenpox and reactivation in the form of HZ. Von Seidlein et al documented that the presentation of zoster as the first recurrence of VZV infection is associated with low CD4+ counts. In the study of Gershon et al, HZ developed in 70% of HIV-infected children with low levels of CD4+ counts at the time of the development of varicella.

The diagnosis of VZV infection can be confirmed by examination of a Tzanck smear and a viral culture of vesicular fluid.

In an effort to prevent severe varicella, the administration of VZ immune globulin has been recommended for use after chicken pox exposure. In view of the potentially higher risk for severe chicken pox in HIV-infected children, intravenous acyclovir is given (1500 mg/m²/d divided in three doses), although oral acyclovir at a dose of 900 mg/m²/dose every 6 hours may be used in less severe cases., For acyclovir-resistant strains which lack thymidine kinase, foscarnet may be effective, even temporarily.

Immunization against VZV with live attenuated vaccine is unlikely to be deleterious. If immunization is offered when CD4+ levels are still normal, there may be a lower rate of reactivation of VZV.

Herpes simplex virus (HSV) infection is common in immunologically normal children, with rapid and usually uneventful recovery. HIV-infected children, however, can develop severe, chronic, and recurrent HSV disease., In one study, as many as 21% of 85 HIV-infected children suffered from HSV infection, and in another study, 120 episodes of HSV stomatitis lasting >2 months were observed in a group of 158 HIV-infected children. Recurrent HSV stomatitis in children is indicative of moderately symptomatic disease in the revised classification system of the CDC for HIV infection. HSV infection correlates primarily with CD4+ cell counts. When CD4+ cell counts exceed 400 cells/mm³, only 13% of ulcerative lesions are HSV associated, whereas when CD4+ counts are <50 cells/mm³, then 58% of all ulcerations contain HSV.,

The most common feature of HSV in pediatric HIV infection is herpetic gingivostomatitis, with painful, recurrent, or chronic ulcerations of the lips, tongue, palate, and buccal mucosa, that interfere with oral intake and cause significant morbidity requiring hospitalization. Recurrences are common and disfiguring and may result in persistent erosions that involve both the vermilion border and the intraoral mucosa and resemble primary infection., Autoinoculation of HSV from the chin to the fingers resulting in herpetic whitlow has also been reported. Prose has observed several cases of herpetic whitlow in children with AIDS. Herpetic whitlow may be progressive, recalcitrant to treatment, and ulcerative and may scar the nail apparatus. Lesions of HSV may appear at other locations such as the soles and the perianal area. HSV can also spread from the oral mucosa to the esophagus, but cutaneous and visceral disseminations usually are rare. In cutaneous dissemination, widespread hemorrhagic vesicles and bullae may develop.

After Tzanck smears and viral cultures have been obtained for the confirmation of the diagnosis, therapy must be instituted. Acyclovir either orally for mild mucocutaneous disease or intravenously for moderate or severe involvement is usually effective., , , , , , Patients with frequent or severe recurrences can be given acyclovir daily for prophylaxis., Acyclovir resistance has been observed in children and in adults. It is attributed to viral deficiency of thymidine kinase and usually presents if acyclovir has not been instituted until the ulcer is large. Foscarnet is used for the treatment of acyclovir-resistant infections., Once lesions due to acyclovir-resistant HSV have healed with foscarnet, then acyclovir suppression may be reinstituted, since thymidine kinase-resistant strains have limited capacity for ganglionic latency. Unfortunately, clinically significant foscarnet-resistant HSV infections may occur. Such infections can be treated with the addition of acyclovir to foscarnet or with a 6-week continuous infusion of parenteral acyclovir.

Infection with human papilloma virus may cause a number of cutaneous manifestations in a child with HIV-related illness, like verruca vulgaris, widespread flat warts, and condylomata acuminata. Warts can be single but usually are multiple., ,

Multiple hemorrhagic verrucae involving the torso and the extremities with resistance to cryotherapy have been described in a child with HIV infection. The case of a 10-year-old HIV-infected boy has been reported with widespread flat warts and tinea versicolor-like lesions. Human papilloma virus-3 was identified within his cutaneous lesions.

Extensive anogenital warts, very resistant to treatment, have also been observed., Sexual abuse might be suspected in children with condylomata acuminata, but this is not always the case. An 18-month-old girl with AIDS who presented with condylomata acuminata had no history of sexual abuse. Topical therapy did not offer any help, but there was spontaneous regression when she reached 22 months of age.

Ordinary warts can be treated with the daily application of a salicylic acid preparation. Hachem et al successfully tried curettage under general anesthesia for widespread flat warts covering almost the entire skin surface. For condylomata acuminata, 20% podophyllin resin can be tried first, but for large lesions, surgical excision might be considered. Another option is intralesional interferon-alfa.

Molluscum contagiosum (MC) is caused by a DNA poxvirus and has been reported with increased frequency in HIV-infected individuals, its incidence ranging between 5% and 18%. An Australian survey revealed positive antibody responses for MC virus in 91% of those with coexistent MCV and HIV infection.

MC in healthy hosts presents with multiple, pearly white, dome-shaped, umbilicated papules, 1–4 mm each, sparing the mouth, palms, and soles. Spontaneous resolution can be expected in 3–12 months. In children with HIV infection, these lesions often involve atypical areas, such as the face and neck, and tend to be more confluent and occasionally extremely numerous, , In addition, giant lesions may occur., , Lim et al noted that unusual features may occur without severe CD4+ cell depletion, but others documented a negative correlation between CD4+ counts and the number of MC lesions., Molluscum dermatitis, a localized eczematous reaction around MC lesions, represents a delayed hypersensitivity reaction to viral antigens but has not been reported yet in HIV-infected patients.

It is important to document the viral inclusions in the central core of MC lesions because cryptococcosis and histoplasmosis may mimic closely those lesions.

In contrast to the usual course in healthy children, molluscum lesions in HIV-infected patients tend to persist and are extremely recalcitrant to conventional therapies. Local destruction (with cryotherapy, curettage, or 50% trichloroacetic acid (TCA) may be attempted., A combination of cryotherapy or 50% TCA and 0.025% tretinoin cream can give good results. Lesions have been noted to clear after the initiation of zidovudine treatment. Resolution of MC lesions with intravenous and topical cidofovir (as a 3% cream in a combination vehicle) has been reported. Generally, MC lesions tend to recur, regardless of the treatment used.

The manifestations of scabies infestation depend on the host’s ability to perceive the infestation and scratch the affected sites. Independently of CD4+ counts, most patients have scabetic burrows at characteristic sites, such as the wrists and finger web spaces. Patients with CD4+ counts <150 cells/mm³ may present with crusted Norwegian scabies., , Scaly, fissured, crusted, erythematous, hyperkeratotic plaques, mainly on the neck, scalp, buttocks, flexures, palms, soles, and web spaces, are present. Atopic dermatitis or psoriasis may be misdiagnosed. A 6-month-old HIV-infected infant developed an eczematous dermatitis later diagnosed as crusted scabies. Prose observed two infants with hundreds of vesicular and crusted papules on the entire skin surface in response to infestation by the scabies mite. Similar cases with extensive vesicular lesions have been reported by others. In Norwegian scabies, the nail bed and plate may be hypertrophic and loaded with mites. Scabies can be diagnosed with the identification of mites, ova, or feces from the skin lesions.

The infestation might be particularly resistant to treatment. Permethrin 5% lotion should be tried first. For resistant cases, gamma benzene hexachloride and ivermectin orally at a single dose are options to be considered.

Pediculosis is particularly common, especially in children with low socioeconomic status.

Papular lesions on the face of two HIV-infected children in relation to Demodex mites have been described., The main defense against Demodex mites are the CD4+ cells, which are defective in HIV infection.

KS is the most common HIV-related cancer in adults and is more prevalent in homosexual men. The disease is rare in children in the Western world. Overall, 33 children from Europe and the United States and 49 adolescents (18 from Europe and 31 from the United States) had KS at the time of AIDS diagnosis., The proportion of cases with KS significantly increases with age, 1.7 years being the average., The disease has been described in a 6-day-old HIV-infected infant. Among 17 children who acquired HIV infection perinatally, only two developed KS lesions, whereas nine of 13 children who acquired the infection postnatally had cutaneous KS. This observation has led to the hypothesis that different routes of HIV infection may be associated with different KS clinical manifestations.

Recently, human herpesvirus-8 (HHV-8) has been identified as the cause of KS. A study conducted in Uganda revealed a higher socioeconomic status among KS-infected individuals, which suggests an enhanced exposure to a possibly sexually transmitted agent or a delayed exposure to a childhood infection. Water as a possible source of HHV-8 transmission is implicated. Prior infection with Epstein-Barr virus may cross-protect against de novo HHV-8 infection or reactivation. KS in children points to a nonsexual mode of transmission. HHV-8 can be acquired as a common childhood infection and may possibly be horizontally transmitted from mother to child during birth or breastfeeding. A study concentrating on the seroprevalence of HHV-8 among Zambian women of childbearing age without KS and mother-child pairs with KS concluded that all children with KS had mothers who were HHV-8-seropositive, while not all children whose mothers had KS were infected with HHV-8. Vertical transmission of KS from an HIV-seropositive mother to her child has been reported.

Before the HIV epidemic, KS was already endemic in Uganda, Zimbabwe, and Zambia, most commonly in older men. Childhood KS was rare. With the advent of the HIV epidemic in these countries, KS has become more common in children., , In Zambia, a 10-fold increase in the incidence has been noted, and in Uganda, a 40-fold increase has been observed. In other countries, however, no obvious increase has been observed.

There is a male preponderance for childhood HIV-related KS, and the median age of presentation is 4 years. The distribution of childhood HIV-related KS is mainly lymphadenopathic and mucocutaneous with two major patterns: orofacial-dominant (79%) and inguinal-genital dominant (13%). KS lesions occasionally exhibit the Koebner phenomenon and appear at sites of previous trauma or infection. Cutaneous lesions range from solitary nodules to widely disseminated plaques or nodules.

Single or combination chemotherapy is the usual therapeutic approach, although it may worsen the underlying immunodeficiency. Systemic interferon-alpha has been used with variable success rates.

NHL turns out to be more common in children and adolescents with AIDS. The proportion of children with NHL at the time of AIDS diagnosis was higher in the United States (0.5%) than in Europe (0.9%). The frequency of this neoplasm tends to increase significantly with age and is more common in boys than in girls. An important role for Epstein-Barr virus has been suggested, and all children have low CD4+ counts at the time of diagnosis. In a British study, seven cases of NHL were identified among 302 HIV-infected children, and two of them had NHL involving the tonsil and soft palate. Chemotherapy is the treatment of choice.

Seborrheic dermatitis (SD) is possibly one of the most common cutaneous manifestations of HIV disease, its incidence ranging from 32–83%. An association if not a causative role for Pityrosporum has been suggested. In children with HIV infection, SD seems to occur with increased frequency, although in some series the usual incidence is observed. Its severity has been correlated with the degree of HIV-related immunodeficiency and the CD4+ cell count., In infants, the disorder may take the form of severe erythema and scaling of the face, scalp, and diaper area, sometimes progressing to erythroderma., Nonscarring alopecia may be one of the sequelae. Older children (between the ages of 2 and 5) may develop the adult form of SB, with a thick, scaly eruption on the nasolabial folds, retroauricular areas, axillae, and scalp, which is unique for HIV infection.