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Skin manifestations of HIV-1 infection in children

      The first pediatric case of AIDS was reported to the Centers for Disease Control and Prevention (CDC) in November 1982, 18 months after the first description of AIDS in adults. It is estimated that 3.5 million women of childbearing age have been infected with HIV-1, and 3000 additional women become infected every day. According to the World Health Organization (WHO), by December 1998, 1.2 million children under the age of 15 years were infected with HIV.
      • Dray-Spira R.
      • Lepage P.
      • Dabis F.
      Prevention of infectious complications of pediatric HIV infection in Africa.
      One million of them live in Africa and in general have been infected through vertical mother-to-child transmission of HIV.
      • Dray-Spira R.
      • Lepage P.
      • Dabis F.
      Prevention of infectious complications of pediatric HIV infection in Africa.
      HIV-1 infection has a significant impact on childhood mortality and morbidity and is one of the leading causes of death, especially among African children.
      The established modes of transmission of HIV-1 infection are through (1) sexual contact, (2) from mother to infant, and (3) through exposure to infected blood (such as transfusion, needle sharing). Transmission of HIV-1 from mother to child (vertical) is the predominant source of acquisition of HIV-1 in children. Data support the transmission during the antepartum and intrapartum periods as well as postpartum by breastfeeding. Zidovudine given antepartum and intrapartum to the mother and the newborn for 6 weeks reduces the risk of maternal-infant HIV transmission by approximately two thirds
      • Connor E.M.
      • Sperling R.S.
      • Gelber R.
      • et al.
      Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment.
      and is safe.
      • Sperling R.S.
      • Shapiro D.E.
      • McSherry G.D.
      • et al.
      Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study.
      Many children, especially hemophiliacs, have been infected through infected blood products, but transfusion-related transmission is now rare in the Western world but still applies for the developing countries. Routes of transmission of HIV in adolescents are similar to those for adults.
      Several studies revealed that perinatal infection had a more varied clinical picture and a worse outcome than infection acquired later in childhood.
      • Tovo P.A.
      • de Martino M.
      • Gabiano C.
      • et al.
      Prognostic factors and survival in children with perinatal HIV-1 infection.
      ,
      Viral infections.
      ,
      • Galli L.
      • de Martino M.
      • Tovo P.A.
      • et al.
      Onset of clinical signs in children with HIV-1 perinatal infection.
      About one third of infants born to HIV-seropositive mothers will have evidence of infection or AIDS by the age of 18 months, and about one fifth of them will die.
      • Sperling R.S.
      • Shapiro D.E.
      • McSherry G.D.
      • et al.
      Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study.
      ,
      • Blanche S.
      • Rouzioux C.
      • Guihard Moscato M.L.
      • et al.
      A prospective study of infants born to women seropositive for human immunodeficiency virus type 1.
      Subsequently, the disease progresses more slowly, and most children remain stable or even improve during the second year.
      • Ades A.E.
      • Newell M.L.
      • Peckham C.S.
      • et al.
      European Collaborative Study: children born to women with HIV-1 infection natural history and risk of transmission.
      The diagnosis of HIV-1 infection is a special diagnostic challenge. In 1994 the CDC revised the classification system published in 1987, aiming not only to establish disease surveillance but also to define its progression. In the current classification system, children are grouped into mutually exclusive categories based on three parameters: (1) infection status (exposed, infected, seroconverter; (2) clinical status (asymptomatic, mild, moderate, or severe symptoms); and (3) immunological status (age-related categories of no, moderate, or severe suppression). Reclassification to a less severe category does not occur even if the child’ s clinical or immune status improves. Recent data suggest that determination of the plasma viral concentration (viral load) in conjunction with CD4+ cell count are more accurate predictors of prognosis and survival than each marker alone. The viral load >5log10 per ml within the first 30 months of life and >4.3log10 after 30 months are associated with an increased risk of disease progression.
      • de Martino M.
      • Tovo P.A.
      • Giaquinto C.
      • et al.
      Committee report. Italian guidelines for antiretroviral therapy in children with human immunodeficiency virus type-1 infection.

      Immunology

      Although HIV-1 is particularly tropic for CD4+ (helper) T lymphocytes, monocytes, macrophages, and central nervous system cells that express CD4+ receptors, abnormalities in humoral immunity may precede the development of the more characteristic ones of cell-mediated immunity. B cells from HIV-infected children demonstrate polyclonal activation and hyperproliferation with hypersecretion of polyclonal immunoglobulins. Despite B-cell activation, HIV-infected children functionally appear hypogammaglobulinemic, with B cells unable to respond efficiently to specific antigens, and consequently, they become extremely prone to devastating bacterial infections. Impaired T-cell immunity is manifested as decreased in vivo and in vitro function of T cells as well as quantitative abnormalities of T cells. The suppressor CD8+ lymphocytes usually increase in number initially, resulting in a decrease of the normal CD4+ to CD8+ ratio, and are not depleted until late in the disease. The most severely affected cells are the CD4+ lymphocytes, whose function and numbers steadily decline as the disease progresses.
      The skin and mucous membranes are the first barriers to be disrupted, so mucocutaneous signs are very important markers of disease progression. In a Nigerian study it has been estimated that skin manifestations can be the presenting feature in as many as 37% of HIV-infected children. The occurrence of certain skin manifestations has been noted to correlate with the CD4+ cell count.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      As the CD4+ cell count declines, more severe and multiple cutaneous manifestations appear that are less responsive to conventional treatment.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      Mucocutaneous manifestations can be divided into infectious and noninfectious ones and are listed in Table 1.
      Table 1Cutaneous Manifestations of HIV-1 Infection in Children
      Infections and infestations
      Fungal infections
      Candidosis
      Dermatophytosis
      Deep fungal infections
      Bacterial infections
      Bacillary angiomatosis
      Mycobacterial infections
      Viral infections
      Varicella zoster infection
      Herpes simplex infections
      Human papilloma virus infection
      Molluscum contagiosum infection
      Other viral infections
      Measles
      Cytomegalovirus infection
      Epstein-Barr virus infection
      Infestations
      Scabies
      Pediculosis
      Demodicosis
      Protozoal infections
      Acanthamoeba infection
      Neoplastic disorders
      Kaposi sarcoma
      Non-Hodgkin lymphoma
      Inflammatory Disorders
      Seborrheic dermatitis
      Atopic dermatitis
      Psoriasis
      Urticaria
      Drug eruptions
      Vasculitis
      Aphthous ulcers
      Nutritional deficiencies
      Miscellaneous
      Alopecia
      Hypertrichosis of the eyelashes
      Hypertrichosis of lanugo type
      HIV infection primary rash
      Sweet syndrome
      Pyoderma gangrenosum
      Gianotti Crosti syndrome
      Erythema dischromicum perstans
      Vitiligo
      Eruptive dysplastic nevi
      Trauma from child abuse

      Fungal infections

      Candidosis

      Candidosis is the most common mucocutaneous manifestation of HIV infection in children, and its incidence has been estimated to range between 20% and 72%.
      • Ades A.E.
      • Newell M.L.
      • Peckham C.S.
      • et al.
      European Collaborative Study: children born to women with HIV-1 infection natural history and risk of transmission.
      ,
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      Although thrush can occur without severe CD4+ cell depletion,
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      it is more common in children with low CD4+ cell counts or symptomatic HIV disease.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      It has been suggested in several studies that thrush is a marker of rapid HIV disease progression and death.
      • Ades A.E.
      • Newell M.L.
      • Peckham C.S.
      • et al.
      European Collaborative Study: children born to women with HIV-1 infection natural history and risk of transmission.
      ,
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      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%.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      Disseminated candidosis is uncommon in AIDS patients but may occur particularly in neutropenic patients and patients with central venous catheters.
      • Walsh T.J.
      • Gonzalez C.
      • Roilides E.
      • et al.
      Fungemia in children infected with the human immunodeficiency virus new epidemiologic patterns, emerging pathogens and improved outcome with antifungal therapy.
      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.
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      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.
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      ,
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      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.
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      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).
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Greenspan D.
      Treatment of oropharyngeal candidiasis in HIV-positive patients.
      In a recent study, erythematous candidosis was found to occur more commonly than pseudomembranous, particularly in children with advanced disease,
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      but this has not been confirmed by others.
      • Moniaci D.
      • Cavallari M.
      • Greco D.
      • et al.
      Oral lesions in children born to HIV-1 positive women.
      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).
      • Moniaci D.
      • Cavallari M.
      • Greco D.
      • et al.
      Oral lesions in children born to HIV-1 positive women.
      ,
      • Flynn P.M.
      • Cunningham C.K.
      • Kerkering T.
      • et al.
      Oropharyngeal candidiasis in immunocompromised children a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.
      ,
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      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.
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      ,
      • Prose N.S.
      HIV infection in children.
      Occasionally, granulomatous lesions may occur.
      • Prose N.S.
      HIV infection in children.
      Chronic candidal paronychia seems to present more commonly between the ages of 2 and 6 years and is sometimes associated with severe nail dystrophy.
      • Prose N.S.
      HIV infection in children.
      Oral candidosis is often difficult to eradicate, as recurrences are high once treatment is discontinued.
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      ,
      • Hernandez-Sampelayo T.
      Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV infected children.
      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.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      ,
      • Greenspan D.
      Treatment of oropharyngeal candidiasis in HIV-positive patients.
      ,
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      ,
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      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.
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      ,
      • Hernandez-Sampelayo T.
      Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV infected children.
      A higher dosage is significantly more effective in eradicating the organism.
      • Flynn P.M.
      • Cunningham C.K.
      • Kerkering T.
      • et al.
      Oropharyngeal candidiasis in immunocompromised children a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.
      The cure rate of fluconazole is reported to be about 90%,
      • Flynn P.M.
      • Cunningham C.K.
      • Kerkering T.
      • et al.
      Oropharyngeal candidiasis in immunocompromised children a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.
      ,
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      ,
      • Hernandez-Sampelayo T.
      Fluconazole versus ketoconazole in the treatment of oropharyngeal candidiasis in HIV infected children.
      but the rate of eradication of the organism ranges between 76% and 82%.
      • Flynn P.M.
      • Cunningham C.K.
      • Kerkering T.
      • et al.
      Oropharyngeal candidiasis in immunocompromised children a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.
      ,
      • Marchisio P.
      • Principi N.
      Treatment of oropharyngeal candidiasis in HIV infected children with oral fluconazole.
      Itraconazole offers an alternative option.
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      Another concern is the emergence of resistant organisms, which largely involves non-albicans species.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Greenspan D.
      Treatment of oropharyngeal candidiasis in HIV-positive patients.
      ,
      • Flynn P.M.
      • Cunningham C.K.
      • Kerkering T.
      • et al.
      Oropharyngeal candidiasis in immunocompromised children a randomized, multicenter study of orally administered fluconazole suspension versus nystatin.
      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
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      and fluconazole given daily or weekly seem effective.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Flaitz C.M.
      • Hicks J.M.
      Oral candidiasis in children with immune suppression clinical appearance and therapeutic considerations.
      ,
      • Greenspan D.
      Treatment of oropharyngeal candidiasis in HIV-positive patients.
      Hepatotoxicity can be a concern with the azole group, especially with ketoconazole.

      Dermatophytoses

      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
      • Don P.C.
      • Shen N.N.
      • Koestenblatt E.K.
      • et al.
      Mucocutaneous fungal colonization in HIV infected children.
      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.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      ,
      • Prose N.S.
      Cutaneous manifestations of pediatric HIV infection.
      Tinea corporis lesions usually are erythematous, scaly, and pruritic plaques, but atypical presentations like flat-topped, discrete papules may also occur.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      T. rubrum is a particularly common isolate,
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      and T. tonsurans can give rise to unusual clinical features. Cases of severe and recurrent tinea capitis have been observed.
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      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.
      • Daniel R.C.
      • Norton L.A.
      • Scher R.K.
      The spectrum of nail disease in patients with human immunodeficiency virus infection.
      Dermatophytic infections are particularly resistant to topical agents, and recurrences after topical and systemic therapy are common.
      • Prose N.S.
      Cutaneous manifestations of pediatric HIV infection.
      Oral griseofulvin may prove to be effective,
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      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.
      • Daniel R.C.
      • Norton L.A.
      • Scher R.K.
      The spectrum of nail disease in patients with human immunodeficiency virus infection.

      Deep fungal infections

      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
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      but are rarely observed in HIV-infected children.
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Cryptococcosis, sporotrichosis, and histoplasmosis may occur in either localized or disseminated forms. Papules, nodules, plaques, ulcers, or abscesses may occur.
      • Angeles A.M.
      Fungal and mycobacterial skin infections.
      Disseminated sporotrichosis with painful ulcers has been described in children.
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      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
      • Sirisanthana V.
      • Sirisanthana T.
      Disseminated Penicillium marneffei infection in human immunodeficiency virus-infected children.
      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).

      Bacterial infections

      An increased susceptibility to bacterial infections has been documented in children suffering from HIV. The bacterial infections encountered are similar to those seen in immunologically normal pediatric patients.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      Generally, children manifest recurrent bacterial infections rather than primary opportunistic ones as seen in adults.
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      Clinical syndromes include bacteremia, urinary tract infection, pneumonia, and skin or soft tissue infections, by frequency of their occurrence.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      The most common isolates are Streptococcus pneumoniae, Haemophilus influenza type B, and Salmonella species,
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      although different bacterial pathogens are being recognized lately. Staphylococcal infections are the most common skin infections, usually presenting as cellulitis, ecthyma, erysipelas, furunculosis (occasionally of disseminated nature), persistent and recurrent folliculitis, and impetigo.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      ,
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      ,
      • Berstein L.J.
      • Kreiger B.Z.
      • Novick B.
      • et al.
      Bacterial infection in the acquired immunodeficiency syndrome of children.
      A case of staphylococcal scalded skin syndrome in a child with AIDS has also been reported.
      • Prose N.S.
      HIV infection in children.
      Pyomyositis has been described in a child with AIDS.
      • Raphael S.A.
      • Wolfson B.J.
      • Parker P.
      • et al.
      Pyomyositis in a child with acquired immunodeficiency syndrome patient report and brief review.
      The initial sites of colonization with S. aureus before infection are the nares.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      Several studies have demonstrated a nasal carriage at approximately 50% of HIV-positive homosexual men at all stages of HIV disease, twice the rate of controls.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      ,
      • Ganesh R.
      • Castle D.
      • McGibbon I.
      • et al.
      Staphylococcal carriage and HIV infection.
      ,
      • Bibel D.J.
      • Aly R.
      • Conant M.A.
      • et al.
      From HIV infection to AIDS changes in the microbial ecology of the skin and nose.
      Gram-negative infections can be quite troublesome. Prose
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      observed severe periorbital infection in a child with AIDS. This form of infection requires rapid intervention with intravenous antimicrobiols to prevent meningitis or sepsis.
      Pseudomonas bacteremia can produce cutaneous manifestations, including ecthyma gangrenosum and a papular rash that appear uncommonly in non-HIV-infected patients.
      • Flores G.
      • Stavola J.J.
      • Noel G.J.
      Bacteremia due to Pseudomonas aeruginosa in children with AIDS.
      Otitis externa due to Pseudomonas has also been reported.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      For the initial presentation of common superficial infections, a Gram stain of purulent material is adequate, and empirical therapy against both streptococci and staphylococci is usually effective.
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      ,
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      For deeper and recurrent infections, culture and susceptibility testing of material obtained from the skin lesions is recommended.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      Culture of material from the nares is also useful to assess the possibility of chronic carriage.
      The treatment will depend on the clinical presentation. Any toxic-appearing child should be admitted for intravenous antibiotic therapy.
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      For those who appear well, oral antibiotics and close follow-up are acceptable. The duration of therapy may exceed that required for HIV-seronegative patients. For recurrent infections, long-term application of mupirocin ointment in the nares may prevent recurrent nasal colonization.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      The use of antiseptic soaps must be cautious because they can cause skin dryness and irritation.
      To prevent serious and recurrent bacterial infections, the use of immune intravenous globulin has been recommended.
      American Academy of Pediatrics
      HIV infection.
      In their survey, Hachem et al
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      attributed the low prevalence of bacterial infections to the preventive therapy with intravenous immune globulin and cotrimoxazole prophylaxis for Pneumocystis carinii pneumonia.

      Bacillary angiomatosis

      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      Subcutaneous and eruptive lesions of BA may also occur.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      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,
      • Paul M.A.
      • Fleischer A.B.
      • Wieselthier J.S.
      • et al.
      Bacillary angiomatosis in an immunocompetent child the first reported case.
      ,
      • Smith K.J.
      • Skelton H.G.
      • Tuur S.
      • et al.
      Bacillary angiomatosis in an immunocompetent child.
      it is rarely seen in HIV-infected children. BA presenting with abdominal visceral granulomas in a child with HIV infection has been reported.
      • Delahoussaye P.M.
      • Osborne B.M.
      Cat-scratch disease presenting as abdominal visceral granulomas.
      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.
      • Malane M.S.
      • Laude T.
      • Chen C.K.
      • et al.
      An HIV positive child with fever and a scalp nodule.
      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.
      • Smith K.J.
      • Skelton H.G.
      • Tuur S.
      • et al.
      Bacillary angiomatosis in an immunocompetent child.
      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      In general, patients with cutaneous disease without visceral involvement or bacteremia respond well to 8–12 days of therapy with erythromycin or doxycycline.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      BA is resistant to penicillin and cephalosporins.

      Mycobacterial infections

      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.
      • Khouri Y.F.
      • Matrucci M.T.
      • Hutto C.
      • et al.
      Mycobacterium tuberculosis in children with human immunodeficiency virus type-1 infection.
      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.
      • Mukadi D.Y.
      • Wiktor S.Z.
      • Coulibali I.M.
      • et al.
      Impact of HIV infection on the development, clinical presentation and outcome of tuberculosis among children in Abidjan, Cote d’ Ivoire.
      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.
      Viral infections.
      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.
      Viral infections.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Cutaneous abscesses, macular lesions, and perianal ulcerations have been reported in HIV-infected adults
      • Angeles A.M.
      Fungal and mycobacterial skin infections.
      but may also occur in pediatric cases.
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      Chemoprophylaxis may be warranted for MAC.
      Viral infections.
      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.
      American Academy of Pediatrics
      HIV infection.
      Severe complications appear to be rare, justifying continued vaccine use.

      Viral infections

      Varicella zoster virus (VZV) infection

      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.
      • Perronne C.
      • Lazanas M.
      • Leport C.
      • et al.
      Varicella in patients infected with the human immunodeficiency virus.
      ,
      • Alessi E.
      • Cusini M.
      • Zerboni R.
      • et al.
      Unusual varicella zoster virus infection in patients with the acquired immunodeficiency syndrome.
      Varicella runs a milder course in HIV-infected children with relatively normal CD4+ counts than that observed in leukemic children.
      • Gershon A.A.
      • Mervish N.
      • LaRussa P.
      • et al.
      Varicella zoster virus infection in children with underlying human immunodeficiency virus infection.
      and does not seem to precede any clinical deterioration. Nevertheless, complications may occur, like hepatitis, pulmonary involvement, disseminated intravascular coagulation,
      • Perronne C.
      • Lazanas M.
      • Leport C.
      • et al.
      Varicella in patients infected with the human immunodeficiency virus.
      superinfection of the skin, or thrombocytopenia.
      • Leibovitz E.
      • Cooper D.
      • Giurgiutiu D.
      • et al.
      Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus.
      Kelley et al
      • Kelley R.
      • Mancao M.
      • Lee F.
      • et al.
      Varicella in children with perinatally acquired human immunodeficiency virus infection.
      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,
      • Leibovitz E.
      • Cooper D.
      • Giurgiutiu D.
      • et al.
      Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus.
      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.
      • Perronne C.
      • Lazanas M.
      • Leport C.
      • et al.
      Varicella in patients infected with the human immunodeficiency virus.
      Von Seidlein et al
      • Von Seidlein L.
      • Gillette S.G.
      • Bryson Y.
      • et al.
      Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1.
      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.
      Viral infections.
      ,
      • Prose N.S.
      HIV infection in children.
      ,
      • Lyall E.G.H.
      • Ogilvie M.M.
      • Smith N.M.
      • et al.
      Acyclovir resistant varicella zoster and HIV infection.
      ,
      • Fisher B.K.
      • Warner L.C.
      Cutaneous manifestations of the acquired immunodeficiency syndrome update 1987.
      ,
      • Pahwa S.
      • Biron K.
      • Lim W.
      • et al.
      Continuous varicella zoster infection associated with acyclovir resistance in a child with AIDS.
      ,
      • Leibovitz E.
      • Kaul A.
      • Rigaud M.
      • et al.
      Chronic varicella zoster in a child infected with human immunodeficiency virus case report and review of the literature.
      Deaths from central nervous system involvement have been reported with this form of infection.
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      ,
      • Pahwa S.
      • Biron K.
      • Lim W.
      • et al.
      Continuous varicella zoster infection associated with acyclovir resistance in a child with AIDS.
      Except for chronic infection, inadequate acyclovir therapy or coinfection may result in hyperkeratotic VZV lesions.
      • Grossman M.C.
      • Grossman M.E.
      Chronic hyperkeratotic herpes zoster and human immunodeficiency virus infection.
      The failure of the lesions to heal may signal the development of a strain of VZV that is resistant to acyclovir.
      • Lyall E.G.H.
      • Ogilvie M.M.
      • Smith N.M.
      • et al.
      Acyclovir resistant varicella zoster and HIV infection.
      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.
      • Grossman M.C.
      • Grossman M.E.
      Chronic hyperkeratotic herpes zoster and human immunodeficiency virus infection.
      The skin lesions tend to be deeper, more extensive, and more painful than in the immunocompetent child.
      • Prose N.S.
      HIV infection in children.
      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.
      • Patterson L.E.
      • Butler K.M.
      • Edwards M.S.
      Clinical herpes zoster shortly following primary varicella in two HIV infected children.
      Von Seidlein et al
      • Von Seidlein L.
      • Gillette S.G.
      • Bryson Y.
      • et al.
      Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1.
      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,
      • Gershon A.A.
      • Mervish N.
      • LaRussa P.
      • et al.
      Varicella zoster virus infection in children with underlying human immunodeficiency virus infection.
      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.
      • Kelley R.
      • Mancao M.
      • Lee F.
      • et al.
      Varicella in children with perinatally acquired human immunodeficiency virus infection.
      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.
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      ,
      • Nicholas S.W.
      The opportunistic and bacterial infections associated with pediatric human immunodeficiency virus disease.
      For acyclovir-resistant strains which lack thymidine kinase, foscarnet may be effective, even temporarily.
      • Lyall E.G.H.
      • Ogilvie M.M.
      • Smith N.M.
      • et al.
      Acyclovir resistant varicella zoster and HIV infection.
      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.
      • Gershon A.A.
      • Mervish N.
      • LaRussa P.
      • et al.
      Varicella zoster virus infection in children with underlying human immunodeficiency virus infection.

      Herpes simplex virus infection

      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.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      In one study, as many as 21% of 85 HIV-infected children suffered from HSV infection,
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      and in another study, 120 episodes of HSV stomatitis lasting >2 months were observed in a group of 158 HIV-infected children.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      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.
      • Blanche S.
      • Rouzioux C.
      • Guihard Moscato M.L.
      • et al.
      A prospective study of infants born to women seropositive for human immunodeficiency virus type 1.
      ,
      • Bagdades E.K.
      • Pillay D.
      • Squire S.B.
      • et al.
      Relationship between herpes simplex virus ulceration and CD4+ counts in patients with HIV infection.
      The most common feature of HSV in pediatric HIV infection is herpetic gingivostomatitis,
      • Berger T.
      Herpes virus infections and HIV disease.
      with painful, recurrent, or chronic ulcerations of the lips, tongue, palate, and buccal mucosa,
      • Prose N.S.
      HIV infection in children.
      that interfere with oral intake and cause significant morbidity requiring hospitalization.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      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.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      Autoinoculation of HSV from the chin to the fingers resulting in herpetic whitlow has also been reported.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      Prose
      • Prose N.S.
      HIV infection in children.
      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.
      • Daniel R.C.
      • Norton L.A.
      • Scher R.K.
      The spectrum of nail disease in patients with human immunodeficiency virus infection.
      Lesions of HSV may appear at other locations such as the soles and the perianal area.
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      HSV can also spread from the oral mucosa to the esophagus, but cutaneous and visceral disseminations usually are rare.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      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.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      ,
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      ,
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      ,
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      Patients with frequent or severe recurrences can be given acyclovir daily for prophylaxis.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      Acyclovir resistance has been observed in children
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      and in adults.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      It is attributed to viral deficiency of thymidine kinase and usually presents if acyclovir has not been instituted until the ulcer is large.
      • Berger T.
      Herpes virus infections and HIV disease.
      Foscarnet is used for the treatment of acyclovir-resistant infections.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      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.
      • Berger T.
      Herpes virus infections and HIV disease.
      Unfortunately, clinically significant foscarnet-resistant HSV infections may occur.
      • Safrin S.
      • Kemmerly S.
      • Plotkin B.
      • et al.
      Foscarnet resistant herpes simplex virus infection in patients with AIDS.
      Such infections can be treated with the addition of acyclovir to foscarnet or with a 6-week continuous infusion of parenteral acyclovir.
      • Safrin S.
      • Kemmerly S.
      • Plotkin B.
      • et al.
      Foscarnet resistant herpes simplex virus infection in patients with AIDS.

      Human papilloma virus infection

      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.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      ,
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Multiple hemorrhagic verrucae involving the torso and the extremities with resistance to cryotherapy have been described in a child with HIV infection.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      The case of a 10-year-old HIV-infected boy has been reported with widespread flat warts and tinea versicolor-like lesions.
      • Prose N.S.
      • Von Knebel-Doeberitz C.
      • Miller S.
      • et al.
      Widespread flat warts associated with human papillomavirus type 5 a cutaneous manifestation of human immunodeficiency virus infection.
      Human papilloma virus-3 was identified within his cutaneous lesions.
      Extensive anogenital warts, very resistant to treatment, have also been observed.
      • Laraque D.
      Severe anogenital warts in a child with HIV infection.
      ,
      • Forman A.B.
      • Prendiville J.S.
      Association of human immunodeficiency virus seropositivity and extensive perineal condylomata acuminata in a child.
      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.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      Ordinary warts can be treated with the daily application of a salicylic acid preparation.
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      Hachem et al
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      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.
      • Prose N.S.
      Guidelines for treatment of skin diseases in children with HIV infection.
      Another option is intralesional interferon-alfa.
      • Laraque D.
      Severe anogenital warts in a child with HIV infection.

      Molluscum contagiosum

      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%.
      • Meadows K.P.
      • Tyring S.K.
      • Pavia A.T.
      • et al.
      Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus infected patients treated with cidofovir.
      An Australian survey revealed positive antibody responses for MC virus in 91% of those with coexistent MCV and HIV infection.
      • Konya J.
      • Thompson C.H.
      Molluscum contagiosum virus Antibody responses in persons with clinical lesions and seroepidemiology in a representative Australian population.
      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
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      and tend to be more confluent and occasionally extremely numerous
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      HIV infection in children.
      ,
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      In addition, giant lesions may occur.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      HIV infection in children.
      ,
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      Lim et al
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      ,
      • Konya J.
      • Thompson C.H.
      Molluscum contagiosum virus Antibody responses in persons with clinical lesions and seroepidemiology in a representative Australian population.
      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.
      • Williams L.R.
      • Webster G.
      Warts and molluscum contagiosum.
      It is important to document the viral inclusions in the central core of MC lesions because cryptococcosis and histoplasmosis may mimic closely those lesions.
      • Rico M.J.
      • Penneys N.S.
      Cutaneous Cryptococcus resembling molluscum contagiosum in a patient with AIDS.
      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      ,
      • Williams L.R.
      • Webster G.
      Warts and molluscum contagiosum.
      A combination of cryotherapy or 50% TCA and 0.025% tretinoin cream can give good results.
      • Williams L.R.
      • Webster G.
      Warts and molluscum contagiosum.
      Lesions have been noted to clear after the initiation of zidovudine treatment.
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      Resolution of MC lesions with intravenous and topical cidofovir (as a 3% cream in a combination vehicle) has been reported.
      • Meadows K.P.
      • Tyring S.K.
      • Pavia A.T.
      • et al.
      Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus infected patients treated with cidofovir.
      Generally, MC lesions tend to recur, regardless of the treatment used.

      Other viral infections

      Measles

      In developing countries, measles has been reported to run a more severe course in HIV-infected children, with estimated fatality rates of 40–70% in Africa.
      • Dray-Spira R.
      • Lepage P.
      • Dabis F.
      Prevention of infectious complications of pediatric HIV infection in Africa.
      The increased mortality has been attributed to a higher rate of measles giant cell pneumonia. Some of the children do not manifest the typical measles exanthem.
      Measles in HIV infected child. United States.

      Cytomegalovirus (CMV) infection

      CMV infection in HIV-infected children may manifest as interstitial pneumonia, encephalitis, myelitis, hepatitis, gastritis, colitis, and/or chorioretinitis.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.
      In AIDS patients, the most common lesions reported to contain CMV have been ulcerations of the orofacial or perineal area.
      • Berger T.
      Herpes virus infections and HIV disease.
      In these reports, HSV has frequently been present as well.
      • Berger T.
      Herpes virus infections and HIV disease.
      Cutaneous CMV infection has been reported in an infant with HIV infection. The infant suffered from a pustular and vesicular diaper dermatitis. CMV infection was documented by biopsy and culture of skin lesions.
      • Thiboutot D.M.
      • Beckford A.
      • Mart C.R.
      • et al.
      CMV diaper dermatitis.
      Hachem et al
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      observed ulcerative lesions on an HIV-infected child’s arms and legs. CMV infection was confirmed by biopsy. Ganciclovir and foscarnet have in vivo and in vitro activity against CMV.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.

      Epstein-Barr virus infection

      Oral hairy leukoplakia, which is related to the Epstein-Barr virus and is characterized by discrete, whitish patches with parallel vertical ridges on the lateral border of the tongue, has been reported to occur rarely in HIV-infected children.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.
      ,
      • Thiboutot D.M.
      • Beckford A.
      • Mart C.R.
      • et al.
      CMV diaper dermatitis.
      ,
      • Katz M.H.
      • Mastrucci M.T.
      • Leggott P.J.
      • et al.
      Prognostic significance of oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Ferguson F.S.
      • Archard H.
      • Nuovo G.J.
      • et al.
      Hairy leukoplakia in a child with AIDS: a rare symptom case report.
      ,
      • Greenspan J.S.
      • Mastrucii M.T.
      • Legott P.J.
      • et al.
      Hairy leukoplakia in a child.
      Oral hairy leukoplakia may resolve with acyclovir treatment.
      • Nicolatou O.
      • Theodoridou N.O.
      • Mostrou G.
      • et al.
      Oral lesions in children with perinatally acquired human immunodeficiency virus infection.
      ,
      • Ramos-Gomez F.
      • Flaitz C.
      • Catapano P.
      • et al.
      Classification, diagnostic criteria and treatment recommendations for orofacial manifestations in HIV infected pediatric patients.

      Infestations

      Scabies

      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.
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      Patients with CD4+ counts <150 cells/mm3 may present with crusted Norwegian scabies.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Prose N.S.
      HIV infection in children.
      ,
      • Tappero J.W.
      • Perkins B.A.
      • Wenger J.D.
      • et al.
      Cutaneous manifestations of opportunistic infections in patients infected with human immunodeficiency virus.
      Scaly, fissured, crusted, erythematous, hyperkeratotic plaques, mainly on the neck, scalp, buttocks, flexures, palms, soles, and web spaces, are present.
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Atopic dermatitis or psoriasis may be misdiagnosed. A 6-month-old HIV-infected infant developed an eczematous dermatitis later diagnosed as crusted scabies.
      • Jukowics P.
      • Ramon M.E.
      • Don P.C.
      • et al.
      Norwegian scabies in an infant with acquired immunodeficiency syndrome.
      Prose
      • Prose N.S.
      HIV infection in children.
      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.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      In Norwegian scabies, the nail bed and plate may be hypertrophic and loaded with mites.
      • Daniel R.C.
      • Norton L.A.
      • Scher R.K.
      The spectrum of nail disease in patients with human immunodeficiency virus infection.
      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 and demodicosis

      Pediculosis is particularly common, especially in children with low socioeconomic status.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      Papular lesions on the face of two HIV-infected children in relation to Demodex mites have been described.
      • Barrio J.
      • Lecona M.
      • Hernanz J.M.
      • et al.
      Rosacea like demodicosis in an HIV positive child.
      ,
      • Sanchez-Viera M.
      • Hernanz J.M.
      • Sampelayo T.
      • et al.
      Granulomatous rosacea in a child infected with the human immunodeficiency virus.
      The main defense against Demodex mites are the CD4+ cells, which are defective in HIV infection.

      Protozoal infections

      Acanthamoeba infection in HIV status has been described in adults.
      • Friedland L.R.
      • Raphael S.A.
      • Deutsch E.S.
      • et al.
      Disseminated Acanthamoeba infection in a child with symptomatic human immunodeficiency virus infection.
      In children it is rare. The case of an 8-year-old child with advanced AIDS has been reported, who developed tender, firm, pink subcutaneous nodules rapidly progressing to deep ulcers.
      • Friedland L.R.
      • Raphael S.A.
      • Deutsch E.S.
      • et al.
      Disseminated Acanthamoeba infection in a child with symptomatic human immunodeficiency virus infection.
      The child had also sinus involvement, and the infection was confirmed by histology. Empirical therapy with ketoconazole and sulfadiazine only temporarily stabilized the progression of the child’s amebic infection, which eventually became generalized.

      Neoplastic disorders

      Kaposi sarcoma (KS)

      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.
      • Orlow S.J.
      • Cooper D.C.
      • Petrea S.
      • et al.
      AIDS associated Kaposi’s sarcoma in Romanian children.
      ,
      • Serraino D.
      • Franceschi S.
      Kaposi’s sarcoma and non Hodgkin’s lymphomas in children and adolescents with AIDS.
      The proportion of cases with KS significantly increases with age, 1.7 years being the average.
      • Orlow S.J.
      • Cooper D.C.
      • Petrea S.
      • et al.
      AIDS associated Kaposi’s sarcoma in Romanian children.
      ,
      • Serraino D.
      • Franceschi S.
      Kaposi’s sarcoma and non Hodgkin’s lymphomas in children and adolescents with AIDS.
      The disease has been described in a 6-day-old HIV-infected infant.
      • Gutierrez-Ortega P.
      • Hierro-Orozco S.
      • Sanchez-Cisneros R.
      • et al.
      Kaposi’s sarcoma in a 6 day old infant with human immunodeficiency virus.
      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.
      • Orlow S.J.
      • Cooper D.C.
      • Petrea S.
      • et al.
      AIDS associated Kaposi’s sarcoma in Romanian children.
      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.
      • Ziegler J.L.
      • Newton R.
      • Katongole-Mbidde E.
      • et al.
      Risk factors for Kaposi’s sarcoma in HIV positive subjects in Uganda.
      Water as a possible source of HHV-8 transmission is implicated.
      • Ziegler J.L.
      • Newton R.
      • Katongole-Mbidde E.
      • et al.
      Risk factors for Kaposi’s sarcoma in HIV positive subjects in Uganda.
      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
      • Kasolo F.C.
      • Mpabalwani E.
      • Gompels U.A.
      Infection with AIDS related herpesviruses in human immunodeficiency virus negative infants and endemic childhood Kaposi’s sarcoma in Africa.
      and may possibly be horizontally transmitted from mother to child
      • He J.
      • Bhat G.
      • Kansaka C.
      • et al.
      Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi’s sarcoma (KS) and mother-child pairs with KS.
      during birth or breastfeeding.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      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.
      • He J.
      • Bhat G.
      • Kansaka C.
      • et al.
      Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi’s sarcoma (KS) and mother-child pairs with KS.
      Vertical transmission of KS from an HIV-seropositive mother to her child has been reported.
      • McCarthy G.A.
      • Kampmann B.
      • Novelli V.
      • et al.
      Vertical transmission of Kaposi’s sarcoma.
      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.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      ,
      • He J.
      • Bhat G.
      • Kansaka C.
      • et al.
      Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi’s sarcoma (KS) and mother-child pairs with KS.
      ,
      • Chitsike I.
      • Siriza S.
      Seroprevalence of human immunodeficiency virus type 1 infection in childhood malignancy in Zimbabwe.
      In Zambia, a 10-fold increase in the incidence has been noted,
      • He J.
      • Bhat G.
      • Kansaka C.
      • et al.
      Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi’s sarcoma (KS) and mother-child pairs with KS.
      and in Uganda, a 40-fold increase has been observed. In other countries, however, no obvious increase has been observed.
      • Macharia W.M.
      Childhood cancers in a referral hospital in Kenya a review.
      There is a male preponderance for childhood HIV-related KS, and the median age of presentation is 4 years.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      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.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      Cutaneous lesions range from solitary nodules to widely disseminated plaques or nodules.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      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.
      • Stickler M.C.
      • Friedman-Kien A.E.
      Kaposi’s sarcoma.

      Non-hodgkin lymphoma (NHL)

      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.
      • Serraino D.
      • Franceschi S.
      Kaposi’s sarcoma and non Hodgkin’s lymphomas in children and adolescents with AIDS.
      An important role for Epstein-Barr virus has been suggested, and all children have low CD4+ counts at the time of diagnosis.
      • Evans J.A.
      • Gibb D.M.
      • Holland F.J.
      • et al.
      Malignancies in UK children with HIV infection acquired from mother to child transmission.
      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.
      • Evans J.A.
      • Gibb D.M.
      • Holland F.J.
      • et al.
      Malignancies in UK children with HIV infection acquired from mother to child transmission.
      Chemotherapy is the treatment of choice.

      Inflammatory dermatoses

      Seborrheic dermatitis (SD)

      Seborrheic dermatitis (SD) is possibly one of the most common cutaneous manifestations of HIV disease, its incidence ranging from 32–83%.
      • Cockerell C.J.
      Seborrheic Dermatitis-like and Atopic Dermatitis-like eruptions in HIV infected patients.
      An association if not a causative role for Pityrosporum has been suggested.
      • Groisser D.
      • Bottone E.J.
      • Lebwohl M.
      Association of Pityrosporum orbiculare (Malassezia furfur) with seborrheic dermatitis in patients with acquired immunodeficiency syndrome (AIDS).
      In children with HIV infection, SD seems to occur with increased frequency,
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      although in some series the usual incidence is observed.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      Its severity has been correlated with the degree of HIV-related immunodeficiency and the CD4+ cell count.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Zuckerman G.
      • Metrou M.
      • Bernstein L.J.
      • et al.
      Neurologic disorders and dermatologic manifestations in HIV infected children.
      In infants, the disorder may take the form of severe erythema and scaling of the face, scalp, and diaper area, sometimes progressing to erythroderma.
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      ,
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      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.
      • Prose N.S.
      HIV infection in children.
      Hydrocortisone cream and 1% or 2% ketoconazole shampoo are the best available treatments.

      Atopic dermatitis

      Parkin et al
      • Parkin J.M.
      • Eales L.J.
      • Galazka A.R.
      • et al.
      Atopic manifestations in the acquired immunodeficiency syndrome response to recombinant interferon therapy.
      documented the association of atopic manifestations with established AIDS. Atopic dermatitis appears to be triggered by HIV seroconversion in genetically predisposed individuals. A shift to the Th2 profile of cytokine production after HIV infection would theoretically support the increased IgE levels and allergic symptoms commonly seen in HIV-infected patients.
      • Bacot B.K.
      • Paul M.E.
      • Navarro M.
      • et al.
      Objective measures of allergic disease in children with human immunodeficiency virus infection.
      In a recent survey, increased serum immunoglobulin E levels were observed in HIV-infected children, just as in adults; however, the elevated serum immunoglobulin E level did not correlate with allergic disease nor with the degree of immune dysfunction.
      • Bacot B.K.
      • Paul M.E.
      • Navarro M.
      • et al.
      Objective measures of allergic disease in children with human immunodeficiency virus infection.
      In certain series, atopic dermatitis does not seem to be more frequent in seropositive children than in the healthy population.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      In other studies, acquired ichthyosis and xerosis, occasionally resulting in prurigo nodularis, have been noted in this particular pediatric setting.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      A British national survey revealed an increased incidence of atopic dermatitis in seropositive hemophiliac children.
      • Ball L.M.
      • Harper J.I.
      Atopic eczema in HIV seropositive hemophiliacs.
      Atopic dermatitis in those children either occurred for the first time after seroconversion or recurred with increased severity.
      Several HIV-infected children, without any history of atopy, develop a severe and generalized eczematous eruption combined with growth retardation and diarrhea.
      • Prose N.S.
      HIV infection in children.
      This syndrome, previously termed Leiner’ s disease, may be caused by several immunological defects, and HIV infection may be an additional cause.
      • Prose N.S.
      HIV infection in children.
      Children with HIV infection and atopic dermatitis are at particular risk for secondary bacterial infections and Kaposi’s varicelliform eruption. Topical steroids, lubrication, and antibiotics against S. aureus are the mainstays of treatment.
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Adult patients with HIV-related atopic dermatitis have responded to therapy with interferon-gamma.
      • Parkin J.M.
      • Eales L.J.
      • Galazka A.R.
      • et al.
      Atopic manifestations in the acquired immunodeficiency syndrome response to recombinant interferon therapy.

      Psoriasis

      In adults with HIV infection, psoriasis may appear suddenly and with extreme severity, while it is subject to precipitous flares and resistance to treatment.
      • Shupack J.L.
      • Stiller M.J.
      • Haber R.S.
      Psoriasis and Reiter’ s syndrome.
      Both plaque and guttate psoriasis in children and adolescents with HIV infection have been observed
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      AIDS-related psoriasis may respond to oral zidovudine and antiretroviral treatment.
      • Kaplan M.
      • Sadick S.
      • Wieder J.
      • et al.
      Antipsoriatic effects of zidovudine in human immunodeficiency virus associated psoriasis.

      Urticaria

      Both cold and idiopathic urticaria have been observed in pediatric HIV-infected patients,
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      but its relation to HIV infection remains unknown.

      Drug eruptions

      Patients with HIV disease are particularly prone to hypersensitivity drug eruptions. Hachem et al
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      reported an incidence of 12% of drug-related rashes among 85 HIV-infected children, whereas Straka et al
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      noted that 16% of 50 children with AIDS developed a hypersensitivity-like eruption to trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia is frequently complicated by morbilliform skin eruptions appearing 8–10 days after initiation of therapy and resolving quickly after discontinuation of the drug. Dusky erythematous macules,
      • Rico M.J.
      • Kory W.P.
      • Gould E.W.
      • et al.
      Interface dermatitis in patients with acquired immunodeficiency syndrome.
      Stevens-Johnson syndrome,
      • Prose N.S.
      Skin manifestations of HIV-1 infection in children.
      and toxic epidermal necrolysis
      • Prose N.S.
      HIV infection in children.
      may also occur. Ampicillin and antituberculous medication are other agents frequently implicated in drug eruptions.
      • Whitworth J.M.
      • Janniger C.K.
      • Oleske J.M.
      • et al.
      Cutaneous manifestations of childhood acquired immunodeficiency syndrome and human immunodeficiency virus infection.
      Discontinuation of the offending medication is mandatory. Substitution of trimethoprim-sulfamethoxazole with aerosolized or intravenous pentamidine for Pneumocystis carinii pneumonia prophylaxis is possible.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.

      Vasculitis

      Leukocytoclastic vasculitis may develop as a result of drug reaction, concomitant infection, or HIV infection itself. Chren et al
      • Chren M.M.
      • Silverman R.A.
      • Sorensen R.U.
      • et al.
      Leucocytoclastic vasculitis in a patient infected with human immunodeficiency virus.
      reported a 9-year-old girl with persistent, palpable purpura of the lower extremities as the sole manifestation of HIV infection. A 3-year-old HIV-infected girl developed palpable purpura complicated with nephropathy.
      • Prose N.S.
      HIV infection in children.
      Three children with vasculitic lesions resembling cutis marmorata have also been reported.
      • Torre D.
      • Sampietro C.
      • Fiori G.P.
      • et al.
      Skin manifestations in infants with AIDS.
      Thrombocytopenia of immunological origin with high levels of circulating immune complexes and antiplatelet antibodies can manifest as petechiae or easy bruising and may lead to life-threatening bleeding.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Ellaurie M.
      • Burns E.
      • Bernstein L.J.
      • et al.
      Thrombocytopenia and human immunodeficiency virus in children.
      Parenteral gamma globulin or oral prednisone may be of benefit.
      • Ellaurie M.
      • Burns E.
      • Bernstein L.J.
      • et al.
      Thrombocytopenia and human immunodeficiency virus in children.

      Aphthous ulcers

      Several forms of recurrent aphthous ulcers are observed in HIV-infected patients. Minor, major, and herpetiform aphthae may occur. At Baylor College of Medicine, 22 episodes of aphthous stomatitis were observed in symptomatic children with HIV infection and only one episode in asymptomatic ones from 1990–1994.
      • Kline M.W.
      Oral manifestations of pediatric human immunodeficiency virus infection a review of the literature.
      This indicates that aphthous ulcerations are a manifestation of moderate to severe disease.
      Before making the diagnosis of aphthous ulceration, one has to consider other infectious or iatrogenic causes. Prolonged granulocytopenia induced by myelosuppressive medication, as well as dideoxycytidine and foscarnet therapy, can all be the causes of oral ulcers.
      One suggested regimen for severe, painful aphthous ulcers is the administration of a topical glycocorticoid solution, but it is imperative to exclude viral causes first.
      • Domachowske J.B.
      Pediatric human immunodeficiency virus infection.

      Nutritional deficiencies

      Oral pathology, anorexia, malabsorption, and diarrhea commonly seen in HIV-infected children can lead to severe nutritional deficiencies. Dry, cracked, and flaky skin and thinning of the hair similar to kwashiorkor can be observed.
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      ,
      • Prose N.S.
      HIV infection in children.
      Pellagralike eruptions have been reported.
      • Penneys N.S.
      • Hicks B.
      Unusual cutaneous lesions associated with acquired immunodeficiency syndrome.
      A follicular petechial rash on the legs of an HIV-infected child and bleeding of the gums were suggestive of scurvy.
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      Straka et al
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      observed zinc levels at least 1 standard deviation below normal in two thirds of pediatric HIV patients. Acrodermatitis enteropathica has been reported in a 14-month-old seropositive child as a presenting sign of HIV infection.
      • Tong T.K.
      • Andrew L.R.
      • Albert A.
      • et al.
      Childhood acquired immunodeficiency syndrome manifesting as acrodermatitis enteropathica.
      Multiple nutritional deficiencies may occur, so prompt nutritional supplementation is mandatory. It is interesting that vitamin A supplementation has been shown to decrease by 30% the overall mortality of HIV-infected infants in developing countries.
      • Dray-Spira R.
      • Lepage P.
      • Dabis F.
      Prevention of infectious complications of pediatric HIV infection in Africa.

      Miscellaneous conditions

      Alopecia due to severe SD,
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      nutritional deficiency, or unknown causes may be observed in the HIV-infected pediatric population.
      • Lim W.
      • Sadick N.
      • Gupta A.
      • et al.
      Skin diseases in children with HIV infection and their association with degree of immunosuppression.
      ,
      • Hachem M.E.
      • Bernardi S.
      • Pianosi G.
      • et al.
      Mucocutaneous manifestations in children with HIV infection and AIDS.
      Hypertrichosis of the eyelashes necessitating frequent trimming has been reported in both adults and children with HIV infection.
      • Kaplan M.H.
      • Sadick N.S.
      • Talmor M.
      Acquired trichomegaly of the eyelashes a cutaneous marker of acquired immunodeficiency syndrome.
      ,
      • Casanova J.M.
      • Puig T.
      • Rubio M.
      Hypertrichosis of the eyelashes in the acquired immunodeficiency syndrome.
      Hypertrichosis of the lanugo type in an infant with HIV-related KS has also been noted.
      • Gutierrez-Ortega P.
      • Hierro-Orozco S.
      • Sanchez-Cisneros R.
      • et al.
      Kaposi’s sarcoma in a 6 day old infant with human immunodeficiency virus.
      An exanthematous eruption associated with the flulike syndrome of primary HIV infection has been documented in adults.
      • Prose N.S.
      HIV infection in children.
      A similar rash has been reported in a 14-month-old girl from Switzerland
      • Straka F.B.
      • Whitaker D.L.
      • Morrison S.H.
      • et al.
      Cutaneous manifestations of the acquired immunodeficiency syndrome in children.
      and in a 10-year-old girl.
      • Blauvelt A.
      • Turner M.
      Gianotti-Crosti syndrome and human immunodeficiency virus infection.
      In a series of 82 HIV-infected children from Uganda, 33% developed a primary HIV rash.
      • Ziegler J.L.
      • Katongole-Mbidde E.
      Kaposi’s sarcoma in childhood an analysis of 100 cases from Uganda and relationship to HIV infection.
      Sweet syndrome has been reported as the presenting manifestation of HIV infection in a 3-month-old infant.
      • Brady R.C.
      • Morris J.M.
      • Connely B.L.
      Sweet’s syndrome as an initial manifestation of pediatric human immunodeficiency virus infection.
      Pyoderma gangrenosum on the left preauricular area and right eyelid has been noted in a child with HIV infection.
      • Graham J.A.
      • Hansen K.K.
      • Rabinowitz L.G.
      • et al.
      Pyoderma gangrenosum in infants and children.
      Gianotti-Crosti syndrome has been observed in two children with concomitant HIV and CMV infection.
      • Blauvelt A.
      • Turner M.
      Gianotti-Crosti syndrome and human immunodeficiency virus infection.
      Other skin disorders like vitiligo,
      • Prose N.S.
      Mucocutaneous disease in pediatric human immunodeficiency virus infection.
      erythema dyschromicum perstans,
      • Venencie P.Y.
      • Foldes C.
      • Laurian Y.
      • et al.
      Erythema dyschromicum perstans following human immunodeficiency virus seroconversion in a child with hemophilia.
      and eruptive dysplastic nevi
      • Duvic M.
      • Lowe L.
      • Rapini R.P.
      • et al.
      Eruptive dysplastic nevi associated with human immunodeficiency virus infection.
      have also occurred, but their relationship to HIV infection is unknown.
      HIV-infected children are more vulnerable to abuse. A peculiar annular eruption in a 7-year-old girl finally proved to be the result of the abusive behavior of her adoptive parent.
      • Solomon B.A.
      • Laude T.
      A peculiar annular eruption in a child with AIDS.

      Conclusions

      Skin diseases may be the presenting sign of HIV infection or may serve as a prognostic marker and an ominous sign of the deterioration of the child’s immunodeficiency. It is important to be able to recognize them and treat them effectively, as they can worsen the quality of life of these children and lead to devastating sequelae.
      More and more HIV-infected children benefit from the new antiviral treatments and survive longer, but unfortunately, these medications are not available worldwide. AIDS is a complex epidemic. The response to the epidemic is not only best practice but also new practice.
      • Forsyth B.W.C.
      • Andiman W.A.
      • O’Connor T.
      Development of a prognosis based clinical staging system for infants infected with human immunodeficiency virus.
      ,
      • Emodi I.J.
      • Okafor G.O.
      Clinical manifestations of HIV infection in children at Enugu, Nigeria.
      ,
      • Yamashita H.
      • Uemura T.
      • Kawashima M.
      Molecular epidemiologic analysis of Japanese patients with molluscum contagiosum.

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