Childhood HIV Disease

The World Health Organization¹ estimates that approximately 2.3 million children are living with the human immunodeficiency virus (HIV) as of 2006. In 2006 alone, 530,000 children were newly infected, an improvement from the 640,000 newly infected in 2004. Not only are the children themselves ravaged by disease, but their primary caregivers have also often succumbed to acquired immune deficiency syndrome (AIDS). This is most prevalent in sub-Saharan Africa, where 18 million children are predicted to be orphaned by AIDS by the end of 2010. Worldwide, the United Nations Children's Fund (UNICEF) predicts the number of children orphaned and made vulnerable by HIV/AIDS is expected to reach 25 million by the end of the decade.

Although 2 strains of HIV have currently been identified, most patients who have AIDS are positive for HIV type 1 (HIV-1) or are positive for both HIV-1 and HIV type 2 (HIV-2). HIV-2 infection is most commonly observed in West Africa.

Vertical transmission of HIV from mother to child is the main route by which childhood HIV infection is acquired; the risk of perinatal acquisition is 25%. Perinatal transmission of infection by the mother accounts for 80% of pediatric HIV disease cases in the United States. Perinatal transmission can occur in utero, during the peripartum period, and from breastfeeding. Other routes of transmission, such as transfusion of blood and blood components, are rare in the United States but still exist in developing countries. Sexual abuse of children and high-risk behaviors in adolescents also contribute to youth HIV infection.

A variety of signs and symptoms manifesting in a child in whom HIV infection was not previously suspected should alert the clinician to the possibility of the disease. The presentations include recurrent bacterial infections, unrelenting fever, unrelenting diarrhea, unrelenting thrush, recurrent pneumonia, chronic parotitis, generalized lymphadenopathy, delay in development with failure to thrive, and significant pruritic dermatoses. Mucocutaneous eruptions may be the first sign of HIV infection and may vary in presentation, depending on the child's immune status.

Pathophysiology

HIV is a retrovirus that exhibits a variety of structural and nonstructural proteins that determine the interaction of the virus with the host's immune system and cellular components. The HIV virus attaches to the host cell by the association of a surface glycoprotein to the CD4 molecule; therefore, it primarily infects CD4⁺ lymphocytes and macrophages.

Once the virus core enters the cell cytoplasm of the host, viral reverse transcriptase copies viral RNA to the DNA of the host. The viral DNA is then transported into the nucleus and incorporated into the DNA of that cell. If activated, viral expression can result in new viral RNA and proteins. New viral core proteins, enzymes, and viral RNA molecules can induce budding, with additional cell infection. The reduction in cell-mediated immunity and secondary B-cell dysfunction result in the immunocompromised state and in the proliferation of opportunistic infections and malignancies. An elevated level of activation-induced cell death resulting from apoptosis of T cells occurs in patients who are HIV positive.

The CD95/Fas receptor/ligand system is necessary for the apoptosis of T cells, and abnormalities in this system are linked with increased T-cell death in patients who are HIV positive. As the immune status deteriorates, an increase in CD95⁺ T cells is found; conversely, a low CD95⁺ T cell count is found in asymptomatic patients who are HIV positive.

Frequency

United States

According to the Centers for Disease Control and Prevention (CDC), the cumulative estimated number of diagnoses of AIDS in children younger than 13 years through 2005 in the United States is 9089. This represents a drop from the 9419 cases reported in 2003. In the United States, the number of new cases of pediatric AIDS is decreasing, mostly because of public health initiatives regarding universal HIV testing for pregnant women and use of zidovudine in infected pregnant women and their newborn infants. In 2005 in the United States, 3764 children younger than 13 years were living with HIV infection, and an estimated 7 children younger than 13 years died from AIDS-related causes that year. These numbers are in stark contrast to what is occurring internationally.

International

Globally, children outside the United States are not faring as well. Everyday, 1400 children become HIV positive and 1000 children die of HIV-related causes. An estimated 2.3 million children worldwide younger than 15 years are living with HIV/AIDS. In sub-Saharan Africa alone, 1.9 million children are living with HIV/AIDS and more than 60% of all new HIV infections occur in women, infants, or young children. As of 2007, 90% of the newly infected children are infants who acquire HIV from their infected mothers. Alarmingly, 90% of babies who acquire the disease from infected mothers are found in sub-Saharan Africa. The prevalence of HIV infection among undernourished children has been estimated to be as high as 25%.

The prevalence of HIV infection in Asia and Europe varies considerably because of varied cultural practices and lack of a national reporting system in many areas. The commercial sex worker industry in countries such as Thailand and in the CaribbeanIslands is responsible for increased HIV transmission to young girls and, vertically, to infants.

Mortality/Morbidity

In 2004, more than half a million children younger than 15 years died from HIV/AIDS. In 2006, this number decreased to 380,000. In 2002, HIV/AIDS was the seventh leading cause of mortality in children in developing countries. The disease progresses rapidly in approximately 10-20% of children who are infected, and they die of AIDS by age 4 years, whereas 80-90% survive to a mean age of 9-10 years. In affected regions of sub-Saharan Africa, the infant mortality rate has increased by 75% due, in part, to the orphaned status of most children. In contrast to much of the developed world, the mortality rates for children younger than 5 years are higher today than those observed in 1990 in many African countries, mostly because of the devastating effects of HIV/AIDS. A 2006 South African study² estimates that HIV/AIDS is the single largest cause of infant and childhood deaths in rural South Africa. HIV/AIDS is now responsible for 332,000 child deaths in sub-Saharan Africa, almost 8% of all child deaths in the region.

Race

In the United States, children from minority communities have been most affected by AIDS. More than 50% of affected children are black, and slightly less than 25% are Hispanic. Of the new childhood HIV cases in 2003, 68% occurred in African Americans. The number of pediatric AIDS cases reported in black non-Hispanic children is 3.4 times higher than in white non-Hispanic children and is 2.6 times higher than that of Hispanic children.

Sex

Young people (aged 15-44 y) account for one of the fastest growing infected groups and account for almost half of all infections. Among young people, young women are more likely to become infected. In sub-Saharan Africa, more than two thirds of all youth infected are young girls. Variations in frequencies in the sexes in other regions of the world depend on the predominance of commercial sex workers and the proportion of a transient and mobile workforce more likely to be separated from family.

Age

Because vertical transmission from mother to child is the main route by which pediatric HIV infection is acquired, most children who are HIV positive should be identified in infancy. Vertical transmission can occur in utero, during delivery, and from breastfeeding. Although current treatment strategies can prevent vertical transmission, the drugs are simply not available in many places, especially in Africa.

Because passive transfer of maternal antibodies to the infant occurs, the standard enzyme-linked immunosorbent assay (ELISA) and Western blot tests cannot be used with diagnostic certainty until age 2 years; however, HIV RNA assays and the HIV DNA polymerase chain reaction (PCR) test can be used for early detection. HIV infection can be diagnosed in most infants by age 1 month and in all infants by age 6 months. The use of at least 2 virologic assays is recommended to confirm positive results, with a final exclusion of HIV infection verified by ELISA or Western blot after age 18 months in infants born to mothers who are HIV positive.

Clinical

History

• A variety of cutaneous conditions may occur in children with HIV.
• Ideally, the diagnosis of HIV in a child is made through perinatal testing. The CDC has issued guidelines for recommended testing and counseling for all pregnant women; however, many women, especially in developing countries and in poorer areas of the developed world, do not have access to or do not avail themselves of the resources available. Thus, for example, the diagnosis of HIV infection may follow an investigation of a prolonged or unusual presentation of an infection or a malignancy.
• Children infected as a result of sexual abuse or drug use may not present with known HIV infection.

Physical

Numerous mucocutaneous disorders have been reported in children infected with HIV. As the CD4⁺ count decreases, an increase in the number and severity of skin manifestations can be expected. Some studies suggest that children infected with HIV become symptomatic from the neonatal period up to age 8 years and that 57% of this group have associated disease within the first year. Dermatologic manifestations occur more frequently in children with advanced HIV disease; many tend to improve after antiretroviral therapy is initiated.

• A high percentage of oral disease has been seen in children infected with HIV, and oral manifestations are often early indicators of infection. The most common oral disease and mucocutaneous presentation of HIV infection is candidiasis caused by Candida albicans. Both the pseudomembranous variant and the atrophic oral variant are most common.
• Pseudomembranous candidiasis manifests as creamy white–to–yellow oral plaques, commonly referred to as thrush. Atrophic candidiasis manifests as distinct areas of erythema with the loss of tongue papillae if the tongue is affected. Hyperplastic candidiasis (with both erythematous and white mucosal coloration symmetrically distributed) and angular cheilitis are 2 additional clinical variants of candidiasis.
• Difficulty in swallowing, inadequate oral intake, or dysphagia may be the initial symptoms of oral or esophageal candidiasis³ and may contribute to the already-compromised nutritional status of the child.
• An inflammatory, destructive, and necrotic process characterizes candidal periodontal disease in the gingival mucosa and the underlying connective tissue.
• The usual symptoms in children with candidal esophagitis are odynophagia, dysphagia, and retrosternal pain.
• Although C albicans is the most commonly identified Candida species, Candida dubliniensis has recently garnered notice as a cause of oral infection that is seen, for the most part, only in patients who are HIV positive.⁴ Other Candida species implicated in HIV-related candidiasis are Candida glabrata and Candida tropicalis.
• Candidiasis may manifest as an unresponsive or recurrent diaper rash or as a chronic paronychia and onychomycosis. In Candida -associated diaper dermatitis, the area covered by the diaper is usually inflamed and erythematous, with satellite lesions extending beyond the central area of involvement. Other intertriginous areas have also been reported, including neck folds and axillary regions.
• Candidal involvement of the proximal nailfolds causes severe paronychia and nail dystrophy. Candidal onychomycosis results in yellow-brown thickened nail plates.
• Linear gingival erythema and median rhomboid glossitis have also been found, especially in children with a low CD4⁺ cell count.
• Children infected with HIV also have a higher rate of dental caries in the primary teeth but a diminished prevalence in the permanent teeth, a finding attributed to the greater number of primary teeth and the delayed eruption of the permanent teeth in these patients. HIV-infected children should be screened and considered at high risk for dental caries, usually secondary to chronic medication use.^5,6

• Oral hairy leukoplakia, which is associated with Epstein-Barr virus, is usually rare in children, but it has been reported in children as the second most common oral presentation after candidiasis in some Asian countries. Results from a 2006 study⁷ suggest that oral hairy leukoplakia may be more common than previously believed; 16.7% of patients demonstrated subclinical, cytological disease, and only 1.7% of children had clinically visible disease.
• Herpes simplex, parotid enlargement, and recurrent aphthous ulcers are also common oral manifestations.
• Dermatophytosis manifesting as an aggressive tinea capitis, corporis, versicolor, or onychomycosis may be challenging to treat. As in adults, Trichophyton rubrum infection in the form of proximal, white, subungual onychomycosis is categorized as a typical nail manifestation of HIV disease.
• Deep fungal infections are not commonly seen in children who are HIV positive.
• Cryptococcosis, sporotrichosis, and histoplasmosis have been reported as either localized or disseminated variants.
• Molluscumlike Cryptococcus papules have been identified in some patients.
• Herpetic infection with herpes simplex virus (HSV) may take the form of herpes labialis; gingivostomatitis; esophagitis; or as chronic erosive, vesicular, and vegetating skin lesions.
• The involved areas of the lips, mouth, tongue, and esophagus are ulcerated, which may result in difficulty with oral nutritional intake.
• Skin lesions usually manifest as chronic erosions, which may have grouped vesicles. The fingers are a frequent site of infection. Pyoderma gangrenosum and ecthyma gangrenosum may be in the differential diagnosis of cutaneous herpetic infections.
• Recurrent or persistent varicella-zoster infection is strongly linked with the CD4⁺ count. Scarring can occur from a severe outbreak, in which lesions may be hyperkeratotic and/or hemorrhagic and involve more than 1 dermatome. Because herpes zoster is usually not seen in children who are immunocompetent, an evaluation for HIV infection should be undertaken in a child with this diagnosis. Children should be evaluated for evidence of dissemination because disastrous sequelae, such as encephalitis, intracranial thrombosis, fulminant hepatitis, disseminated intravascular coagulation, pneumonitis, and retinal necrosis, have been reported in patients with dissemination.
• Human papillomavirus infection, which may mimic the tinea versicolor–like rash in epidermodysplasia verruciformis, is noted. Large areas of flat warts most commonly occur on the forehead, the temples, the neck, and the upper body. Unusually large treatment-resistant condylomata are reported in children who are HIV positive.
• Widespread molluscum contagiosum can occur in pediatric AIDS patients. Molluscum contagiosum may manifest as a diffuse eruption of umbilicated papules involving areas (eg, face) usually not affected in patients who are immunocompetent. Molluscum lesions tend to be more persistent in patients with HIV infection. Some lesions are large and may be confused with Cryptococcus neoformans lesions. Molluscum tends to improve with antiretroviral therapy.
• Recurrent bacterial infections are seen in children who are HIV positive because of the abnormal B-cell response and consequent defective humoral immunity. A variety of bacterial infections occurs, the most common of which is caused by Staphylococcus aureus. As the CD4⁺ count decreases, invasive bacterial infections, including sepsis and pneumonia, occur.
• Sepsis, otitis media, impetigo, cellulitis, and furunculosis have been reported. Although the infections may initially manifest in a manner similar to that in a child who is not immunocompromised, widespread and persistent infection should prompt consideration of HIV status. Acral lesions should be sought if sepsis is a concern because a pustule on the sole may be the first sign of sepsis.
• Atypical presentations, such as plaquelike staphylococcal folliculitis, are also reported.
• Rare conditions, such as ecthyma gangrenosum as a result of infection by Pseudomonas aeruginosa, are also noted. In this disorder, hemorrhagic necrotic bullae that eventually form a black eschar manifest primarily on the extremities and the gluteal and perineal regions.
• Bacillary angiomatosis caused by Bartonella henselae and Bartonella quintana is rare in children but has been reported.⁸ Bacillary angiomatosis is considered by some to be an AIDS-defining opportunistic infection, typically seen with a CD4⁺ count less than 200 cells/m L. Clinically and histologically, the lesions often resemble pyogenic granulomas and Kaposi sarcoma. They often begin as pinpoint papules, which enlarge to become red nodules and usually involve the face or the upper torso. In addition to the cutaneous findings, these patients may have lymphadenopathy, abdominal symptoms, anemia, and an elevated alkaline phosphatase level.
• Mycobacterial infections caused by Mycobacterium tuberculosis and Mycobacterium avium are increasing in incidence in children who are HIV positive.
• Children who are HIV positive and have tuberculosis are usually extremely sick. Usually, pulmonary disease is present, but extrapulmonary findings can also occur.
• Acute pustular eruptions, widespread keratotic papules with hyperkeratotic palms and soles, tuberculous lymphadenitis, purple necrotic lesions, and ulcerations have been reported in patients who are HIV positive and have mycobacterial infections.
• Mycobacterium haemophilum often causes disseminated infection in patients with AIDS. Diffuse swelling and induration of the periarticular soft tissue and nodular formation are reported in patients infected with M haemophilum.
• Pneumocystis carinii pneumonia is the primary AIDS-defining illness and occurs in 7-20% of patients who have not been administered prophylaxis and are younger than 1 year. Most commonly, P carinii pneumonia manifests with cough, dyspnea, tachypnea, and fever. The incidence of P carinii pneumonia is declining in areas where AIDS medications are available, but it continues to shorten life expectancy in areas in which access to antiretrovirals is limited.
• Scabies in children infected with HIV may progress from a widespread pruritic papular eruption to a crusted variant as the CD4⁺ count decreases. This crusted (Norwegian) variant is characterized by an extremely high mite count and thus is very contagious. Secondary bacterial infection may complicate crusted scabies.
• In regions of the world where measles vaccination is not routinely administered and where HIV is endemic, the potential for serious measles infection exists.⁹ Measles typically manifests with an erythematous macular eruption of the trunk with caudal spread. Koplik spots (small blue-white dots surrounded by erythematous rings on the buccal mucosa) are the most common oral manifestation seen. In children who are immunocompromised, measles may manifest without skin involvement but with more severe complications.
• Death from pneumonitis and encephalitis has been reported in African children with both HIV infection and measles.
• Noma (cancrum oris) is a necrotic disease of tissues of the mouth.¹⁰ This disease quickly spreads to surrounding bone and soft tissue and is often associated with immunodeficient states, such as AIDS. Noma predominately occurs in young children from sub-Saharan Africa and is often associated with measles.
• Seborrheic dermatitis may be a manifestation of HIV in children who present outside of the usual neonatal and adolescent timeframes or who present with generalized disease. An association between Pityrosporum orbiculare growth in the presence of waning CD4⁺ cells and Langerhans cells has been postulated.
• The eczematous periorofacial eruption of acrodermatitis enteropathica caused by nutritional deficiency of zinc, secondary to diarrhea-induced malabsorption, has been reported. Other vitamin deficiencies can also be expected because of poor oral intake or diarrhea.
• Metabolic abnormalities have been reported in association with pediatric HIV disease. Lipodystrophy associated with insulin resistance and dyslipidemia occurs in children who are HIV positive (similar to adults who are HIV positive) and may be attributed to highly active antiretroviral therapy, although individual variations may make certain children more susceptible.¹¹ See also Lipodystrophy, HIV. Variations in presentation include peripheral lipoatrophy, truncal lipohypertrophy, and combined versions of these presentations. A more severe presentation occurs at puberty. Thyroid abnormalities with hypothyroidism have also occurred in children infected perinatally.¹²
• A variety of skin conditions, including exaggerated eczema, psoriasis, drug eruptions (including morbilliform eruptions and Stevens-Johnson syndrome), intense reactions to arthropod bites,¹³ alopecia, and trichomegaly, have been reported in children who are HIV positive. Children with HIV infection are at risk for child abuse because of family stressors; therefore, unusual skin lesions should be evaluated for potential signs of exogenous injury.
• A higher incidence of neoplasia is noted in children with HIV infection than in noninfected children.
• B-cell lymphoproliferative diseases, including non-Hodgkin lymphoma, Burkitt lymphoma, and smooth muscle tumors, have been identified.
• The prevalence of HIV-associated malignancies has been reported to be as high as 2%. A 2005 evaluation of 2969 pediatric patients with AIDS in the United States from 1993-2003 revealed that the incidence of malignancy is 1.56 cases per 1000 person-years, a number lower than European counterparts but significantly higher than noninfected children.
• Kaposi sarcoma is unusual in children; however, an African study has shown the childhood incidence of Kaposi sarcoma has risen more than 40-fold in the years after AIDS. Previously thought to only occur in males, it has been reported in both males and females born to mothers who are infected with HIV in high-risk groups for Kaposi sarcoma or in children infected postnatally by blood products. The most common sites of AIDS-related Kaposi sarcoma in children are the orofacial and the inguinal or genital regions