AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

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.

The following Medscape Resource Centers may be of interest:

• HIV Pathogenesis Resource Center
• HIV Transmission & Prevention Resource Center

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 Caribbean Islands 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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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/mL. 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.¹⁴
  • 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.¹⁵

Causes

Low CD4⁺ counts are correlated with many of the cutaneous and systemic manifestations of the disease.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Prompt diagnosis of HIV infection is critical. As such, the CDC recommends prenatal HIV testing as the standard of care for all pregnant women in the United States. Diagnosis of HIV infection in infants is aided by HIV culture or DNA/RNA PCR; positive results are confirmed by repeating the test. In suspected cases, HIV testing should occur immediately in the newborn period (ie, before the infant is aged 48 h), at age 1-2 months, and again at age 3-6 months. Testing at age 14 days may allow for earlier detection of HIV in infants who had negative test results within the first 48 hours of life. By approximately age 1 month, PCR testing has a 96% sensitivity and 99% specificity to identify HIV.
• • The 2006 Working Group¹⁶ recommendations for diagnosing infants are as follows:
  • • Because of the persistence of the maternal HIV antibody, infants younger than 18 months require virologic assays that directly detect HIV in order to diagnose HIV infection.
    • Virologic diagnostic testing in infants with known perinatal HIV exposure is recommended at birth to 14 days, at 1–2 months, and at 3–6 months. Preferred virologic assays include HIV DNA PCR and HIV RNA assays.
    • An antibody test to document seroreversion to HIV antibody–negative status in uninfected infants is recommended at age 12–18 months.
    • In children 18 months and older, HIV antibody assays can be used for diagnosis. 
  • The Working Group does not recommend use of the currently approved HIV p24 antigen assay for infant diagnosis in the United States because the sensitivity and specificity of the assay in the first months of life is less than that of other HIV virologic tests.
• Monitor CD4⁺ levels or percentages in infants or patients newly diagnosed with HIV at 3- to 4-month intervals to assess patients' immune status. In children younger than 6 years, the 2006 Working Group recommends using CD4 percentages over absolute CD4 counts for monitoring disease progression because of inherent age-related changes in absolute CD4 counts.
• Monitor for opportunistic infections.
• • Perform a CBC count with differential and a urinalysis every 1-3 months in infants. Older child can be screened every 3-6 months (CBC count) or yearly (urinalysis).
  • Culture urine samples monthly for the presence of cytomegalovirus (CMV) until age 2 months and then at 2-month intervals until age 12 months. 
• Assess HIV RNA levels twice at baseline and then every 3-4 months. (Consistently use the same HIV RNA assay method to monitor a particular patient.) More frequent testing of HIV RNA levels and CD4 counts may be necessary for children who have virologic or clinical deterioration or when initiating or changing antiretroviral therapy.
• If the mother is HIV positive, use serologic tests to screen the infant for hepatitis B, hepatitis C, syphilis, and toxoplasmosis.
• Decreased levels of albumin, serum immunoglobulin G, and CD8⁺ T cells are linked with fatality in children.
• Monitor laboratory studies in accordance with drug therapy protocols and clinical status (eg, lipid profile in a patient with lipodystrophy).

Imaging Studies

• Perform chest radiography, CT scanning, MRI, echocardiography, and ECG for baseline determinations and subsequently as clinically indicated.

Other Tests

• Perform history and physical examinations at regular intervals (eg, every 2 wk initially in infancy, with an increase in intervals as the child ages and the immune status stabilizes).
• Obtain an audiologic evaluation at age 2 years or sooner if concern exists.
• Obtain dental examinations at age 1-2 years.
• Obtain a neurodevelopmental evaluation every 3-6 months.
• Obtain an ophthalmologic evaluation for CMV, tuberculosis, and toxoplasmosis infections, as well as for corneal ulceration, which is often secondary to underlying nutritional deficits.
• Obtain a cerebrospinal fluid analysis in patients with neurologic disease (based on risk factors of the area and the clinical presentation of the child).

Procedures

• Perform endoscopy when esophageal candidiasis is suggested.
• Perform a Mantoux test for tuberculosis at age 6 months. (Test patients with control skin tests [eg, tetanus, mumps] to ensure absence of anergy.)
• Isolation of acid-fast bacteria in patients in whom pulmonary infection is suggested may be attempted with gastric lavage; it is sensitive in 32% and 48.8% of cases of pulmonary meningitis and tubercular meningitis, respectively.

Histologic Findings

Biopsy may be considered to clearly determine the presence of an infectious or malignant cutaneous lesion. Maintain a high index of suspicion for a wide array of infections and malignancies, and the appropriate staining and tissue preparation should be requested.

Staging

• Clinical categories are based on the 1998 CDC guidelines¹⁷ for antiretroviral treatment of pediatric AIDS (review and modification of the 1994 CDC HIV pediatric classification system for clinical categories in children younger than 13 y).
• • Category N: Children are asymptomatic. No signs or symptoms attributed to HIV infection are present, or patients have only 1 category A disorder.
  • Category A: Children are mildly symptomatic. Patients have 2 or more of the following conditions but no category B or C condition:
  • • Lymphadenopathy (³0.5 cm at more than 2 sites; bilateral = 1 site [ie, at the same anatomical location bilaterally])
    • Hepatomegaly
    • Splenomegaly
    • Dermatitis
    • Parotitis
    • Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media
• • Category B: Children are moderately symptomatic. Patients have symptomatic conditions not in category A or category C but that result from HIV infection. Some category B disorders are as follows:
  • • Anemia (<8 g/dL), neutropenia (<1000/mL), or thrombocytopenia (<100,000/mL) persisting longer than 30 days
    • Bacterial meningitis, pneumonia, or sepsis (single episode)
    • Candidiasis, oropharyngeal (ie, thrush), persisting for longer than 2 months in children aged 6 months
    • Cardiomyopathy
    • CMV infection with onset before age 1 month
    • Diarrhea (recurrent or chronic)
    • Hepatitis
    • HSV stomatitis (recurrent, ie, >2 episodes within 1 y)
    • HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month
    • Herpes zoster (ie, shingles) involving at least 2 distinct episodes or more than 1 dermatome
    • Leiomyosarcoma
    • Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex
    • Nephropathy
    • Nocardiosis
    • Fever lasting 1 month
    • Toxoplasmosis with onset before age 1 month
    • Varicella (disseminated, ie, complicated chickenpox
  • Category C: Patients are severely symptomatic. Patients have any condition listed in the 1987 surveillance case definition for AIDS, except for lymphoid interstitial pneumonia, which is now considered a category B condition.
• Immunologic categories with CD4⁺ T cell counts and percentages (based on CDC 1994 revised HIV pediatric classification system) are as follows:
• • Patients younger than 12 months
  • • Nonsuppressed (category 1) - CD4⁺ count greater than 1500 cells/mL (³25%)
    • Moderate suppression (category 2) - CD4⁺ count equal to 750-1499 cells/mL (15-24%)
    • Severe suppression (category 3) - CD4⁺ count less than 750 cells/mL (<15%)
  • Patients aged 1-5 years
  • • Nonsuppressed (category 1) - CD4⁺ greater than or equal to 1000 cells/mL (³25%)
    • Moderate suppression (category 2) - CD4⁺ count equal to 500-999 cells/mL (15-24%)
    • Severe suppression (category 3) - CD4⁺ less than 500 cells/mL (£15%)
  • Patients aged 6-12 years
  • • Nonsuppressed (category 1) - CD4⁺ count greater than 500 cells/mL (³25%)
    • Moderate suppression (category 2) - CD4⁺ equal to 200-499 cells/mL (15-24%)
    • Severe suppression (category 3) - CD4⁺ less than 200 cells/mL (<15%)

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Appropriate antiretroviral therapy and treatment of specific infections and malignancies are critical in treating patients who are HIV positive. Intervening early may prevent damage to the immune system and potentially retard infection dissemination. The reverse transcriptase inhibitors are composed of the dideoxynucleosides and the nonnucleoside reverse transcriptase inhibitors (NRTIs). By inhibiting viral reverse transcriptase, HIV replication is suppressed. Protease inhibitors (PIs) prevent the late stages of viral replication by interfering with the formation of structural proteins of the virion core. Combination antiretroviral therapy is recommended for all infants, children, and adolescents.

The following are the 2006 Working Group goals for treating pediatric patients with HIV infection:  

• Reducing HIV-related mortality and morbidity
• Restoring and preserving immune function
• Maximally and durably suppressing viral replication
• Minimizing drug-related toxicity
• Maintaining normal physical growth and neurocognitive development
• Improving quality of life

The following are several important factors to consider in making treatment decisions about when to initiate antiretroviral therapy:

• Severity of HIV disease
  
• Risk of disease progression
  
• Laboratory assessments (eg, CD4⁺ count, plasma HIV RNA levels)
  
• Availability of appropriate and palatable drug formulations
  
• Adverse effects of the antiretroviral medications
  
• Effect of initial treatment regimen choice on later therapeutic options
  
• Presence of comorbidities that may affect drug choices
  
• Potential antiretroviral drug interactions with required concomitant medications
  
• Ability of the child and caregiver to adhere to treatment regimen

A high prevalence of infections, such as candidiasis and varicella-zoster virus infection, must be anticipated, and appropriate prevention and treatment strategies must be initiated.

As the disease progresses, wasting is noted, with weight loss and growth retardation in children. Low protein stores can be countered by increasing the intake of amino acids, specifically threonine and methionine.

Address abnormalities in psychological and neurologic development, due, in part, to the tropism of the virus for CNS tissue in children who are HIV positive.

Surgical Care

Surgical intervention is needed if an underlying neoplasm exists or intervention (eg, feeding tube) is indicated.

Consultations

• Consult a pediatric HIV specialist to assist in the treatment of children with HIV disease.
• Appropriate specialty referrals for evaluation are warranted and include an audiologist, an ophthalmologist, a dentist, and a neurodevelopmental specialist (see Other Tests).

Diet

• Initiate oral supplementation with increased energy intake as high as 150% of the US recommended daily allowance for calories and protein when nutritional deficits are identified.
• If necessary, enteral supplementation with tube feedings may be warranted.
• Pay special attention to protein deficits.
• Some studies have shown that appetite stimulants, such as megestrol acetate and human recombinant growth hormone, can improve growth and weight.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children established treatment recommendations categorized by age.

Children younger than 12 months

The group recommends initiating antiretroviral treatment in all infants younger than 12 months who have clinical or immunologic symptoms of HIV infection, regardless of HIV RNA level. It also recommends therapy in asymptomatic infants younger than 12 months with a CD4 count of less than 25%. It recommends considering therapy in those younger than 12 months who are asymptomatic with a normal immune status.

Children aged 1-4 years

The Working Group recommends treating all children aged 1-4 years who have AIDS or significant HIV-related symptoms and for patients who are asymptomatic or have mild symptoms and a CD4 of less than 20%. It recommends considering treatment in patients who are asymptomatic or have mild symptoms and CD4 levels of 20-24% or with HIV RNA levels greater than or equal to 100,000 copies/mL. It recommends deferring treatment in asymptomatic patients and in those with CD4 counts greater than 25% and HIV RNA levels less than or equal to 100,000 copies/mL.

Children aged 4-12 years

The Working Group recommends treating all children age 4-12 years who have AIDS or significant HIV-related symptoms and for patients who are asymptomatic or have mild symptoms and a CD4 level of less than 15%. It recommends considering treatment in patients who are asymptomatic or have mild symptoms and CD4 levels of 15-24% or with HIV RNA levels greater than or equal to 100,000 copies/mL. It recommends deferring treatment in asymptomatic patients and in those with CD4 levels greater than 25% and HIV RNA levels less than or equal to 100,000 copies/mL.

Children 13 years or older

The Working Group recommends treating all children older than 13 years who have AIDS or significant HIV-related symptoms and for patients who are asymptomatic or have mild symptoms and a CD4 count less than 200 cells/mL. It recommends considering treatment in patients who are asymptomatic or have mild symptoms and CD4 counts of 201-350 cells/mL or with HIV RNA levels greater than or equal to 100,000 copies/mL. It recommends deferring treatment in asymptomatic patients and in those with CD4 counts greater than 350 cells/mL and HIV RNA levels less than or equal to 100,000 copies/mL.

Some pediatric HIV experts recommend that all children younger than 1 year be treated empirically, even if they are considered to be immunocompetent. Other specialists believe that treatment should be postponed until the immune status deteriorates or CD4⁺ counts decrease. Given that the risk of disease progression is slower in children older than 1 year, treatment deferment may be considered for older children. Although in adults the goal of therapy is to achieve undetectable levels of HIV RNA, in children only a reduction in the numbers of HIV RNA copies may be seen.

When treating older children, some advocate considering a child's Tanner stage when determining dosing regimens. Adolescents in early puberty (Tanner stages I and II) should be treated according to pediatric dosing guidelines. Adolescents in late puberty (Tanner stage IV) and postpubertal adolescents should follow adult dosing guidelines.

The 2006 Working Group generally preferred recommendation for children includes a combination antiretroviral regimen in previously untreated children with 1 non-NRTI (NNRTI) or 1 PI combined with a 2-drug NRTI combination. It recommends using a 3-drug NRTI regimen only when an NNRTI or a PI cannot be used.

For children younger than 3 years or for children who cannot swallow tablets, the preferred NNRTI-based treatment recommendations include 2 NRTIs plus nevirapine. For children 3 years and older, it is 2 NRTIs plus efavirenz. Nevirapine may be used as an alternative for efavirenz for children  3 years or older.

The preferred PI-based regimen for children is 2 NRTIs plus lopinavir/ritonavir. The alternate recommendation for children older than 2 years is 2 NRTIs plus nelfinavir.

Currently, no nucleoside analogue–based regimen is strongly recommended. Two-drug NRTI regimens may be used in combination with additional agents. The preferred combination is zidovudine plus lamivudine, didanosine, or emtricitabine. A second preferred combination is didanosine plus lamivudine or emtricitabine. An alternative nucleoside analogue–based regimen is abacavir plus zidovudine, lamivudine, emtricitabine, or stavudine.

The following antiretroviral regimens are generally not recommended and should only be considered in unique exceptions: monotherapy, 2 NRTIs alone, tenofovir plus abacavir plus lamivudine or emtricitabine as a triple-NRTI regimen, tenofovir plus didanosine plus lamivudine or emtricitabine as a triple-NRTI regimen.

Several considerations have been established to guide clinicians regarding when to make changes in an antiretroviral regimen. Virologic considerations include inadequate response after 8-12 weeks or unsuppressed HIV RNA levels after 4-6 months. Viral rebound is another virologic consideration for changing antiretroviral therapy, as is demonstrated by (1) repeated detection of HIV RNA levels of greater than 400 copies/mL when previously undetectable or (2) a greater than 3-fold increase in HIV RNA copy number for children 2 years or older or a greater than 5-fold increase for children younger than 2 years.

Immunologic considerations that warrant a change in antiretrovirals includes a change in immunologic classification, persistent CD4⁺ declines, or a rapid decrease in absolute CD4⁺ T-cell  count.

Incomplete immunologic response to therapy is likely in children with severe immune suppression who have not improved their CD4 percentage by at least 5 percentage points. The 2006 Working Group also classifies children aged 4-6 years who do not increase their CD4 count by 50 cell/mL above baseline as incomplete immunologic responders. The Working Group also states that  a persistent immunologic decline of 5 percentage points or decline to below pretreatment CD4 absolute counts in children aged 4-6 years may also warrant an antiretroviral therapy change.

Clinical considerations include neurodevelopmental deterioration, growth failure, severe or recurrent infection or illness, and an adverse change in clinical category status.

Other drugs, as appropriate for specific infections or malignancies, are required. More specifically, P carinii pneumonia prophylaxis is recommended in patients who are HIV positive and younger than 1 year and in older children based on CD4⁺ counts.

Drug Category: Antiretroviral agents

These agents inhibit reverse transcriptase, thereby causing chain termination when incorporated into a growing viral strand.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Based on the patient's living arrangements and stage of infection, inpatient care may be warranted at some time during the patient's illness.
• • The extensive testing required to rule out an underlying infection or a malignancy may be easiest performed if the child is admitted to a health care facility.
  • If an infection or a malignancy is detected, hospital admission may be appropriate. For example, if intravenous antibiotics are given, a child is usually admitted to the hospital. A serious reaction to an antiviral drug may also mandate hospitalization to follow up on the progression of the reaction and to observe the patient if new drugs are begun.

Further Outpatient Care

• Maintain an established vaccination schedule in children who are HIV positive to protect them against vaccine-preventable illnesses.
• Based on the child's age and immune status, clinical outpatient follow-up is necessary. CD4⁺ counts must be closely monitored, and neurodevelopment should be frequently assessed. In younger children, evaluations should occur every 1-6 months. In older children, a review of systems is advised every 3 months and a physical evaluation should be performed every year. CD4⁺ counts must be checked every 3-6 months.
• Accurate and routine height and weight documentation is important in children with AIDS because HIV is known to adversely affect growth rates in children. Evidence¹⁸ indicates that children with improved height growth velocity are less likely to exhibit virologic or immunologic failure and less likely to have clinical disease progression.
• Examinations by specialists should occur routinely. The patient should follow up with an ophthalmologist every 6-12 months and a dentist every 3-6 months.
• The requirement of laboratory monitoring for the specific antiviral drug dictates the frequency of laboratory monitoring.

Deterrence/Prevention

• To prevent the spread of HIV disease, appropriate education on the transmission of the virus is needed. School-based programs and community-based interventions should be emphasized.
• • A focus on abstinence and/or condom use with partner notification is important. Behavioral modification to reduce drug abuse is also critical. Immunizations to prevent the spread of other viruses, such as hepatitis B, can reduce sexual transmission of these additional infections.
  • A focus of prenatal screening and maternal care can assist in preventing babies being born with HIV infection. According to the World Health Organization's most recent report, transmission from infected mothers to infants can be reduced to just 2% with successful interventions. Unfortunately, these interventions may not be widely available in areas where they are needed most because of high HIV burdens. Without intervention, 20-25% of infants will become infected by vertical transmission from their infected mothers.
• The prevention of perinatal transmission of HIV by administering zidovudine chemoprophylaxis to pregnant women has made a dramatic impact on lessening the burden of pediatric HIV disease.
• • More and more developing countries are adopting and implementing antiretroviral therapy for HIV-infected pregnant women. According to the World Health Organization, as of 2004, more than 100 low- and middle-income countries have established Preventing Mother to Child Transmission programs. Although many mothers are not receiving antiretrovirals at this time, the trend is towards improvement; now, approximately 10% of infected mothers globally receive antiretrovirals.
  • In most the significantly affected area, sub-Saharan Africa, 3 countries have made dramatic strides. Namibia, South Africa, and Swaziland have more than doubled their maternal antiretroviral prophylaxis rates from 2004 to 2005.
• In addition to antiretrovirals, elective cesarian delivery and strict avoidance of breastfeeding can decrease the risk of infant infection to 2%. In developed and industrialized nations, these practices have dramatically reduced the number of new pediatric HIV cases.

Complications

• Because the immunosuppressed state allows for a wide variety of illnesses, significant complications of HIV infection are expected.
  
  
  • The neurologic state of patients infected with HIV is of paramount importance. Routine screening and appropriate therapy to treat such infections is necessary. As outlined above, adherence to a regular follow-up schedule is important.
  • The numerous medications that children with HIV infection take make appropriate laboratory and clinical follow-up important. The possibility of cross-reactions with the many drugs must be addressed.

Prognosis

• Although HIV infection is usually deadly in children, especially in developing countries, the development of new antiretroviral drugs is promising. The lack of access to antiretroviral agents by children in developing countries is of particular concern.
• The nutritional status of the child and the diligence with which viral replication is controlled are paramount in determining the outcome of most children with HIV disease.
• Aggressive treatment of opportunistic infections prevents the more deleterious effects of secondary disease from progressing and further weakening the patient.
• The social setting of children and the stressors to which they are exposed have also been linked to the progression of the disease.

Patient Education

• Educate the child's caregiver about the specifics of maintaining infection control. This is of paramount importance.
• Instruct caregivers to identify opportunistic infections, which must be treated early.
• For excellent patient education resources, visit eMedicine's Immune System Center, Sexually Transmitted Diseases Center, and Yeast and Fungal Infections Center. Also, see eMedicine's patient education articles HIV/AIDS, Rapid Oral HIV Test, and Candidiasis (Yeast Infection).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials