ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Ongoing viral replication leads to cellular and humoral immunodeficiency and end-organ pathology.
Immunodeficiency is staged by monitoring CD4 T-lymphocyte count decline.
As immunodeficiency progresses, patients are at risk for bacteremia, infections by pathogens such as herpes zoster, and Mycobacterium tuberculosis, and opportunistic infections such as P jiroveci, cytomegalovirus, and Mycobacterium avium complex (MAC) infection.
Patients with progressive HIV disease are also at risk for encephalopathy, nephropathy, hepatitis, cardiomyopathy, chronic diarrhea, and pulmonary disease.
HIV-infected individuals have higher rates of non-Hodgkin’s lymphoma and cervical and anal neoplasia.
The CDC published revised disease staging for HIV-infected adults, adolescents, and children in 2014 (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm) (Tables 41–1 and 41–3). Stages 1, 2, and 3 are determined by categories of age-adjusted absolute CD4 T-lymphocyte counts and percentages that indicate progressively severe immune suppression; stage 3 is defined as AIDS (see Table 41–3). AIDS is also diagnosed in individuals having one or more of the severe opportunistic illnesses or other serious conditions listed in Table 41–1. An individual’s staging may vary with time, improving or worsening depending on the outcome of the patient’s treatment course. The WHO has established a clinical staging system that is used widely outside the United States (Table 41–4). Risk of progression to AIDS or death for a child at specific ages can be determined with CD4 parameters and HIV viral load (tables for risk calculation found at https://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv/440/appendix-c–supplemental-information).
Table 41–3.HIV infection stage based on age-specific CD4 T-lymphocyte counts and percentages of total lymphocytes. ||Download (.pdf) Table 41–3. HIV infection stage based on age-specific CD4 T-lymphocyte counts and percentages of total lymphocytes.
| ||Age of Child |
| ||< 1 y ||1–5 y ||≥ 6 y |
|Stage ||Cells/μL ||% ||Cells/μL ||% ||Cells/μL ||% |
|1. ||≥ 1500 ||≥ 34 ||≥ 1000 ||≥ 30 ||≥ 500 ||≥ 26 |
|2. ||750–1499 ||26–33 ||500–999 ||22–29 ||200–499 ||14–25 |
|3. ||< 750 ||< 26 ||< 500 ||< 22 ||< 200 ||< 14 |
Table 41–4. World Health Organization clinical staging of HIV for infants and children with established HIV infection. ||Download (.pdf) Table 41–4. World Health Organization clinical staging of HIV for infants and children with established HIV infection.
|Clinical stage 1: Asymptomatic |
| Asymptomatic |
| Persistent generalized lymphadenopathy |
|Clinical stage 2: Mild symptoms |
| Unexplained persistent hepatosplenomegaly |
| Papular pruritic eruptions |
| Fungal nail infection |
| Angular cheilitis |
| Lineal gingival erythema |
| Extensive wart virus infection |
| Extensive molluscum contagiosum |
| Recurrent oral ulcerations |
| Unexplained persistent parotid enlargement |
| Herpes zoster |
| Recurrent or chronic upper respiratory tract infections (otitis media, otorrhea, sinusitis, or tonsillitis) |
|Clinical stage 3: Advanced symptoms |
| Unexplained moderate malnutrition or wasting not adequately responding to standard therapy |
| Unexplained persistent diarrhea |
| Unexplained persistent fever |
| Persistent oral candidiasis (after first 6–8 wk of life) |
| Oral hairy leukoplakia |
| Acute necrotizing ulcerative gingivitis or periodontitis |
| Lymph node tuberculosis |
| Pulmonary tuberculosis |
| Severe recurrent bacterial pneumonia |
| Symptomatic lymphoid interstitial pneumonitis |
| Chronic HIV-associated lung disease including bronchiectasis |
| Unexplained anemia, neutropenia, thrombocytopenia |
|Clinical stage 4: Severe symptoms |
| Unexplained severe wasting, stunting, or severe malnutrition not responding to standard therapy |
| Pneumocystis pneumonia |
| Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection, or meningitis but excluding pneumonia) |
| Chronic herpes simplex infection |
| Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) |
| Extrapulmonary tuberculosis |
| Kaposi sarcoma |
| Cytomegalovirus infection: retinitis or cytomegalovirus infection affecting another organ, with onset at age older than 1 mo |
| Central nervous system toxoplasmosis (after 1 mo of life) |
| Extrapulmonary cryptococcosis |
| HIV encephalopathy |
| Disseminated endemic mycosis (coccidiomycosis or histoplasmosis) |
| Disseminated nontuberculous mycobacterial infection |
| Chronic cryptosporidiosis (with diarrhea) |
| Chronic isosporiasis |
| Cerebral or B-cell non-Hodgkin lymphoma |
| Progressive multifocal leukoencephalopathy |
| Symptomatic HIV-associated nephropathy or HIV-associated -cardiomyopathy |
2. Infections related to immunodeficiency
Bacteremia, especially due to Streptococcus pneumoniae, occurs at rates of 3 per 100 child-years without ART and decreases to 0.36 per 100 child-years with ART, but this remains at least three times higher than in HIV-uninfected children. Infections with M tuberculosis are a major cause of morbidity in countries with high rates of endemic tuberculosis (TB). Given the frequency of coinfection, diagnosis of M tuberculosis in a child is an indication for HIV testing. Likewise, children with HIV infection and their family members should have annual TB testing if there is potential for M tuberculosis exposure. Herpes zoster (shingles) occurs 10 times more frequently among untreated HIV-infected children compared with age-matched healthy children.
Late-stage immunodeficiency is accompanied by susceptibility to a variety of opportunistic pathogens. Pneumonia caused by P jiroveci is a common AIDS-defining diagnosis in children with unrecognized HIV infection who, therefore, are not receiving PCP prophylaxis. The incidence is highest between ages 2 and 6 months and is often fatal during this period. Symptoms are difficult to distinguish from those of viral or atypical pneumonia (see Chapter 43). Persistent candidal mucocutaneous infections (oral, cutaneous, and vaginal) are common. Candidal esophagitis occurs with more advanced disease. Cytomegalovirus (CMV) infections may result in disseminated disease, hepatitis, gastroenteritis, retinitis, and encephalitis. Disseminated infection with MAC, presenting with fever, night sweats, weight loss, diarrhea, fatigue, lymphadenopathy, hepatomegaly, anemia, and granulocytopenia, may occur in those who have CD4 T-lymphocyte counts below 50–100/μL. A variety of diarrheal pathogens that cause mild, self-limited symptoms in healthy persons may result in severe, chronic diarrhea in HIV-infected persons. These include Cryptosporidium parvum, Microsporidia, Cyclospora, Isospora belli, Giardia lamblia, and bacterial pathogens. Chronic parvovirus infection manifested by anemia can occur.
HIV infection may directly affect a variety of organ systems and produce disease manifestations that include encephalopathy, pneumonitis, hepatitis, diarrhea, hematologic suppression, nephropathy, and cardiomyopathy. On average, HIV-infected children have lower than normal neuropsychological functioning. In many children, neuropsychological deficits do not normalize when ART is started, despite suppression of viremia. Without ART, findings include acquired microcephaly, progressive motor deficit, ataxia, pseudobulbar palsy, and failure to attain (or loss of) developmental milestones.
Lymphoid interstitial pneumonitis, which is common in untreated children with HIV infection, is characterized by a diffuse peribronchial and interstitial infiltrate composed of lymphocytes and plasma cells. It may be asymptomatic or associated with dry cough, hypoxemia, dyspnea or wheezing on exertion, and clubbing of the digits. Children with this disorder frequently have enlargement of the parotid glands and generalized lymphadenopathy.
Children with HIV are at increased risk of malignancy. The most commonly occurring tumors are non-Hodgkin lymphomas, which may occur at unusual extranodal sites (central nervous system, bone, gastrointestinal tract, liver, or lungs). Human papillomavirus infection of the cervix is more likely to progress to neoplasia, and the rate of progression is not altered by ART. Anal carcinoma due to human papillomavirus is also a concern. Kaposi sarcoma, a skin and mucous membrane malignancy that is common in HIV-infected MSM with advanced disease, is also observed among HIV-infected African children, but it is rare in children in the United States.
The hallmark of HIV disease progression is decline in the absolute number and percentage of CD4 T lymphocytes and an increasing percentage of CD8 T lymphocytes. The CD4 T-lymphocyte values are predictive of the child’s risk of opportunistic infections. Healthy infants and children have CD4 T-lymphocyte numbers that are much higher than in adults; these gradually decline to adult levels by age 5–6 years. Hence, age-adjusted values must be used when assessing a child’s absolute CD4 T-lymphocyte count (see Table 41–3). CD4 T-lymphocyte percentage is used when CD4 T-cell count is not available.
Hypergammaglobulinemia of IgG, IgA, and IgM is characteristic in untreated HIV. Late in the disease, some individuals may become hypogammaglobulinemic. Hematologic abnormalities (anemia, neutropenia, and thrombocytopenia) may occur due to effects of HIV disease or ART. Cerebrospinal fluid (CSF) may either be normal or may be associated with elevated protein and a mononuclear pleocytosis; HIV NAT may be positive in CSF.
C. Differential Diagnosis
HIV infection should be in the differential diagnosis for children being evaluated for immunodeficiency. Depending on the degree of immunosuppression, the presentation in HIV infection may be similar to that of B-cell (eg, hypogammaglobinemia), T-cell, or combined immunodeficiencies (eg, severe combined immunodeficiency) (see Chapter 33). HIV infection should also be considered in the evaluation of individuals with failure to thrive, developmental delay, chronic lung disease, and M tuberculosis infection. Chronic HIV infection presenting with generalized lymphadenopathy or hepatosplenomegaly may resemble infections with viruses such as Epstein-Barr virus or CMV in children or adolescents. Because blood tests are definitive for the diagnosis of HIV infection, the diagnosis can be readily established or excluded. In rare cases, HIV-infected people with hypogammaglobulinemia have falsely negative antibody tests but may be diagnosed with a nucleic acid–based test. Because recognized maternal or behavioral risk factors may not always be elicited, testing for HIV should be performed if the patient has signs consistent with HIV-associated disease even when the history or maternal testing early in pregnancy does not suggest increased risk.
SA: Pneumococcal conjugate vaccine in HIV-infected and HIV-exposed, uninfected children. Expert Rev Vaccines 2017;16(5):453–465
RA, and Mellins CM for the Pediatric HIV/AIDS Cohort Study. Brain and cognitive development among youth with perinatally acquired human immunodeficiency virus infection in the United States. J Pediatric Infect Dis Soc 2016;5(suppl 1):S1–S5; PMCID: PMC5181541. https://www.ncbi.nlm.nih.gov/pubmed/27856670