Chapter 54. Infections in HIV-Infected Children

Infection with the human immunodeficiency virus (HIV) induces a secondary immune deficiency, rendering the host susceptible to infection. The immunosuppressive combination of HIV infection in the setting of the immature pediatric immune system represents an ideal medium for opportunistic pathogens to thrive and the challenge rests with the pediatrician to diagnose, treat, and prevent these infections.

Infections in HIV-infected children occur in two broad groups: opportunistic infections (OI) and nonopportunistic infections. OI are defined by the Centers for Disease Control and Prevention (CDC) disease classification of pediatric HIV infection (see Table 53–1 in Chapter 53).1,2 Nonopportunistic infections represent all other known pathogens. The description of an infection as an OI is helpful in defining an AIDS-related illness (ARI), but does not mean that the nonopportunistic infections are any less common or severe.

In the United States, earlier detection of HIV infection through screening of pregnant women as well as the widespread use of highly active antiretroviral therapy (HAART) and pneumocystis prophylaxis have dramatically decreased the rates of AIDS-related OI in children. These advances have converted pediatric HIV in most children from an acute life-threatening condition to a chronic illness. Despite these advances, OI continue to occur in this population.

The epidemiology of infections in the HIV-infected child in the United States has dramatically altered after the introduction of HARRT in 1996 and its subsequent widespread use. In the pre-HAART era, the five most common OI, which all occurred at an event rate of greater than 1 per 100 patient-years, were serious bacterial infection, herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jiroveci pneumonia (PCP, formerly called Pneumocystis carinii pneumonia), and mucosal candidiasis (Table 54–1).3 Other less common opportunistic conditions included cytomegalovirus (CMV) disease particularly retinitis, tuberculosis, invasive fungal disease other than mucosal candidiasis, toxoplasmosis, and progressive multifocal leukoencephalopathy. In the HAART era, opportunistic illnesses occur mainly in two settings: as the presenting sign of a child in whom the diagnosis of HIV was previously unknown and in known HIV-infected children with a persistently low CD4+ T-lymphocyte percentage.4 Following the introduction of HAART, the four most common OI, all of which occur at a lower event rate than the pre-HAART era, are now bacterial pneumonia, herpes zoster, oral candidiasis, and dermatophyte infections (Table 54–1).5

This chapter will focus on the care of infections in the HIV-infected child in the United States. See Chapter 55 for an approach to the HIV-exposed child and Chapter 53 for a more general approach to managing the HIV-infected child.

The immunodeficiency caused by HIV-infection is due to a progressive decline in both number and function of T-lymphocytes.6 Effective antiretroviral therapy has addressed one of these shortcomings—immune reconstitution is associated with a rise in T-lymphocytes, often into the normal range for age. However, a critical question is whether this new T-cell population is fully functional or not.7 Recent work in a group of HIV-infected children following HAART demonstrated poor cellular immune responses, which may indicate persistent functional immune deficits in these children despite a normal CD4+ T-lymphocyte count.7

In the absence of HAART, infection with HIV leads to chronic immune activation and the progressive functional impairment and loss of CD4+ cells.8–11 HIV infection also causes CD8+ T-cell depletion in up to 50% of patients.12–14 The resultant T-cell dysregulation leads to immunodeficiency and AIDS, but the mechanisms leading to T-cell depletion remain controversial.15 Evidence exists for a number of mechanisms including impaired thymic production, direct lysis of CD4+ cells, and apoptosis of uninfected bystander T cells. Impaired thymic production of naïve T cells over time reduces the size of the T-cell pool.16,17 Direct lysis of infected CD4+ cells also contributes to T-cell depletion.18 However, most of the apoptotic T cells in the peripheral blood and lymph nodes of HIV-infected patients are uninfected.13,19–23 Apoptosis of uninfected bystander T cells is caused by activation-induced cell death of mature T cells following chronic immune activation in addition to HIV-mediated mechanisms.11,24,25 HIV-1 induces apoptosis in uninfected T cells by several mechanisms including cytotoxic effects of HIV-1 proteins and envelope glycoproteins (Env), which have been implicated as the major cause of bystander cell death in T cells and other cell types.26–34 Nonreplicating virions induce a proapoptotic signal in uninfected CD4+ T cells through a CXCR4- or CXCR5-mediated pathway that does not require CD4 signaling or membrane fusion.31,35 In addition, soluble, virion, or cell-associated HIV-1 envelope glycoproteins can prime uninfected T cells for activation-induced apoptosis.28,30

The slope of the CD4+ cell decline depends on the viral load. In one adult study the median rate of decline in the absence of therapy was 4%/year for each log10HIV RNA c/mL.36 The slope of CD4+ cell decline increases in late-stage disease. The catastrophic decline in numbers of CD4+ and CD8+ T-lymphocytes is usually reversed by an appropriate HAART regimen.

In the United States, the goal is to offer prenatal HIV testing for all pregnant women. In reality, however, not all women are screened for HIV and as a result, there are still children who acquire HIV perinatally and are diagnosed only when they present with symptomatic HIV infection. In these children, the pathogenesis of their symptoms is usually because of a progressive decline in both number and function of T-lymphocytes. When the CD4 percentage falls below 25%, their risk for infection is increased and when it falls below 15%, they are at substantial risk for opportunistic pathogens.

The exact pathogenesis of the immune reconstitution syndrome is still being elucidated. In an HIV-infected individual who has received several weeks of HAART, the cell-mediated immune response is restored, which may result in an inflammatory reaction to hitherto dormant pathogens, such as MAC antigens, and lead to local symptoms. Manifestations of the immune reconstitution syndrome are varied and depend on the causative pathogen and on the vigor of the host's immune response. Symptoms vary from painful lymphadenopathy 1–12 weeks after initiating HAART, as is seen in some cases of MAC-induced immune reconstitution, to severe symptoms requiring hospitalization in others.37,38 The clinician needs to be vigilant for symptoms and signs of this syndrome when commencing HAART in children who have a low CD4 count.

The clinical diagnosis of an opportunistic infection in an HIV-infected child depends on a high index of suspicion as signs and symptoms are frequently more nuance than in the immunocompetent child. The clinical features of the most important OI in HIV-infected children are summarized in Table 54–2.

Bacterial Pneumonia

Bacterial pneumonia may present with classic symptoms of fever, cough, and labored breathing, but more subtle signs such as a change in exercise tolerance may be the only presenting feature. Symptoms are frequently more indolent when the cause of pneumonia is an opportunistic pathogen, such as Pneumocystis jiroveci or Mycobacterium tuberculosis. With the latter, systemic symptoms such as weight loss, night sweats, and intermittent fever may be prominent. Clinical examination may reveal lobar or diffuse pulmonary involvement depending on the pathogen. In PCP, the lungs are often remarkably clear to auscultation. The finding of a tachypneic child with oxygen saturation lower than expected for the clinical picture is highly suggestive of PCP. Sinusitis may complicate a preceding viral upper respiratory tract infection and requires a high index of suspicion, particularly in patients who are nonverbal.

Varicella

Chickenpox caused by varicella zoster virus (Figure 54–1) may be seen in HIV-infected children and presents with fever and skin lesions at multiple stages of development. It may be complicated by pneumonia or secondary bacterial infection of the skin. After primary infection, the virus becomes latent in the dorsal root ganglia and may reactivate to cause herpes zoster (Figure 54–2). Zoster occurs 7–20 times more frequently in HIV-infected children than in their HIV-uninfected peers.39 The incidence of zoster has declined since 2000, likely representing the combined effects of varicella zoster immunization and immune reconstitution secondary to HAART.40 Children who are on HAART at the time of their primary varicella infection have been shown to be at lower risk of subsequently developing zoster than those who develop primary varicella off HAART. In HIV-infected children, zoster occurs in a dermatomal distribution and may be single or multidermatomal.40 In the early phases of zoster, patients may present with a sharp or burning dermatomal pain in the absence of skin lesions. Careful follow-up will reveal the diagnosis when the characteristic rash appears a day or two later.

Mucosal and Cutaneous Fungal Infections

Oropharyngeal candidiasis (Figure 54–3) is a frequent finding in many children in the first few months of life. However, thrush that is particularly unresponsive to therapy, is recurrent, occurs in a child older than a year of age, and is not preceded by a course of antibiotics or inhaled steroids should prompt the clinician to consider the diagnosis of a coexistent immunodeficiency, such as HIV.

A detailed skin examination of an HIV-infected child may reveal cutaneous dermatophyte infections (Figure 54–4), widespread molluscum contagiosum, severe scabies (Figure 54–5), or pronounced genital warts caused by human papilloma virus (Figure 54–6). Any of these signs may also be found in a child who has been a long-term nonprogressor. This small group of children who acquire HIV perinatally are relatively asymptomatic as they coexist with HIV for up to a decade or more while their CD4 count slowly declines. Eventually they present with features of AIDS, which may include cutaneous findings.

Central Nervous System Infections

Central nervous system infections such as cryptococcal meningitis may have an indolent course. Subtle symptoms reported by parents include behavior changes, headaches, and a gradual decline in school achievement. If the diagnosis is not made during this phase, symptoms progress to reflect the underlying meningitis or space-occupying lesion. CMV or toxoplasmosis may present with changes in visual acuity. These visual changes may be reported by older HIV-infected children but annual ophthalmology screening visits are advocated for children who are not able to give a reliable visual history and have a low CD4 count. On Fundoscopic examination, CMV retinitis is characterized by white and yellow retinal infiltrates often associated with retinal hemorrhages.

The discipline of carefully constructing and reviewing one's differential diagnosis is a valuable one when caring for an HIV-infected child with a possible OI. We recommend constructing a differential diagnosis based on the presenting symptoms and signs (Table 54–3). Careful observation of the clinical course and underlying pathologic mechanisms may also provide the key to making a microbiologic diagnosis.

The accurate microbiologic diagnosis of infection in HIV-infected children ensures targeted and effective therapy in a population who are prone to infection with a plethora of organisms. Using a carefully crafted list of differential diagnoses, the clinician should prioritize testing for those infections that are most likely in each clinical setting. While a microbiologic diagnosis is the ultimate goal this should be obtained with due thought to any possible morbidity from the diagnostic procedure itself.

Rapid diagnostic tests such as pharyngeal streptococcal antigen, stool rotavirus antigen, or nasopharyngeal viral antigen screening are frequently revealing in children with the appropriate clinical syndrome. For example, the diagnosis of varicella zoster infection, which can be challenging in an immunocompromised host, has been revolutionized by newer molecular diagnostic techniques. Where available, polymerase chain reaction (PCR) testing has become the gold standard. Rapid antigen testing is less sensitive, but is useful in an emergency department setting given its faster turnaround time. Culture of the virus is sometimes available and reference laboratories use this technique to assess whether the infecting strain was vaccine or wild type varicella virus. The Tzanck smear, whereby cells from a fresh blister are smeared on a slide and stained to look for characteristic herpes-related changes, is no longer recommended because of its relatively poor sensitivity and specificity.41

A blood culture to screen for bacteremia should be performed in a febrile HIV-infected child when the source of fever is not readily apparent. When infection with MAC is suspected (Figure 54–7), multiple blood cultures sent in using isolator tubes might be required to detect the organism.38 The microbiology laboratory will then place the blood directly onto mycobacterial broth media, such as Lowenstein-Jensen medium, or they will concentrate the blood and place it in mycobacterial broth media. Standard blood cultures may detect rapid-growing mycobacteria but will not detect MAC leading to the potentially false assumption that the patient is not infected by this organism. A negative acid-fast stain performed on a blood culture specimen should be interpreted with caution—the majority of these stains are negative even in patients whose blood cultures subsequently culture MAC.

Patients with subtle features suggesting meningitis, such as a chronic headache or behavioral changes, should have a lumbar puncture to assess the cell count, chemistry, and culture of the cerebrospinal fluid (CSF). The early diagnosis of meningitis in an immune-compromised child is difficult, given the propensity for underwhelming symptoms and signs. A high index of suspicion and a low threshold to rule out meningitis with a spinal tap will enhance the clinician's chances of making this challenging diagnosis. If there is clinical suspicion for an intracranial space occupying lesion or hydrocephalus such as is sometimes seen in cryptococcal meningitis, this should be evaluated by head imaging.

In an HIV-infected child who has a low CD4 count, cryptococcal infection should be suspected, particularly if the child is in the age range of 6–12 years. Blood and CSF should be sent for cryptococcal antigen testing. Antigen is detected in CSF or serum specimens from more than 90% of patients with cryptococcal meningitis. Where antigen detection is not available, cryptococcus may also be visualized by examining India ink-stained samples of CSF. Occasionally, CSF cryptococcal antigen detection may be negative in patients with culture-proven meningitis. Three possible reasons for this include infection with a nonencapsulated strain of cryptococcus, low antigen titers, or very high antigen titers, which give a false negative result—the prozone phenomenon.42,43 The latter reverts to positive when the antigen test is repeated after diluting the sample of CSF. Cryptococcal antigen titers in CSF can be helpful in evaluating response to therapy or ongoing relapse. However, changes in serum, rather than CSF, antigen titers do not correlate with clinical response.44

Identifying the microbiologic cause of pneumonia in HIV-infected children is challenging. Rapid viral diagnostics, blood cultures, sputum cultures, bronchoalveolar lavage specimens, pleural fluid aspirate, and lung biopsy may all be used to diagnose the etiology. The diagnosis of PCP is suggested by a ground glass appearance on chest radiography but is usually only confirmed after identifying the organism from bronchoalveolar lavage fluid. Serum lactate dehydrogenase is frequently elevated in children with PCP but is not specific for this condition.44Mycobacterium tuberculosis may be isolated from early morning gastric aspirates and, because of the variable yield of this technique, at least three samples are usually sent for both Ziehl-Neelsen staining and mycobacterial culture.

Imaging of the affected organ system frequently clinches the diagnosis. The chest radiograph is particularly helpful in cases of pneumonia and pulmonary tuberculosis (Figures 54–8 and 54–9). Computed tomography of the head may reveal sinusitis, hydrocephalus or an intracranial abscess. Magnetic resonance imaging is often required to diagnose the early features of progressive multifocal leukoencephalopathy. In this setting, CSF should be tested for JC virus by PCR. In a child who has had untreated HIV for some time, the electrocardiogram may reveal evidence of left ventricular hypertrophy caused by HIV-associated cardiomyopathy. In more severe cases, the echocardiogram demonstrates cardiac dysfunction.

The management of infections in HIV-infected children is focused primarily on preventing infection using a three-tiered approach. The primary goal is immune reconstitution using HAART. The HIV-infected child is further protected by inducing active immunity to common childhood pathogens by vaccination. In patients without documented immune response to vaccines or where vaccination may not have occurred, passive immunization is practiced, following exposure to certain pathogens such as varicella zoster virus. The third tier is the use of antibiotic prophylaxis.

HIV clinicians use the CDC guidelines to decide when to initiate antibiotic prophylaxis and the reader is referred to this source for pathogen-specific recommendations.45Table 54–4 summarizes key elements of the CDC treatment and prophylaxis guidelines and Table 54–5 tabulates selected adverse reactions of antimicrobials commonly used to manage infections in HIV-infected children. The decision to commence prophylaxis depends on the child's age, CD4+ T-lymphocyte percentage and count. For example, PCP prophylaxis with an agent such as trimethoprim-sulfamethoxazole is recommended for all HIV-infected children younger than the age of a year regardless of their CD4+ T-lymphocyte percentage and count, as even those children with counts in the normal range carry a higher risk of acquiring PCP. For MAC, the risk of infection increases as the child's CD4+ T-lymphocyte percentage and count fall—the prophylaxis guidelines reflect this.

Despite recent improvements in microbiologic diagnostic capabilities, including the introduction of PCR-based molecular technology, the clinician may still be faced with the challenge of caring for an HIV-infected child with an acute fever of unknown origin. Figure 54–10 describes an approach to such a patient.

Treatment of infections in HIV-infected children is targeted at the causative organism. In the acute setting where the cause is not yet known, broad-spectrum antibacterial coverage may be necessary for a 24–48-hour period. Local antibiograms should be consulted when choosing empiric antimicrobial therapy. Empiric coverage may also include fungal, mycobacterial, or viral agents depending on the clinical syndrome. A valuable resource is the CDC recommendations on treating OI among HIV-infected children.44 When PCP is suspected, it is important to begin therapy as soon as possible as this may prove lifesaving in a condition that still carries a high mortality. The clinician does not need to wait until a bronchoalveolar lavage has been performed to confirm the diagnosis, as this will remain positive for PCP for at least 48 hours after therapy has commenced.

The duration of therapy depends on the underlying condition. For tuberculosis or MAC therapy lasts for at least 6–9 months and frequently longer. Treatment of these conditions should be done in consultation with a pediatric infectious diseases expert with expertise in pediatric HIV infection. For tuberculosis, principles for treating the HIV-infected child are the same as for the HIV-uninfected child except that ceratin modifications may be required given drug interactions with HAART. For initial therapy, before culture and sensitivity data are known, a four-drug regimen is recommended to allow for the possibility of a resistant organism. For MAC, initial empiric therapy should include at least two drugs, a macrolide (clarithromycin or azithromycin are frequently used) and ethambutol. Rifabutin is frequently added as a third drug, particularly in children with disseminated disease or more severe symptoms. For uncomplicated bacterial pneumonia, a 5–7 day course of antibiotics is sufficient. PCP is usually treated for 21 days and is followed by commencing prophylaxis (see Chapter 52 for prophylaxis recommendations and dosing). Trimethoprim-sulfamethoxazole at a high dose of 15–20 mg/kg/day is the recommended treatment for PCP. A short course of corticosteroids in moderate to severe cases of PCP should be started within 72 hours of diagnosis and has been associated with decreased mortality, less need for ventilation and reduced respiratory failure.46–48

The course and prognosis of infection in HIV-infected children is determined by three main factors—the host, the organism, and the treatment. Key host factors include age and immune status. Younger children are generally more likely to experience a stormy course and a higher mortality particularly from PCP. By contrast, immune reconstitution syndrome seems to be less common in younger children who perhaps have not had the same degree of exposure to the causative pathogens such as Mycobacterium tuberculosis or MAC. The child's immune status, as measured by CD4+ T-lymphocyte percentage and count, impacts their ability to clear the organism and those with lower counts are more likely to fare more poorly.

Virulence and disease burden of the offending organism both play an important role in diseases course and prognosis. Invasive bacterial disease caused by pneumococcus or secondary group A streptococcal infection following chicken pox can both be rapidly fatal. More indolent infections, such as those caused by MAC or dermatophytes, generally follow a less fulminant course.

Prompt commencement of appropriate antimicrobial therapy impacts disease course and prognosis. Early consideration of drug interactions will ensure appropriate dosing. Once the patient is nearing discharge, attention to issues that may affect adherence will be time well spent.

1. The four most prevalent infections in the post-HAART era are bacterial pneumonia, herpes zoster, dermatophyte infections, and oral candidiasis.

2. In children with a CD4+ T-lymphocyte count <100 cells/mL, PCP and MAC infection can be prevented in the majority of cases by using appropriate antimicrobial prophylaxis.

3. In the initial stages, signs and symptoms of cryptococcal meningitis are subtle requiring a high index of suspicion to make the diagnosis.

4. A high lactate dehydrogenase level is not specific for PCP—start treatment and organize a Bronchial Alveolar Lavage (BAL) to confirm the diagnosis.

5. For the latest guidelines on treating or preventing infections in HIV-infected children, visit http://aidsinfo.nih.gov/Guidelines and click on the appropriate, updated guideline.