Management of Infants and Children with HIV Infection
Author: Steven G. Rothrock, MD, FACEP, Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, FL.
Peer Reviewer: Michael Muszynski, MD, FAAP, Director, Residency in Pediatrics; Chief, Division of Pediatric Infectious Disease, Arnold Palmer Hospital for Women and Children, Orlando, FL.
Editor: Larry B. Mellick MD, MS, FAAP, FACEP, Chief of Service and Chairman, Director of Emergency Medicine, Medical College of Georgia, Augusta, GA.
Editor’s NoteOver the past decade, the global pandemic of HIV has spread to every continent, with nearly 13 million cases worldwide.1 Of these cases, 1 million have occurred in children.1,2 While the spread of HIV has not abated, medical knowledge concerning the pathophysiology, diagnosis, and management of HIV-infected infants and children has grown exponentially. Early diagnostic and treatment protocols based on data extrapolated from adult studies were the cornerstone of therapy for HIV-infected children. However, research into pediatric-specific aspects of HIV has improved the ability of clinicians to make rational diagnostic and management decisions regarding HIV-infected children.
Several important advances have dramatically changed the approach to children with HIV. Importantly, treatment of infected mothers with AZT has been shown to reduce the rate of vertical transmission of HIV.3 While diagnosis of HIV infection in adults is relatively straightforward, the presence of maternal anti-HIV IgG, which crosses the placenta, potentially confuses diagnostic efforts in infants less than 18 months old. However, newer assays allow for accurate identification of most infants as young as 3 months old with HIV. Moreover, age-specific serum markers and other disease-specific tests are important tools for monitoring infants and children with HIV. Thus, choice of laboratory tests used to diagnose and monitor HIV must take into consideration the patient’s age, each laboratory’s ability, and the sensitivity and specificity of particular lab assays that are currently available.
With an increased ability to diagnose, monitor, and prevent disease progression, it is important that clinicians be able to identify undiagnosed infants and children with HIV. An increased awareness of the varied clinical presentations of HIV in infants and children may serve this goal. An understanding of the normal disease course, common complications of HIV disease, and therapy will improve the ability of clinicians to care for children with HIV. Early intervention, aggressive prophylaxis against common pathogens, and antiretroviral treatment will also likely improve the overall health and survival of HIV-infected infants and children.
Since the first childhood cases were reported in 1983, the number of children infected with HIV has grown almost exponentially. As of December 1994, the WHO estimated that over 1 million children had acquired HIV worldwide.1 By 1993, over 4000 cases of AIDS in children less than 13 years old had been reported to the Centers for Disease Control and Prevention (CDC), with an estimated 10,000-20,000 children infected with HIV (with most not yet exhibiting severe symptoms).2 While newer therapies have the potential to decrease vertical transmission (mother to fetus) of HIV, with a resulting decreased rate of new neonatal cases, the number of adolescents (age, 13-19) with HIV is doubling every 2-3 years.1,3 Furthermore, the median life span of children with perinatally acquired HIV has risen from six years to nine years due to newer therapies and better supportive care.4 Thus, physicians will increasingly be called upon to care for a larger population of infants and children who are surviving longer with HIV.
HIV-1 is an RNA virus and is a member of the retroviridae family of virusesa group of viruses causing disease in goats, sheep, horses, and monkeys in addition to humans.5 Several unique properties of HIV contribute to its pathogenicity.5,6
HIV has an outer envelope docking protein (gp120) that interacts with the CD4 protein lining the outer surface of helper T cells.6 Another protein (gp41) with other sequences of viral envelope proteins facilitates fusion of the viral envelope with the cellular membrane, allowing viral RNA entry.6 Once the viral RNA is within the cell, it is transcribed to DNA using the enzyme reverse transcriptase that was originally packaged in the whole viron. Viral replication then occurs with production of new virus particles.5,6 (See Figure 1.) The life cycle of the virus allows for disruption of the host’s immune system and eventual destruction of helper T cells and other cells that carry the CD4 protein on their outer surface (e.g., monocytes, macrophages, astrocytes, oligodendrocytes).5,6
To date, 90% of HIV cases in infants and children (< 12 years) have been acquired perinatally.1 Without treatment, the vertical transmission rate of HIV has been reported at approximately 25% (12-52%).1,7,8 Factors that increase vertical transmission of HIV include mothers with AIDS-defining illness, maternal active sexually transmitted disease, premature rupture of membranes, delivery before 34 weeks’ gestation, placental membrane inflammation, maternal p24 antigenemia, maternal CD4 count less than 700 cells/mm3, maternal HIV-1 RNA levels 190,000 copies/mm3, and, possibly, vaginal delivery.1,7-9 In 1994, zidovudine treatment was found to decrease the vertical transmission rate of HIV in neonates from 26% to 8% if initiated in the second trimester, with continuous IV therapy during delivery and oral therapy continued in the newborn infant for six weeks postpartum.10 Importantly, this therapy has the potential to decrease the number of new neonatal cases of HIV by over 65% per year.10 Some authors have noted that those who still develop HIV (after mothers were treated with zidovudine) may be more likely to harbor zidovudine-resistant HIV infection.10,11 This may make treatment of HIV in infants and children more difficult in the future.
Another important route for vertical transmission of HIV is breast feeding. It has been estimated that this route leads to HIV infection in up to 14-20% of infants.1 For this reason, HIV-infected mothers should not breast feed. The WHO still recommends breast feeding in developing countries with a high rate of death due to malnutrition and diarrheal disease.1,2
Blood transfusion accounts for ~10% of HIV cases in infants and children up to 12 years old.1 This number is expected to decrease. Most cases acquired via this route occurred prior to March 1985, when the blood supply was not routinely tested for HIV.1 For this reason, nearly 75% of children with severe hemophilia A and 50% with hemophilia B are HIV-positive, with lesser rates in those with moderate and mild hemophilia.1 With today’s more accurate testing, the risk of transmitting HIV via transfusion has fallen to 1 in 40,000-60,000.1,2 New heat treatment techniques for factor VIII concentrates and recombinant factor preparations have virtually eliminated the risk of HIV for hemophiliacs.
For 1% of infants and children 12 years or younger, the route of HIV transmission is unknown.1 Importantly, clinicians must consider the possibility of sexual abuse in this population. At one pediatric AIDS center, 14 out of 94 cases of pediatric HIV were transmitted through sexual abuse.12
The number of AIDS cases occurring in adolescents (13-19 years) is relatively small, with fewer than 1000 cases reported by late 1992.1 However, underreporting is a problem since a number of states (e.g., Florida) require only that cases of AIDS (severe HIV infection) and not HIV infection be reported. Moreover, the number of new cases of HIV is rising ~77% every two years, making this one of the fastest-growing populations of HIV patients in the country.1 Unprotected sex and IV drug use are the most common causes within this age group.1
HIV is a disease that has spread from several epicenters in the United States, generally areas with large population centers, large homosexual populations, and high rates of IV drug use.13 Perinatally acquired HIV occurs most frequently in areas with high HIV seroprevalence among childbearing women. (See Figure 2.) National HIV seroprevalence data show the highest incidence of HIV among women of childbearing age in the following locations: New York City (1.25% seroprevalence), Washington DC (0.9%), New Jersey (0.55%), and Florida (0.54%), compared to a national seroprevalence rate of 0.17% (or 1.7 HIV-infected women per 1000 live births).13
In the past, children and adults were defined as being HIV-positive (a positive blood test without symptoms or with minor symptoms) or as having AIDS (one of a set of serious disorders related to immune dysfunction: currently CDC Clinical Category C).14 Experts no longer make the distinction between these two definitions for children, as all patients are now considered HIV-positive with different levels of symptoms, immunosuppression, and infection.14
In 1994, the CDC published a new classification system for children younger than 13 years with HIV.14 This classification system is simpler than the prior system and is based on the presence of symptoms, the degree of immunosuppression based on CD4 count, and the patient’s age.14 (See Table 1.) Importantly, while CD4 counts are used to follow and categorize adults, their variation with age can lead to confusion in children. Infants and young children normally have higher CD4 counts that decline over the first few years of life; therefore, different CD4 counts are used to identify the level of immunosuppression in infants and young children. (See Table 2.) Moreover, children may develop opportunistic infections at higher CD4 counts compared to older children and adults.14,15 With this classification system, children should never be reclassified to a less severe category from a more severe category.14
Diagnosis of HIV in infants is confounded by the presence of maternal anti-HIV IgG antibodies that cross the placenta, which persists for 12-18 months.1,15 Therefore, all infants born to HIV-infected mothers are HIV-antibody-positive at birth. For this reason, testing that relies on detection of IgG (e.g., Western blot and ELISA) can give false-positive results until age 18 months and should not be relied upon in patients up to this age.16 In children older than 18 months, HIV tests consist of an initial ELISA test, which is nearly 99% sensitive, with positive testing confirmed by the more specific Western blot test.16
A diagnosis of HIV infection can now be made with certainty in nearly 50% of neonates and 95% of infants older than 3 months with polymerase chain reaction (PCR), viral culture, or acid-dissociated p24 antigen assays.17 PCR is an in vitro technique for amplification of specific nucleic acid sequences of HIV to levels that are readily detectable in the laboratory.16 Sensitivity of PCR has been reported at 27% for neonates 0-4 days old, 55% for those at 0-15 days, and nearly 98% at 16-90 days.18 It has been postulated that viral levels are much higher in neonates who acquire HIV during pregnancy (intrauterine) compared to those who acquire the disease during delivery (intrapartum).19 This may explain why PCR detects a subset of cases in neonates (intrauterine infection) but fails to detect most cases of HIV (intrapartum acquisition) within the first few days of delivery.19 HIV viral blood culture is a technically difficult and expensive test (~$500) with greater than 95% sensitivity for detecting HIV in infants older than 1 month. The p24 antigen tests are performed via an ELISA technique.20 This technique has less sensitivity (~70% sensitivity at 3 months) compared to other tests, while specificity approaches 95%.20 In general, demonstration of IgG antibody via ELISA and a confirmatory test (Western blot) establishes the diagnosis of HIV in any child older than 18 months.16 Under 18 months, at least two confirmatory assays (any combination of HIV culture, PCR, or p24 antigen) for the presence of HIV are required before a definitive diagnosis can be made.16 (See Figure 3.)
Early retrospective studies of pediatric HIV painted a bleak picture since they often concentrated on children who were diagnosed early in their disease course and had a rapid clinical deterioration.21 More recent prospective longitudinal studies have shown that HIV presents in a bimodal pattern, with 20-30% developing severe immune deficiency and AIDS-defining illness (clinical Category C) before age 1 year while most children have a slowly progressive course, with a greater than five-year survival.1 Those who are very young (< 6-12 months) and those who are greater than 5 years have mortality rates that are 1.5-2.0 times higher than children aged 1-5 years.22 Currently, it is believed that many infants with early clinical deterioration acquired HIV during pregnancy, allowing the virus to attack an immature immune system and therefore causing a more profound immune deficiency.19 Increases in mortality after age 5 are primarily associated with a progressive decline in the immune system.22,23
Common presentations of HIV in infants include failure to thrive, recurrent bacteremia and bacterial infections, generalized lymphadenopathy, and progressive neurologic decline with failure to attain normal neurologic and developmental milestones.1 Failure to thrive occurs from chronic infections, malabsorption, chronic diarrhea, increased nutritional requirements, and overall poor nutrition.24 Encephalopathy is another common presenting feature of HIV, resulting in developmental delay or loss of milestones.25 HIV directly invades and destroys cells within the central nervous system, while damage may also occur from opportunistic infection, malnutrition, and the effects of toxins.25
While HIV causes a progressive decline in T cell lines, immunoglobulin levels are often elevated early in the disease.26 However, these immunoglobulins are often dysfunctional, and children are unable to mount a prolonged antigen antibody response to bacterial infections.26 For this reason, recurrent bacterial infections, often with the same agent, are frequently seen in HIV. Recurrent bacteremia, pneumonia, otitis media, and sinusitis due to the usual pathogens seen in normal children are the most common bacterial infections in children with HIV.1,27 Therefore, initial empiric therapy for simple bacterial infections (e.g., otitis media, sinusitis, cellulitis, and bacterial pneumonia) should parallel treatment used in immunocompetent children. In children with CD4 counts greater than 200 cells/mm3, IV immunoglobulin has been shown to significantly reduce the incidence of serious bacterial infections, the rate of deterioration of CD4 counts, and total days of hospitalization for infections, although no effect on mortality has been noted.1,28 A double-blind, placebo-controlled study in symptomatic HIV-infected children found that the benefits of IV immunoglobulin (IVIG) were not greater than standard AZT with PCP prophylaxis with TMP/SMX.28 Accepted indications for IVIG treatment in pediatric HIV include: 1) recurrent, invasive bacterial disease (especially with encapsulated organisms); 2) HIV-related hypogammaglobulinemia; 3) bronchiectasis; 4) documented inability to produce protective antibody to important immunizations (e.g., measles, Hib); and 5) HIV-related ITP.1,26
Pinkert et al detailed the presenting features of children with known and unsuspected HIV who presented to one pediatric emergency department.29 Fever was the most common presenting complaint (50%), followed by respiratory symptoms (21%), and GI symptoms (8%). Importantly, many children were not receiving appropriate outpatient treatment, as 87% with known HIV had CD4 counts below thresholds for PCP prophylaxis, and 52% were not receiving any therapy.21 The majority of children had an acute infection, with 33% described as serious. Eight of 92 children had positive blood cultures for S. pneumoniae (3), S. faecalis (2), E. coli (1), Torulopsis glabrata (1), and Staphylococcus species (1possibly a skin contaminant). Half of the positive blood cultures were in children with temperatures below 38°C, although three-quarters had central lines with a history of a fever. Importantly, a white blood count was useless in discriminating between children with and without bacteremia.29 Thus, clinicians must diligently search for bacterial infections in all HIV-positive children who present with a history of fever, regardless of the presenting temperature or white blood cell (WBC) count. Empiric antibiotic therapy should be considered for all of these patients (especially those with central lines). Only children who are well-appearing, with no obvious infection or only minor infection, should be considered for outpatient therapy with closely coordinated follow-up.
For the foreseeable future, many infants and children will be undiagnosed until symptoms related to HIV infection develop. Persaud found that 18% of HIV-infected children cared for at one children’s hospital were not diagnosed until they were 4 years old or older.30 Diagnoses that eventually prompted consideration of HIV in these children included recurrent bacterial infections in 31%, hematological disorders (e.g., ITP, neutropenia, anemia) in 16%, PCP in 9%, followed by developmental delay, recurrent skin conditions, weight loss, malignancy, and nephropathy.30 This study’s findings underscore the need for physicians to consider the diagnosis of HIV in many children who present with rare or unusual complaints.
While a subset of infants and young children may present with frequent bacterial infections and rapid progression of disease, most children with HIV manifest a more gradual onset of disease, with predominant findings within the reticuloendothelial system (e.g., generalized lymphadenopathy, parotitis, lymphoid interstitial pneumonia, and hepatosplenomegaly).1,2 Children who present with these disorders have a better prognosis and a longer survival compared to infants with onset of disease in the first year of life.1,2
Complications and Natural Progression of HI
While infants and children with HIV are at risk for developing a wide array of bacterial, viral, fungal, and parasitic infections, some diseases are almost ubiquitous in this population. The most common opportunistic infections reported in children with AIDS include Pneumocystis carinii pneumonia, recurrent bacterial infections, candidiasis, cytomegalovirus (CMV) disease, and Mycobacterium avium-intracellulare complex (MAC).31 (See Table 4.) The absolute CD4 lymphocyte count appears to be an important predictor of the risk of specific infections. HIV-infected children with a CD4 count less than 200 cells/mm3 are six times more likely than those with a count greater than 200 cells/mm3 to develop opportunistic infections, three times more likely to develop serious bacterial infections, twice as likely to develop viral infections, and slightly more prone to developing minor bacterial infections. The risk of acquiring PCP rises dramatically at CD4 levels less than 200 cells/mm3, while CMV and MAC infections become more common at CD4 levels less than 50 cells/mm3.1,32 Furthermore, after an individual develops an opportunistic infection, they may never be completely cured, and that infection may resurface as immunodeficiency worsens.33
Pulmonary Disease. Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection in infants and children who are HIV-positive and may be the first presenting infection.33,34 Of infants and children with HIV, 43-53% will acquire PCP.31,34,35 Compared to adults, this is a much more virulent disease, with mortality from a first infection near 50%, rising to nearly 100% for subsequent episodes.2,31 Early studies found that infants less than 1 year old have a more virulent course (with a 30% one-year survival) after acquiring PCP compared to older infants and children, who have a 48% one-year survival following PCP.2 While recent improvements in management have decreased mortality, PCP is still an extremely lethal disease. Clinicians must be aware of the typical and atypical presentations of this disorder, key diagnostic features, and appropriate management.
The most common symptoms of PCP are nonproductive cough, fever and dyspnea with a gradual or explosive onset.36 Most cases occur in infants 18 months or younger with rapidly progressive immunosuppression.34 In contrast to adults, a depressed CD4 count is not required for development of PCP. In fact, 10% of infants with PCP have CD4 counts above 1500 cells/mm3.31,37 Typically, fever is present, bilateral rales are heard, and tachypnea is prominent. Infants and children are hypoxic, with a markedly elevated A-a gradient averaging 60-80 mmHg. (A-a gradient at sea level = 150 - [PaO2 + PCO2/0.8], with normal A-a gradient < 10-15).34 Chest radiography may initially appear normal; abnormal blood gas findings can be the only clue to the presence of PCP.36 As the infection progresses, bilateral perihilar and interstitial infiltrates develop.38 Advanced disease leads to a ground-glass appearance to the lung fields.38 PCP may cause subpleural cavities and emphysematous blebs, predisposing patients to recurrent air leaks (e.g., pneumothorax, bronchopulmonary fistulas) that can be extremely difficult to manage.39 Differentiating PCP from other pulmonary infections (e.g., viral pneumonia and tuberculosis) can be difficult. One clue is an elevated LDH, averaging 780-795 U/L in children with PCP.34 Children who are old enough to cooperate can have induced sputum sent for PCP prep. However, definitive diagnosis may require bronchoscopy with bronchoalveolar lavage or tracheal aspirate.36
Due to the high rates of respiratory failure, pulmonary complications, and mortality, admission is mandatory for infants and children with PCP.1,15 Treatment consists of IV TMP/SMX (20 mg/kg/d divided qid), supportive respiratory care, and close monitoring for respiratory failure.31 TMP/SMX allergy is a common problem seen in children with HIV, with rates that surpass those seen in the normal population. Many centers routinely desensitize patients to TMP/SMX if they are allergic. Trimetrexate with leucovorin rescue is often used in patients not responding to TMP/SMX. Pentamidine is an alternative also used for nonresponders.31 Recently, steroid therapy (either IV methylprednisolone or prednisone 1 mg/kg/d for 5 days followed by 0.5 mg/kg/d for 5 days) was shown to reduce the need for mechanical ventilation (from 64% to 24%) and the mortality rate (from 30% to 0%) in children with PCP.34 Due to its dramatic effects on outcome, steroid therapy should be considered the standard of care for children with PCP.
Prophylaxis for PCP with oral TMP/SMX has been show to decrease the development of PCP by 75% and mortality by 67% in infants and children at risk.37,40Alternatives include dapsone and aerosolized pentamidine.40 The CDC recommends prophylaxis for all HIV-positive infants younger than 12 months since the predictive value of the CD4 count is unreliable at this age.37,41 Over 12 months, prophylaxis is recommended for severe immunosuppression (see Table 2), all children with prior episodes of PCP, most children with rapidly declining CD4 counts or percentage, or severely symptomatic HIV disease (Category C).33 (See Table 3.)
Lymphoid interstitial pneumonia (LIP) is the most common pulmonary disorder that must be differentiated from PCP. In contrast to PCP, LIP is a chronic disorder that occurs in older children with a less virulent HIV disease course.1 While the exact cause of LIP is unproven, some evidence links this pneumonia to an atypical pulmonary response to the Epstein-Barr virus.1 LIP is associated with nodular lymphoid hyperplasia in the bronchi and bronchiolar epithelium that causes alveolar capillary block. A diffuse reticulonodular pattern is seen on chest radiography, often before symptoms are noted.1 Gradual onset of tachypnea, cough, hypoxia, normal auscultatory findings or minimal rales, digital clubbing, and improvement with oral corticosteroids are typical of this disorder.1
Many other causes of pneumonia occur in children with HIV. Bacterial pneumonia due to typical pathogens (e.g., S. pneumoniae) is frequent in children, while gram-negative bacteria (e.g., Pseudomonas aeruginosa) are often associated with terminal respiratory disease, respiratory failure, and death.1 Other pathogens causing respiratory disease include MAC, CMV, tuberculosis, Aspergillus, Cryptococcus, Histoplasma, RSV, parainfluenza, influenza, adenovirus, and lymphoma.1
Radiographic differentiation between various causes of pulmonary disease can be extremely difficult in HIV-infected children. A review of chest x-ray findings in PCP found that diffuse infiltrates were noted in 53%, patchy infiltrates in 32%, focal infiltrates in 10%, while 5% had normal radiographs.38 A recent study of thin-section low-dose chest CT in children with HIV-associated respiratory disorders found that ground-glass haziness was seen exclusively with PCP, reticulonodular thickening only with LIP, while adenopathy was noted in those with lymphoma, MAC, or M. tuberculosis.42
In general, all HIV-infected children with new lower-tract respiratory infections require hospital admission, appropriate diagnostic measures, aggressive therapy tailored toward preventing respiratory failure, and antimicrobials effective against the specific organism causing symptoms. Failure to improve with initial therapy should prompt a search for a second infectious agent, as coexisting pathogens exist in 10-20% of HIV-infected children with pneumonia.38,43
Cardiac Disease. Nearly 20% of HIV-infected infants and children will develop congestive heart failure or cardiomyopathy.44 The causes of cardiomyopathy in HIV are varied and include direct toxic effect of HIV, viral infection, malnutrition (especially selenium), pulmonary insufficiency, anemia, and medications.1 A recent study found that children receiving zidovudine had an 8.4-fold greater risk of developing cardiomyopathy compared to those receiving didanosine.45 Zidovudine may directly inhibit cardiac mitochondrial DNA chain replication.45 All children with cardiac or unexplained pulmonary deterioration should be considered for echocardiography. Serial cardiac examination and echocardiography should also be performed on all children receiving zidovudine.45
Pericardial effusion, while common in pediatric HIV, is generally non-purulent, nonfibrinous, and usually asymptomatic.
Neurologic Symptoms in HIV. HIV can directly damage several neuronal cell types. Many cells within the central nervous system have CD4 receptors that are recognized by HIV-1. This leads to direct cell infection with eventual damage. Indirect effects from toxins produced by HIV, cytokines, malnutrition, and central nervous system infection also play a role in damaging the developing neurologic system in HIV-infected children.46
Developmental delay with an early and persistent delay in motor development and deceleration in mental development in late infancy is typical of HIV infection and may be the initial manifestation of disease.38 In fact, progressive encephalopathy is the most common neurological finding in HIV, occurring in 50-65% of infected children.47,48 Impaired postnatal brain growth, cerebral atrophy, secondary microcephaly, and arrest or loss of developmental milestones in infancy are common manifestations.46,48 Among older infected children and adolescents, short-term memory loss, hand tremors, slowing in fine motor skills, attention difficulties, apathy, depression, and emotional lability may predominate.46,47
Corticospinal deterioration occurs with weakness and initial hypotonia, progressing to spasticity, tremor, ataxia, gait disturbances, and, less commonly, rigidity and extrapyramidal signs.47 At autopsy, myelin or axonal damage of the corticospinal tracts is found in up to 65% of children.47
While gradual developmental decline and corticospinal deterioration are common in HIV, acute neurological decompensation (e.g., seizure or altered mentation) may be a harbinger of a life-threatening disorder. The list of diseases causing neurological decompensation in HIV is extensive. Hypoglycemia and hypoxia should be ruled out immediately in these patients, followed by a search for other serious infectious and metabolic disorders. After initial resuscitation, cranial computerized tomography (with contrast) or magnetic resonance imaging should be performed to rule out mass lesions (e.g., abscesses, lymphoma, or bleeding due to thrombocytopenia). Classic head CT findings in pediatric HIV are cerebral atrophy with or without calcifications of the basal ganglia.25,46,47 Importantly, chronic progressive disorders, medication-related complications, and many infectious disorders initially will not manifest abnormal CT findings. Lumbar puncture with routine CSF analysis for common bacterial pathogens, in addition to common opportunistic infections (see Table 5), should be performed if cranial CT is normal. Finally, cerebrovascular disease must be considered if initial evaluation is negative. Direct damage of the cerebrovascular wall is found in 25% of children with HIV at autopsy.46 This can lead to acute stroke, occurring in ~1.3% of HIV-infected children per year.46
Gastrointestinal Disorders. Gastrointestinal symptoms are prominent in infants and children with HIV. Chronic diarrhea, dysphagia, vomiting, and pharyngitis can lead to malnutrition, inhibit prophylaxis and treatment of infectious disorders, and contribute to new infections. HIV-related disorders can affect any site within the gastrointestinal system. Identification and treatment of such disorders may allow for prolonged symptom-free periods, improved nutrition, and increased ability to fight and treat other serious infections.
The esophagus is commonly involved in HIV infection. Odynophagia and dysphagia occur following infection with Candida, herpes simplex virus, and CMV. Mucosal candidiasis is common in advanced disease, occurring in up to 70% of all HIV-positive children.48 Candidal esophagitis causes discrete linear or irregular filling defects that tend to be longitudinally oriented with a shaggy or cobblestone appearance on barium swallow.49,50 Thrush is not always present.49 Treatment with nystatin is ineffective; either fluconazole or ketoconazole is necessary.49,50 If the patient does not improve, amphotericin B is used. CMV infects the endothelial cells of the capillaries of the enteric mucosa, causing a vasculitis and inflammation that is often limited to the distal esophagus, while HSV-1 causes numerous shallow discrete ulcers at the midesophagus or near the left main bronchus with sparing of the rest of the esophagus.49 Other disorders that affect the mediastinum (e.g., lymphoma or tuberculosis) can directly compress the esophagus or predispose to fistula or sinus tract formation.50 Due to the wide array of disorders causing dysphagia and odynophagia, clinicians should consider radiographic evaluation for all children without classic features of candidal disease (e.g., thrush) and all who do not respond to initial therapy.
The stomach is relatively resistant to opportunistic infection compared to other areas of the GI tract. CMV is the most common organism, with contiguous involvement from a distal esophagus site, GE junction involvement, or involvement of the gastric fundus.49 CMV may cause clinical and radiographic findings of hypertrophic pyloric stenosis with muscular wall thickening and prepyloric antral narrowing.49 Biopsy confirms the diagnosis.49 HIV-related neoplasms (most commonly non-Hodgkin’s lymphoma and Kaposi’s sarcoma) also affect the stomach.49
Recurrent, chronic, and acute diarrhea occurs in 40% of HIV-positive children and is the leading cause of death from HIV in Africa and developing nations.32,49,50 Causes of diarrhea are varied and include infections, medications, and mucosal injury from malnutrition.32 (See Table 6.) No pathogen or cause can be identified in a significant number of cases.32
Common bacterial infections account for a large number of cases of diarrhea. Typical features include fever and bloody or heme-positive stool. Development of bacteremia is common in bacterial diarrhea, with almost half of bacteria isolated from the blood of HIV-infected children identified as enteric pathogens.32 For this reason, parenteral antibiotic therapy should be considered for most HIV-infected children with fever and presumed bacterial diarrhea. MAC causes infection involving the bone marrow, lungs, liver, mesenteric lymph nodes, and the GI tract.32 MAC typically occurs late in HIV infection, when CD4 counts fall below 50 cells/mm3.32 No effective therapy for MAC infection is available at present, although azithromycin, clarithromycin, ethambutol, ciprofloxacin, amikacin, and rifampin have been used individually with variable success.32 MAC prophylaxis with rifabutin is recommended for children with CD4 counts less than 75 cells/mcL.15
Common parasitic infections include Giardia and Cryptosporidium. Giardia causes a watery diarrhea, bloating, and abdominal pain.32 Diagnosis is confirmed by stool analysis for ova and parasite or duodenal aspirate.32 Treatment consists of metronidazole or furazolidone.32 Cryptosporidium causes a chronic secretory diarrhea that can be debilitating and severely compromise a child’s nutritional status.32 Cryptosporidium infects the small and large intestines, as well as the mucosa of the gallbladder, bile ducts, and pancreatic duct, resulting in cholangitis and pancreatitis.32 Typically, serum alkaline phosphatase is elevated when the bile ducts are involved. There is no effective therapy for Cryptosporidium infections, although long-term azithromycin has been used with minimal success. Trials with paromycin, petrazuril, atovaquone, and bovine anti-Cryptosporidium immunoglobulin are underway in adults.31
Rotavirus is the most common cause of viral enteritis in HIV-infected children, although adenovirus, CMV, herpes simplex, astrovirus, picornavirus, and calcivirus have been identified. In contrast to immunocompetent children, rotavirus causes a chronic diarrhea that may become disseminated and involve other organs, most notably the liver. Treatment is generally supportive, although enterally administered serum immunoglobulin can be effective. Adenovirus may result in fulminant hepatitis, GI bleeding, and may occur as part of a disseminated adenovirus infection affecting the lungs, bone marrow, heart, and brain. Ribavirin and serum immunoglobulin may be therapeutic. CMV is a common cause of ulcerative lesions anywhere along the GI tract, and treatment consists of ganciclovir or foscarnet.32
In general, initial diagnostic evaluation for diarrhea should include stool studies for WBC, blood, and possibly rotavirus. Obtain C. difficile toxin if any blood or WBC is found (especially if the patient is on antibiotics). Send stool for ova and parasite and consider colonoscopy with intestinal biopsy if no readily identifiable cause is found. Treatment of dehydration and electrolyte disorders is essential, as are antimicrobials directed against identified pathogens.
Pancreas and liver involvement are common during opportunistic infections. Many organisms (hepatitis B, CMV, HSV, MAC, PCP, fungi, granulomatous disease) and drugs can cause hepatic inflammation and cholestasis.32 Pancreatitis can occur from direct infection (e.g., CMV) or typically from medications (especially pentamidine and didanosine).32 Pancreatitis occurs in up to 17% of patients and portends a poor prognosis.51
Colitis and proctitis manifest as hematochezia, mucous stools, abdominal pain, and fever in children with HIV. Prominent organisms that cause colitis include Shigella, Salmonella, and CMV. CMV has been blamed for the most severe complications in children, including typhilitis, pneumatosis, toxic megacolon, ischemia, and perforation. If these complications are suspected, early surgical consultation should be obtained. CT findings in CMV colitis include bowel wall thickening, distortion and ulceration of the mucosal surface, and pericolic inflammation (especially around the cecum). CMV colitis has been successfully treated with IV ganciclovir.50
Malignancy. Malignancies are uncommon in children with HIV. They represent 1.7% of HIV-defining illnesses in children.52 The most common malignancies include Burkitt’s lymphoma, immunoblastic lymphoma, non-Hodgkin’s lymphoma, and primary CNS lymphoma.52 In contrast to adults, Kaposi’s sarcoma is rare in children, with only 25 cases reported prior to 1996.52 However, when Kaposi’s sarcoma occurs in children, skin manifestations are rare, occurring in only 12%.53 The primary sites of development include the lymphatic and GI system.52
Other Manifestations of HIV. Dental infections and poor oral hygiene are common in HIV. Studies of children referred to ENT specialists and dentists have identified multiple caries in 60%, oral candidiasis in 70%, sialadenitis in 15%, while a significant number of children have parotid gland enlargement, parotitis, gingivostomatitis, aphthous ulcers, herpes labialis, and leukoplakia.48,54 Severe apthous stomatitis often requires topical steroid (e.g., dexamethasone swish and spit-out or fluoro-steroid in orabase) or even systemic steroids (prednisone). Identification and treatment of oral disorders is essential to keep children from becoming malnourished.
Dermatologic disorders in children with HIV tend to be severe and less responsive to traditional therapy. The occurrence of many skin disorders correlates with CD4 cell counts. Viral diseases are prone to dissemination. Measles is of particular concern, as there have been a significant number of deaths from giant cell pneumonia in these children. The illness may be associated with the characteristic clinical signs and symptoms of generalized rash, coryza, conjunctivitis, cough, and Koplik spots or may frequently occur without the typical rash. Administer gamma globulin to all HIV-positive children exposed to measles whether or not they have been vaccinated.15 Varicella also can cause severe illness in the immunocompromised host. Therefore, administer varicella immune globulin within 96 hours to all HIV-positive children exposed to varicella; once illness begins, all patients need IV acyclovir.15 If herpes zoster occurs, oral acyclovir may be used if children are not ill-appearing.15
Gram-positive skin infections commonly encountered include ecthyma, cellulitis, erysipelas, furunculosis, folliculitis, and impetigo. The most frequently identified organism is S. aureus. Bacillary angiomatosis, a cutaneous vascular disorder caused by rickettsial-like organisms Bartonella helensii and Bartonella quintani, causes pinpoint papules that grow to become several centimeters in diameter. Although this disorder is less common in children compared to adults, it can be deadly with involvement of viscera.53
AIDS nephropathy occurs primarily in older symptomatic children and may result from a direct effect of HIV on renal epithelial cells.1 Asymptomatic proteinuria and renal salt wasting are common in pediatric HIV. A wide range of renal disorders, including nephrotic syndrome, focal glomerulosclerosis, mesangial hyperplasia, and segmental necrotizing glomerulonephritis, have also been reported in HIV-infected children.1 Prior to administration of potentially nephrotoxic agents, renal function studies are mandatory.
Ocular disorders and blindness (especially due to CMV) are less common in children with HIV compared to adults.1 It is expected that as children survive longer with HIV, many uncommon and previously unreported diseases may occur that will necessitate development of new treatment strategies.
Infants and children with perinatally acquired HIV are usually cared for by ill parents or caretakers who also harbor the virus. Caretakers often do not have the health, financial ability, or community support to adequately ensure that their child is receiving appropriate ongoing care. In one study, only 48% of HIV-positive children who presented to a large urban pediatric emergency department were receiving adequate prophylaxis for PCP.21 When seeing HIV-positive children with minor or unrelated illness, clinicians can make a significant impact by reviewing the records for recent CD4 counts and medication lists and ensuring that infants and children with HIV are receiving appropriate treatment. Involvement of social service personnel and closely coordinated follow-up will ensure that children receive appropriate nutrition, medication, and social support so that they may lead a longer, healthier life.
Health care workers are at risk for acquiring HIV in the workplace. A recent study of health care workers who acquired HIV at work found that blood from needlesticks accounted for 94% of exposures, while 6% involved other sharp objects. Importantly, only a handful of cases of HIV have ever been reported from urine or feces. Transmission via saliva (which contains < 1 particle/mL) has not been reported. Risk factors for transmission of HIV include: 1) a device visibly contaminated with the patient’s blood; 2) a procedure that involved a needle placed directly in a vein or artery; 3) a deep puncture or wound to the health care worker regardless of visible blood; and 4) a terminal illness in the source patient.55 Treatment with zidovudine reduced the rate of transmission of HIV by 79%.55 Based on this study, in June 1996, the CDC published recommendations for treating health care workers after occupational exposure to HIV.55,56 (See Table 7.)
The pharmacopoeia of medications used to treat HIV infection is continuously expanding. Importantly, therapies that are intended to prevent or treat disease and prolong life have important side effects that may contribute to clinical deterioration in infants and children with HIV. Many therapies adversely affect bone marrow, leading to anemia, neutropenia, or thrombocytopenia. Other common side effects are GI related (vomiting, diarrhea, hepatitis, or pancreatitis). All HIV patients seen by primary care physicians should have their medication lists examined to ensure that symptoms are not related to therapy.57 (See Table 8.)
As the population of children with HIV expands and improvements in therapy occur, the chance that clinicians who care for children will be confronted with this disease will also grow. The range of complaints and disorders that may prompt an HIV-infected infant or child to visit his or her physician is broad and can include abnormalities of almost every organ system. With the exception of infectious disease specialists, most clinicians cannot be knowledgeable about every complication of HIV infection in children. To ensure the best outcome, however, clinicians must have an understanding of common and life-threatening complications that occur in this population. Prompt diagnosis and treatment of life-threatening complications, a cautious, conservative approach to management, close coordination with other physicians who treat th epatient, and attention to details such as nutrition and each child’s social situation will ensure the best outcome for HIV-infected children. Finally, every effort should be made to identify HIV infection in pregnant women so that therapies to prevent vertical transmission can be offered.
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Physician CME Questions
32. Which of the following confirms the diagnosis of HIV in a 12-month-old infant?
a. Two consecutive positive IgG tests (ELISA or Western blot)
b. A positive IgM antibody assay
c. A positive IgG test in the mother
d. Two positive tests consisting of either polymerase chain reaction, HIV culture, or p24 antigen assay.
33. Which of the following is true concerning bacteremia in infants with HIV?
a. Encapsulated organisms (e.g., S. pneumoniae and H. influenzae type b) are common pathogens.
b. Fever is an unreliable sign of bacteremia.
c. Salmonella gastroenteritis frequently leads to bacteremia.
d. All of the above
34. Side effects of zidovudine (AZT) therapy include:
a. anemia, leukopenia, and thrombocytopenia.
b. hepatitis.
c. cardiomyopathy
d. all of the above
17. Chest radiographs in Pneumocystis carinii pneumonia typically reveal:
A. lobar infiltrates.
B. hilar lymphadenopathy.
C. bilateral interstitial infiltrates.
D. pleural effusions.
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