CLINICAL

IMAGING

1992;16:145-151

145

REVIEW

HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN CHILDREN

JEFFREY

J. LARKIN,

MD

The incidence of Acquired Immune Deficiency Syndrome (AIDSJ in the pediatric population is increasing. Estimates are that in 1993 AIDS will be among the five leading causes of death in children. AIDS progresses more rapidly in children than in adults. It also has features that are unique to children, such as recurrent bacterial infections, bronchus-associated lymphoid tissue (BALT), and basal ganglia calcification. This review is written with emphasis on aspects of AIDS unique to children. Features of AIDS that are similar in adults are not discussed. KEY

WORDS:

Pediatric AIDS; Bronchus-associated lymphoid tissue (BALT); Lymphadenopathy syndrome; Basal ganglia calcification; Kaposi’s sarcoma INTRODUCTION In 1986 Pediatric AIDS (PAIDS) accounted for 1.5% of the total number of AIDS cases in the United States, and the prevalence is increasing (1). The first cases in children were observed between 1979 and 1983. By 1987 the Center for Disease Control (CDC) had reported 450 cases of AIDS in children under 13 years of age (2). Such estimates represent only 20% of children with symptomatic HIV (human immunodeficiency virus) infection. Estimates are that in 1993 AIDS will be among the five leading causes of death in that same age group.

From the Department of Radiology, SUNY Health Science Center at Syracuse, Syracuse, New York. Address reprint requests to: David A. Dowe, MD, Clinical Assistant Instructor, Chief Resident, Department of Radiology, SUNY Health Science Center at Syracuse, Syracuse, NY 13210. Received May 1991; accepted November 1991. 0 1992 by Elsevier Science Publishing Co., Inc. 655

Avenue

of the Americas,

0899-7071/92/$5.00

New

York,

NY

10010

A drug-addicted mother or a mother who is a consort of a drug-addicted or bisexual father is the source of 70% of the cases reported (3). About 13%-20% of cases are a result of the patient being a recipient of an HIV-infected blood product (2, 3). Adolescents acquiring the infection from adult types of behavior account for 10% of the cases. In the remaining cases, the risk factors are unknown (2). The average interval between infection and the manifestation of AIDS symptoms is shorter in children than in adults (4). This more aggressive course results from the development of the disease at a time of immunologic immaturity (5). Repeated infections in utero with various strains of the HIV virus, and the smaller mass of immuno-competent cells relative to the size of the viral inoculum are also significant factors (5). These factors also contribute to the disparity in the radiologic manifestations of the disease in children and adults. This review will emphasize aspects of AIDS that are unique to children. Features of pediatric aids that are similar in adults, such as pneumocystis pneumonia, will not be discussed. RECtrRRENT

BACTERIAL INFECTION

When an adult is infected with the HIV virus, the memory cells of his immune system are resistant to the attack of the virus. Therefore, even though adult patients succumb to a variety of opportunistic infections and neoplasms, they remain immunocompetent to common bacterial pathogens to which they have been previously exposed (4). When an infant or child is infected with the HIV virus, they usually have not yet been exposed to the antigens of common pathogens and, therefore, have not formed memory cells. As a result, children with AIDS often present with recurrent bacterial infections secondary to common pathogens. These infections usually occur within the

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first 3 years of age and commonly precede opportunistic infections. Eighty percent of pediatric AIDS patients will have serous otitis media, acute otitis media, or chronic otitis media with an effusion (6). Cholesteatoma formation is rare. Common causative organisms include staphylococcus aureus, streptococcus pneumoniae, pseudomonas aeruginosa, or candida albicans (6). Sinusitis caused by pseudomonas aeruginosa or opportunistic organisms such as pneuymocystis carinii has been reported (7). Bacterial pneumonia, urinary tract infection, meningitis, osteomyelitis, and septic arthritis have also been known to occur in pediatric AIDS patients (1). In one study, sepsis occurring without an identifiable cause was the most common presentation of bacterial infection followed closely by urinary tract infection and bacterial pneumonia. Salmonella enteritis may be associated with severe bacteremia and may relapse despite adequate treatment (8).

MANIFESTATIONS

IN THE THORAX

Bronchus-Associated

Lymphoid

Tissue

In the normal child, large quantities of lymphoid tissue are present in the lungs in the form of welldeveloped lymphoid aggregates located predominately in the proximal airways. Bronchus-associated lymphoid tissue (BALT) is characterized by wellorganized placques of lymphoid tissue localized to the submucosa of the bronchial tree (9). This condition is not seen in adult AIDS patients. It is believed to develop secondary to antigenic stimulation of the normal infantile pulmonary lymphoid tissue, perhaps by viral infection (12). The agent most commonly implicated is the Epstein-Barr virus (10). Histologically, BALT is considered to be a lymphoproliferative disorder or lymphoid--associated disorder at the benign end of a spectrum of disease that includes lymphoid interstitial pneumonia, aggressive lymphoma, and immunoblastic lymphoma at its malignant end. Radiographically, BALT usually presents a fine miliary pattern while lymphocytic pneumonia is more reticulonodular; however, authors are quick to point out that these entities are often indistinguishable (11)(Figure 1).

Lymphoid

Interstitial

Pneumonia

Lymphoid interstitial pneumonia [LIP) is the second most common pulmonary manifestation of pediatric AIDS following pneumocystis carinii pneumonia.

FIGURE 1. Bronchus-associated lymphoid tissue. A diffuse, fine miliary pattern is characteristic of this condition, but it is often indistinguishable from lymphoid interstitial pneumonia.

LIP occurs more frequently in children with AIDS than in adults with the disease. The sequence of infection with the HIV and Epstein-Barr viruses is believed to explain this difference in prevalence. In adults, the Epstein-Barr virus is contracted long before the patient acquires the human immunovirus. In infants and children, HIV infection, which is often contracted in utero, precedes infection with the Epstein-Barr virus. It is believed that the Epstein-Barr virus triggers the hyperplasia of the pulmonary lymphoid tissue previously exposed to the human immunovirus, resulting in LIP. LIP rarely coexists with an opportunistic infection but may be difficult to distinguish clinically from pneumocystis carinii pneumonia. Patients with LIP frequently have a positive serology for the Epstein-Barr virus, as well as a marked polyclonal hypergammaglobulinemia. As opposed to pneumocystis pneumonia, which has been associated with elevated serum LDH levels, the LDH level in LIP is usually normal (8). It usually affects older children than does pneumocystis pneumonia. LIP has an insidious onset with a slow progressive course. Coughing, digital clubbing secondary to chronic hypoxia, salivary gland enlargement, and generalized lymphadenopathy are frequently

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ents as an interstitial infiltrate with lower zone predominance. It is less nodular than LIP associated with pediatric AIDS, and there is an absence of hilar or mediastinal adenopathy in these older patients.

Mycobacterium

FIGURE 2. Lymphoid interstitial pneumonia. The course, nodular pattern appearing as an alveolar infiltrate in some areas is typical for advanced LIP.

Avium Intracellulare

Infection

Mycobacterium avium intracellulare (MAI) occurs in 8% of pediatric AIDS patients younger than 3 years of age. This prevalence is lower than is seen in adults (2). In children, it may be associated with severe malabsorption and a protein-losing enteropathy (8). Diffuse lymphadenitis and disseminated disease are frequent clinical associations (I 3). Pathologically, caseating granulomas and giant cell reaction are less often seen than with mycobacterium tuberculosis infections (8). Chest radiographs in pediatric AIDS patients infected with MA1 present a nonspecific nodular or alveolar infiltrate. A miliary pattern has not yet been described (9). Areas of lobar collapse as well as hilar and mediastinal adenopathy are known to occur. The chest x-ray may be normal, yet the patient may still have positive sputum smear or culture with disseminated disease (13). MANIFESTATIONS IN THE GASTROINTESTINAL TRACT

seen in LIP (8). Common clinical features seen in pneumocystis pneumonia such as tachypnea, chest wall retraction, fever, diminished breath sounds, wheezing, and rhonchi are much less common in LIP. Pathologic examination reveals lymphocytes, plasma cells, and immunoblasts diffusely infiltrating alveolar septae and peribronchial walls. Lymphoid nodules with or without germinal centers as well as multinucleated giant cells are also seen (2). Radiographically, LIP results in a reticular interstitial infiltrate that later becomes course and nodular; nodules have been reported to be 0.5 mm-2 mm in size (8). Patchy alveolar infiltrates may develop. Mediastinal and hilar adenopathy are common, but pleural effusions are uncommon (Figure 2) (11). Frequently, radiographic findings are more marked than the clinical findings (2). LIP associated with pediatric AIDS differs from the classic LIP described by Carrington and Liebow in 1966 (12). Classic LIP is a rare idiopathic disease of middle-aged females. Many observers consider it to be a low-grade lymphoma. It probably occurs secondary to abnormal immunoregulation and is rarely associated with T-cell abnormalities. In adults it is associated with systemic diseases such as Sjogren’s syndrome, monoclonal gammopathies, and autoimmune hemolytic anemia. Radiographically, it pres-

The Lymphadenopathy

Syndrome

Abdominal and retroperitoneal adenopathy is often the first sign of pediatric AIDS (8). Periaortic, mesenteric, pericaval, and portahepatis lymph nodes are the most commonly involved groups. This may be the only clinical manifestation of AIDS, but usually there is associated hepatosplenomegaly or constitutional symptoms (2). The “lymphadenopathy syndrome” is diagnosed if two noncontiguous sites of lymph-node enlargement persist for 3 or more months in the absence of an identifiable cause (4). Commonly, the adenopathy is generalized. The lymphadenopathy syndrome is usually virally induced, but may be secondary to mycobacterium avium intracellulare (9). Infection can result from hematogenous dissemination, direct extension from a contiguous focus, or from lymphogenous spread (9). The MA1 organism frequently is found coexisting in the liver, lung, bone, and bone marrow, as well as in the blood (9). Nodal enlargement is usually easily diagnosed by ultrasonography (Figure 3A). The involved lymph nodes are often uniformly hyperechoic but may be hypoechoic. The “sandwich sign” results from compression of the celiac axis or the superior mesenteric artery by large bulky adenopathy (9) (Figure 3B).

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considered the structural analog of BALT. Radiographs are usually normal. Cryptosporidiosis, an opportunistic GI-tract infection, is seen less commonly than it is in adults. It presents as chronic, watery diarrhea without blood or mucus (14). Radiographically, this condition shows separated tubular small bowel loops lacking mucosal architecture. It resembles graft versus host disease (15). Pneumatosis intestinalis has been associated with pneumocystic pneumonia in one case. Leukemia and steroid therapy have also been associated with pneumatosis intestinalis (9); the underlying mechanism is unknown. Burkitt’s and other gastrointestinal lymphomas are rare in children with AIDS.

MANIFESTATIONS IN THE CENTRAL NERVOUS SYSTEM

Encephalopathy

FIGURE 3.

The lymphadenopathy syndrome. (A) Multiple enlarged, slightly hyperechoic lymph nodes (t) are compressing the mesenteric vessels. (B) Bulky adenopathy once again compressing the mesenteric artery ( t ) and vein ( ft ) on this intravenous contrast-enhanced CT image. Reprinted with permission from Amodio J, Abramson S, Berdon WE, Levy J. Pediatric AIDS. Semin Roentgen01 1987;22:73.

Diarrhea

in Pediatric

AIDS

Ninety-four percent of pediatric AIDS patients demonstrate failure to thrive and 39% have chronic debilitating diarrhea [S). Diarrhea is typically caused by common enteric bacterial pathogens. Pathologically, gut-associated lymphoid tissue (GALT) representing hyptertrophy of Peyer’s patches is seen. GALT can be

At least 95% of children with AIDS will develop some form of central nervous system (CNS) involvement (8, 16). HIV-induced encephalopathy occurs in 10%50% of children with HIV infection (2). It is a more common cause of neurologic complications in both children and adults, than focal lesions due to opportunistic infections or neoplasm (16). Clinically, it may present with cognitive impairment, failure to thrive, loss of developmental milestones, cerebellar signs such as dystonic posturing, progressive motor dysfunction with long track signs, and impaired brain growth with microcephaly. In one study, 50% of children with HIV encephalopathy had a head circumference in the second percentile (17). Seizures are rare. The disease is progressive, but neurologic deficits evolve in a stepwise pattern with plateaus of stable neurologic status alternating with periods of more rapid neurologic deterioration (17). At pathologic examination, a perivascular mononuclear cell infiltrate is found (18). The most common radiographic finding is diffuse cerebral atrophy with dilated ventricles and cerebrospinal fluid spaces (CSF) spaces (16) (Figure 4). Lesions may be focal or somewhat diffuse. They are not well seen on Tl-weighted magnetic resonance (MR) images of the brain but, on T&weighted images, they present areas of high signal in the periventricular white matter, brain stem, cerebellum, or internal capsule. The cerebral cortex is spared. Computed tomography (CT) may show no abnormal-

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Cytomegalovirus

IN CHILDREN

149

Encephalitis

Cytomegalovirus (CMV) encephalitis occurs in 25% of adults with AIDS, but is rare in children (17). In addition to encephalitis, CMV may also cause severe ventriculitis and subependymal necrosis. The disease affects both adults and children in a similar manner. At autopsy, microglial nodules are detected in the white and gray matter with or without CMV (18). Giant cells are also intranuclear inclusions found. CT and MR images are usually normal but diffuse hypodensity of white matter and diffuse periventricular enhancement have been reported (20).

Calcification

in the Basal Ganglia

Basal ganglia calcifications are a nonspecific but common finding in pediatric AIDS, occurring in over 50% of cases (18) (Figure 5). They are rarely found in adult patients with AIDS. The greater frequency of calcification of the basal ganglia in children and its predilection for this region of the brain (8) may be

FIGURE 4. HIV encephalopathy. Serial CT scans over a 6month period (A-D) exhibit progressive, diffuse cerebral atrophy with dilated ventricles and CSF spaces. Published with permission from Belman AL, Diamond G, Dickson D, et al. Pediatric acquired immunodeficiency syndrome: Neurologic syndromes. Am J Dis Child 1988;142:31.

ity or diffuse white

matter

Progressive

low density with minimal

Multifocal

in the contrast

periventricular enhancement.

Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), is a slowly progressive demyelinating disease caused by a papovavirus (JC, SV-40) infection of the oligo-

dendrocyte (2). It occurs in pediatric and adult patients who are immunocompromised from a variety of causes including AIDS (19). The process produces focal lesions that demonstrate increased T2-weighted signal in the subcortical white matter and centrum semiovale. On CT studies, focal zones of decreased density are seen in the cerebral white matter. They may enhance with contrast.

FIGURE 5. Basal ganglia calcification. Diffuse calcification of the basal ganglia and frontal horn white matter. Published with permission from Rajendra Pahwa, M.D., and Proceedings of the National Academy of Sciences of the United States of America, 1987;84:3828.

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related to the fact that calcium and iron levels are higher in the developing brain and are found in highest concentration in the basal ganglia and the midbrain. It has been proposed that human immunodeficiency virus attacks blood vessels and their supporting glia directly (17);this leads to disruption of the blood-brain barrier, anoxia, and disruption of membrane bound vesicles resulting in release of calcium and iron stores. At autopsy, focal deposits containing both iron and calcium salts in small and large vessels of the basal ganglia have been detected (18). This process occasionally extends into the thalamus and deep white matter. The degree of calcification does not correlate with the degree of HIVinduced encephalitis (18).

AIDS Embryopathy

in Children

AIDS embryopathy results from in utero infection with the HIV virus. It has not been associated with isolated amphetamine, cocaine, heroine, or methadone abuse in nonHIV infected individuals (8). It occurs more often following early intrauterine infection when the central nervous system is developing. Craniofacial abnormalities, resembling fetal alcohol syndrome (microcephaly, hypertelorism, and a flat nose) are common findings. A high box-like forehead, patulous lips with a prominent upper vermilion border, triangular philtrum, and upward or downward obliquity of the eyes have also been seen (4, 8). The palmar creases are normal with AIDS embryopathy, a finding that assists in distinguishing it from the fetal alcohol syndrome (8). The first clue to the diagnosis may be intrauterine growth retardation identified at ultrasonography.

SALIVARY-GLAND

ENLARGEMENT

Salivary-gland enlargement is more common in pediatric AIDS than adult AIDS. It occurs in 20%-30% of cases (6). Some observers believe that salivary-gland enlargement in association with recurrent bacterial infections in any organ system is diagnostic of pediatric AIDS in children younger than 5 years of age. In adults, parotid enlargement associated with a siccalike syndrome, LIP, and a circulating CD8 lymphocytosis has been seen mostly in black patients with the HLA-DR5 histocompatability antigen. These patients have shown an as yet unexplained resistance to opportunistic infections and none have died of AIDS (22). It is usually bilateral and painful and may persist for months or years. Absence of fever and presence of xerostomia are typical clinical correlations (7). An elevated amylase is found only during the initial period of enlargement. Enlargement of the salivary glands may occur with lymphoid interstitial pneumonia. Salivary-gland enlargement is frequently accompanied by cervical lymphadenopathy, which may be a part of the lymphadenopathy syndrome discussed under GI tract manifestations [15]. Oral hairy leukoplakia has been detected in pediatric AIDS (2, 22). It presents as a white thickening on the ventral and lateral aspect of the tongue. As is the case with LIP, it is theorized that oral hairy leukoplakia may be caused by Epstein-Barr virus infection occurring in a child already harboring the human immunodeficiency virus (7). Such enlargement may be a useful feature in differential diagnosis because salivary-gland enlargement is not associated with pneumocystis carinii pneumonia, a condition with which lymphoid intestinal pneumonia is often confused.

KAPOSI’S SARCOMA Meningitis Meningitis occurring in children with AIDS is rather frequent; in one study, 11.6% of pediatric AIDS patients developed meningeal infection (17). Meningitis often results from common bacterial pathogens, such as Streptococcus pneumoniae, Escherischia coli, and Haemophilus influenzae. However, unlike AIDS-related meningitis in adults, infection caused by Candida albicans, Cryptococcus neoformans, and other fungi-induced meningitides are rare. Tuberculous meningitis and meningovascular syphilis, are also rare. Aseptic meningitis has also been known to occur (17).In contrast to adult AIDS patients, central nervous system toxoplasmosis is rarely seen in children (16,21).

Kaposi’s sarcoma is rare in pediatric AIDS, occurring in fewer than 5% of cases (3, 7). Although the cause of Kaposi’s is unknown, some authors hypothesize that Kaposi’s sarcoma may be secondary to longstanding or repeated cytomegalovirus infections (23). This might explain why it is much more common in adults as this virus less commonly affects children with AIDS. In children it is not uncommon to have extracutaneous Kaposi’s sarcoma only (23). Lesions have been found in the liver, spleen, and lymph nodes at autopsy without any detectable skin lesions. This form of Kaposi’s sarcoma is very aggressive and runs a fulminant course. It may be complicated by hemorrhage leading to anemia and even shock (23). Adults with the disease usually demonstrate discrete

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skin lesions, later associated with large lesions in the lung, liver, lymph nodes, and gastrointestinal tract (23). In children, other skin neoplasms are even rarer than Kaposi’s sarcoma. Isolated cases of immunoblastic lymphoma or nonHodgkin’s lymphoma have been reported (23).

Pediatric AIDS is clinically and radiologically different from adult AIDS. The differences are related to the time of infection in relation to immune-system maturity. Children are antigenically naive and have not had sufficient time to develop antibodies to common pathogens before their immune system is destroyed by the human immunodeficiency virus infection. Common manifestations of pediatric AIDS are thought to be the result of triggering of a previously dormant HIV infection by viral cofactors. The most common virus cited in the literature is the EpsteinBarr virus. In contrast to adults, pediatric AIDS patients more commonly have recurrent bacterial infections with common pathogens, lymphoid interstitial pneumonia, abdominal and retroperitoneal adenopathy, basal ganglia calcification, and salivary-gland enlargement. Disease processes more common in adult AIDS patients are mycobacterium avium intracellulare of both the pulmonary and gastrointestinal organ systems, GI lymphoma, cryptosporidiosis, and central nervous system toxoplasmosis. The authors are grateful to John A. Kirkpatrick, Jr., MD, Chairman of Radiology, Boston Children’s Hospital, Boston, Massachusetts, who reviewed the manuscript and supplied Figures 1 and 2.

M. Head deficiency

of pediatric acquired J Perinatol 1988;8(2):154-

and neck findings in pediatric acquired symdrome. Laryngoscope 1987;97(6):

7. Chanock S, McIntosh K. Pediatric infection with the human immunodeficiency virus: Issues for the otorhinolaryngologist. Otolaryngol Clin North Am 1989;22(3):637-660. Pediatric

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S, Berdon 9. Amodio J, Abramson Semin Roentgen01 1987:22:66-76.

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JA, Isaacs H, Saxon A, Keens TG, Richards 10. Church Lymphoid interstitial pneumonitis and hypogammaglobulinemia in children. Am Rev Respir Dis 1981;124:491-496.

W.

11. Zimmerman BL, Haller JO, Price AP, Thelmo WL, Fikrig S. Children with AIDS. Is pathologic diagnosis possible based on chest radiographs? Pediat Radio1 1987;17:303-307. 12. Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am 1973;57:809-843, 13. Marinelli D, Albeda S, Williams TM, et al. Nontuberculous mycobacterial infection in AIDS: clinical, pathologic and radiographic features. Radiology 1986;160:77-82. 14. Berkowitz osporidiosis syndrome.

CD, Seidell JS. Spontaneous in children with acquired Am J Dis Child 1985;139:967.

resolution of cryptimmunodeficiency

M, Zwann F. Radiologic features 15. Schimmelpinnick bowel injury in graft versus host disease. Gastrointest 1982;7:29-33. 16. Price DB, Inglese CM, Jacobs J, et al. Pediatric ologic and neurodevelopmental findings. 1988;18:445-448,

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17. Belman AL, Diamond G, Dickson D, et al. Pediatric acquired immunodeficiency syndrome: neurologic syndromes. Am J Dis Child 1988;142:29-35. 18. Dickson D, Belman A, Park Y, et al. Central nervous system pathology in pediatric AIDS: an autopsy study. APMIS suppl, 1989;8:40-57. 19. Lee SH, Rao KCVG. In Cranial Computed Tomography and MRI, 2nd ed. New York: McGraw Hill, 1987, pp 723-724. 20. Post MJD, Hensley GT, Moskowitz LB, Fischl M. Cytomegalic inclusion virus encephalitis in patients with AIDS: CT, clinical and pathologic correlation. AJR 1986;146:1229-1234.

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