Immunologic considerations in pediatric HIV infection

N a n c y W a d e , MD

From Section of Allergy/Immunology, Albany Medical Center, Albany, New York

Helper T lymphocytes that express the CD4 (T4) cell-sur- face molecule play a key role in human immunodeficiency virus infection. The CD4 molecule, found in lower concen- trations on monocytes, macrophages, dendritic and glial cells, and possibly certain endothelial cells in the intestine, serves as the high-affinity receptor for HIV. The HIV viral envelope protein, gpl20, binds to a region of CD4; this in- teraction allows the virion to be internalized and uncoated. The viral genomic RNA is then transcribed by reverse transcriptase to a proviral DNA that is subsequently incor- porated into the host DNA. The virus may then remain latent for prolonged periods. However, at any time during this proviral period the virus can return to its infectious state; this usually occurs when its host T cell is activated in response to other immunologic stimuli, such as viral infections. Once the virus is activated, its proviral DNA is transcribed into messenger RNA, ultimately leading to protein synthesis, virus assembly, and release of viral par- ticles. 1

Several mechanisms of CD4 cell death have been pro- posed, including cytolysis as a result of active viral repli- cation and the development of syneytia. In vitro, as new virions bud from the plasma membrane, the host lympho- cytes fuse with surrounding uninfected CD4 cells, produc- ing multinucleated giant cells and leading to the death of both infected and uninfected cells. 2, 3 Other CD4 positive cells, such as monocytes and macropbages, harbor the virus yet seem relatively resistant to its cytopathic effects. Thus these cells may serve as important reservoirs of infec- tion. 1

I M M U N O L O G I C A B N O R M A L I T I E S

Active HIV replication ultimately leads to deterioration of the immune system. Both cellular and humoral immuno- logic abnormalities have been described during the course of HIV infection.

Abnormalities of cellular immunity. As the disease

progresses, the percentage and absolute number of cD4 positive lymphocytes decreases. The actual decline in number is out of proportion to the number of infected cells, possibly because of destruction of uninfected cells through syncytial formation. In adults, the total number of CD4 positive T cells correlates closely with disease stage. 4 In children, however, opportunistic disease has been observed in infants with CD4 counts as high as 1500/mm3. 5

The proliferation of T cells in response to antigen is im- paired even in some persons with asymptomatic HIV infec- tion. However, mitogenic responses may remain normal even when antigenic responses are abnormal. As the disease progresses, delayed hypersensitivity skin tests become non- reactive.

I AIDS Acquired immune deficiency syndrome gp Glycoprotein HIV Human immunodeficiency virus

Natural killer cell numbers remain normal, but cytotox- icity is decreased as a result of reduced cytokine production. Monocytes exhibit both abnormal chemotaxis and killing, probably secondary to decreased production of inductive signals from CD4 lymphocytes. There is an increased secretion of monokines such as interleukin 1 and tumor necrosis factor. 1

Abnormalities of humoral immunity. One of the earliest immunologic manifestations of acquired immune defi- ciency syndrome is a polyclonal hypergammaglobulinemia, which is possibly related to infection by such viruses as Ep- stein-Barr virus, cytomegalovirus, or HIV itself. Despite the elevated levels of immunoglobulins, there is an abnormal antibody response to new antigens. Some of these abnor- malities can be related to B cell dependence on helper T cell functions. However, T cell-independent responses are also abnormal. 6

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S 6 Wade The Journal of Pediatrics July 1991

l o b l e I. Recommendations for immunologic evaluations

of the HIV-infected child

Baseline evaluations Quantitative immunoglobulin measurements (IgG, IgM,

IgA) Assessment of total lymphocyte count Lymphocyte subset counts and CD4/CD8 ratio

Additional evaluations: Specific antibody assays:

Tetanus, poliomyelitis, diphtheria, pertussis, respiratory viruses (protein antigens, IgG function)

Hemophilus or pneumococcal antibodies (polysaccharide antigens, primarily IgG2 function)

lsoagglutinins (IgM function) Positive after 6 to 12 months of age

Assessments of cellular immunity: Complete blood cell and differential blood cell count Absolute CD4 cell count and CD4/CD8 ratio Delayed hypersensitivity skin tests: Candida, tetanus

toxoid, purified protein derivative (tuberculin) In vitro mitogen stimulation

C L I N I C A L P R E S E N T A T I O N

Children with HIV infection may have clinical manifes- tations of humoral immunodeficiencies, such as recurrent and persistent bacterial infections. This increased fre- quency of bacterial infections reflects the poor response to new antigens and the increased frequency of new antigen exposure in childhood. However, as the immune system de- teriorates, symptoms develop that are more typical of a mixed cellular and humoral immunodeficiency, with chronic candidiasis, failure to thrive, diarrhea, and bacterial and opportunistic infections. Clinical findings may be normal despite abnormal immune measurements; symptomatic

children may have apparently normal laboratory measure-

ments.

I M M U N O L O G I C E V A L U A T I O N

Baseline immunologic examination of the HIV- infected child should be done at the initial evaluation

and at 3-month intervals. The studies encompassed in these assessments are presented in Table I. Although measures of CD4 cell counts are a critical part of these evaluations, the usefulness of CD4 counts in the pediat- ric population with HIV infection has not been well studied, and normative, age-specific values are not well established. Many physicians still rely on the CD4 count as a marker of disease severity in these children. How- ever, it should be kept in mind that even children with high CD4 levels are at risk for opportunistic infection. Infants with CD4 counts as high as 1500/mm 3 and who

have Pneumocystis pneumonia have recently been de- scribed. 5

With the limitations of this measurement in mind, CD4 counts as a rule should be >2500/mm 3 in a nonimmunode- ficient child younger than 1 year, and <2000/ram 3 by the time the child is 2 years of age. A CD4 count <600/mm 3 in an older child is highly suggestive of immune deficiency; a count of <400/ram 3 suggests profound T cell deft- ciency.8, 9 Data representing the distribution of absolute

and percentage CD4 cell counts from healthy children are listed in Table II. s

When abnormal levels of CD4 cells are detected, it is im- portant to check with the laboratory to see which mono- clonal antibodies have been used to assess CD4 positive cells. CD4 polymorphisms have been described by mono-

clonal antibody data. For instance, approximately 4% of American blacks lack the OKT4 epitope but express OKT4a-e. 7 Thus most laboratories use a more universal monoclonal antibody to detect CD4, 7 but this should be verified before a diagnosis is made. The ratio of CD4 to CD8 cells is another useful assessment of cellular immu-

nity. Typically, the CD4/CD8 ratio in healthy children is 1.4 to 1.8.

Delayed hypersensitivity skin tests can yield additional information on the status of cellular immunity. Tests for Candida, tetanus toxoid, and purified protein derivative (tuberculin) usually produce positive results in a child older than 1 year, in an immunized child, or in a child with a his- tory of thrush.

If skin testing is negative, an in vitro mitogen stimulation assay may yield useful information. The response to pokeweed mitogen often is abnormal at very early stages of HIV infection. The in vitro T cell response to antigen or mixed lymphocyte culture also can be assessed. This response often is aberrant before mitogenic studies yield abnormal results.

S U M M A R Y

The pervasive effect of HIV infection on the immune system requires that the clinician be alert to the variety of immunologic abnormalities that can result from this dis- ease. The tests described in this section provide guidelines for testing the HIV-infected child. Additional information on immunologic evaluations in the child with indeterminate HIV infection status can be found in the article on ambu- latory care.

R E F E R E N C E S

1. Fauci A. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 1988;239:617-22.

Volume 119 Immunologic considerations in pediatric H I V infection S 7 Number l, Part 2

Table I I . Age-adjusted CD4 lymphocyte values in healthy children

I-6 7-12 13-24 25-74 Age (mo) n 106 28 46 29

Absolute CD4 counts 5th to 95th %ile 1153-5285 967-5289 739-4463 505-2831 Median 3211 3128 2601 1668

Percentage CD4 cells 5th to 95th %ile 36.3-67.1 32.8-63.0 31.2-60.4 32.2-52.0 Median 51.6 47.9 45.8 42.I

CD4/CD8 ratio 5th to 95th %ile 0.9-3.5 0.8-3.4 0.6-3.4 0.7-2.1 Median 2.2 2.1 2.0 1.4

2. Sodroski J, Goh WC, Rosen C, Dayton A, Terwilliger E, Ha- seltine W. Role of the HTLV III/LAV envelope in syncytium formation and cytopathicity. Nature 1986;322:470.

3. Iochim HL. Immunopathogenesis of human immunodefi- ciency virus infection. Cancer Res 1990;54:5612S-7S.

4. Polk BF, Fox R, Brookmeyer R, et al. Predictors of the acquired immune deficiency syndrome developing in a cohort of seropositive and homosexual men. N Engl J Med 1987; 316:61-5.

5. Leibovitz E, Rigaud M, Pollack H, et al. Pneumocystis carinii pneumonia in infants infected with the human immunodefi- ciency virus with more than 450 CD4 T lymphocytes per cubic millimeter. N Engl J Med 1990;323:531-3.

6. Bernstein L J, Ochs HD, Wedgewood R J, Rubenstein A: De- fective humoral immunity in pediatric acquired immunodefi- ciency syndrome. J PEDIATR 1985;107:352-7.

7. Fuller RC, Tvevithick JE, Fuller AA, et aI. Antigenic poly- morphism of the T4 differentiation antigen expressed on the human T helper/induced lymphocytes. Human Immunol 1984;9:89-102.

8. Niven P, Skuza C, Chadwick E, et al. Age related changes of lymphocyte phenotypes in healthy children. Pediatr Res 1990; 27:155A.

9. Stiehm R. Immunologic disorders in infants and children. Philadelphia: WB Saunders, 1989.