Acquired Immunodeficiency Syndrome (AIDS) has taken the world by storm, and its impact in the pediatric population is emerging as a serious public health problem in large urban areas. For reasons to be explained below, New York has the dubious honor of being among the regions with the highest incidence of pediatric AIDS, and the Beth Israel Medical Center, in charge of the largest drug rehabilitation program in the city, takes care of a significant pediatric population with this disease. To understand the immunologic aspects of pediatric AIDS, it is important to review briefly some significant epidemiologic factors associated with this disease in adults. This review will be followed by a description of the salient aspects of AIDS and its impact on the immune system.
In June 1981 the Centers for Disease Control published the unusual occurrence of a cluster of Pneumo' cystis carinii pneumonia among previously healthy male homosexuals in Los Angeles. This publication was followed by an equally surprising report of an aggressive form of Kaposi's sarcoma affecting young homosexual men in New York and California. P carinii pneumonia was usually the final event in severely immunocompromised individuals and Kaposi's sarcoma was a rare, indolent form of skin cancer seen primarily in elderly men. These patients were found to have a severe derangement of their immune system that soon would become known as the Acquired Immunodeficiency Syndrome (AIDS).
As AIDS came to be associated with sexually active young homosexual men, it was clear that some aspect related to their sexual lifestyle was causing a change in their immune systems resulting in an inability to protect themselves from infection. Soon thereafter, AIDS began to present itself in heterosexual intravenous drug users and in mid-1982 it was described for the first time among hemophiliacs receiving factor VIII concentrate. Shortly afterward, AIDS became associated with blood transfusions, and AIDS transmission from male intravenous drug addicts, heterosexuals, and homosexuals to their female sexual partners was confirmed.
These epidemiologic facts led to hypotheses of an infectious etiology with transmission through blood and its products. In 1983 and 1984, a pathogenic retrovirus was found in AIDS patients and first labeled AIDS-associated retrovirus (ARV). L. Montaigner and coinvestigators from the Paris Pasteur Institute called it lymphadenopathy-associated virus (LAV) and R. C. Gallo and associates at the National Cancer Institute characterized it as a human T cell lymphotropic virus, HTLV-III. It is now termed human immunodeficiency virus (HIV).
More than 1 million people in the United States are believed to be infected with this virus, of which between 5% to 15% will eventually develop AIDS over the next several years. A bird's-eye view would show that AIDS in the adult is predominantly a disease of males who are young, white, urban, and homosexual or IV drug abusers. The affected females are linked to either intravenous drug use or sexual contact with affected men.
More than 300 cases of AIDS have been reported in the pediatric age group as of late 1986. Their epidemiologic and demographic factors follow closely those of the adult female cases, indicating that perinatal transmission is the principal mechanism of infection.1·2 Approximately half of the nation's cases of pediatric AIDS have been reported in New York City and, of these, about 80% have one or both parents with AIDS or at risk of developing AIDS, primarily because of IV drug abuse. The rest of the pediatric cases are related to transfusions of either blood or factor VIII concentrates.3
The immunologic studies of AIDS patients revealed abnormalities that could be traced to a subset of Tlymphocytes, the T4 helper cells which were the target cells of the newly discovered family of RNA retroviruses, now called HlV.4 Previously identified viruses of this family include HTLV-I (human T cell lymphotropic virus type I), associated with a rare form of adult T cell leukemia with clinical immunosuppression. Initially investigators had problems growing HlV in vitro because the virus itself killed the cells in which it was cultured, through a direct cytopathic effect. Eventually it was found to grow in a special T cell leukemia line called H9.
Once inside the host T cell, the virus copies its RNA into DNA through the enzyme reverse transcriptase. Viral DNA then integrates itself into the host cell genome where it exists in the form of a provirus. It will not be reproduced until the host T cell is stimulated to divide by an antigen. Reproduction causes T cell death with virus release and spread to other T cells, thus repeating and accelerating the process. Eventually there is depletion of the host T cell subset with clinical manifestations of acquired immunodeficiency. This unique combination of antigenic stimulation of the cell, with its dormant virus, leading to subsequent cell and virus multiplication and eventual cell death is the crux of AIDS pathophysiology.
Clinical disease correlates are as follows: In homosexuals, anal intercourse introduces not only the virus but also semen into the recipient's circulation because the anal mucosa is less resistant to trauma than the vaginal mucosa; semen is an additional antigenic stimulus. In IV drug abusers, the shared, dirty needles introduce the virus, and the impurities of the injected material provide the additional chronic antigenic stimulus. In hemophiliacs, the blood products introduce virus plus multiple blood proteins which act as additional chronic antigenic stimulants.
This virus has been isolated most often from patients' blood and semen, but also from urine, vaginal secretions, bone marrow, lymph nodes and spleen, and more rarely from cerebrospinal fluid, brain and neural tissue, tears, saliva, and breast milk.5
The role of HlV as the etiologic agent of AIDS was supported by the study of the prevalence of antibody to HIV in the population. It is of interest that antibody to HIV does not confer immunity to it nor prove its actual presence, but rather appears to indicate exposure of the host to live, infective virus.6 The antibody was found in patients with AIDS and the AIDS related complex (ARC) and in high percentages of members of the risk groups discussed previously. 7 On the other hand, it has been conspicuously absent from sera of people with no known risk factors for AIDS.8 Analysis of stored sera shows the appearance of HIV antibody in the United States by 1978.
There are several serologic tests available to detect HIV antibody. An enzyme-linked immunosorbent assay (ELISA), which uses a spectrophotometric technique to detect the amount of antibody that binds to virus antigens, is widely used. The virus is grown in a special T cell leukemia line called H9. The sensitivity of the different ELISA kits approved by the FDA averages approximately 95% and their specificity is on the order of 99%. False-positive ELISA tests may be found in multiparous women and blood transfusion recipients who received antibody with their transfusion product. They may also represent cross-reactivity with some HLA antigens from the H9 cell line.
The Western blot assay confirms the presence of antibodies in the patient's serum to viral subunit proteins, which have been electrophoretically separated, because it is considered to be more specific than the ELISA test. Based on the available evidence, it became necessary for blood banks to screen donor blood for the presence of HIV antibody. Since early 1985, 0.26% of USA specimens tested were found to be repeatedly positive for HIV antibody by the ELISA method.
A normal immune response against invading pathogens results from the cooperation of mononuclear phagocytes (MNPs) with T- and B-lymphocytes and antibody producing plasma cells. Because this subject is covered extensively in several articles in this and the past issue, a brief overview should suffice.
The first line of defense against infection is the MNP which engulfs the microorganism and generates interleukin 1 (IL-I) which activates T cells. The activated T cells produce interleukin 2 (IL-2) and other lymphokines which contribute to the activation of other T and B cells.
The T cells develop in the thymus where they acquire different surface antigens and functional characteristics. Helper or inducer T cells bear T4 (Leu 3) antigen and account for 60% to 70% of circulating T cells. Suppressor T cells, which inhibit the responses of other T and B cells, display the T8 (Leu 2) antigen and ate also cytotoxic; normally they represent about half as many T cells as T4 cells. B cells mature in the bone marrow, and when stimulated by IL-2 and antigen, divide and differentiate into antibody secreting plasma cells.
From this description, it becomes clear that the T4 or helper cells play a key role in modulation of the immune response by recognizing foreign antigens and secreting IL-2, leading to the proliferation of other T and B cells which eventually transform into plasma cells. The depletion of T4 cells, therefore, would have a devastating effect on the host's immune response. Virtually all the infectious complications of AIDS can be traced to the effects of HIV on T4 cells. Generalized lymphopenia results mainly from a decrease in the absolute number of T4 cells with increased susceptibility to infections and neoplasms. Decreased delayed hypersensitivity may result in cutaneous anergy as the production of lymphokines and proliferative responses to specific antigens are impaired.
Other complications which may arise include decreased Chemotaxis, cell killing, and diminished production of IL-I in response to foreign antigens by the MNP. B cell function is also affected by the loss of T4 cells, resulting in the inability to generate specific and effective antibody responses to specific antigens.9 As a consequence, AIDS patients are at an increased risk of acquiring opportunistic infections as well as common bacterial infections. Elevated serum immunoglobulins are usually found in AIDS patients due to nonspecific immunoglobulin production secondary to B cell deregulation with a poor antibody response to specific antigens.
AIDS IN PEDIATRICS
Because most pediatric AIDS cases are transmitted perinatally, the geographic, racial, and ethnic distribution parallels that seen in adult female AIDS patients. New York, New Jersey, Florida, and California have reported 75% of pediatric cases in the USA, 80% of those affected being black or Hispanic.10
The median age of onset of symptoms in patients with high-risk parents is between 4 and 6 months. For infants who develop AIDS as a result of blood product transfusion, the median incubation period is estimated to be 8 months; in older children it extends to about 14 months.11
The inability to respond appropriately to new antigens, due to the loss of T cell regulation of B cell function, leaves the AIDS infant as vulnerable to common bacterial infections as are congenital agammaglobulinemia patients. This occurs at a later stage in the natural history of pediatric AIDS. It has become clear that the effect of HIV infection on the child's immune system is somewhat different than on the adult's. Early signs present in adults such as lymphopenia, abnormal lymphocyte mitogenic responses to phytohemagglutinin (PHA) and concanavalin A (Con A) as well as in the mixed lymphocyte culture are not usually found in children. 12 The histology of the thymus, which in adults becomes depleted of lymphocytes, is initially normal in children who may maintain normal T-lymphocyte function for a relatively long time despite opportunistic infections.
Low serum thymulin levels and poor in vitro lymphocyte responses to diverse antigens were the earliest abnormalities noted in infants with proven HIV infections.13 It is thought that thymulin is but one of many peptides able to affect thymic differentiation; its deficiency may be compensated by other hormones and therefore is not associated with peripheral T cell immaturity or functional T cell defects.
It has also been postulated that HIV infection of T4 cells may alter their antigen receptors to the extent that they are no longer able to recognize foreign antigens. This would explain the already mentioned defects in specific lymphocyte antigen responses.14,15 Later in the course of the disease, the numerical depletion of T cells becomes the most important immunologic deficiency manifesting itself through numerous abnormalities of cell-mediated immunity. As the disease progresses, up to 65% of children may exhibit a reversal of the usual T4/T8 ratio due to a low total T4 cell count.16 This coincides, as expected, with a poor lymphocyte mitogenic response to PHA and Con A. 17 The thymus becomes depleted of T- lymphocytes to the point where at post mortem examination it appears to depict complete involution. 18
B cells are affected early as children with HlV infection begin to experience recurrent bacterial infections with or without sepsis in a fashion reminiscent of patients suffering from hypo- or agammaglobulinemia; however, as it happens, the levels of IgG and IgD immunoglobulin are especially elevated while IgM levels are variable. The hypergammaglobulinemia is polyclonal and is associated with an increased number of plasma cells.19,20 This paradoxical phenomenon can be explained by an increase in T8 suppressor cells at the expense of a decreased number of helper T4 cells. The suppressor cell population fails to respond in vitro to Con A, and T cells from these patients demonstrate deficient in vitro suppression of immunoglobulin production by pokeweed mitogen (PWM), therefore failing to dampen the stimulated antibody secreting cells.21 This is expressed also by an increased incidence of autoimmune phenomena and an elevation of the level of circulating immune complexes.
An alternate or complementary mechanism explaining this aberrant humoral immunity relates to the activity of the Epstein-Barr virus (EBV) of infectious mononucleosis. It is known that EBV can transform B cells into a proliferating population leading to hypergammaglobulinemia, independent of T cell cooperation. The importance of this explanation is to document EBV infection serologically in children with AIDS, and to recover EBV-DNA from lung and lymph nodes of children with pulmonary lymphoid hyperplasia (PLH).22 Hypergammaglobulinemia has also been observed in children without serologic evidence of EBV infection.
Because cytomegalovirus (CMV) is another herpesvirus infection frequently encountered in pediatric AIDS and may also be another antigenic stimulant of T4 lymphocytes with HIV dissemination, CMV may play a role in the polyclonal activation of B cells and subsequent hypergammaglobulinemia. Infection with CMV may also be responsible for the parotitis frequently encountered as" an associated infection in AIDS children.
These B cell abnormalities result in a poor mitogenic response to PWM and to Staphyhcoccus aureus Cowan strain long before the HIV infection causes T cell defects. This suggests that the initial B cell deficiency in children with AIDS may be related to the fact that the infection takes place during the immune system's development at a time when B cells undergo maturation and differentiation with an already competent cellular immune system. To a lesser degree, B cells are also affected in adults with AIDS. It has been suggested that due to increased B cell activation, B cells are rendered unable to respond well to new antigenic stimuli.23
In summary, the immunologic abnormalities found in children with the AIDS-ARC spectrum are the consequence of a generalized lack of regulation of the immune system. Cells from these patients are also incapable of specific cytotoxic as well as humoral immune responses, while at the same time producing an inappropriate amount of immunoglobulin, immune complexes, and tissue injury.24
The clinical expression of all these immune phenomena in the pediatric population has been well characterized over the last few years. Opportunistic infections by pathogens which are relatively nonvirulent but able to cause morbidity to an immunocompromised host are typical of pediatric AIDS. Entities such as P carinii pneumonia (PCP), esophageal candidiasis, chronic herpes simplex, disseminated infection with Mycobacterium avium and enteric cryptosporidiosis are among the most frequently encountered in this group of patients.25
Pulmonary pathology is a prominent finding in pediatric AIDS. Lymphoid interstitial pneumonia (LIP) with insidious onset of respiratory distress and eventual hypoxemia is due to extensive interstitial infiltrates. Pulmonary lymphoid hyperplasia (PLH) involves interstitial infiltration of lymphocytes and an associated widening of the mediastinum due to enlargement of the lymph nodes, representing another aspect of the inappropriate behavior of the lymphoid tissue in this disease.26 This is also manifested in the salivary gland enlargement which is so common in these children.
Thrombocytopenia, one of the major hematologic complications of children with ARC-AIDS, reflects B cell deregulation with the production of autoantibodies and immune complexes, thus leading to peripheral platelet destruction.27
Failure to thrive with developmental and neurologic abnormalities may be the result of the HIV intrauterine insult complicated by prematurity or low birth weight, frequently found in children with HIV infection.28 These abnormalities may also reflect injury to the CNS, as well as the medical and social consequences of repeated hospitalizations, separation from family, and disturbed home environment with inappropriate caretaking.
AIDS can be viewed as one of the experiments in nature that encompasses all aspects of the immune system. A similar situation is encountered in hematology with disseminated intravascular coagulation, where all the components of the clotting mechanism are involved as a consequence of its extreme deregulation. These experiments in nature have historically been beneficial only in that they allow a rapid and practical understanding of the phenomena under study. It is hoped, and the velocity of scientific breakthroughs seems to confirm it, that this new scourge of humanity will in the end be conquered and that at the same time humanity will acquire a better understanding of itself.
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