Textbook of Pediatric HIV Care available in Hardcover
Textbook of Pediatric HIV Care
- ISBN-10:
- 0521821533
- ISBN-13:
- 9780521821537
- Pub. Date:
- 04/28/2005
- Publisher:
- Cambridge University Press
- ISBN-10:
- 0521821533
- ISBN-13:
- 9780521821537
- Pub. Date:
- 04/28/2005
- Publisher:
- Cambridge University Press
Textbook of Pediatric HIV Care
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Overview
Product Details
| ISBN-13: | 9780521821537 |
|---|---|
| Publisher: | Cambridge University Press |
| Publication date: | 04/28/2005 |
| Pages: | 784 |
| Product dimensions: | 8.86(w) x 11.10(h) x 1.50(d) |
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Cambridge University Press
0521821533 - Textbook of Pediatric HIV Care - by Jennifer S. Read and Steven L. Zeichner
Excerpt
Introduction
Steven L. Zeichner and Jennifer S. Read
Bethesda, MD, USA
Introduction
When we were in training to be pediatricians we diagnosed and treated some of the first children infected with HIV seen in our hospitals. We watched as most of them died quickly, within the first year or two of life, and we saw many of their parents die too. Over the following few years we witnessed the wards of our hospitals fill with children infected with HIV, at least in part because the growing epidemic was not viewed as a serious threat to the population as a whole, a threat that needed to be confronted with the determination and the resources appropriate to the magnitude of that threat.
As the epidemic expanded we initially had few effective therapies, either for HIV infection itself or for the opportunistic infections that complicate the disease. The numbing morbidity and mortality of HIV infection in children grew; we continued to see our patients and their parents die. Slowly, we saw more effective treatments for opportunistic infections and for HIV infection itself come into use. We saw the development of serological tests to diagnose HIV infection, of the first antiretroviral agents and agents for the prevention and treatment of opportunistic infections, of more effective antiretroviral agents, of methods to employ antiviral agents in effective combinations that can drive the viral load to low levels, of assays to determine viral load and methods to use the viral load assays to measure the effectiveness of antiretroviral therapy, of methods to assess whether a patient's virus is resistant to antiretroviral agents and approaches to select optimum combinations of antiretroviral agents, and of therapeutic approaches that dramatically decrease the likelihood that an infected mother will transmit HIV to her newborn.
Now, at least here in the USA and in other rich nations, effective approaches to treat HIV disease and its complications, and to prevent transmission, are in widespread use. Many of our patients are well, our wards are empty, and we have many fewer new patients. We have seen what happens when HIV disease in children is not treated, and we have seen the dramatic benefits that effective therapy for HIV disease can provide. We organized this book in the hope that a clear presentation of the management strategies available for HIV disease and its complications will help healthcare providers offer the most effective management strategies possible to their patients and that a clear presentation of the pathophysiology of HIV disease in children will help providers thoughtfully employ those management strategies.
The first edition of the Handbook of Pediatric HIV Care was intended mainly as a ready reference for practitioners who were working together with specialists to care for children with HIV infection. However, both non-specialists and specialists in the care of children with HIV infection seemed to find the book helpful. We hope that this textbook will continue to provide the information that will help non-specialists collaborate with specialists in caring for children with HIV infection, to help educate students, trainees, and others who are new to the pediatric HIV field, and satisfy the needs of specialists who may find the book useful as a ready reference.
The World Health Organization estimates that during 2003 close to one million children were infected with HIV and more than half a million died. These numbers will almost certainly continue to increase. The knowledge and technology now exist to prevent most of those infections and to keep many of the children who are infected alive and healthy for a long time, but the necessary financial, societal, and political resources have not been dedicated toward those goals, so children will continue to be infected and children will continue to die. We hope that at some not too distant time we will not need to edit a revised edition of this book.
PART I
Scientific basis of pediatric HIV care
1
Normal development and physiology of the immune system
Sherilyn Smith, M.D. and Ann J. Melvin, M.D., M.P.H.
Department of Pediatrics, University of Washington, Division of Pediatric Infectious Disease,
Children's Hospital and Medical Center, Seattle, WA
1.1 Overview
Clinicians involved in the care of children with HIV infection are faced with the dual challenge of understanding the effect of HIV on the immune system and applying this knowledge to patients who, even under normal circumstances, have an immature and changing immune response. Understanding the function of the immune system and the developmental differences in the immune system of children compared with adults will facilitate and improve patient care. This knowledge will aid in effectively interpreting laboratory results, help define disease risk, and improve the understanding of the manifestations and outcome of HIV infection in children. This chapter provides a framework for understanding the unique features of the developing pediatric immune system and how it may affect the course of HIV infection in children.
The functions of the vertebrate immune system include discrimination between self and foreign antigens, the development of a memory response to antigens, recognition of neoplasms and the elimination of pathogens that invade the host. The immune system can be divided into two separate components based on the rapidity and specificity of the response. The "innate arm" of the immune system provides a rapid, non-specific response to pathogens and provides the first line of defense against invading microbes. It also acts as a surveillance system and facilitates the initiation of the antigen-specific phase of the immune system. The major components of innate immunity include barriers (both epithelial and mucosal), complement and other opsonins, the spleen, phagocytes (both of macrophage and neutrophil origins), and NK (natural killer) cells.
The antigen-specific phase of immunity is directed at specific antigens or components of the invading microbe and is a sustained, amplifiable response. The aspects of this inducible portion of the immune system are the cellular and humoral immune response. The interaction of these two components serves to control infection and form long-term immunity against the same or similar organisms. Intact innate and antigen-specific immunity are necessary for full protection from pathogenic microbes and the establishment of long-term immunity induced by vaccinations. Table 1.1 summarizes the major functions of the innate and antigen-specific portions of the immune system and the types of infections that can result from dysfunction of its components.
1.2 Components and function of the immune system
1.2.1 Innate immune system
Barriers
The first line of defense against invading microbes is an intact barrier at both mucosal and epithelial surfaces. The skin, respiratory, gastrointestinal, and urogenital mucosa are the main components of this portion of the immune system. They exclude potential pathogens by forming a relatively impenetrable barrier between the environment and the host. Specialized cells (including ciliated respiratory epithelia that aid in removal of bacteria and particulate matter), and localized chemical barriers (such as stomach acid, the mucus layer in the respiratory and gastrointestinal tracts, and fatty acids in the skin and
| Immune system component | Function | Developmental differences | Infections associated with dysfunction |
| Innate | |||
| Epithelial barriers/mucosal defense | Impede entrance of microorganisms Present antigen Sample environment | Epithelial barriers decreased in premature infants Decreased IgA-adult levels by 6-8 years | Low virulence organisms: coagulase negative staphylococcus, opportunistic gram negative bacteria, fungi |
| Complement/ opsonins | Amplify the immune response Facilitate phagocytosis Chemoattractants | Terminal complement levels decreased in neonates | Encapsulated organisms Recurrent infections with Neisseria species Recurrent/recalcitrant skin infections |
| Phagocytes | Engulf and kill microorganisms Present antigens to T cells (macrophages) Elaborate immune active substances including cytokines and chemotactic factors | Monocytes: decreased chemotaxis, decreased cytokine production - adult function by 6 years Neutrophils: decreased bone marrow pool in neonates, decreased chemotaxis - adult levels by 1 year | Staphylococcus aureus Low virulence organisms: other staphylococci, gram negative opportunistic bacteria, fungi |
| Spleen | Filters intravascular organisms Aids with opsonization Antibody formation | Encapsulated organisms (S. pneumoniae, Salmonella, H. influenzae) Develop severe or recurrent infections | |
| Natural killer (NK) cells | Lyse cells presenting "non-self" antigens (e.g. tumor or viral proteins) | Decreased ADCC, decreased cytolytic activity | Recurrent/severe viral infections with members of the Herpes virus family |
| Dendritic cells | Capture and present antigens to lymphocytes | Decreased ability to present antigen | ? |
| Antigen specific T cells | Cell-mediated immunity Elaboration of cytokines Regulation of the immune response Cytolysis Increases the efficiency of B cell function by providing "help" | Increased absolute numbers - decline to adult levels by late childhood Naïve phenotype in neonate (90%) decreased cytokine production, costimulatory molecule expression, and ability to provide "help" to B cells - normalizes throughout infancy with antigenic exposure | Infections with "unusual" organisms: intracellular bacteria (Listeria, mycobacteria) Fungi (Aspergillus, Candida) Viruses (especially HSV, VZV, CMV, HHV-8) Protozoa (Giardia, Pneumocystis carinii) |
| B cells | Humoral immunity (formation of antibody to specific antigens) | Unable to respond to polysaccharide antigens until ∼2 years of age | Encapsulated organisms Enteroviral infections Recurrent GI or sinopulmonary infections Inability to respond to vaccines |
ADCC - antibody-dependent cell-mediated cytotoxicity; CMV - cytomegalovirus; HHV-8 - human herpesvirus-8; HSV - herpes simplex virus; VZV - varicella-zoster virus.
cerumen) impede entrance of pathogens. Breaches in these barriers may result in disease caused by normally low virulence organisms such as coagulase negative staphylococcus. In most cases the disruption occurs when foreign bodies such as central venous catheters, endotracheal tubes, and indwelling urinary catheters and gastrostomy tubes are placed.
Mucosal immunity
Another component of the innate immune system is a series of lymphoid tissue aggregates (mucosal-associated lymphoid tissues), located at sites that interface with the environment. These lymphoid aggregates (such as Peyer's patches in the intestines) provide a mechanism for continuous sampling of the environment, recognition of foreign antigens, and sites for early initiation of an antigen-specific response [1, 2]. A specific immunoglobulin, secretory IgA, is synthesized in the mucosal associated lymphoid tissues and adds to the local defense in the gastrointestinal and respiratory tracts.
Opsonins
Opsonins are proteins that bind to the surface of bacteria and facilitate phagocytosis. Acute phase reactants (C-reactive protein, fibronectin, etc.), complement, and antibody are the major components of this system. Complement is a collection of proteins that are activated by proteases in a sequential manner. Among its many functions, complement plays an important role in the killing and clearance of invasive bacteria. There are two major methods for activating complement: the classical pathway (antibody binds bacterial antigen which then is complexed with C1, a component of the complement system), which begins a series of proteolytic reactions that activates additional complement components and the alternate pathway (bacterial antigen directly binds the C3b component of the complement pathway) which also activates the cascade. Both pathways converge, and result in formation of a complex that lyses the bacteria. In addition to bacterial clearance, complement is also involved in some of the clinical signs associated with infection including vasodilatation, erythema, and induration [3].
Spleen
The spleen is an important part of the innate immune system and acts as a filter that efficiently removes opsonized bacteria. Absence or dysfunction of the spleen predisposes to overwhelming infection with encapsulated organisms. The spleen is also an important site of antibody production.
Macrophages
Macrophages and monocytes are major effector cells of the innate immune response and are responsible for the killing and clearance of invading microbes. Macrophages, which are present in most tissues, migrate to sites of infection and phagocytose foreign substances. In addition, macrophages elaborate a large number of cytokines (see below) and growth factors. The cytokines may either amplify (e.g. IL-6, TNF-α, IL-1) or dampen (TGF-β) an evolving immune response [4]. Elaborated growth factors may also have direct antimicrobial functions (IFN-α, M-CSF) or induce proliferation and differentiation of nearby T cells.
Neutrophils
Neutrophils are resident blood phagocytes that can adhere to endothelial cells and then migrate between the endothelial cells to sites of infection. They phagocytose microbes that are coated with immunoglobulins or complement. They are particularly important in the host defense against bacteria and fungi. Neutrophils kill phagocytosed pathogens via the respiratory burst (generation of reactive oxygen metabolites) or by degranulation with release of substances that directly kill pathogens or potentiate the effects of the respiratory burst.
Natural killer cells
Natural killer (NK) cells are specialized lymphocytes important in the early recognition of non-self proteins and are particularly important in the early response to viral infections. Viruses often down-regulate host major histocompatibility complex molecules (see below) on the surface of infected cells. The lack of these molecules causes the NK cells to recognize them as foreign, making them targets for lysis.
Dendritic cells
Dendritic cells (DC) are antigen-presenting cells that capture antigen and present it to lymphocytes. DCs are a complex system of bone-marrow derived cells that develop from either lymphoid or myeloid precursors. In general, there are three major DC populations: (a) Langerhans cells, which reside in tissues and migrate to T-cell areas of lymphoid organs after antigen uptake, where they are known as interdigitating cells; (b) myeloid DCs (also known as interstitial or dermal DCs), which become germinal center DCs in lymphoid follicles; and (c) plasmacytoid DCs which reside in the T cell areas of lymphoid tissues [5]. Langerhans cells and myeloid DCs are primarily derived from myeloid progenitor cells while plasmacytoid DCs are derived from lymphoid progenitors [6].
In the tissues, DCs are largely immature and function primarily to take up and process antigen. As they migrate to lymphoid tissues they undergo a maturation process to become effective antigen-presenting cells [5]. The different populations of DCs appear to have different primary functions. Langerhans cells are potent activators of CD8+ cytotoxic T cells [7] and promote T helper type 1 (Th1) responses in CD4+ T cells. Myeloid DCs also promote Th1 responses and are known as DC1 cells, while plasmacytoid DCs induce Th2 responses [8] and are thus known as DC2 cells.
Toll-like receptors
Toll-like receptors are a recently described family of transmembrane proteins that play an important role in the initiation of the innate immune response. To date, there have been 10 Toll-like receptors cloned that are designated TLR1-10. These molecules, first discovered in flies, are conserved across species and serve as an "early warning system" for recognition of microbial antigens. Most studies have focused on the ability of these proteins to recognize whole bacteria (such as Escherichia coli, Staphylococcus aureus and Mycobacterium tuberculosis) or bacterial products (such as lipopolysaccharide or CpG DNA). Toll-like receptors also recognize non-bacterial products such as yeast and respiratory syncytial virus. Activation of toll-like receptors results in the release of chemokines and other inflammatory mediators from dendritic cells and macrophages and modulates the expression of chemokine receptors on dendritic cells [9]. It is likely that several toll-like receptors act in concert to recognize foreign material and induce intracellular reactions that lead to immune activation [10].
1.2.2 Antigen-specific immunity
Cell-mediated immunity
T cells
T lymphocytes, or thymus-dependent lymphocytes, are essential components of the cellular immune system. These cells mediate delayed-type hypersensitivity reactions, regulate the development of antigen-specific antibody responses and provide specific host defense against a variety of organisms. Distinct sub-populations of T lymphocytes that express different cell surface proteins have been identified through the use of monoclonal antibodies. As different monoclonal antibodies may recognize similar cell surface proteins, a system has been developed which uses a cluster of differentiation (CD) nomenclature [11]. The lymphocyte subsets are identified through the use of flow cytometry techniques (fluorescent antibody cell sorting or FACS analysis). A summary of the function of lymphocytes and commonly used nomenclature is found in Table 1.2.
T cell receptor complex
T lymphocytes bear antigen-specific T cell receptors (TCR), which are required for the recognition and binding of foreign antigen. TCRs are composed of either alpha (α) and beta (β) chains or gamma (γ) and delta (δ) chains. Each of the chains has a variable amino-terminal portion involved in antigen recognition and a carboxy-terminal region that is constant. As the T lymphocytes mature, rearrangement of dispersed segments V (variable), D (diversity, β-chain only), J (joining) and C (constant) of the alpha, beta, gamma and delta chain genes of the TCR occurs so that these gene segments are contiguous [12], creating a unique TCR within each individual T cell with specific capacity to recognize particular antigens. It is through this gene rearrangement that the TCR diversity necessary for the recognition of thousands of antigens is developed. The predominant T cell type in lymphoid organs and in the peripheral circulation express a TCR with α/β chains (α/β T cells). T cells that express the γ/δ TCR chains (γ/δ T cells) are less abundant and located primarily in certain mucosal tissues such as the intestinal epithelium [13].
MHC molecules
Antigen-presenting cells present antigen to T cells in the form of short peptides complexed with major histocompatibility complex (MHC) molecules. These cell surface molecules were initially identified as the major antigens involved in the acceptance or rejection of transplanted tissues. Tissue transplanted from a donor whose cells express different MHC molecules than do the recipient cells will be recognized as "non-self" and be rejected. Similarly, when foreign antigens are complexed with MHC molecules, the complex is recognized as non-self by the TCR and an immune response is initiated [14]. Class Ⅰ MHC molecules are expressed on the surface of most cells and present endogenous antigens derived from the intracellular compartment of the cell (e.g. protein antigens derived from viruses infecting the host cells). Class Ⅱ MHC molecules exist primarily on the cell surface of "professional" antigen-presenting cells (monocytes, macrophages, dendritic cells, and B cells) and are able to present proteins which originate outside or within the cell (e.g. proteins derived from phagocytosed bacteria). CD4+ (helper/inducer) T cells preferentially recognize exogenous antigen bound to class Ⅱ MHC molecules, and CD8+ (cytotoxic) T cells preferentially recognize endogenous antigen bound to class Ⅰ MHC molecules [15].
| Lymphocyte type | Function | Type of antigen receptor | Common cell surface markers |
| T Lymphocytes | |||
| Helper | Regulation of the immune response Development of "memory" response to antigens | αβ T cell receptor | CD3+,CD4+, CD8- |
| Th1 | Cell-mediated Immunity - control of intracellular pathogens, DTH response Activates macrophages via cytokine elaboration (IFN-γ and IL-2) | αβ T cell receptor | CD3+,CD4+, CD8- |
| Th2 | Stimulates B lymphocyte differentiation and proliferation (humoral immunity) Elaborates cytokines involved primarily in the allergic response (IL-4, IL-5, IL-10) | αβ T cell receptor | CD3+,CD4+, CD8- |
| Cytotoxic | Lysis of tumor cells, virus-infected cells Stimulates cell-mediated immunity via cytokine production | αβ T cell Receptor | CD3+, CD4-, CD8+ |
| B lymphocytes | Production of antigen-specific immunoglobulins (humoral immune response) | Immunoglobulin molecules (IgG, IgM, IgE, IgA) | Fc receptors, MHC Ⅱ molecules CD20, CD19 |
| Natural killer (NK) lymphocytes | Lysis of virus-infected cells and tumor cells lacking MHC class Ⅰ; antibody-dependent cellular cytotoxicity | CD16, CD56 |
Antigen presentation
The initiation of a specific immune response to protein antigens begins when the TCR on mature T cells recognizes short peptides that have been processed and bound in a cleft in the MHC molecule of the antigen-presenting cell (APC). The CD3 molecule with which the TCR is invariably associated, mediates signal transduction from the TCR to the interior of the T cell. The TCR/ CD3 complex is essential for proper antigen recognition. Additional molecules expressed by T cells, termed accessory molecules, must also interact with the antigen-presenting cell to insure an appropriate T cell-mediated response [16]. Two of the major accessory molecules expressed by T cells are the CD4 and CD8 molecules. The extracellular portion of these molecules binds to the invariant regions of the class Ⅰ or class Ⅱ MCH molecules on antigen-presenting cells. Other molecules including CD28 and members of a class of proteins called integrins act as costimulatory signals for the induction of an appropriate immune response to vaccines and certain pathogens. Through TCR-MHC-antigen interaction, the T cell is activated, further differentiates and initiates the process to respond to the foreign protein. There are surface markers on T cells that change once the T cell TCR has encountered its specific antigen (cognate antigen) [11]. A subset of the adult peripheral CD4+ T cells (CD45RA+ CD29low) appear to be naïve cells that have not encountered specific antigen and form the pool of cells capable of responding to novel antigens. It is hypothesized that after an initial encounter with antigen, these cells develop into memory T cells with an altered phenotype (CD45RO+ CD29hi) [17]. These memory T cells are capable of rapid proliferation as well as increased cytokine production after rechallenge with a previously encountered antigen, allowing for a more rapid and expanded secondary host-response.
CD4+ T cells
The majority of peripheral α/β T cells also express CD4 or CD8 surface antigens. CD4+ T cells are generally referred to as the helper/inducer subset because of their central role in the induction and regulation of most aspects of the immune response. A major function of CD4+ T cells is to provide help to B cells for the production of antigen-specific antibody. B cells process internalized antigen and present antigen fragments bound to self-MHC molecules, thus activating CD4+ T cells. During the cell to cell interaction between B cells and CD4+ T cells, there is upregulation of various membrane molecules which increase the efficiency of the B cell - T cell interaction [18, 19]. In addition, CD40 ligand appears on the surface of the activated T cell. The interaction between CD40 on the B cell with CD40 ligand on the CD4+ T cell is essential for a normal humoral immune response [20]. Through both cell-cell contact and the production of cytokines, CD4+ cells are essential for the development of a normal antibody response including activating B-cells into antibody-secreting cells with the ability to undergo the antibody class switch process (see below). In addition, CD4+ T cells provide help for the generation of both the cytotoxic (see below) and suppressor function of CD8+ T cells. Memory T cells which are able to initiate a rapid immune response to previously encountered antigens (see above) are CD4+ T cells.
Th1 vs Th2 T cells
There appear to be two functionally distinct subsets of CD4 cells that are distinguished primarily by their relative expression of certain cytokines [21]. Th1 cells, which preferentially produce interferon-gamma and IL-2 enhance cellular immunity and macrophage activity. Th1 cells are important in the regulation of delayed-type hypersensitivity responses including granuloma formation and the killing of intracellular pathogens. Th2 cells produce IL-4, IL-5 and IL-10, and are involved in the regulation of humoral immunity. These cytokines play an important role in the development of allergic diseases, as IL-4 is essential for IgE production and IL-5 induces the proliferation and differentiation of eosinophils [22, 16]. Whether naïve CD4+ T cells differentiate into Th1 or Th2 cells depends on a variety of factors including the cytokine milieu, antigen dose and the nature of the specific antigen.
CD8+ T cells
CD8+ T cells are often referred to as the cytotoxic / suppressor subset due to their role as cytotoxic T cells as well as their role in the suppression of various immune responses [15]. The activation of CD8+ T cells by recognition of antigen bound to class Ⅰ MHC molecules results in the generation of antigen-specific cytolytic activity. As nearly all host cells express class Ⅰ MHC molecules, these cytolytic T lymphocytes (CTL) can respond to a viral infection of most host cells [16]. Through the production of several cytokines, particularly IL-2, CD4+ cells provide help to CD8+ T cells for the development of an effective CTL response [23].
Cytokines
Cytokines are soluble proteins produced by a variety of cells that modulate the immune response. The cytokines express their effects either locally or systematically by interacting with specific membrane receptors expressed by their target cells. Different cytokines may perform similar functions and affect multiple cell types, and may be functionally linked, either with synergistic or opposing effects. Cytokine functions include: (a) the regulation of lymphocyte growth and differentiation; (b) mediation of inflammation; and (c) the regulation of hematopoesis. Cytokines affecting T cells include the interleukins (IL), interferons, growth factors, and tumor necrosis factor (TNF) [16] (Table 1.3).
Chemokines
Chemokines are a relatively recently discovered family of cytokines whose primary role is regulation of chemotaxis [24]. There are over 40 chemokines grouped into four families. The largest families are comprised of the alpha and beta chemokines. Beta chemokines have two adjacent cysteine residues (CC) and alpha chemokines have one amino acid separating the first two cysteine residues (CXC). Chemokines appear to be produced by almost all cell types, particularly in response to inflammation. Proinflammatory cytokines such as interleukin 1 and TNF alpha [25], lymphokines such as IFN gamma and IL-4 [26], as well as bacterial LPS and viral infection can stimulate chemokine production.
Chemokines bind to specific receptors on the target cells. Most chemokine receptors bind more than one chemokine, however CC chemokine receptors bind only CC chemokines and CXC receptors only CXC chemokines. Different types of leucocytes express different chemokine receptors. Some receptors are restricted to specific cell types, while others are widely expressed (Table 1.4).
Chemokines play an important role in inflammatory disease. The type of inflammatory cells infiltrating the area of inflammation is determined partly by the subgroup of chemokines expressed by the affected tissue. For example, the concentration of the chemokine IL-8 is increased in alveolar fluid from patients with pneumonia, resulting in an influx of neutrophils [27]. In contrast, in viral meningitis, the concentration of chemokines IP-10 and MCP-1 in the cerebrospiral fluid (CSF) is increased, recruiting monocytes and lymphocytes [28]. The chemokine system provides an important link between the innate and adaptive immune systems. Dendritic cells pick up foreign antigen in the tissues to carry to regional lymph nodes where naïve B and T cells are activated. The activated cells then traffic back to sites of inflammation. The chemokine system regulates this dendritic cell and lymphocyte trafficking - bringing the antigen-loaded dendritic cells and naïve lymphocytes together to generate the adaptive immune response and then delivering the adaptive effector response to sites of inflammation and infection [9].
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