Infections in Asplenic Patients

After discovery of the spleen, which occurred sometime during the dawn of human dissection, its true role in health and disease remained a mystery for many generations. At the time of Galen, the spleen was thought to be important in removing “black choler” from the body; black choler (or black bile), according to Hippocrates, was one of the four humors thought to regulate bodily functions. The spleen and its various secretions were also implicated in a number of emotional imbalances. Excess black choler due to splenic failure was thought to be the cause of melancholy, whose name is derived from the words for “black” and “bile.” Further, a person described as “splenetic” was hot-tempered or hasty in judgment, and “venting one's spleen” suggests a burst of pent-up anger. Black choler, a cold humor, was believed to counteract the effects of the two hot humors (blood and phlegm). Although the fourth humor, yellow bile, was known to be excreted by the gallbladder into the intestine, the mode of excretion of black bile was not known to the ancients.

More recently the spleen has been recognized for its important role in protecting vertebrates from infection. It represents approximately 25% of the total lymphoid mass of the human body and contains half the body's monocytes and immunoglobulin-producing B lymphocytes. Although not vital to human survival, the spleen plays an important role in the host's ability to combat both invasive bacteria, particularly those possessing polysaccharide capsules, and intraerythrocytic parasites.

Anatomy of the Spleen

The embryonic precursor of the spleen is the mesenchyme of the dorsal mesogastrium, and the splenic red and white pulp are developed by the sixth month of fetal life. Normally located posteriorly in the left side of the peritoneal cavity, the spleen sits below the diaphragm, and its hilum, which contains the splenic artery and vein, is in close proximity to the tail of the pancreas. The normal organ is roughly the size of the patient's fist and weighs between 80 and 200 g in adult males and 70 and 180 g in adult females, but it can quickly enlarge in response to infection or inflammation. Aerated blood enters the spleen from the aorta via the splenic artery and short gastric arteries and, like the thymus, the spleen possesses only efferent lymphatic vessels. The normal spleen, which receives approximately 6% of the cardiac output, is surrounded by a fibromuscular capsule.

The spleen consists of three anatomically distinct zones: red pulp, white pulp (seen as white nodules on the cut surface), and marginal zone ( Fig. 311.1 ). Red pulp, the largest component of the spleen, is composed of a complex network of endothelium-lined venous sinuses and the Billroth cords, which contain fibrils, connective tissue, and large numbers of macrophages. White pulp, made up of islands within the red pulp that are composed of reticular structures that surround penicilliary arterioles, contains primarily T lymphocytes within the periarteriolar lymphoid sheath, as well as fewer B lymphocytes and natural-killer lymphocytes. Lymphoid follicles arise within this sheath, and on immunologic stimulation, the activated follicles form germinal centers similar to those seen in reactive lymph nodes. Located at the intersection of the red pulp and white pulp, the marginal zones are composed primarily of B cells (including memory cells) but also contain both T cells and antigen-presenting cells, such as Toll-like receptor–bearing macrophages or dendritic cells. Thus white pulp and the marginal zones, where antigen-presenting cells, bacterial antigens, and T and B lymphocytes are in close proximity, are sites of considerable importance in the coordinated immune response to circulating antigens.

FIG. 311.1, Normal splenic architecture in the adult human.

Function of the Spleen

The contribution of the spleen to controlling overwhelming infection was first recognized in 1952 by King and Schumacker, who reported life-threatening bacterial infections in splenectomized infants. Since then, the mechanisms by which the spleen combats bacterial infection, such as filtration, phagocytosis, and opsonization of bacteria, as well as regulation of inflammatory responses, have been carefully elucidated. The percentage of CD8 ⁺ T cells is higher in the spleen than in the peripheral blood, leading to an inverse splenic CD4/CD8 ratio. Further, both CD4 and CD8 cell populations in the spleen show a higher number of activated cells, and the splenic CD8 ⁺ T cells show a more differentiated cytotoxic CD27 ⁻ CD45RA ⁺ memory phenotype. The multiple types of immune cells in close approximation within the spleen engage in complex interactions; are subject to the varied effects of autocrine and paracrine signaling; and migrate into, within, and out of the spleen—all contributing to the extraordinary repertoire of innate and adaptive immune responses important in protecting the host against bacterial and parasitic infections.

Regulation of Inflammation

The impact of the spleen on inflammation is evident by the increased production of proinflammatory cytokines during sepsis, which is, in part, mediated by nicotinic acetylcholine receptors in the spleen. This inflammatory response can be dampened by vagal nerve stimulation or the administration of nicotine. In normal mice, administration of nicotine protected from polymicrobial sepsis by decreasing production of the proinflammatory mediator, high mobility group box-1 (HMGB1), but in splenectomized mice, administration of nicotine failed to reduce HMGB1 levels and decreased survival during sepsis. Similarly, although vagal nerve stimulation suppresses tumor necrosis factor (TNF) production in response to endotoxin administration in intact mice, no decrease was noted in splenectomized mice. This decrease in TNF production after vagal nerve stimulation occurs through stimulation of splenic acetylcholine-producing T cells by norepinephrine. These findings suggest that loss of control of inflammation through this newly appreciated inflammatory reflex pathway may play a role in the inflammatory storm seen during postsplenectomy sepsis. Further, cytokines produced by splenic macrophages appear to modulate the febrile response to bacterial components, including lipopolysaccharide.

Filtration and Clearance

The red pulp serves as a filter that provides grooming (antibody removal), pitting (intracellular material removal), and culling (cell destruction) functions to clear the blood of debris. As peripheral blood percolates through the splenic sinusoids, damaged cellular elements, senescent erythrocytes, cell-associated antibodies, circulating unopsonized bacteria, erythrocytes harboring malarial or babesial parasites, and foreign particles are removed, and platelets, erythrocytes, and iron are sequestered. The major defect associated with infectious risk of patients with asplenia or hyposplenia is impaired clearance of poorly opsonized particulate antigens, such as bacteria.

Adaptive Immunity

After exposure of the host to microbial antigens (e.g., through vaccination or bacteremia), T cell–dependent B-cell activation in the spleen begins through antigen interactions with T-helper lymphocytes, stimulating B lymphocytes to rapidly differentiate into either antigen-presenting cells or immunoglobulin M (IgM)-producing plasma cells. After activation in the marginal zone, B and T cells, along with dendritic cells, are attracted to the periarteriolar lymphoid sheath of the splenic white pulp by cell-specific chemokines, where they facilitate T cell–dependent B-cell responses. Activated B cells undergo further maturation and clonal expansion in the splenic germinal centers, where, through contact with activated T cells, they undergo isotype switching into plasma cells capable of producing high-affinity antibodies or switched memory B cells. Antigen-specific plasma cells that have differentiated in the white pulp lodge in the red pulp in close proximity to macrophages, where antigenic sampling occurs. This process is mediated by upregulation of CXC-chemokine receptor 4 (CXCR4), which binds CXC-chemokine ligand 12 (CXCL12) expressed in the red pulp. Generation of IgM and IgG2 antibodies against polysaccharide antigens, which represent largely T-cell–independent responses, occurs in the marginal zone of the spleen and is profoundly compromised by splenectomy.

Innate Immunity

The marginal zone of the spleen is responsible for trapping and processing circulating antigens in the course of peripheral blood circulating through its rich beds of macrophages. Marginal zone macrophages are proficient in processing carbohydrate antigens through lectin receptors on their surfaces and through their scavenger activities. Unlike other B-cell lineages, marginal zone B cells, characterized as IgM ⁺ IgD ⁺ CD27 memory cells, develop during ontogeny and mutate their immunoglobulin receptors during the first years of life without prior engagement in an immune response. On stimulation with thymus-independent polysaccharide antigens expressed by encapsulated bacteria, the prediversified IgM memory B cells of the marginal zone do not differentiate into switched memory cells, but, rather, represent an immediate innate immune defense, as opposed to a memory-dependent adaptive defense, against invading pathogens. Thus, in asplenic hosts, this polysaccharide-specific immune function is lost, placing the patients at increased risk of infection with polysaccharide-encapsulated bacteria.

Hematopoiesis/Hemostasis

During the second trimester of fetal life, hematopoiesis actively occurs in the spleen and then wanes in the third trimester, although hematopoietic stem cells remain in the spleen through adult life. In the face of bone marrow failure, such as myelofibrosis, extramedullary hematopoiesis may occur in the spleen with the appearance of erythroid and megakaryocytic, and, to a lesser extent, myeloid precursors. Further, the spleen contributes to hemostasis through the production of factor VIII and von Willebrand factor.

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