Chapter 440. The Spleen and Lymph Nodes

The spleen is the largest lymphoid organ in the body and plays a vital role in hematologic functions as well as in the defense of the body against invading pathogens.

The spleen is first identifiable during the fifth week of embryogenesis. It weighs about 10 to 11 g at birth and enlarges throughout childhood until it reaches its maximum size of 100 to 200 g by adulthood.1 The spleen receives its blood supply via the splenic artery and drains into the portal system via the splenic vein. The spleen has two major compartments: the white pulp (which serves the immunologic functions) and the red pulp (the area where blood is filtered). A marginal zone separates the red and white pulp and functions primarily for presentation and processing of antigens.

White Pulp

Arterioles entering the splenic tissue become surrounded by T lymphocytes (periarteriolar lymphoid sheaths). B lymphocytes also lie adjacent to the arterioles within germinal centers. Due to the angle of the small artery branches leaving the central arteries and entering the white pulp, the plasma is effectively “skimmed off” into the white pulp. The remaining erythrocytes then enter the red pulp.

Red Pulp

The red pulp is the largest area of the spleen. It is composed of splenic sinuses as well as an open meshwork of passages (the cords of Billroth). Ninety percent of the blood entering the spleen flows directly, but slowly, through the cords, allowing the macrophages lining their walls to remove aged and damaged red blood cells and particulate matter. In these cords, the red blood cells are forced to squeeze through narrow fenestrations between endothelial cells before entering the sinuses and eventually draining into the splenic vein.

Reservoir

The spleen receives about 6% of the cardiac output, but at any one time contains only about 50 mL of blood.1 About 30% of the circulating platelet mass is sequestered within the spleen. In cases of splenomegaly, a higher volume of blood may become trapped (see “Hypersplenism/Asplenia,” below).

Hematopoiesis

Throughout the second trimester, the spleen plays an active role in hematopoiesis. At birth, little to no splenic hematopoiesis continues. However, in some disease states, such as myelofibrosis, osteopetrosis, or severe hemolytic anemia, the spleen can resume its hematopoietic functions.

Red Blood Cell Clearance

Culling

Due to the unique structure and harsh environment of the spleen’s red pulp, it plays a key role in the removal or culling of aged or damaged red cells from the circulation. Young, normal red cells are able to tolerate the demands of this environment, but as cells age or are damaged, they become rigid and can no longer maneuver through the splenic cords and pass through the small slits between endothelial cells into the sinuses. These cells are sequestered in the spleen where they ultimately undergo phagocytosis by macrophages.

Pitting

A unique function of the spleen is to selectively remove intraerythrocyte inclusions while allowing the intact red cell to reenter the circulation. This “pitting” function removes rigid inclusions, such as Howell-Jolly bodies, Heinz bodies, iron granules, malarial parasites, and membrane surface pits or pocks, as the erythrocytes traverse narrow fenestrations in the red pulp.

Remodeling

Young reticulocytes generally spend their first few days sequestered in the spleen where they are remodeled as surface area is reduced, unnecessary cytoplasmic organelles and surface adhesion molecules are removed, and the membrane surface becomes more negatively charged.

Immune Function

The spleen is the principal site of phagocytosis of blood-borne antigens and antibody-coated cells. Particulate antigens interact directly with macrophages and other antigen-presenting cells in the periarteriolar lymphoid sheaths. Microorganisms, particularly encapsulated bacteria, are also removed by the splenic macrophages. When antibody-coated cells, including red cells and platelets, pass through the spleen, they may also undergo phagocytosis by macrophages.1 For example, in autoimmune hemolytic anemia, red cells coated in IgG are recognized by the splenic macrophages whose receptors bind to the Fc region of the IgG molecule. Portions of the erythrocyte membrane are subsequently removed, thus rendering them spherocytic. These inflexible spherocytes are then less capable of passing through the splenic environment and become trapped in the spleen and ultimately destroyed.

The spleen also produces antibodies after splenic macrophages present blood-borne antigens to the lymphocytes in the white pulp. In the absence of a spleen, an individual will have a reduced capacity to produce specific IgM and decreased ability to phagocytize microorganisms; the individual will therefore be susceptible to overwhelming sepsis from primarily encapsulated bacteria such as Streptococcus pneumoniae or Haemophilus influenzae type b (see below).

Although the normal spleen is usually not palpable on physical exam, the splenic tip may be felt in approximately 3% to 5% of normal children and adolescents.2 As the spleen enlarges, it moves downward, and the lower pole may cross the midline toward the right lower quadrant. Palpation of the spleen with the patient in the supine position should begin in the right lower quadrant of the abdomen and should move diagonally to the left upper quadrant. This method will ensure that the examiner does not overlook a massively enlarged spleen. Occasionally, a mildly enlarged spleen may be best palpated with the patient in the right lateral decubitus position. In addition, ultrasonography may be used to assess splenic size as well as to differentiate the spleen from other abdominal masses.

Etiology

Mild splenomegaly may occur in many diseases in which there is an abundant immune response (eg, infectious mononucleosis, cytomegalovirus, or subacute bacterial endocarditis). It is also frequently seen in individuals with chronic hemolysis (eg, hereditary spherocytosis, sickle cell disease, thalassemia intermedia or major, or pyruvate kinase deficiency). Congestive splenomegaly can occur with cirrhosis or following portal or splenic vein thrombosis. Infiltrative splenomegaly can occur with Gaucher disease and may be the presenting feature. Chronic myelogenous leukemia, sarcoidosis, myeloproliferative disorders, and lymphoma are other more rare etiologies of splenomegaly in children. Splenomegaly may also occur secondary to large hemangiomas, splenic cysts, and other malformations, and these may be identified on imaging studies.

Hypersplenism

In general, the term hypersplenism describes a tetrad of (1) splenomegaly, (2) any combination of cytopenias, (3) compensatory bone marrow hyperplasia, and (4) improvement after splenectomy. Hypersplenism most commonly is associated with congestive splenomegaly resulting from pooling of blood in the enlarged spleen. The degree of cytopenia varies greatly, and in the case of congestive splenomegaly, the blood cells may be released from the spleen in times of need; therefore, these patients are not at an increased risk of bleeding or infection. Occasionally, however, hypersplenism results in marked destruction of the red cells and platelets so that splenectomy may be indicated.

Hyposplenism/Asplenia

Assessing Splenic Function

Several hematologic changes occur following splenectomy or in patients with congenital or acquired hyposplenism and can be diagnostic. Howell-Jolly bodies (intracellular nuclear remnants) become apparent in peripheral red blood cells and can be visualized under light microscopy on a routine blood smear. Red cell surface “pits” are not cleared following splenectomy or in patients with functional asplenia. Therefore, an elevated pit count, or percentage of red cells with pits, is a sensitive and specific marker of hyposplenia. However, visualization requires specialized optical contrast microscopy not readily available in clinical laboratories. Technetium-99m-sulfur colloid or technetium-99m-labeled heat-damaged red cell spleen scans may also be used to evaluate for the presence or absence of a functioning spleen as well as to document the location of any accessory splenic tissue.

In addition to Howell-Jolly bodies, nonspecific hematologic changes following splenectomy may include the appearance of target cells, acanthocytes, red cell fragments, and basophilic stippling in smears of peripheral blood. Leukocyte counts and platelet counts often rise following splenectomy and may persist for years.

Congenital Asplenia

Heterotaxy disorders can generally present with polysplenia or asplenia. Ivemark syndrome is associated with congenital absence of the spleen in addition to cyanotic congenital heart defects, dextrocardia or mesocardia, abdominal heterotaxy, and symmetrically trilobed lungs, in addition to other abnormalities.3

Isolated congenital asplenia without heterotaxy or heart defects is a rare recessively transmitted condition, usually discovered incidentally in the workup of a child with episodes of severe sepsis. A mutation of a homeobox gene designated as HOX11 that regulates embryonic splenogenesis may be the cause of this rare disorder.4

Medical Conditions Associated with Hyposplenism

The most common medical condition associated with functional hyposplenism is sickle cell disease. Children with sickle cell anemia develop this complication during infancy and early childhood because of alterations in splenic circulation caused by intrasplenic sickling. Despite splenic enlargement, its function is paradoxically reduced, as evidenced by circulating Howell-Jolly bodies and increased percentage of pocked red blood cells. These children are at high risk of bacterial sepsis and meningitis, especially in the first 5 years of life. As a child with sickle cell disease grows older (typically by age 5 years) the spleen shrinks in size and becomes atrophic due to repeated episodes of autoinfarction.

Hyposplenism has also been described in a variety of immunologic and autoimmune disorders (see Table 440-2). Some of these diseases have been reported to be accompanied by an increased risk of bacterial sepsis and are associated with circulating Howell-Jolly bodies and pitted erythrocytes.

Surgical Splenectomy

Indications for splenectomy can be conveniently divided into medical (hematologic) and surgical categories. Medical indications include congenital hemolytic anemias, such as hereditary spherocytosis or immune thrombocytopenic purpura. Splenectomy is often indicated in these conditions since the intrinsically abnormal or antibody-coated red blood cells or platelets are prematurely destroyed by the spleen. In storage diseases such as Gaucher disease, massive splenomegaly may develop and become a mechanical burden.

Total splenectomy is generally performed via an open laparotomy; however, laparoscopic techniques are gaining popularity and may be suitable when the spleen is not massively enlarged. Partial splenectomy is also a feasible alternative in some patients; however, the benefit of this procedure (control of the primary condition as well as preservation of splenic phagocytic and immunologic functions) remains controversial.1

Splenosis

In up to 23% of splenectomies performed for abdominal trauma, small remnants of the ruptured spleen will become implanted in the omentum or on peritoneal surfaces of the abdominal cavity and will retain some splenic phagocytic activity.5 This phenomenon is known as splenosis. Accessory spleens, usually located in the splenic hilum, are found in as many as 10% to 15% of normal individuals. Hypertrophy of accessory spleens or splenosis may cause recurrence of immune thrombocytopenic purpura or autoimmune hemolytic anemia after an initially successful splenectomy.

Splenic Cysts

There are two types of splenic cysts. Pseudocysts result from intrasplenic infarction or hemorrhage with subsequent liquefaction of splenic tissue and blood within a fibrous capsule. Epidermoid splenic cysts contain clear fluid and have an epidermal lining.

Consequences of Hyposplenia/Asplenia

The most concerning complication of functional hyposplenism or splenectomy is the risk of bacterial sepsis. Bacteremia in an asplenic host may evolve rapidly into fatal sepsis, sometimes referred to as overwhelming postsplenectomy infection (OPSI) syndrome. Encapsulated organisms including S pneumoniae, H influenza type b, and Neisseria meningitidis are the primary organisms responsible for OPSI. Asplenic patients also appear to be at increased risk of serious infections with Bartonella bacilliformis. The incidence of OPSI varies according to the underlying condition associated with the hyposplenism or for which splenectomy was performed, with patients with sickle cell disease or malignancy at greatest apparent risk. Children younger than 5 years of age appear at highest risk, and the risk is thought to decrease as the interval following splenectomy increases.1 Nonetheless, reports of postsplenectomy sepsis have occurred in individuals many decades following splenectomy, so asplenic individuals likely remain at risk of bacterial infections for life. No studies, however, have evaluated the risk of OPSI in the present era of routine vaccination with heptavalent pneumococcal conjugate vaccine.

Splenectomy or functional asplenia may also be associated with an increased risk of thrombotic events and pulmonary arterial hypertension. Limited evidence in persons with hereditary spherocytosis has suggested that prior splenectomy may increase the risk of arteriothrombotic events such as myocardial infarction or stroke.6 The prevalence of asplenia has been reported to be increased in persons with pulmonary arterial hypertension, and this complication is common in children and adults with sickle cell disease and functional asplenia and thalassemia following splenectomy.7-9 Portal venous thrombosis is a recognized complication of surgical splenectomy and may be more common following laparoscopic procedures and in patients with very large spleens. The reasons for this increased risk of vascular and thrombotic complications after splenectomy is likely multifactorial and may include a change in lipid profiles, thrombocytosis, procoagulant changes in the red blood cell membrane, and decreased nitric oxide bioavailability when ongoing intravascular hemolysis is present.10

Management of Children with Asplenia/Hyposplenism

Prophylactic therapy with oral penicillin twice daily or an equivalent antibiotic is strongly recommended for infants or young children who have hyposplenia or asplenia.11 In a prospective double-blind trial of sickle cell disease patients less than 3 years old with functional hyposplenia, oral penicillin prophylaxis was shown to reduce the incidence of bacteremia by 84%.12 A second controlled study showed no significant benefit of penicillin prophylaxis after 5 years of age.13 The emergence of penicillin-resistant pneumococci may reduce the effectiveness of penicillin prophylaxis.

Children with asplenia or splenic dysfunction should be immunized with vaccines against S pneumoniae, H influenzae type b, and N meningitidis. The 23-valent pneumococcal polysaccharide vaccine is currently recommended for all children with anatomic or functional asplenia at 24 months of age, with a second dose given 3 to 5 years later. The heptavalent pneumococcal conjugate vaccine is immunogenic in infants and should be given according to recommended vaccination schedules. The conjugate H influenzae type b vaccine has virtually eliminated infections caused by this pathogen. Current recommendations also include vaccinating children with anatomic or functional asplenia who are older than age 2 years with the tetravalent meningococcal polysaccharide or conjugate vaccine, depending on age. If a child requires an elective splenectomy, these immunizations should be given at least 2 weeks in advance of surgery if feasible, but are also effective when given after splenectomy.14,15

Parents of children with splenic dysfunction must be educated to regard significant febrile illnesses (⩾ 101.5°F) as signaling a potentially life-threatening situation that mandates prompt evaluation by a physician. After a blood culture has been obtained, a parenteral broad-spectrum antibiotic, currently a third-generation cephalosporin, should be administered. A syndrome of severe and frequently fatal infection by Capnocytophaga canimorsus acquired from a sometimes trivial dog bite has been reported, so asplenic patients should be treated empirically with amoxicillin/clavulanic acid after dog bites.

Special Precautions in Children with Enlarged Spleens

Acutely enlarged spleens that are not protected by the rib cage (eg, as in infectious mononucleosis) are at increased risk of rupture following splenic trauma. Children with massive or acute splenomegaly should avoid contact sports and other physical activities associated with significant risk of abdominal injury.16 The risk of splenic rupture following trauma in patients with chronic, moderately enlarged spleens (eg, hereditary spherocytosis) is not well-established.

Structure

Lymph nodes are small bean-shaped organs that are connected by lymphatic vessels and are located throughout the body. Lymph nodes are covered a fibrous capsule under which lies the subcapsular sinus. Lymph enters the sinus via the afferent lymphatic vessel, flows through trabeculae into the center of the node, and subsequently leaves the node through the efferent lymphatics. The parenchyma of the node is made up of the cortex, paracortex, and medulla.

The cortex, the outer part of the lymph node, is its most cellular region. The cortex primarily contains B lymphocytes densely packed in areas known as lymphoid follicles, the predominant area for lymphocyte proliferation. The paracortex consists mainly of T lymphocytes that do not aggregate as follicles. The deeper medulla contains the extensions of the cortical parenchyma known as medullary cords. Plasma cells are predominant here and are actively involved in immunoglobulin synthesis.

Function

Lymph nodes are the primary site for interaction between antigens carried within the lymph and phagocytic cells. Lymph nodes also participate in clearance of malignant cells via the phagocytic activity of macrophages. B and T lymphocytes aggregate and proliferate within the nodes in response to antigenic stimulation. The B lymphocytes may become activated, leading to plasma cell formation and antibody production. T lymphocytes present in the node may initiate cytotoxic immune responses following activation by specific antigens.

Lymphadenopathy

The approach to a child with lymphadenopathy can often be challenging. Most instances of lymphadenopathy represent transient, reactive processes that resolve without any intervention. However, lymphadenopathy may also be the presenting feature of a serious underlying illness. Therefore, a careful and thorough history and physical exam must be undertaken to look for clues to the etiology of the enlarged nodes. Helpful information may include the duration of the adenopathy, whether the nodes are tender, the presence of systemic systems, or recent localized infections in the area from which the nodes drain. Recent contact with cats or rodents should be elicited. Current medications should be reviewed, as some drugs can cause a generalized adenopathy specifically or through a serum sickness-like reaction. A complete assessment of all superficial nodes should be performed to determine if the adenopathy is generalized or localized to only 1 region. Enlargement of the lymph node may be due either to proliferation of lymphocytes or other cells present in the lymph node or to infiltration by other circulating white blood cells or malignant cells.17eTable 440.1 lists some of the more common etiologies of childhood lymphadenopathy.

The evaluation of the child with lymphadenopathy should be based on the history and physical findings. Generally, tender lymph nodes in the anterior cervical region are indicative of upper respiratory infections. Axillary adenopathy may be observed in cat-scratch fever. Bacterial lymphadenitis is usually accompanied by fever with tender nodes and signs of overlying inflammation of the skin or fluctuance of the node. Massive bilateral cervical adenopathy may be present in conditions such as sarcoidosis, sinus histocytosis with massive lymphadenopathy (Rosai-Dorfman disease), and systemic lupus erythematosus. Inguinal adenopathy may accompany sexually transmitted diseases. The presence of enlarged supraclavicular or posterior cervical nodes should raise the suspicion of a possible malignancy. Nodes that are rock hard or very firm and rubbery might also suggest a malignant etiology.17

The management of a child with regional lymphadenopathy should be individually tailored based on the suspected etiology. In general, asymptomatic adenopathy may include close observation and/or a trial of antibiotic therapy over a 2- to 4-week period. A lymph node biopsy may be indicated if the node continues to enlarge rapidly or fails to resolve in the 4-week period. Other indications for early lymph node biopsy may include constitutional symptoms such as prolonged fevers, weight loss, night sweats, fatigue, bone pain, or abnormal screening laboratory studies. The workup of generalized adenopathy may include complete blood counts; blood cultures and/or serologic testing for bacteria, fungus, Epstein-Barr virus, cytomegalovirus, toxoplasmosis, and HIV; and a chest radiograph to evaluate for the presence of a mediastinal mass or adenopathy. If the etiology of the generalized adenopathy is not clear following these tests, a lymph node biopsy may be warranted.17