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InternalMed_Harrison. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis d. Chlamydial—lymphogranuloma venereum, trachoma e. Parasitic—toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis f. Rickettsial—scrub typhus, rickettsialpox, Q fever 2. Immunologic diseases a. b. c. d. e. f. g. h. Drug hypersensitivity—diphenylhydantoin, hydralazine, allopurinol, primidone, gold, carbamazepine, etc. i. j. k. l. m. Autoimmune lymphoproliferative syndrome n. IgG4-related disease o. 3. Malignant diseases a. Hematologic—Hodgkin’s disease, non-Hodgkin’s lymphomas, acute or chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis, amyloidosis b. 4. Lipid storage diseases—Gaucher’s, Niemann-Pick, Fabry, Tangier 5. 6. a. b. c. d. e. f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) g. h. i. g. k. Vascular transformation of sinuses l. Inflammatory pseudotumor of lymph node m.


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InternalMed_Harrison. a. b. c. d. e. f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) g. h. i. g. k. Vascular transformation of sinuses l. Inflammatory pseudotumor of lymph node m. Congestive heart failure Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus. with cervical adenopathy and a history of tobacco use. Localized or regional adenopathy implies involvement of a single anatomic area. Generalized adenopathy has been defined as involvement of three or more noncontiguous lymph node areas. Many of the causes of lymphadenopathy (Table 79-1) can produce localized or generalized adenopathy, so this distinction is of limited utility in the differential diagnosis. Nevertheless, generalized lymphadenopathy is frequently associated with nonmalignant disorders such as infectious


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases mononucleosis (Epstein-Barr virus [EBV] or cytomegalovirus [CMV]), toxoplasmosis, AIDS, other viral infections, systemic lupus erythematosus (SLE), and mixed connective tissue disease. Acute and chronic lymphocytic leukemias and malignant lymphomas also produce generalized adenopathy in adults.


InternalMed_Harrison

InternalMed_Harrison. The site of localized or regional adenopathy may provide a useful clue about the cause. Occipital adenopathy often reflects an infection of the scalp, and preauricular adenopathy accompanies conjunctival infections and cat-scratch disease. The most frequent site of regional adenopathy is the neck, and most of the causes are benign—upper respiratory infections, oral and dental lesions, infectious mononucleosis, or other viral illnesses. The chief malignant causes include metastatic cancer from head and neck, breast, lung, and thyroid primaries. Enlargement of supraclavicular and scalene nodes is always abnormal. Because these nodes drain regions of the lung and retroperitoneal space, they can reflect lymphomas, other cancers, or infectious processes arising in these areas. Virchow’s node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian


InternalMed_Harrison

InternalMed_Harrison. node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are nonneoplastic causes of supraclavicular adenopathy. Axillary adenopathy is usually due to injuries or localized infections of the ipsilateral upper extremity. Malignant causes include melanoma or lymphoma and, in women, breast cancer. Inguinal lymphadenopathy is usually secondary to infections or trauma of the lower extremities and may accompany sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or chancroid. These nodes may also be involved by lymphomas and metastatic cancer from primary lesions of the rectum, genitalia, or lower extremities (melanoma).


InternalMed_Harrison

InternalMed_Harrison. The size and texture of the lymph node(s) and the presence of pain are useful parameters in evaluating a patient with lymphadenopathy. Nodes <1.0 cm2 in area (1.0 cm × 1.0 cm or less) are almost always secondary to benign, nonspecific reactive causes. In one retrospective analysis of younger patients (9–25 years) who had a lymph node biopsy, a maximum diameter of >2 cm served as one discriminant for predicting that the biopsy would reveal malignant or granulomatous disease. Another study showed that a lymph node size of 2.25 cm2 (1.5 cm × 1.5 cm) was the best size limit for distinguishing malignant or granulomatous lymphadenopathy from other causes of lymphadenopathy. Patients with node(s) ≤1.0 cm2 should be observed after excluding infectious mononucleosis and/or toxoplasmosis unless there are symptoms and signs of an underlying systemic illness.


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InternalMed_Harrison. The texture of lymph nodes may be described as soft, firm, rubbery, hard, discrete, matted, tender, movable, or fixed. Tenderness is found when the capsule is stretched during rapid enlargement, usually secondary to an inflammatory process. Some malignant diseases such as acute leukemia may produce rapid enlargement and pain in the nodes. Nodes involved by lymphoma tend to be large, discrete, symmetric, rubbery, firm, mobile, and nontender. Nodes containing metastatic cancer are often hard, nontender, and non-movable because of fixation to surrounding tissues. The coexistence of splenomegaly in the patient with lymphadenopathy implies a systemic illness such as infectious mononucleosis, lymphoma, acute or chronic leukemia, SLE, sarcoidosis, toxoplasmosis, cat-scratch disease, or other less common hematologic disorders. The patient’s story should provide helpful clues about the underlying systemic illness.


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InternalMed_Harrison. Nonsuperficial presentations (thoracic or abdominal) of adenopathy are usually detected as the result of a symptom-directed diagnostic workup. Thoracic adenopathy may be detected by routine chest radiography or during the workup for superficial adenopathy. It may also be found because the patient complains of a cough or wheezing from airway compression; hoarseness from recurrent laryngeal nerve involvement; dysphagia from esophageal compression; or swelling of the neck, face, or arms secondary to compression of the superior vena cava or subclavian vein. The differential diagnosis of mediastinal and hilar adenopathy includes primary lung disorders and systemic illnesses that characteristically involve mediastinal or hilar nodes. In the young, mediastinal adenopathy is associated with infectious mononucleosis and sarcoidosis. In endemic regions, histoplasmosis can cause unilateral paratracheal lymph node involvement that mimics lymphoma. Tuberculosis can also cause unilateral


InternalMed_Harrison

InternalMed_Harrison. with infectious mononucleosis and sarcoidosis. In endemic regions, histoplasmosis can cause unilateral paratracheal lymph node involvement that mimics lymphoma. Tuberculosis can also cause unilateral adenopathy. In older patients, the differential diagnosis includes primary lung cancer (especially among smokers), lymphomas, metastatic carcinoma (usually lung), tuberculosis, fungal infection, and sarcoidosis.


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InternalMed_Harrison. Enlarged intraabdominal or retroperitoneal nodes are usually malignant. Although tuberculosis may present as mesenteric lymphadenitis, these masses usually contain lymphomas or, in young men, germ cell tumors.


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InternalMed_Harrison. The laboratory investigation of patients with lymphadenopathy must be tailored to elucidate the etiology suspected from the patient’s history and physical findings. One study from a family practice clinic evaluated 249 younger patients with “enlarged lymph nodes, not infected” or “lymphadenitis.” No laboratory studies were obtained in 51%. When studies were performed, the most common were a complete blood count (CBC) (33%), throat culture (16%), chest x-ray (12%), or monospot test (10%). Only eight patients (3%) had a node biopsy, and half of those were normal or reactive. The CBC can provide useful data for the diagnosis of acute or chronic leukemias, EBV or CMV mononucleosis, lymphoma with a leukemic component, pyogenic infections, or immune cytopenias in illnesses such as SLE. Serologic studies may demonstrate antibodies specific to components of EBV, CMV, HIV, and other viruses; Toxoplasma gondii; Brucella; and so on. If SLE is suspected, antinuclear and anti-DNA antibody studies


InternalMed_Harrison

InternalMed_Harrison. studies may demonstrate antibodies specific to components of EBV, CMV, HIV, and other viruses; Toxoplasma gondii; Brucella; and so on. If SLE is suspected, antinuclear and anti-DNA antibody studies are warranted.


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InternalMed_Harrison. The chest x-ray is usually negative, but the presence of a pulmonary infiltrate or mediastinal lymphadenopathy would suggest tuberculosis, histoplasmosis, sarcoidosis, lymphoma, primary lung cancer, or metastatic cancer and demands further investigation.


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InternalMed_Harrison. A variety of imaging techniques (computed tomography [CT], magnetic resonance imaging [MRI], ultrasound, color Doppler ultrasonography) have been used to differentiate benign from malignant lymph nodes, especially in patients with head and neck cancer. CT and MRI are comparably accurate (65–90%) in the diagnosis of metastases to cervical lymph nodes. Ultrasonography has been used to determine the long axis, short axis, and a ratio of long to short (L/S) axis in cervical nodes. An L/S ratio of <2.0 has a sensitivity and a specificity of 95% for distinguishing benign and malignant nodes in patients with head and neck cancer. This ratio has greater specificity and sensitivity than palpation or measurement of either the long or the short axis alone.


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InternalMed_Harrison. The indications for lymph node biopsy are imprecise, yet it is a valuable diagnostic tool. The decision to biopsy may be made early in a patient’s evaluation or delayed for up to 2 weeks. Prompt biopsy should occur if the patient’s history and physical findings suggest a malignancy; examples include a solitary, hard, nontender cervical node in an older patient who is a chronic user of tobacco; supraclavicular adenopathy; and solitary or generalized adenopathy that is firm, movable, and suggestive of lymphoma. If a primary head and neck cancer is suspected as the basis of a solitary, hard cervical node, then a careful ENT examination should be performed. Any mucosal lesion that is suspicious for a primary neoplastic process should be biopsied first. If no mucosal lesion is detected, an excisional biopsy of the largest node should be performed. Fine-needle aspiration should not be performed as the first diagnostic procedure. Most diagnoses require more tissue than such aspiration can


InternalMed_Harrison

InternalMed_Harrison. biopsy of the largest node should be performed. Fine-needle aspiration should not be performed as the first diagnostic procedure. Most diagnoses require more tissue than such aspiration can provide, and it often delays a definitive diagnosis. Fine-needle aspiration should be reserved for thyroid nodules and for confirmation of relapse in patients whose primary diagnosis is known. If the primary physician is uncertain about whether to proceed to biopsy, consultation with a hematologist or medical oncologist should be helpful. In primary care practices, <5% of lymphadenopathy patients will require a biopsy. That percentage will be considerably larger in referral practices, i.e., hematology, oncology, or ENT.


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InternalMed_Harrison. Two groups have reported algorithms that they claim will identify more precisely those lymphadenopathy patients who should have a biopsy. Both reports were retrospective analyses in referral practices. The first study involved patients 9–25 years of age who had a node biopsy performed. Three variables were identified that predicted those young patients with peripheral lymphadenopathy who should undergo biopsy; lymph node size >2 cm in diameter and abnormal chest x-ray had positive predictive values, whereas recent ENT symptoms had negative predictive values. The second study evaluated 220 lymphadenopathy patients in a hematology unit and identified five variables (lymph node size, location [supraclavicular or nonsupraclavicular], age [>40 years or <40 years], texture [nonhard or hard], and tenderness) that were used in a mathematical model to identify patients requiring a biopsy. Positive predictive value was found for age >40 years, supraclavicular location, node size >2.25 cm2, hard


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InternalMed_Harrison. tenderness) that were used in a mathematical model to identify patients requiring a biopsy. Positive predictive value was found for age >40 years, supraclavicular location, node size >2.25 cm2, hard texture, and lack of pain or tenderness. Negative predictive value was evident for age <40 years, node size <1.0 cm2, nonhard texture, and tender or painful nodes. Ninety-one percent of those who required biopsy were correctly classified by this model. Because both of these studies were retrospective analyses and one was limited to young patients, it is not known how useful these models would be if applied prospectively in a primary care setting.


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InternalMed_Harrison. Most lymphadenopathy patients do not require a biopsy, and at least half require no laboratory studies. If the patient’s history and physical findings point to a benign cause for lymphadenopathy, careful follow-up at a 2to 4-week interval can be used. The patient should be instructed to return for reevaluation if there is an increase in the size of the nodes. Antibiotics are not indicated for lymphadenopathy unless strong evidence of a bacterial infection is present. Glucocorticoids should not be used to treat lymphadenopathy because their lympholytic effect obscures some diagnoses (lymphoma, leukemia, Castleman’s disease), and they contribute to delayed healing or activation of underlying infections. An exception to this statement is the life-threatening pharyngeal obstruction by enlarged lymphoid tissue in Waldeyer’s ring that is occasionally seen in infectious mononucleosis. CHAPTER 79 Enlargement of Lymph Nodes and Spleen


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 79 Enlargement of Lymph Nodes and Spleen The spleen is a reticuloendothelial organ that has its embryologic origin in the dorsal mesogastrium at about 5 weeks of gestation. It arises in a series of hillocks, migrates to its normal adult location in the left upper quadrant (LUQ), and is attached to the stomach via the gastrolienal ligament and to the kidney via the lienorenal ligament. When the hillocks fail to unify into a single tissue mass, accessory spleens may develop in around 20% of persons. The function of the spleen has been elusive. Galen believed it was the source of “black bile” or melancholia, and the word hypochondria (literally, beneath the ribs) and the idiom “to vent one’s spleen” attest to the beliefs that the spleen had an important influence on the psyche and emotions. In humans, its normal physiologic roles seem to be the following: 1.


InternalMed_Harrison

InternalMed_Harrison. Maintenance of quality control over erythrocytes in the red pulp by removal of senescent and defective red blood cells. The spleen accomplishes this function through a unique organization of its parenchyma and vasculature (Fig. 79-1). 2. Synthesis of antibodies in the white pulp. 3. The removal of antibody-coated bacteria and antibody-coated blood cells from the circulation. An increase in these normal functions may result in splenomegaly. The spleen is composed of red pulp and white pulp, which are Malpighi’s terms for the red blood–filled sinuses and reticuloendothelial Secondary follicle with germinal center (B cell area) PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. FIguRE 79-1 Schematic spleen structure. The spleen comprises many units of red and white pulp centered around small branches of the splenic artery, called central arteries. White pulp is lymphoid in nature and contains B cell follicles, a marginal zone around the follicles, and T cell–rich areas sheathing arterioles. The red pulp areas include pulp sinuses and pulp cords. The cords are dead ends. In order to regain access to the circulation, red blood cells must traverse tiny openings in the sinusoidal lining. Stiff, damaged, or old red cells cannot enter the sinuses. RE, reticuloendothelial. (Bottom portion of figure from RS Hillman, KA Ault: Hematology in Clinical Practice, 4th ed. New York, McGraw-Hill, 2005.) cell–lined cords and the white lymphoid follicles arrayed within the red pulp matrix. The spleen is in the portal circulation. The reason for this is unknown but may relate to the fact that lower blood pressure allows less rapid flow and minimizes damage to normal


InternalMed_Harrison

InternalMed_Harrison. the red pulp matrix. The spleen is in the portal circulation. The reason for this is unknown but may relate to the fact that lower blood pressure allows less rapid flow and minimizes damage to normal erythrocytes. Blood flows into the spleen at a rate of about 150 mL/min through the splenic artery, which ultimately ramifies into central arterioles. Some blood goes from the arterioles to capillaries and then to splenic veins and out of the spleen, but the majority of blood from central arterioles flows into the macrophage-lined sinuses and cords. The blood entering the sinuses reenters the circulation through the splenic venules, but the blood entering the cords is subjected to an inspection of sorts. To return to the circulation, the blood cells in the cords must squeeze through slits in the cord lining to enter the sinuses that lead to the venules. Old and damaged erythrocytes are less deformable and are retained in the cords, where they are destroyed and their components recycled.


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InternalMed_Harrison. the cord lining to enter the sinuses that lead to the venules. Old and damaged erythrocytes are less deformable and are retained in the cords, where they are destroyed and their components recycled. Red cell–inclusion bodies such as parasites (Chaps. 248 and 250e), nuclear residua (Howell-Jolly bodies, see Fig. 77-6), or denatured hemoglobin (Heinz bodies) are pinched off in the process of passing through the slits, a process called pitting. The culling of dead and damaged cells and the pitting of cells with inclusions appear to occur without significant delay because the blood transit time through the spleen is only slightly slower than in other organs.


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InternalMed_Harrison. The spleen is also capable of assisting the host in adapting to its hostile environment. It has at least three adaptive functions: (1) clearance of bacteria and particulates from the blood, (2) the generation of immune responses to certain pathogens, and (3) the generation of cellular components of the blood under circumstances in which the marrow is unable to meet the needs (i.e., extramedullary hematopoiesis). The latter adaptation is a recapitulation of the blood-forming function the spleen plays during gestation. In some animals, the spleen also serves a role in the vascular adaptation to stress because it stores red blood cells (often hemoconcentrated to higher hematocrits than normal) under normal circumstances and contracts under the influence of β-adrenergic stimulation to provide the animal with an autotransfusion and improved oxygen-carrying capacity. However, the normal human spleen does not sequester or store red blood cells and does not contract in response to sympathetic


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InternalMed_Harrison. the animal with an autotransfusion and improved oxygen-carrying capacity. However, the normal human spleen does not sequester or store red blood cells and does not contract in response to sympathetic stimuli. The normal human spleen contains approximately one-third of the total body platelets and a significant number of marginated neutrophils. These sequestered cells are available when needed to respond to bleeding or infection.


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InternalMed_Harrison. APPROACH TO THE PATIENT: The most common symptoms produced by diseases involving the spleen are pain and a heavy sensation in the LUQ. Massive splenomegaly may cause early satiety. Pain may result from acute swelling of the spleen with stretching of the capsule, infarction, or inflammation of the capsule. For many years, it was believed that splenic infarction was clinically silent, which, at times, is true. However, Soma Weiss, in his classic 1942 report of the self-observations by a Harvard medical student on the clinical course of subacute bacterial endocarditis, documented that severe LUQ and pleuritic chest pain may accompany thromboembolic occlusion of splenic blood flow. Vascular occlusion, with infarction and pain, is commonly seen in children with sickle cell crises. Rupture of the spleen, from either trauma or infiltrative disease that breaks the capsule, may result in intraperitoneal bleeding, shock, and death. The rupture itself may be painless.


InternalMed_Harrison

InternalMed_Harrison. A palpable spleen is the major physical sign produced by diseases affecting the spleen and suggests enlargement of the organ. The normal spleen weighs <250 g, decreases in size with age, normally lies entirely within the rib cage, has a maximum cephalocaudad diameter of 13 cm by ultrasonography or maximum length of 12 cm and/or width of 7 cm by radionuclide scan, and is usually not palpable. However, a palpable spleen was found in 3% of 2200 asymptomatic, male, freshman college students. Follow-up at 3 years revealed that 30% of those students still had a palpable spleen without any increase in disease prevalence. Ten-year follow-up found no evidence for lymphoid malignancies. Furthermore, in some tropical countries (e.g., New Guinea), the incidence of splenomegaly may reach 60%. Thus, the presence of a palpable spleen does not always equate with presence of disease. Even when disease is present, splenomegaly may not reflect the primary disease but rather a reaction to it. For


InternalMed_Harrison

InternalMed_Harrison. the presence of a palpable spleen does not always equate with presence of disease. Even when disease is present, splenomegaly may not reflect the primary disease but rather a reaction to it. For example, in patients with Hodgkin’s disease, only two-thirds of the palpable spleens show involvement by the cancer.


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InternalMed_Harrison. Physical examination of the spleen uses primarily the techniques of palpation and percussion. Inspection may reveal fullness in the LUQ that descends on inspiration, a finding associated with a massively enlarged spleen. Auscultation may reveal a venous hum or friction rub.


InternalMed_Harrison

InternalMed_Harrison. Palpation can be accomplished by bimanual palpation, ballotment, and palpation from above (Middleton maneuver). For bimanual palpation, which is at least as reliable as the other techniques, the patient is supine with flexed knees. The examiner’s left hand is placed on the lower rib cage and pulls the skin toward the costal margin, allowing the fingertips of the right hand to feel the tip of the spleen as it descends while the patient inspires slowly, smoothly, and deeply. Palpation is begun with the right hand in the left lower quadrant with gradual movement toward the left costal margin, thereby identifying the lower edge of a massively enlarged spleen. When the spleen tip is felt, the finding is recorded as centimeters below the left costal margin at some arbitrary point, i.e., 10–15 cm, from the midpoint of the umbilicus or the xiphisternal junction. This allows other examiners to compare findings or the initial examiner to determine changes in size over time. Bimanual palpation


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InternalMed_Harrison. cm, from the midpoint of the umbilicus or the xiphisternal junction. This allows other examiners to compare findings or the initial examiner to determine changes in size over time. Bimanual palpation in the right lateral decubitus position adds nothing to the supine examination.


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InternalMed_Harrison. Percussion for splenic dullness is accomplished with any of three techniques described by Nixon, Castell, or Barkun: 1. Nixon’s method: The patient is placed on the right side so that the spleen lies above the colon and stomach. Percussion begins at the lower level of pulmonary resonance in the posterior axillary line and proceeds diagonally along a perpendicular line toward the lower midanterior costal margin. The upper border of dullness is normally 6–8 cm above the costal margin. Dullness >8 cm in an adult is presumed to indicate splenic enlargement. 2. Castell’s method: With the patient supine, percussion in the lowest intercostal space in the anterior axillary line (eighth or ninth) produces a resonant note if the spleen is normal in size. This is true during expiration or full inspiration. A dull percussion note on full inspiration suggests splenomegaly. 3.


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InternalMed_Harrison. 3. Percussion of Traube’s semilunar space: The borders of Traube’s space are the sixth rib superiorly, the left midaxillary line laterally, and the left costal margin inferiorly. The patient is supine with the left arm slightly abducted. During normal breathing, this space is percussed from medial to lateral margins, yielding a normal resonant sound. A dull percussion note suggests splenomegaly.


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InternalMed_Harrison. Studies comparing methods of percussion and palpation with a standard of ultrasonography or scintigraphy have revealed sensitivity of 56–71% for palpation and 59–82% for percussion. Reproducibility among examiners is better for palpation than percussion. Both techniques are less reliable in obese patients or patients who have just eaten. Thus, the physical examination techniques of palpation and percussion are imprecise at best. It has been suggested that the examiner perform percussion first and, if positive, proceed to palpation; if the spleen is palpable, then one can be reasonably confident that splenomegaly exists. However, not all LUQ masses are enlarged spleens; gastric or colon tumors and pancreatic or renal cysts or tumors can mimic splenomegaly.


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InternalMed_Harrison. The presence of an enlarged spleen can be more precisely determined, if necessary, by liver-spleen radionuclide scan, CT, MRI, or ultrasonography. The latter technique is the current procedure of choice for routine assessment of spleen size (normal = a maximum cephalocaudad diameter of 13 cm) because it has high sensitivity and specificity and is safe, noninvasive, quick, mobile, and less costly. Nuclear medicine scans are accurate, sensitive, and reliable but are costly, require greater time to generate data, and use immobile equipment. They have the advantage of demonstrating accessory splenic tissue. CT and MRI provide accurate determination of spleen size, but the equipment is immobile and the procedures are expensive. MRI appears to offer no advantage over CT. Changes in spleen structure such as mass lesions, infarcts, inhomogeneous infiltrates, and cysts are more readily assessed by CT, MRI, or ultrasonography. None of these techniques is very reliable in the detection of patchy


InternalMed_Harrison

InternalMed_Harrison. such as mass lesions, infarcts, inhomogeneous infiltrates, and cysts are more readily assessed by CT, MRI, or ultrasonography. None of these techniques is very reliable in the detection of patchy infiltration (e.g., Hodgkin’s disease).


InternalMed_Harrison

InternalMed_Harrison. Many of the diseases associated with splenomegaly are listed in Table 79-2. They are grouped according to the presumed basic mechanisms responsible for organ enlargement: 1. Hyperplasia or hypertrophy related to a particular splenic function such as reticuloendothelial hyperplasia (work hypertrophy) in diseases such as hereditary spherocytosis or thalassemia syndromes that require removal of large numbers of defective red blood cells; immune hyperplasia in response to systemic infection (infectious mononucleosis, subacute bacterial endocarditis) or to immunologic diseases (immune thrombocytopenia, SLE, Felty’s syndrome). 2. Passive congestion due to decreased blood flow from the spleen in conditions that produce portal hypertension (cirrhosis, Budd-Chiari syndrome, congestive heart failure). 3. Infiltrative diseases of the spleen (lymphomas, metastatic cancer, amyloidosis, Gaucher’s disease, myeloproliferative disorders with extramedullary hematopoiesis).


InternalMed_Harrison

InternalMed_Harrison. 3. Infiltrative diseases of the spleen (lymphomas, metastatic cancer, amyloidosis, Gaucher’s disease, myeloproliferative disorders with extramedullary hematopoiesis). The differential diagnostic possibilities are much fewer when the spleen is “massively enlarged,” palpable more than 8 cm below the left costal margin or has a drained weight of ≥1000 g (Table 79-3). The vast majority of such patients will have nonHodgkin’s lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, chronic myeloid leukemia, myelofibrosis with myeloid metaplasia, or polycythemia vera.


InternalMed_Harrison

InternalMed_Harrison. The major laboratory abnormalities accompanying splenomegaly are determined by the underlying systemic illness. Erythrocyte counts may be normal, decreased (thalassemia major syndromes, SLE, cirrhosis with portal hypertension), or increased (polycythemia vera). Granulocyte counts may be normal, decreased (Felty’s syndrome, congestive splenomegaly, leukemias), or increased (infections or inflammatory disease, myeloproliferative disorders). Similarly, the platelet count may be normal, decreased when there is enhanced sequestration or destruction of platelets in an enlarged spleen (congestive splenomegaly, Gaucher’s disease, immune thrombocytopenia), or increased in the myeloproliferative disorders such as polycythemia vera.


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InternalMed_Harrison. The CBC may reveal cytopenia of one or more blood cell types, which should suggest hypersplenism. This condition is characterized by splenomegaly, cytopenia(s), normal or hyperplastic bone marrow, and a response to splenectomy. The latter characteristic is less precise because reversal of cytopenia, particularly granulocytopenia, is sometimes not sustained after splenectomy. The cytopenias result from increased destruction of the cellular elements secondary to reduced flow of blood through enlarged and congested cords (congestive splenomegaly) or to immune-mediated mechanisms. In hypersplenism, various cell types usually have normal morphology on the peripheral blood smear, although the red cells may be spherocytic due to loss of surface area during their longer transit through the enlarged spleen. The increased marrow production of red cells should be reflected as an increased reticulocyte production index, although the value may be less than expected due to increased sequestration


InternalMed_Harrison

InternalMed_Harrison. spleen. The increased marrow production of red cells should be reflected as an increased reticulocyte production index, although the value may be less than expected due to increased sequestration of reticulocytes in the spleen.


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InternalMed_Harrison. The need for additional laboratory studies is dictated by the differential diagnosis of the underlying illness of which splenomegaly is a manifestation. Splenectomy is infrequently performed for diagnostic purposes, especially in the absence of clinical illness or other diagnostic tests that suggest underlying disease. More often, splenectomy is performed for symptom control in patients with massive splenomegaly, for disease control in patients with traumatic splenic rupture, or for correction of cytopenias in patients with hypersplenism or immune-mediated destruction of one or more cellular blood elements. Splenectomy is CHAPTER 79 Enlargement of Lymph Nodes and Spleen Enlargement Due to Increased Demand for Splenic Function PART 2 Cardinal Manifestations and Presentation of Diseases Reticuloendothelial system hyperplasia (for removal of defective erythrocytes) Response to infection (viral, bacterial, fungal, parasitic)


InternalMed_Harrison

InternalMed_Harrison. Reticuloendothelial system hyperplasia (for removal of defective erythrocytes) Response to infection (viral, bacterial, fungal, parasitic) Malaria Enlargement Due to Abnormal Splenic or Portal Blood Flow Extramedullary hematopoiesis Myelofibrosis Marrow damage by toxins, radiation, strontium Marrow infiltration by tumors, leukemias, Gaucher’s disease Leukemias (acute, chronic, lymphoid, myeloid, monocytic) Myeloproliferative syndromes (e.g., polycythemia vera, essential Metastatic tumors (melanoma is most common)


InternalMed_Harrison

InternalMed_Harrison. Leukemias (acute, chronic, lymphoid, myeloid, monocytic) Myeloproliferative syndromes (e.g., polycythemia vera, essential Metastatic tumors (melanoma is most common) Hemangiomas, fibromas, lymphangiomas necessary for staging of patients with Hodgkin’s disease only in those with clinical stage I or II disease in whom radiation therapy alone is contemplated as the treatment. Noninvasive staging of the spleen in Hodgkin’s disease is not a sufficiently reliable basis for treatment decisions because one-third of normal-sized spleens will be involved with Hodgkin’s disease and one-third of enlarged spleens will be tumor-free. The widespread use of systemic therapy to test all stages of Hodgkin’s disease has made staging laparotomy with splenectomy aThe spleen extends >8 cm below the left costal margin and/or weighs >1000 g.


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InternalMed_Harrison. unnecessary. Although splenectomy in chronic myeloid leukemia (CML) does not affect the natural history of disease, removal of the massive spleen usually makes patients significantly more comfortable and simplifies their management by significantly reducing transfusion requirements. The improvements in therapy of CML have reduced the need for splenectomy for symptom control. Splenectomy is an effective secondary or tertiary treatment for two chronic B cell leukemias, hairy cell leukemia and prolymphocytic leukemia, and for the very rare splenic mantle cell or marginal zone lymphoma. Splenectomy in these diseases may be associated with significant tumor regression in bone marrow and other sites of disease. Similar regressions of systemic disease have been noted after splenic irradiation in some types of lymphoid tumors, especially chronic lymphocytic leukemia and prolymphocytic leukemia. This has been termed the abscopal effect. Such systemic tumor responses to local therapy directed


InternalMed_Harrison

InternalMed_Harrison. some types of lymphoid tumors, especially chronic lymphocytic leukemia and prolymphocytic leukemia. This has been termed the abscopal effect. Such systemic tumor responses to local therapy directed at the spleen suggest that some hormone or growth factor produced by the spleen may affect tumor cell proliferation, but this conjecture is not yet substantiated.


InternalMed_Harrison

InternalMed_Harrison. A common therapeutic indication for splenectomy is traumatic or iatrogenic splenic rupture. In a fraction of patients with splenic rupture, peritoneal seeding of splenic fragments can lead to splenosis—the presence of multiple rests of spleen tissue not connected to the portal circulation. This ectopic spleen tissue may cause pain or gastrointestinal obstruction, as in endometriosis. A large number of hematologic, immunologic, and congestive causes of splenomegaly can lead to destruction of one or more cellular blood elements. In the majority of such cases, splenectomy can correct the cytopenias, particularly anemia and thrombocytopenia. In a large series of patients seen in two tertiary care centers, the indication for splenectomy was diagnostic in 10% of patients, therapeutic in 44%, staging for Hodgkin’s disease in 20%, and incidental to another procedure in 26%. Perhaps the only contraindication to splenectomy is the presence of marrow failure, in which the enlarged spleen is the


InternalMed_Harrison

InternalMed_Harrison. for Hodgkin’s disease in 20%, and incidental to another procedure in 26%. Perhaps the only contraindication to splenectomy is the presence of marrow failure, in which the enlarged spleen is the only source of hematopoietic tissue.


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InternalMed_Harrison. The absence of the spleen has minimal long-term effects on the hematologic profile. In the immediate postsplenectomy period, leukocytosis (up to 25,000/μL) and thrombocytosis (up to 1 × 106/μL) may develop, but within 2–3 weeks, blood cell counts and survival of each cell lineage are usually normal. The chronic manifestations of splenectomy are marked variation in size and shape of erythrocytes (anisocytosis, poikilocytosis) and the presence of Howell-Jolly bodies (nuclear remnants), Heinz bodies (denatured hemoglobin), basophilic stippling, and an occasional nucleated erythrocyte in the peripheral blood. When such erythrocyte abnormalities appear in a patient whose spleen has not been removed, one should suspect splenic infiltration by tumor that has interfered with its normal culling and pitting function.


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InternalMed_Harrison. The most serious consequence of splenectomy is increased susceptibility to bacterial infections, particularly those with capsules such as Streptococcus pneumoniae, Haemophilus influenzae, and some gram-negative enteric organisms. Patients under age 20 years are particularly susceptible to overwhelming sepsis with S. pneumoniae, and the overall actuarial risk of sepsis in patients who have had their spleens removed is about 7% in 10 years. The case–fatality rate for pneumococcal sepsis in splenectomized patients is 50–80%. About 25% of patients without spleens will develop a serious infection at some time in their life. The frequency is highest within the first 3 years after splenectomy. About 15% of the infections are polymicrobial, and lung, skin, and blood are the most common sites. No increased risk of viral infection has been noted in patients who have no spleen. The susceptibility to bacterial infections relates to the inability to remove opsonized bacteria from the bloodstream


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InternalMed_Harrison. increased risk of viral infection has been noted in patients who have no spleen. The susceptibility to bacterial infections relates to the inability to remove opsonized bacteria from the bloodstream and a defect in making antibodies to T cell–independent antigens such as the polysaccharide components of bacterial capsules. Pneumococcal vaccine should be administered to all patients 2 weeks before elective splenectomy. The Advisory Committee on Immunization Practices recommends that these patients receive repeat vaccination 5 years after splenectomy. Efficacy has not been proven for this group, and the recommendation discounts the possibility that administration of the vaccine may actually lower the titer of specific pneumococcal antibodies. A more effective pneumococcal conjugate vaccine that involves T cells in the response is now available (Prevenar, 7-valent). The vaccine to Neisseria meningitidis should also be given to patients in whom elective splenectomy is planned. Although


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InternalMed_Harrison. that involves T cells in the response is now available (Prevenar, 7-valent). The vaccine to Neisseria meningitidis should also be given to patients in whom elective splenectomy is planned. Although efficacy data for H. influenzae type b vaccine are not available for older children or adults, it may be given to patients who have had a splenectomy.


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InternalMed_Harrison. Splenectomized patients should be educated to consider any unexplained fever as a medical emergency. Prompt medical attention with evaluation and treatment of suspected bacteremia may be life-saving. Routine chemoprophylaxis with oral penicillin can result in the emergence of drug-resistant strains and is not recommended. In addition to an increased susceptibility to bacterial infections, splenectomized patients are also more susceptible to the parasitic disease babesiosis. The splenectomized patient should avoid areas where the parasite Babesia is endemic (e.g., Cape Cod, MA).


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InternalMed_Harrison. Surgical removal of the spleen is an obvious cause of hyposplenism. Patients with sickle cell disease often suffer from autosplenectomy as a result of splenic destruction by the numerous infarcts associated with sickle cell crises during childhood. Indeed, the presence of a palpable spleen in a patient with sickle cell disease after age 5 suggests a coexisting hemoglobinopathy, e.g., thalassemia or hemoglobin C.


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InternalMed_Harrison. In addition, patients who receive splenic irradiation for a neoplastic 413 or autoimmune disease are also functionally hyposplenic. The term hyposplenism is preferred to asplenism in referring to the physiologic consequences of splenectomy because asplenia is a rare, specific, and fatal congenital abnormality in which there is a failure of the left side of the coelomic cavity (which includes the splenic anlagen) to develop normally. Infants with asplenia have no spleens, but that is the least of their problems. The right side of the developing embryo is duplicated on the left so there is liver where the spleen should be, there are two right lungs, and the heart comprises two right atria and two right ventricles. Disorders of granulocytes and Steven M. Holland, John I. Gallin


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InternalMed_Harrison. Disorders of granulocytes and Steven M. Holland, John I. Gallin Leukocytes, the major cells comprising inflammatory and immune responses, include neutrophils, T and B lymphocytes, natural killer (NK) cells, monocytes, eosinophils, and basophils. These cells have specific functions, such as antibody production by B lymphocytes or destruction of bacteria by neutrophils, but in no single infectious disease is the exact role of the cell types completely established. Thus, whereas neutrophils are classically thought to be critical to host defense against bacteria, they may also play important roles in defense against viral infections.


InternalMed_Harrison

InternalMed_Harrison. The blood delivers leukocytes to the various tissues from the bone marrow, where they are produced. Normal blood leukocyte counts are 4.3–10.8 × 109/L, with neutrophils representing 45–74% of the cells, bands 0–4%, lymphocytes 16–45%, monocytes 4–10%, eosinophils 0–7%, and basophils 0–2%. Variation among individuals and among different ethnic groups can be substantial, with lower leukocyte numbers for certain African-American ethnic groups. The various leukocytes are derived from a common stem cell in the bone marrow. Three-fourths of the nucleated cells of bone marrow are committed to the production of leukocytes. Leukocyte maturation in the marrow is under the regulatory control of a number of different factors, known as colony-stimulating factors (CSFs) and interleukins (ILs). Because an alteration in the number and type of leukocytes is often associated with disease processes, total white blood cell (WBC) count (cells per μL) and differential counts are informative. This chapter


InternalMed_Harrison

InternalMed_Harrison. an alteration in the number and type of leukocytes is often associated with disease processes, total white blood cell (WBC) count (cells per μL) and differential counts are informative. This chapter focuses on neutrophils, monocytes, and eosinophils. Lymphocytes and basophils are discussed in Chaps. 372e and 376, respectively.


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InternalMed_Harrison. CHAPTER 80 Disorders of Granulocytes and Monocytes Important events in neutrophil life are summarized in Fig. 80-1. In normal humans, neutrophils are produced only in the bone marrow. The minimum number of stem cells necessary to support hematopoiesis is estimated to be 400–500 at any one time. Human blood monocytes, tissue macrophages, and stromal cells produce CSFs, hormones required for the growth of monocytes and neutrophils in the bone marrow. The hematopoietic system not only produces enough neutrophils (~1.3 × 1011 cells per 80-kg person per day) to carry out physiologic functions but also has a large reserve stored in the marrow, which can be mobilized in response to inflammation or infection. An increase in the number of blood neutrophils is called neutrophilia, and the presence of immature cells is termed a shift to the left. A decrease in the number of blood neutrophils is called neutropenia.


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InternalMed_Harrison. Neutrophils and monocytes evolve from pluripotent stem cells under the influence of cytokines and CSFs (Fig. 80-2). The proliferation phase through the metamyelocyte takes about 1 week, while the maturation phase from metamyelocyte to mature neutrophil takes PART 2 Cardinal Manifestations and Presentation of Diseases Stem O2, .OH,C3acell Diapedesis Activation of other limbs of host defense Redness (Rubor) O2 –, H2 Edema (Tumor) Pain (Dolor) Warmth (Calor) Chemokines, other chemoattractants Fever HOCl (bleach) Macrophages IL-1, TNF-˜IL-8, TNF-˜, IL-12 Integrins Increased endothelial stickiness Selectins Vasodilation Fluid Leakage Recruitment Cytokine secretion


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InternalMed_Harrison. FIguRE 80-1 Schematic events in neutrophil production, recruitment, and inflammation. The four cardinal signs of inflammation (rubor, tumor, calor, dolor) are indicated, as are the interactions of neutrophils with other cells and cytokines. G-CSF, granulocyte colony-stimulating factor; IL, interleukin; PMN, polymorphonuclear leukocyte; TNF-α, tumor necrosis factor α. FIguRE 80-2 Stages of neutrophil development shown schematically. Granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) are critical to this process. Identifying cellular characteristics and specific cell-surface markers are listed for each maturational stage. CD33, CD13, CD15 CD33, CD13, CD15 CD33, CD13, CD15, CD14, CD11b CD33, CD13, CD15, CD14, CD11b CD33, CD13, CD15, CD14, CD11b CD10, CD16 CD33, CD13, CD15, CD14, CD11b CD10, CD16 Condensed, band– shaped nucleus Condensed, multilobed nucleus Secondary granule.


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InternalMed_Harrison. another week. The myeloblast is the first recognizable precursor cell and is followed by the promyelocyte. The promyelocyte evolves when the classic lysosomal granules, called the primary, or azurophil, granules are produced. The primary granules contain hydrolases, elastase, myeloperoxidase, cathepsin G, cationic proteins, and bactericidal/ permeability-increasing protein, which is important for killing gram-negative bacteria. Azurophil granules also contain defensins, a family of cysteine-rich polypeptides with broad antimicrobial activity against bacteria, fungi, and certain enveloped viruses. The promyelocyte divides to produce the myelocyte, a cell responsible for the synthesis of the specific, or secondary, granules, which contain unique (specific) constituents such as lactoferrin, vitamin B12–binding protein, membrane components of the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase required for hydrogen peroxide production, histaminase, and receptors for


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InternalMed_Harrison. vitamin B12–binding protein, membrane components of the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase required for hydrogen peroxide production, histaminase, and receptors for certain chemoattractants and adherence-promoting factors (CR3) as well as receptors for the basement membrane component, laminin. The secondary granules do not contain acid hydrolases and therefore are not classic lysosomes. Packaging of secondary granule contents during myelopoiesis is controlled by CCAAT/enhancer binding protein-ε. Secondary granule contents are readily released extracellularly, and their mobilization is important in modulating inflammation. During the final stages of maturation, no cell division occurs, and the cell passes through the metamyelocyte stage and then to the band neutrophil with a sausage-shaped nucleus (Fig. 80-3). As the band cell matures, the nucleus assumes a lobulated configuration. The nucleus of neutrophils normally contains up to four segments (Fig.


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InternalMed_Harrison. neutrophil with a sausage-shaped nucleus (Fig. 80-3). As the band cell matures, the nucleus assumes a lobulated configuration. The nucleus of neutrophils normally contains up to four segments (Fig. 80-4). Excessive segmentation (more than five nuclear lobes) may be a manifestation of folate or vitamin B12 deficiency or the congenital neutropenia syndrome of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) described below. The Pelger-Hüet anomaly (Fig. 80-5), an infrequent dominant benign inherited trait, results in neutrophils with distinctive bilobed nuclei that must be distinguished from band forms. Acquired bilobed nuclei, pseudo Pelger-Hüet anomaly, can occur with acute infections or in myelodysplastic syndromes. The physiologic role of the normal multilobed nucleus of neutrophils is unknown, but it may allow great deformation of neutrophils during migration into tissues at sites of inflammation.


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InternalMed_Harrison. In severe acute bacterial infection, prominent neutrophil cytoplasmic granules, called toxic granulations, are occasionally seen. Toxic granulations are immature or abnormally staining azurophil granules. Cytoplasmic inclusions, also called Döhle bodies (Fig. 80-3), can be seen during infection and are fragments of ribosome-rich endoplasmic reticulum. Large neutrophil vacuoles are often present in acute bacterial infection and probably represent pinocytosed (internalized) membrane. FIguRE 80-3 Neutrophil band with Döhle body. The neutrophil with a sausage-shaped nucleus in the center of the field is a band form. Döhle bodies are discrete, blue-staining, nongranular areas found in the periphery of the cytoplasm of the neutrophil in infec-tions and other toxic states. They represent aggregates of rough endoplasmic reticulum.


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InternalMed_Harrison. FIguRE 80-4 Normal granulocyte. The normal granulocyte has a segmented nucleus with heavy, clumped chromatin; fine neutrophilic granules are dispersed throughout the cytoplasm. Neutrophils are heterogeneous in function. Monoclonal antibodies have been developed that recognize only a subset of mature neutrophils. The meaning of neutrophil heterogeneity is not known. The morphology of eosinophils and basophils is shown in Fig. 80-6. Specific signals, including IL-1, tumor necrosis factor α (TNF-α), the CSFs, complement fragments, and chemokines, mobilize leukocytes from the bone marrow and deliver them to the blood in an unstimulated state. Under normal conditions, ~90% of the neutrophil pool is in the bone marrow, 2–3% in the circulation, and the remainder in the tissues (Fig. 80-7).


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InternalMed_Harrison. The circulating pool exists in two dynamic compartments: one freely flowing and one marginated. The freely flowing pool is about one-half the neutrophils in the basal state and is composed of those cells that are in the blood and not in contact with the endothelium. Marginated leukocytes are those that are in close physical contact with the CHAPTER 80 Disorders of Granulocytes and Monocytes FIguRE 80-5 Pelger-Hüet anomaly. In this benign disorder, the majority of granulocytes are bilobed. The nucleus frequently has a spectacle-like, or “pince-nez,” configuration. FIguRE 80-6 Normal eosinophil (left) and basophil (right). The eosinophil contains large, bright orange granules and usually a bilobed nucleus. The basophil contains large purple-black granules that fill the cell and obscure the nucleus.


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases endothelium (Fig. 80-8). In the pulmonary circulation, where an extensive capillary bed (~1000 capillaries per alveolus) exists, margination occurs because the capillaries are about the same size as a mature neutrophil. Therefore, neutrophil fluidity and deformability are necessary to make the transit through the pulmonary bed. Increased neutrophil rigidity and decreased deformability lead to augmented neutrophil trapping and margination in the lung. In contrast, in the systemic postcapillary venules, margination is mediated by the interaction of specific cell-surface molecules called selectins. Selectins are glycoproteins expressed on neutrophils and endothelial cells, among others, that cause a low-affinity interaction, resulting in “rolling” of the neutrophil along the endothelial surface. On neutrophils, the molecule L-selectin (cluster determinant [CD] 62L) binds to glycosylated proteins on endothelial cells (e.g.,


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InternalMed_Harrison. in “rolling” of the neutrophil along the endothelial surface. On neutrophils, the molecule L-selectin (cluster determinant [CD] 62L) binds to glycosylated proteins on endothelial cells (e.g., glycosylation-dependent cell adhesion molecule [GlyCAM1] and CD34). Glycoproteins on neutrophils, most importantly sialyl-Lewisx (SLex, CD15s), are targets for binding of selectins expressed on endothelial cells (E-selectin [CD62E] and P-selectin [CD62P]) and


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InternalMed_Harrison. FIguRE 80-7 Schematic neutrophil distribution and kinetics between the different anatomic and functional pools. other leukocytes. In response to chemotactic stimuli from injured tissues (e.g., complement product C5a, leukotriene B4, IL-8) or bacterial products (e.g., N-formylmethionylleucylphenylalanine [f-metleu-phe]), neutrophil adhesiveness increases through mobilization of intracellular adhesion proteins stored in specific granules to the cell surface, and the cells “stick” to the endothelium through integrins. The integrins are leukocyte glycoproteins that exist as complexes of a common CD18 β chain with CD11a (LFA-1), CD11b (called Mac-1, CR3, or the C3bi receptor), and CD11c (called p150,95 or CR4). CD11a/CD18 and CD11b/CD18 bind to specific endothelial receptors (intercellular adhesion molecules [ICAM] 1 and 2).


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InternalMed_Harrison. On cell stimulation, L-selectin is shed from neutrophils, and E-selectin increases in the blood, presumably because it is shed from endothelial cells; receptors for chemoattractants and opsonins are mobilized; and the phagocytes orient toward the chemoattractant source in the extravascular space, increase their motile activity (chemokinesis), and migrate directionally (chemotaxis) into tissues. The process of migration into tissues is called diapedesis and involves the crawling of neutrophils between postcapillary endothelial cells that open junctions between adjacent cells to permit leukocyte passage. Diapedesis involves platelet/endothelial cell adhesion molecule (PECAM) 1 (CD31), which is expressed on both the emigrating leukocyte and the endothelial cells. The endothelial responses (increased blood flow from increased vasodilation and permeability) are mediated by anaphylatoxins (e.g., C3a and C5a) as well as vasodilators such as histamine, bradykinin, serotonin, nitric oxide,


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InternalMed_Harrison. (increased blood flow from increased vasodilation and permeability) are mediated by anaphylatoxins (e.g., C3a and C5a) as well as vasodilators such as histamine, bradykinin, serotonin, nitric oxide, vascular endothelial growth factor (VEGF), and prostaglandins E and I. Cytokines regulate some of these processes (e.g., TNF-α induction of VEGF, interferon [IFN] γ inhibition of prostaglandin E).


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InternalMed_Harrison. In the healthy adult, most neutrophils leave the body by migration through the mucous membrane of the gastrointestinal tract. Normally, neutrophils spend a short time in the circulation (half-life, 6–7 h). Senescent neutrophils are cleared from the circulation by macrophages in the lung and spleen. Once in the tissues, neutrophils release enzymes, such as collagenase and elastase, which may help establish abscess cavities. Neutrophils ingest pathogenic materials that have been opsonized by IgG and C3b. Fibronectin and the tetrapeptide tuftsin also facilitate phagocytosis.


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InternalMed_Harrison. With phagocytosis comes a burst of oxygen consumption and activation of the hexose-monophosphate shunt. A membrane-associated NADPH oxidase, consisting of membrane and cytosolic components, is assembled and catalyzes the univalent reduction of oxygen to superoxide anion, which is then converted by superoxide dismutase to hydrogen peroxide and other toxic oxygen products (e.g., hydroxyl radical). Hydrogen peroxide + chloride + neutrophil myeloperoxidase generate hypochlorous acid (bleach), hypochlorite, and chlorine. These products oxidize and halogenate microorganisms and tumor cells and, when uncontrolled, can damage host tissue. Strongly cationic proteins, defensins, elastase, cathepsins, and probably nitric oxide also participate in microbial killing. Lactoferrin chelates iron, an important growth factor for microorganisms, especially fungi. Other enzymes, such as lysozyme and acid proteases, help digest microbial debris. After 1–4 days in tissues, neutrophils die. The apoptosis of


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InternalMed_Harrison. growth factor for microorganisms, especially fungi. Other enzymes, such as lysozyme and acid proteases, help digest microbial debris. After 1–4 days in tissues, neutrophils die. The apoptosis of neutrophils is also cytokine-regulated; granulocyte colony-stimulating factor (G-CSF) and IFN-γ prolong their life span. Under certain conditions, such as in delayed-type hypersensitivity, monocyte accumulation occurs within 6–12 h of initiation of inflammation. Neutrophils, monocytes, microorganisms in various states of digestion, and altered local tissue cells make up the inflammatory exudate, pus. Myeloperoxidase confers the characteristic green color to pus and may participate in turning off the inflammatory process by inactivating chemoattractants and immobilizing phagocytic cells.


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InternalMed_Harrison. Neutrophils respond to certain cytokines (IFN-γ, granulocytemacrophage colony-stimulating factor [GM-CSF], IL-8) and produce cytokines and chemotactic signals (TNF-α, IL-8, macrophage inflammatory protein [MIP] 1) that modulate the inflammatory response. In the presence of fibrinogen, f-met-leu-phe or leukotriene B4 induces IL-8 production by neutrophils, providing autocrine amplification of inflammation. Chemokines (chemoattractant cytokines) are small proteins CHAPTER 80 Disorders of Granulocytes and Monocytes Diapedesis CD18 CD11a,b CD31


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InternalMed_Harrison. FIguRE 80-8 Neutrophil travel through the pulmonary capillaries is dependent on neutrophil deformability. Neutrophil rigidity (e.g., caused by C5a) enhances pulmonary trapping and response to pulmonary pathogens in a way that is not so dependent on cell-surface receptors. Intraalveolar chemotactic factors, such as those caused by certain bacteria (e.g., Streptococcus pneumoniae), lead to diapedesis of neutrophils from the pulmonary capillaries into the alveolar space. Neutrophil interaction with the endothelium of the systemic postcapillary venules is dependent on molecules of attachment. The neutrophil “rolls” along the endothelium using selectins: neutrophil CD15s (sialyl-Lewisx) binds to CD62E (E-selectin) and CD62P (P-selectin) on endothelial cells; CD62L (L-selectin) on neutrophils binds to CD34 and other molecules (e.g., GlyCAM-1) expressed on endothelium. Chemokines or other activation factors stimulate integrin-mediated “tight adhesion”: CD11a/CD18 (LFA 1) and CD11b/CD18


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InternalMed_Harrison. binds to CD34 and other molecules (e.g., GlyCAM-1) expressed on endothelium. Chemokines or other activation factors stimulate integrin-mediated “tight adhesion”: CD11a/CD18 (LFA 1) and CD11b/CD18 (Mac-1, CR3) bind to CD54 (ICAM-1) and CD102 (ICAM-2) on the endothelium. Diapedesis occurs between endothelial cells: CD31 (PECAM-1) expressed by the emigrating neutrophil interacts with CD31 expressed at the endothelial cell-cell junction. CD, cluster determinant; GlyCAM, glycosylation-dependent cell adhesion molecule; ICAM, intercellular adhesion molecule; PECAM, platelet/endothelial cell adhesion molecule.


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InternalMed_Harrison. produced by many different cell types, including endothelial cells, fibroblasts, epithelial cells, neutrophils, and monocytes, that regulate neutrophil, monocyte, eosinophil, and lymphocyte recruitment and activation. Chemokines transduce their signals through heterotrimeric G protein– linked receptors that have seven cell membrane–spanning domains, the same type of cell-surface receptor that mediates the response to the classic chemoattractants f-met-leu-phe and C5a. Four major groups of chemokines are recognized based on the cysteine structure near the N terminus: C, CC, CXC, and CXXXC. The CXC cytokines such as IL-8 mainly attract neutrophils; CC chemokines such as MIP-1 attract lymphocytes, monocytes, eosinophils, and basophils; the C chemokine lymphotactin is T cell tropic; the CXXXC chemokine fractalkine attracts neutrophils, monocytes, and T cells. These molecules and their receptors not only regulate the trafficking and activation of inflammatory cells, but specific chemokine


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InternalMed_Harrison. chemokine fractalkine attracts neutrophils, monocytes, and T cells. These molecules and their receptors not only regulate the trafficking and activation of inflammatory cells, but specific chemokine receptors also serve as co-receptors for HIV infection (Chap. 226) and have a role in other viral infections such as West Nile infection and atherogenesis.


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InternalMed_Harrison. Defects in the neutrophil life cycle can lead to dysfunction and compromised host defenses. Inflammation is often depressed, and the clinical result is often recurrent, severe bacterial and fungal infections. Aphthous ulcers of mucous membranes (gray ulcers without pus) and gingivitis and periodontal disease suggest a phagocytic cell disorder. Patients with congenital phagocyte defects can have infections within the first few days of life. Skin, ear, upper and lower respiratory tract, and bone infections are common. Sepsis and meningitis are rare. In some disorders, the frequency of infection is variable, and patients can go for months or even years without major infection. Aggressive management of these congenital diseases has extended the life span of patients well beyond 30 years.


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InternalMed_Harrison. Neutropenia The consequences of absent neutrophils are dramatic. Susceptibility to infectious diseases increases sharply when neutrophil counts fall below 1000 cells/μL. When the absolute neutrophil count (ANC; band forms and mature neutrophils combined) falls to <500 cells/μL, control of endogenous microbial flora (e.g., mouth, gut) is impaired; when the ANC is <200/μL, the local inflammatory process is absent. Neutropenia can be due to depressed production, increased peripheral destruction, or excessive peripheral pooling. A falling neutrophil count or a significant decrease in the number of neutrophils below steady-state levels, together with a failure to increase neutrophil counts in the setting of infection or other challenge, requires investigation. Acute neutropenia, such as that caused by cancer chemotherapy, is more likely to be associated with increased risk of infection than neutropenia of long duration (months to years) that reverses in response to infection or carefully


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InternalMed_Harrison. caused by cancer chemotherapy, is more likely to be associated with increased risk of infection than neutropenia of long duration (months to years) that reverses in response to infection or carefully controlled administration of endotoxin (see “Laboratory Diagnosis and Management,” below).


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InternalMed_Harrison. Some causes of inherited and acquired neutropenia are listed in Table 80-1. The most common neutropenias are iatrogenic, resulting from the use of cytotoxic or immunosuppressive therapies for malignancy or control of autoimmune disorders. These drugs cause neutropenia because they result in decreased production of rapidly growing progenitor (stem) cells of the marrow. Certain antibiotics such as chloramphenicol, trimethoprim-sulfamethoxazole, flucytosine, vidarabine, and the antiretroviral drug zidovudine may cause neutropenia by inhibiting proliferation of myeloid precursors. Azathioprine and 6-mercaptopurine are metabolized by the enzyme thiopurine methyltransferase (TMPT), hypofunctional polymorphisms in which are found in 11% of whites and can lead to accumulation of 6-thioguanine and profound marrow toxicity. The marrow suppression is generally dose-related and dependent on continued administration of the drug. Cessation of the offending agent and recombinant human G-CSF usually


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InternalMed_Harrison. profound marrow toxicity. The marrow suppression is generally dose-related and dependent on continued administration of the drug. Cessation of the offending agent and recombinant human G-CSF usually reverse these forms of neutropenia.


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InternalMed_Harrison. Another important mechanism for iatrogenic neutropenia is the effect of drugs that serve as immune haptens and sensitize neutrophils or neutrophil precursors to immune-mediated peripheral destruction. This form of drug-induced neutropenia can be seen within 7 days of exposure to the drug; with previous drug exposure, resulting in preexisting antibodies, neutropenia may occur a few hours after Drug-induced—alkylating agents (nitrogen mustard, busulfan, chlorambucil, cyclophosphamide); antimetabolites (methotrexate, 6-mercaptopurine, 5-flucytosine); noncytotoxic agents (antibiotics [chloramphenicol, penicillins, sulfonamides], phenothiazines, tranquilizers [meprobamate], anticonvulsants [carbamazepine], antipsychotics [clozapine], certain diuretics, anti-inflammatory agents, antithyroid drugs, many others) Hematologic diseases—idiopathic, cyclic neutropenia, Chédiak-Higashi syndrome, aplastic anemia, infantile genetic disorders (see text) Tumor invasion, myelofibrosis


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InternalMed_Harrison. Hematologic diseases—idiopathic, cyclic neutropenia, Chédiak-Higashi syndrome, aplastic anemia, infantile genetic disorders (see text) Tumor invasion, myelofibrosis Nutritional deficiency—vitamin B12, folate (especially alcoholics) Infection—tuberculosis, typhoid fever, brucellosis, tularemia, measles, infectious mononucleosis, malaria, viral hepatitis, leishmaniasis, AIDS


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InternalMed_Harrison. Autoimmune disorders—Felty’s syndrome, rheumatoid arthritis, lupus erythematosus Drugs as haptens—aminopyrine, α-methyldopa, phenylbutazone, mercurial diuretics, some phenothiazines Granulomatosis with polyangiitis (Wegener’s) administration of the drug. Although any drug can cause this form of neutropenia, the most frequent causes are commonly used antibiotics, such as sulfa-containing compounds, penicillins, and cephalosporins. Fever and eosinophilia may also be associated with drug reactions, but often these signs are not present. Drug-induced neutropenia can be severe, but discontinuation of the sensitizing drug is sufficient for recovery, which is usually seen within 5–7 days and is complete by 10 days. Readministration of the sensitizing drug should be avoided, because abrupt neutropenia will often result. For this reason, diagnostic challenge should be avoided.


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InternalMed_Harrison. Autoimmune neutropenias caused by circulating antineutrophil antibodies are another form of acquired neutropenia that results in increased destruction of neutrophils. Acquired neutropenia may also be seen with viral infections, including infection with HIV. Acquired neutropenia may be cyclic in nature, occurring at intervals of several weeks. Acquired cyclic or stable neutropenia may be associated with an expansion of large granular lymphocytes (LGLs), which may be T cells, NK cells, or NK-like cells. Patients with large granular lymphocytosis may have moderate blood and bone marrow lymphocytosis, neutropenia, polyclonal hypergammaglobulinemia, splenomegaly, rheumatoid arthritis, and absence of lymphadenopathy. Such patients may have a chronic and relatively stable course. Recurrent bacterial infections are frequent. Benign and malignant forms of this syndrome occur. In some patients, a spontaneous regression has occurred even after 11 years, suggesting an immunoregulatory defect as


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InternalMed_Harrison. infections are frequent. Benign and malignant forms of this syndrome occur. In some patients, a spontaneous regression has occurred even after 11 years, suggesting an immunoregulatory defect as the basis for at least one form of the disorder. Glucocorticoids, cyclosporine, and methotrexate are commonly used to manage these cytopenias.


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InternalMed_Harrison. Hereditary Neutropenias Hereditary neutropenias are rare and may manifest in early childhood as a profound constant neutropenia or agranulocytosis. Congenital forms of neutropenia include Kostmann’s syndrome (neutrophil count <100/μL), which is often fatal and due to mutations in the antiapoptosis gene HAX-1; severe chronic neutropenia (neutrophil count of 300–1500/μL) due to mutations in neutrophil elastase (ELANE); hereditary cyclic neutropenia, or, more appropriately, cyclic hematopoiesis, also due to mutations in neutrophil elastase (ELANE); the cartilage-hair hypoplasia syndrome due to mutations in the mitochondrial RNA-processing endoribonuclease RMRP; Shwachman-Diamond syndrome associated with pancreatic insufficiency due to mutations in the Shwachman-Bodian-Diamond syndrome gene SBDS; the WHIM (warts, hypogammaglobulinemia,


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases infections, myelokathexis [retention of WBCs in the marrow]) syndrome, characterized by neutrophil hypersegmentation and bone marrow myeloid arrest due to mutations in the chemokine receptor CXCR4; and neutropenias associated with other immune defects, such as X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and CD40 ligand deficiency. Mutations in the G-CSF receptor can develop in severe congenital neutropenia and are linked to leukemia. Absence of both myeloid and lymphoid cells is seen in reticular dysgenesis, due to mutations in the nuclear genome-encoded mitochondrial enzyme adenylate kinase-2 (AK2).


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InternalMed_Harrison. Maternal factors can be associated with neutropenia in the newborn. Transplacental transfer of IgG directed against antigens on fetal neutrophils can result in peripheral destruction. Drugs (e.g., thiazides) ingested during pregnancy can cause neutropenia in the newborn by either depressed production or peripheral destruction. In Felty’s syndrome—the triad of rheumatoid arthritis, splenomegaly, and neutropenia (Chap. 380)—spleen-produced antibodies can shorten neutrophil life span, while large granular lymphocytes can attack marrow neutrophil precursors. Splenectomy may increase the neutrophil count in Felty’s syndrome and lower serum neutrophilbinding IgG. Some Felty’s syndrome patients also have neutropenia associated with an increased number of LGLs. Splenomegaly with peripheral trapping and destruction of neutrophils is also seen in lysosomal storage diseases and in portal hypertension.


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InternalMed_Harrison. Neutrophilia Neutrophilia results from increased neutrophil production, increased marrow release, or defective margination (Table 80-2). The most important acute cause of neutrophilia is infection. Neutrophilia from acute infection represents both increased production and increased marrow release. Increased production is also associated with chronic inflammation and certain myeloproliferative diseases. Increased marrow release and mobilization of the marginated leukocyte pool are induced by glucocorticoids. Release of epinephrine, as with vigorous exercise, excitement, or stress, will demarginate neutrophils in the spleen and lungs and double the neutrophil count in minutes. Cigarette smoking can elevate neutrophil counts above the normal range. Leukocytosis with cell counts of 10,000–25,000/μL occurs in response to infection and other forms of acute inflammation and results from both release of the marginated pool and mobilization of marrow reserves. Persistent neutrophilia with cell


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InternalMed_Harrison. occurs in response to infection and other forms of acute inflammation and results from both release of the marginated pool and mobilization of marrow reserves. Persistent neutrophilia with cell counts of ≥30,000–50,000/μL is called a leukemoid reaction, a term


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InternalMed_Harrison. Idiopathic Drug-induced—glucocorticoids, G-CSF Infection—bacterial, fungal, sometimes viral Inflammation—thermal injury, tissue necrosis, myocardial and pulmonary infarction, hypersensitivity states, collagen vascular diseases Myeloproliferative diseases—myelocytic leukemia, myeloid metaplasia, polycythemia vera Drugs—epinephrine, glucocorticoids, nonsteroidal anti-inflammatory agents Stress, excitement, vigorous exercise Leukocyte adhesion deficiency type 1 (CD18); leukocyte adhesion deficiency type 2 (selectin ligand, CD15s); leukocyte adhesion deficiency type 3 (FERMT3) Metabolic disorders—ketoacidosis, acute renal failure, eclampsia, acute poi Other—metastatic carcinoma, acute hemorrhage or hemolysis Abbreviation: G-CSF, granulocyte colony-stimulating factor. Cause of Indicated Dysfunction Adherence-aggregation Aspirin, colchicine, alcohol, glucocorti-Neonatal state, hemodialysis Leukocyte adhesion deficiency types 1, 2, coids, ibuprofen, piroxicam and 3


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InternalMed_Harrison. Adherence-aggregation Aspirin, colchicine, alcohol, glucocorti-Neonatal state, hemodialysis Leukocyte adhesion deficiency types 1, 2, coids, ibuprofen, piroxicam and 3 Deformability Leukemia, neonatal state, diabetes mellitus, immature neutrophils Chemokinesis-chemotaxis Glucocorticoids (high dose), auranofin, Thermal injury, malignancy, malnutrition, Chédiak-Higashi syndrome, neutrophilcolchicine (weak effect), phenylbu-periodontal disease, neonatal state, systemic specific granule deficiency, hyper IgE–recurtazone, naproxen, indomethacin, lupus erythematosus, rheumatoid arthritis, rent infection (Job’s) syndrome (in some interleukin 2 diabetes mellitus, sepsis, influenza virus patients), Down’s syndrome, α-mannosidase infection, herpes simplex virus infection, deficiency, leukocyte adhesion deficiencies, acrodermatitis enteropathica, AIDS Wiskott-Aldrich syndrome


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InternalMed_Harrison. Microbicidal activity Colchicine, cyclophosphamide, gluco-Leukemia, aplastic anemia, certain neutrope-Chédiak-Higashi syndrome, neutrophil-specorticoids (high dose), TNF-α-blocking nias, tuftsin deficiency, thermal injury, sepsis, cific granule deficiency, chronic granulomaantibodies neonatal state, diabetes mellitus, malnutri-tous disease, defects in IFNγ/IL-12 axis tion, AIDS Abbreviations: IFNγ, interferon γ; IL, interleukin; TNF-α, tumor necrosis factor alpha. often used to distinguish this degree of neutrophilia from leukemia. In a leukemoid reaction, the circulating neutrophils are usually mature and not clonally derived. Abnormal Neutrophil Function Inherited and acquired abnormalities of phagocyte function are listed in Table 80-3. The resulting diseases are best considered in terms of the functional defects of adherence, chemotaxis, and microbicidal activity. The distinguishing features of the important inherited disorders of phagocyte function are shown in Table 80-4.


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InternalMed_Harrison. dISORdERS OF AdHESION Three main types of leukocyte adhesion deficiency (LAD) have been described. All are autosomal recessive and result in the inability of neutrophils to exit the circulation to sites of infection, leading to leukocytosis and increased susceptibility to infection (Fig. 80-8). Patients with LAD 1 have mutations in CD18, the common component of the integrins LFA-1, Mac-1, and p150,95, leading to a defect in tight adhesion between neutrophils and the endothelium. The heterodimer formed by CD18/CD11b (Mac-1) is also the receptor for the complement-derived opsonin C3bi (CR3). The CD18 gene is located on distal chromosome 21q. The severity of the defect determines the severity of clinical disease. Complete lack of expression of the leukocyte integrins results in a severe phenotype in which inflammatory stimuli do not increase the expression of leukocyte integrins on neutrophils or activated T and B cells. Neutrophils (and monocytes) from patients with LAD 1 adhere poorly


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InternalMed_Harrison. in which inflammatory stimuli do not increase the expression of leukocyte integrins on neutrophils or activated T and B cells. Neutrophils (and monocytes) from patients with LAD 1 adhere poorly to endothelial cells and protein-coated surfaces and exhibit defective spreading, aggregation, and chemotaxis. Patients with LAD 1 have recurrent bacterial infections involving the skin, oral and genital mucosa, and respiratory and intestinal tracts; persistent leukocytosis (resting neutrophil counts of 15,000–20,000/μL) because cells do not marginate; and, in severe cases, a history of delayed separation of the umbilical stump. Infections, especially of the skin, may become necrotic with progressively enlarging borders, slow healing, and development of dysplastic scars. The most common bacteria are Staphylococcus aureus and enteric gram-negative bacteria. LAD 2 is caused by an abnormality of fucosylation of SLex (CD15s), the ligand on neutrophils that interacts with selectins on endothelial


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InternalMed_Harrison. are Staphylococcus aureus and enteric gram-negative bacteria. LAD 2 is caused by an abnormality of fucosylation of SLex (CD15s), the ligand on neutrophils that interacts with selectins on endothelial cells and is responsible for neutrophil rolling along the endothelium. Infection susceptibility in LAD 2 appears to be less severe than in LAD 1. LAD 2 is also known as congenital disorder of glycosylation IIc (CDGIIc) due to mutation in a GDP-fucose transporter (SLC35C1). LAD 3 is characterized by infection susceptibility, leukocytosis, and petechial hemorrhage due to impaired integrin activation caused by mutations in the gene FERMT3.


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InternalMed_Harrison. dISORdERS OF NEUTROPHIL gRANULES The most common neutrophil defect is myeloperoxidase deficiency, a primary granule defect inherited as an autosomal recessive trait; the incidence is ~1 in 2000 persons. Isolated myeloperoxidase deficiency is not associated with clinically compromised defenses, presumably because other defense systems such as hydrogen peroxide generation are amplified. Microbicidal activity of neutrophils is delayed but not absent. Myeloperoxidase deficiency may make other acquired host defense defects more serious, and patients with myeloperoxidase deficiency and diabetes are more susceptible to Candida infections. An acquired form of myeloperoxidase deficiency occurs in myelomonocytic leukemia and acute myeloid leukemia.


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InternalMed_Harrison. Chédiak-Higashi syndrome (CHS) is a rare disease with autosomal recessive inheritance due to defects in the lysosomal transport protein LYST, encoded by the gene CHS1 at 1q42. This protein is required for normal packaging and disbursement of granules. Neutrophils (and all cells containing lysosomes) from patients with CHS characteristically have large granules (Fig. 80-9), making it a systemic disease. Patients with CHS have nystagmus, partial oculocutaneous albinism, and an increased number of infections resulting from many bacterial agents. Some CHS patients develop an “accelerated phase” in childhood with a hemophagocytic syndrome and an aggressive lymphoma requiring bone marrow transplantation. CHS neutrophils and monocytes have impaired chemotaxis and abnormal rates of microbial killing due to slow rates of fusion of the lysosomal granules with phagosomes. NK cell function is also impaired. CHS patients may develop a severe disabling peripheral neuropathy in adulthood that can


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InternalMed_Harrison. due to slow rates of fusion of the lysosomal granules with phagosomes. NK cell function is also impaired. CHS patients may develop a severe disabling peripheral neuropathy in adulthood that can lead to bed confinement.


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InternalMed_Harrison. Specific granule deficiency is a rare autosomal recessive disease in which the production of secondary granules and their contents, as well as the primary granule component defensins, is defective. The defect in killing leads to severe bacterial infections. One type of specific granule deficiency is due to a mutation in the CCAAT/enhancer binding protein-ε, a regulator of expression of granule components. A dominant mutation in C/EBP-ε has also been described.


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InternalMed_Harrison. CHRONIC gRANULOMATOUS dISEASE Chronic granulomatous disease (CGD) is a group of disorders of granulocyte and monocyte oxidative metabolism. Although CGD is rare, with an incidence of ~1 in 200,000 individuals, it is an important model of defective neutrophil oxidative metabolism. In about two-thirds of patients, CGD is inherited as an X-linked recessive trait; 30% of patients inherit the disease in an autosomal recessive pattern. Mutations in the genes for the five proteins that assemble at the plasma membrane account for all patients with CGD. Two proteins (a 91-kDa protein, abnormal in X-linked CGD, and a 22-kDa protein, absent in one form of autosomal recessive CGD) form the heterodimer cytochrome b-558 in the plasma membrane. Three other proteins (40, 47, and 67 kDa, abnormal in the other autosomal recessive forms of CGD) are cytoplasmic in origin and interact with the cytochrome after cell activation to form NADPH oxidase, required for hydrogen peroxide production. Leukocytes


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InternalMed_Harrison. other autosomal recessive forms of CGD) are cytoplasmic in origin and interact with the cytochrome after cell activation to form NADPH oxidase, required for hydrogen peroxide production. Leukocytes from patients with CGD have severely diminished hydrogen peroxide production. The genes involved in each of the defects have been cloned and sequenced and the chromosome locations identified. Patients with CGD characteristically have increased numbers of infections


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InternalMed_Harrison. CHAPTER 80 Disorders of Granulocytes and Monocytes Chronic Granulomatous Diseases (70% X-Linked, 30% Autosomal Recessive) Severe infections of skin, ears, lungs, liver, and bone with catalase-positive microorganisms such as Staphylococcus aureus, Burkholderia cepacia complex, Aspergillus spp., Chromobacterium violaceum; often hard to culture organism; excessive inflammation with granulomas, frequent lymph node suppuration; granulomas can obstruct GI or GU tracts; gingivitis, aphthous ulcers, seborrheic dermatitis No respiratory burst due to the lack of one of five DHR or NBT test; no superoxide and H2O2 NADPH oxidase subunits in neutrophils, monocytes, production by neutrophils; immunoblot and eosinophils for NADPH oxidase components; genetic PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Recurrent infections of skin, ears, and sinopulmonary tract; Abnormal chemotaxis, impaired respiratory burst Lack of secondary (specific) granules in delayed wound healing; decreased inflammation; bleed-and bacterial killing, failure to upregulate chemotac-neutrophils (Wright’s stain), no neutrophiling diathesis tic and adhesion receptors with stimulation, defect specific granule contents (i.e., lactoferrin), no in transcription of granule proteins; defect in CEBPE defensins, platelet α granule abnormality; genetic detection Clinically normal except in patients with underlying dis-No myeloperoxidase due to preand posttransla-No peroxidase in neutrophils; genetic detecease such as diabetes mellitus; then candidiasis or other tional defects in myeloperoxidase deficiency tion fungal infections


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InternalMed_Harrison. Type 1: Delayed separation of umbilical cord, sustained Impaired phagocyte adherence, aggregation, neutrophilia, recurrent infections of skin and mucosa, gin-spreading, chemotaxis, phagocytosis of C3bi-coated givitis, periodontal disease particles; defective production of CD18 subunit common to leukocyte integrins Type 2: Mental retardation, short stature, Bombay (hh) Impaired phagocyte rolling along endothelium; due blood phenotype, recurrent infections, neutrophilia to defects in fucose transporter Type 3: Petechial hemorrhage, recurrent infections Impaired signaling for integrin activation resulting in impaired adhesion due to mutation in FERMT3 Reduced phagocyte surface expression of the CD18-containing integrins with monoclonal antibodies against LFA-1 (CD18/ CD11a), Mac-1 or CR3 (CD18/CD11b), p150,95 (CD18/CD11c); genetic detection Reduced phagocyte surface expression of Sialyl-Lewisx, with monoclonal antibodies against CD15s; genetic detection


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InternalMed_Harrison. Reduced phagocyte surface expression of Sialyl-Lewisx, with monoclonal antibodies against CD15s; genetic detection Abbreviations: C/EBPε, CCAAT/enhancer binding protein-ε; DHR, dihydrorhodamine (oxidation test); DOCK8, dedicator of cytokinesis 8; GI, gastrointestinal; GU, genitourinary; HPV, human papilloma virus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; IRAK4, IL-1 receptor–associated kinase 4; LFA-1, leukocyte function–associated antigen 1; MyD88, myeloid differentiation primary response gene 88; NADPH, nicotinamide–adenine dinueleotide phosphate; NBT, nitroblue tetrazolium (dye test); NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; NK, natural killer; STAT1–3, signal transducer and activator of transcription 1–3; TLR, Toll-like receptor; TNF, tumor necrosis factor.


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InternalMed_Harrison. FIguRE 80-9 Chédiak-Higashi syndrome. The granulocytes contain huge cytoplasmic granules formed from aggregation and fusion of azurophilic and specific granules. Large abnormal granules are found in other granule-containing cells throughout the body.


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InternalMed_Harrison. due to catalase-positive microorganisms (organisms that destroy their own hydrogen peroxide) such as S. aureus, Burkholderia cepacia, and Aspergillus species. When patients with CGD become infected, they often have extensive inflammatory reactions, and lymph node suppuration is common despite the administration of appropriate antibiotics. Aphthous ulcers and chronic inflammation of the nares are often present. Granulomas are frequent and can obstruct the gastrointestinal or genitourinary tracts. The excessive inflammation is due to failure to downregulate inflammation, reflecting failure to inhibit the synthesis of, degradation of, or response to chemoattractants or residual antigens, leading to persistent neutrophil accumulation. Impaired killing of intracellular microorganisms by macrophages may lead to persistent cell-mediated immune activation and granuloma formation. Autoimmune complications such as immune thrombocytopenic purpura and juvenile rheumatoid arthritis are also


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InternalMed_Harrison. macrophages may lead to persistent cell-mediated immune activation and granuloma formation. Autoimmune complications such as immune thrombocytopenic purpura and juvenile rheumatoid arthritis are also increased in CGD. In addition, for unexplained reasons, discoid lupus is more common in X-linked carriers. Late complications, including nodular regenerative hyperplasia and portal hypertension, are increasingly recognized in long-term survivors of severe CGD.


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InternalMed_Harrison. dISORdERS OF PHAgOCYTE ACTIVATION Phagocytes depend on cell-surface stimulation to induce signals that evoke multiple levels of the inflammatory response, including cytokine synthesis, chemotaxis, and antigen presentation. Mutations affecting the major pathway that signals through NF-κB have been noted in patients with a variety of infection susceptibility syndromes. If the defects are at a very late stage of signal transduction, in the protein critical for NF-κB activation known as the NF-κB essential modulator (NEMO), then affected males develop ectodermal dysplasia and severe immune deficiency with susceptibility to bacteria, fungi, mycobacteria, and viruses. If the defects in NF-κB activation are closer to the cell-surface receptors, in the proteins transducing Toll-like receptor signals, IL-1 receptor–associated kinase 4 (IRAK4), and myeloid differentiation primary response gene 88 (MyD88), then children have a marked susceptibility to pyogenic infections early in life but


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InternalMed_Harrison. signals, IL-1 receptor–associated kinase 4 (IRAK4), and myeloid differentiation primary response gene 88 (MyD88), then children have a marked susceptibility to pyogenic infections early in life but develop resistance to infection later.


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InternalMed_Harrison. The mononuclear phagocyte system is composed of monoblasts, promonocytes, and monocytes, in addition to the structurally diverse tissue macrophages that make up what was previously referred to as the reticuloendothelial system. Macrophages are long-lived phagocytic 421 cells capable of many of the functions of neutrophils. They are also secretory cells that participate in many immunologic and inflammatory processes distinct from neutrophils. Monocytes leave the circulation by diapedesis more slowly than neutrophils and have a half-life in the blood of 12–24 h.


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InternalMed_Harrison. After blood monocytes arrive in the tissues, they differentiate into macrophages (“big eaters”) with specialized functions suited for specific anatomic locations. Macrophages are particularly abundant in capillary walls of the lung, spleen, liver, and bone marrow, where they function to remove microorganisms and other noxious elements from the blood. Alveolar macrophages, liver Kupffer cells, splenic macrophages, peritoneal macrophages, bone marrow macrophages, lymphatic macrophages, brain microglial cells, and dendritic macrophages all have specialized functions. Macrophage-secreted products include lysozyme, neutral proteases, acid hydrolases, arginase, complement components, enzyme inhibitors (plasmin, α2-macroglobulin), binding proteins (transferrin, fibronectin, transcobalamin II), nucleosides, and cytokines (TNF-α; IL-1, -8, -12, -18). IL-1 (Chaps. 23 and 372e) has many functions, including initiating fever in the hypothalamus, mobilizing leukocytes from the bone marrow, and


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InternalMed_Harrison. nucleosides, and cytokines (TNF-α; IL-1, -8, -12, -18). IL-1 (Chaps. 23 and 372e) has many functions, including initiating fever in the hypothalamus, mobilizing leukocytes from the bone marrow, and activating lymphocytes and neutrophils. TNF-α is a pyrogen that duplicates many of the actions of IL-1 and plays an important role in the pathogenesis of gram-negative shock (Chap. 325). TNF-α stimulates production of hydrogen peroxide and related toxic oxygen species by macrophages and neutrophils. In addition, TNF-α induces catabolic changes that contribute to the profound wasting (cachexia) associated with many chronic diseases.


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InternalMed_Harrison. Other macrophage-secreted products include reactive oxygen and nitrogen metabolites, bioactive lipids (arachidonic acid metabolites and platelet-activating factors), chemokines, CSFs, and factors stimulating fibroblast and vessel proliferation. Macrophages help regulate the replication of lymphocytes and participate in the killing of tumors, viruses, and certain bacteria (Mycobacterium tuberculosis and Listeria monocytogenes). Macrophages are key effector cells in the elimination of intracellular microorganisms. Their ability to fuse to form giant cells that coalesce into granulomas in response to some inflammatory stimuli is important in the elimination of intracellular microbes and is under the control of IFN-γ. Nitric oxide induced by IFN-γ is an important effector against intracellular parasites, including tuberculosis and Leishmania.


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InternalMed_Harrison. Macrophages play an important role in the immune response (Chap. 372e). They process and present antigen to lymphocytes and secrete cytokines that modulate and direct lymphocyte development and function. Macrophages participate in autoimmune phenomena by removing immune complexes and other substances from the circulation. Polymorphisms in macrophage receptors for immunoglobulin (FcγRII) determine susceptibility to some infections and autoimmune diseases. In wound healing, they dispose of senescent cells, and they contribute to atheroma development. Macrophage elastase mediates development of emphysema from cigarette smoking.


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InternalMed_Harrison. Many disorders of neutrophils extend to mononuclear phagocytes. Monocytosis is associated with tuberculosis, brucellosis, subacute bacterial endocarditis, Rocky Mountain spotted fever, malaria, and visceral leishmaniasis (kala azar). Monocytosis also occurs with malignancies, leukemias, myeloproliferative syndromes, hemolytic anemias, chronic idiopathic neutropenias, and granulomatous diseases such as sarcoidosis, regional enteritis, and some collagen vascular diseases. Patients with LAD, hyperimmunoglobulin E–recurrent infection (Job’s) syndrome, CHS, and CGD all have defects in the mononuclear phagocyte system. Monocyte cytokine production or response is impaired in some patients with disseminated nontuberculous mycobacterial infection who are not infected with HIV. Genetic defects in the pathways regulated by IFN-γ and IL-12 lead to impaired killing of intracellular bacteria, mycobacteria, salmonellae, and certain viruses (Fig. 80-10).


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InternalMed_Harrison. CHAPTER 80 Disorders of Granulocytes and Monocytes IL-2RCD14IL-1518?TLRLPSIL-12IL-2IFN˜TNF°IFN˜RTNF°R˛1˛2AFBSalm.T/NKM˝STAT1GATA2ISG1512NRAMP1NEMOIRF8 PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. FIguRE 80-10 Lymphocyte-macrophage interactions underlying resistance to mycobacteria and other intracellular pathogens such as Salmonella, Histoplasma, and Coccidioides. Mycobacteria (and others) infect macrophages, leading to the production of IL-12, which activates T or NK cells through its receptor, leading to production of IL-2 and IFN-γ. IFN-γ acts through its receptor on macrophages to upregulate TNF-γ and IL-12 and kill intracellular pathogens. Other critical interacting molecules include signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 8 (IRF8), GATA2, and ISG15. Mutant forms of the cytokines and receptors shown in bold type have been found in severe cases of nontuberculous mycobacterial infection, salmonellosis and other intracellular pathogens. AFB, acid-fast bacilli; IFN, interferon; IL, interleukin; NEMO, nuclear factorκB essential modulator; NK, natural killer; TLR, Toll-like receptor; TNF, tumor necrosis factor.


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InternalMed_Harrison. Certain viral infections impair mononuclear phagocyte function. For example, influenza virus infection causes abnormal monocyte chemotaxis. Mononuclear phagocytes can be infected by HIV using CCR5, the chemokine receptor that acts as a co-receptor with CD4 for HIV. T lymphocytes produce IFN-γ, which induces FcR expression and phagocytosis and stimulates hydrogen peroxide production by mononuclear phagocytes and neutrophils. In certain diseases, such as AIDS, IFN-γ production may be deficient, whereas in other diseases, such as T cell lymphomas, excessive release of IFN-γ may be associated with erythrophagocytosis by splenic macrophages.


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InternalMed_Harrison. Autoinflammatory diseases are characterized by abnormal cytokine regulation, leading to excess inflammation in the absence of infection. These diseases can mimic infectious or immunodeficient syndromes. Gain-of-function mutations in the TNF-α receptor cause TNF-α receptor–associated periodic syndrome (TRAPS), which is characterized by recurrent fever in the absence of infection, due to persistent stimulation of the TNF-α receptor (Chap. 392). Diseases with abnormal IL-1 regulation leading to fever include familial Mediterranean fever due to mutations in PYRIN. Mutations in cold-induced autoinflammatory syndrome 1 (CIAS1) lead to neonatal-onset multisystem autoinflammatory disease, familial cold urticaria, and Muckle-Wells syndrome. The syndrome of pyoderma gangrenosum, acne, and sterile pyogenic arthritis (PAPA syndrome) is caused by mutations in PSTPIP1. In contrast to these syndromes of overexpression of proinflammatory cytokines, blockade of TNF-α by the antagonists infliximab,


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InternalMed_Harrison. pyogenic arthritis (PAPA syndrome) is caused by mutations in PSTPIP1. In contrast to these syndromes of overexpression of proinflammatory cytokines, blockade of TNF-α by the antagonists infliximab, adalimumab, certolizumab, golimumab, or etanercept has been associated with severe infections due to tuberculosis, nontuberculous mycobacteria, and fungi (Chap. 392).


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InternalMed_Harrison. Monocytopenia occurs with acute infections, with stress, and after treatment with glucocorticoids. Drugs that suppress neutrophil production in the bone marrow can cause monocytopenia. Persistent severe circulating monocytopenia is seen in GATA2 deficiency, even though macrophages are found at the sites of inflammation. Monocytopenia also occurs in aplastic anemia, hairy cell leukemia, acute myeloid leukemia, and as a direct result of myelotoxic drugs.