NURS 8022 Exam 2 Study Guide.docx

Exam 2 Study Guide Blood Cells Pluripotential cells are in bone marrow and differentiate into the major blood cells Erythrocytes (RBC) Most abundant cells of the blood (48% in men; 42% in women) normal levels 4.2-6.1 x 10^6/mcl; Hgb 12-18 g/dL Responsible for tissue oxygenation Contain hemoglobin wh...

Exam 2 Study Guide Blood Cells Pluripotential cells are in bone marrow and differentiate into the major blood cells Erythrocytes (RBC) Most abundant cells of the blood (48% in men; 42% in women) normal levels 4.2-6.1 x 10^6/mcl; Hgb 12-18 g/dL Responsible for tissue oxygenation Contain hemoglobin which carries gasses and electrolytes Hgb is the molecule of heme and globin; Hct is the percentage volume of blood that is RBC about 67% of total body Fe is bound to heme in RBC (hemoglobin) and muscle cells (myoglobin); 30% is stored in macrophages; less than 3% is lost daily in urine, sweat, bile, and minor bleeding Have 120 day life cycle d/t inability to go through mitosis; removed and replaced by spleen Have biconcavity and reversible deformity provides surface area optimal for gas diffusion enables RBC to shape like torpedo to squeeze through microcirculation Hgb is O2 carrying protein of RBC each Hgb molecule has 2 pairs of globin chains, 4 complexes of iron + heme heme is large, flat, iron-protoporphyrin disk that is synthesized in mitochondria and each heme can carry one molecule of O2 Each Hgb molecule has 4 hemes; each Hgb molecule can carry 4 molecules of O2 CO competitively binds to heme affinity is 200-300x greater than O2 therefore even a small increase in CO can affect Hgb ability to carry/transport O2 Globin is formed by polyribosomes in reticulocytes Each Hgb molecule has 2 pairs of polypeptide globin chains combo of pairs that forms determines type of globin chain; several different globin chains most common chain is Hgb A: 2 alpha chains and 2 beta chains Hgb F (fetal): 2 alpha chains and 2 gamma chains SHAPE MATTERS must be able to squeeze through the tiniest capillaries (membrane facilitates – abnormality that causes RBC membrane to not be flexible they will get stuck and destroyed) RBC is just a sack of Hgb: no nucleus, no mitochondria, only Hgb and some enzymes surrounded by a membrane since they lack mitochondria they have NO ATP; they depend on glycolysis for energy deficiencies are 2 enzymes resulting in anemia G6PD and pyruvate kinase deficiency pyruvate kinase is necessary for glycolysis – its absence can result in damage and death to RBCs G6PD is involved in protecting RBC against oxidative stress regulation of RBC mass balance between production and destruction; about 1% produced/day and about 1% destroyed/day production regulated by erythropoietin destruction of senescent (old) RBCs changes on outer surface attract macrophages tissue macrophages in spleen digest RBC heme and globin dissociate (break apart) easily globin is broken down into component amino acids iron is liberated from heme, oxidized, and recycled (transferrin to ferritin) ferritin is the major Fe storage protein apoferritin = ferritin without attached Fe (precursor) hemosiderin are ferritin micelles (normal in small amounts); lg amounts or in lungs or subq tissue can be a pathological condition transferrin is the Fe bound to apotransferrin transfers Fe in circulation Fe for Hgb production is carried by transferrin to bone marrow where it binds to transferrin receptors on erythroblasts transferrin-Fe complex binds to transferrin receptor on erythroblast’s plasma membrane it moves into cell by endocytosis Fe is released (dissociated) from transferrin dissociated transferrin is returned to bloodstream for reuse porphyrin of heme is metabolized into bilirubin transported to liver and conjugated excreted as bile into intestine transformed into urobilinogen most urobilinogen excreted with feces; some through kidneys (urine) alterations in RBC too many RBC – polycythemia not enough RBC – anemia Leukocytes (WBC) Defend body against infection and remove debris Classified by structure and function Granulocytes – phagocytes Produced by process called granulopoiesis in the bone marrow 3 Types of blood cells Neutrophils (most numerous, 55%) Defend against infection. Are referred to as polymorphonuclear neutrophils (PMNs). Serve as phagocytes in early inflammation. Ingest and destroy microorganisms and debris and then die in 1 or 2 days. Basophils (<1%) Contains histamine. Increase at the sites of allergic inflammatory reactions and parasitic infection, particularly exoparasites (e.g., ticks). Secrete inflammatory mediators (e.g., histamine, chemotactic factors for eosinophils and neutrophils). Contribute to the local inflammatory response. Eosinophils (1% to 4%) Are capable of amoeboid movement and phagocytosis. Ingest antigen-antibody complexes and viruses. Release cytokines and leukotrienes that augment the inflammatory response. Increase in type I hypersensitivity allergic reactions and asthma. Increase and attack parasitic infections. Mast Cells (not a blood cell, rather in the tissues) Are highly similar to basophils. Are the central cells in inflammation. Are found in vascularized connective tissue. Activation and degranulation affect body cells. Increased permeability of blood vessels and smooth muscle contraction Also contain IgE receptors Membrane-bound granules are in their cytoplasm. Granules containing enzymes are capable of destroying microorganisms. Catabolized debris is ingested during phagocytosis. Are involved in inflammatory and immune functions. Are capable of amoeboid movement (diapedesis – movement to help granulocytes migrate through vessel walls and then to sites where their action is needed) Agranulocytes Monocytes and macrophages (phagocytes) – make up the mononuclear phagocyte system (MPS) Are found in tissue and lymphoid organs. Provide the main line of defense against bacteria in the bloodstream. Cleanse the blood by removing old, injured, or dead blood cells. Monocytes: Are the precursor to macrophage and dendritic cells. Macrophages Remove old and damaged cells and large molecules from circulation. Are the major “antigen-processing” and “antigen-presenting” cells that initiate immune responses. Initiate wound healing and tissue remodeling. Dendritic cells Extend projections (dendrites) into the tissue and take on a “neuron like” appearance. Are the “antigen-processing” and “antigen-presenting” cells that initiate immune responses. Lymphocytes – immunocytes (36% of leukocytes) Are the major cells of the immune system. Are mature T, B, and plasma cells Natural killer cells are lymphocyte-like cells Lifespan: Days, months, or years, depending on the type Natural killer (NK) cells (5% to 10%) Found mainly in the peripheral blood and spleen Kill tumor cells and virally infected cells recognize infected cells and tumors by changes in MHC I (surface molecule) Do not have to be induced by antigens Produce cytokines involved in the immune responses Arise from stem cells in the bone marrow. Two populations of progenitor cells Common lymphoid progenitors Some remain in the bone marrow; others undergo differentiation into the B-cell lineage, are released into circulation, and undergo further maturation in the peripheral lymphoid organs. Common myeloid progenitors Further differentiate into basophils, mast cells, eosinophils, and megakaryocytes, and granulocyte/monocyte progenitors Thrombocytes (PLT) 150-400 k/mm3 is normal range drops below 100k/mm3 then become thrombocytopenic; prolongation of normal clotting may result; bone marrow infections, immune disorders, etc Cell membrane: glycoproteins on surface repulse adherence to “normal” endothelium AND promote adherence to injured endothelium contains phospholipids that activate several stages in blood clotting cascade Irregularly shaped cytoplasmic fragments Formed by the fragmentation of megakaryocytes (large cells) Essential for blood coag and control of bleeding incapable of mitotic division; no nucleus or DNA granules are generally proinflammatory stimulated to release biochemicals when there is an injury to the blood vessel adp, atp, ca, serotonin, histamine = collagen is released platelets begin to clump together and form a platelet plug live for 5-9 days and then removed by spleen; eliminated by tissue macrophage system produced in bone marrow and stored in spleen where they are slowly released active and have many functions: stick to damaged blood vessel walls; participate in clotting factors actin, myosin, thrombosthenin allow platelet to contract synthesize enzymes, store calcium ions synthesize ATP and ADP synthesize prostaglandins fibrin-stabilizing factor growth factor affecting vascular endothelial cells/vascular smooth muscle/fibroblasts (eventually repairs damaged vascular walls Iron Basics 
 Fe absorption from duodenum and upper jejunum is about 1-1.5 mg/day absorption is enhanced by meat, poultry, fish and inhibited by carbonates, tannate (tea), oxalate (spinach, rhubarb), phosphates (veggies), and clay HCl promotes absorption loss: 1 mg/day males average; menstruating women additional 14 mg/period Liver secretes apotransferrin Apotransferrin binds with free iron (transferrin) Transferrin binds with receptors in intestinal epithelial cells Released into blood capillaries (plasma transferrin) Excess iron → liver & bone marrow Apoferritin → Ferritin Hemosiderin: Small quantity (excess iron) collects in cells (insoluble) Anemias Anemia is a reduction in the total number of erythrocytes in the circulating blood or in the quality or quantity of hemoglobin impaired erythrocyte production acute or chronic blood loss increased erythrocyte destruction combination of the above Hereditary hemolysis Sickle cell trait or disease Acquired hemolysis Immune mechanisms (blood transfusion reaction) Infection (Malaria, clostridial) Drugs (quinidine, penicillin, methyldopa) Liver or kidney disease Toxins (chemical, venoms) Classifications Etiologic factor (cause) Size Identified by terms that end in “-cytic” Macrocytic (large), microcytic (small), normocytic (normal) Hemoglobin content Identified by terms that end in “-chromic” Normochromic (normal amount), hypochromic (decreased amount) Anisocytosis – RBCs present in various sizes & Polycytosis – RBCs present in various shapes Clinical manifestations hypoxia – reduced O2-carrying capacity syncope, angina, compensatory tachycardia, and organ dysfunction Classic anemia S/S – fatigue, weakness, dyspnea, elevated HR, and pallor Evaluating Anemia Physical Exam Laboratory Studies (CBC) Hgb: Males: 13.5-17 g/dL; Females:12-15.5 g/dL Hct: Males: 41-50%; Females: 35-46% RDW: < 15% MCV: 78 – 100 femtoliter (Normocytic, Microcytic, Macrocytic) MCHC: 32-34 gm/dl MCH: 27-34 (hyper or hypochromia) Reticulocytes: new RBC Microcytic-Hypochromic Anemias Are characterized by RBCs that are abnormally small and contain reduced amounts of hemoglobin. Causes Disorders of iron metabolism Disorders of porphyrin and heme synthesis Disorders of globin synthesis Iron Deficiency Anemia (IDA) Most common type of anemia worldwide Highest risk: Older adults, women, infants, and those living in poverty Associated with cognitive impairment in children Causes Inadequate dietary intake Excessive blood loss Chronic parasite infestations Metabolic or functional iron deficiency Menorrhagia (excessive bleeding during menstruation) Most common physiologic cause: Menstruation Avg menstrual flow 50 ml but can vary by 5X. Women with increased menstrual loss require increased intake 3-4 mg/day which equals dietary consumption of 30-40 mg/d For men and postmenopausal women a good indicator of malignancy 10-17% will be from malignancy older age, male, elevated LDH, low ferritin Most common pathophysiologic cause: GI bleed Bleeding ulcer, diverticular disease, hemorrhoids, Inflammatory Bowel Disease (1/3 of patients) Others Lead poisoning Intravascular hemolysis (prosthetic heart valve) Pregnancy Pregnancy is nonpathologic; increase nutritional demand....need to increase dietary consumption to meet the 2-5 mg/d need (20-50mg daily) Ferritin Protein that stores iron Most sensitive test for IDA Transferrin Transports iron in the blood Saturation is typically measured indirectly by assessing the total iron binding capacity (TIBC) Total Iron Binding Capacity (TIBC) Measure of available transferrin that is left unbound to iron Low transferrin that is saturated with iron = high TIBC = more capacity to bind or high Total iron binding capacity Diagnostic Manifestations Low MCV Low MCH High RDW (>15) Low initial reticulocyte count Elevated reticulocyte count once treatment and supplementation with Fe begins - can be high after treatment Ferritin low Low serum Iron (normal 50-75mcg/dL) TIBC high (meaning that transferrin saturation is decreased) Clinical Manifestations Vary from none in mild anemia to severe with Hgb <7 Mild (Hgb 10-12) – likely no symptoms Moderate (Hgb 7-11) – Mod: s/s particularly if no cardiac reserve Palpitations, dyspnea, exercise intolerance, angular stomatitis, glossitis, pallor, Koilonychia (abnormally thin nails which have lost their convexity becoming flat or even concave in shape aka “spoon nails”), pica (craving nonfood items like ice or dirt) Severe (Hgb < 7) – postural hypotension, dizziness, weak, gastritis, paresthesia, lethargy Elderly: lethargy and confusion Don’t dismiss it as normal aging! Sideroblastic Anemia Caused by a defect in mitochondrial heme synthesis. Altered mitochondrial metabolism causes ineffective iron uptake and results in dysfunctional hemoglobin synthesis. Intracellular iron accumulates Can be d/t ETOH abuse, lead poisoning Ringed sideroblasts in the bone marrow are diagnostic. Sideroblasts – erythroblasts contain iron granules that have not been synthesized into hemoglobin. Clinical features r/t anemia (moderate- HCT 20-30%) MCV usually normal, can be increased or decreased Serum iron is elevated Transferrin saturation is high Clinical manifestations Iron overload (hemochromatosis) Enlarged spleen (splenomegaly) and liver (hepatomegaly) Refer to Hematologist Acquired of Hereditary Thalassemia From the Greek thalassa ("sea") and -emia ("blood"). Affects those of Southeast Asian, Mediterranean, North African, Middle Eastern, and Asian descent Autosomal recessive blood disorder Diagnostic test is hemoglobin electrophoresis Characterized by abnormal formation of hemoglobin Results from mutation that causes loss of one or both of alpha globin chains or one or both of beta globin chains Abnormal hemoglobin formed results in improper oxygen transport and destruction of red blood cells; result in anemia Anemia is microcytic hypochromic (low MCV, low MCHC) “target cells” may be seen Can cause complications Iron overload, bone deformities, and CV illness. May confer a degree of protection against malaria Macrocytic-Normochromic or Megaloblastic Anemias Folate, B12 deficiency, poisons, some antiviral drugs and some chemo agents Patho: Deoxyribonucleic acid (DNA) synthesis is defective. Due to deficiencies in vitamin B12 or folate RBCs do not form sufficiently and are released prematurely Vitamin B12 (Cobalamin) deficiency All B12 comes from diet – everything that flies, walks, swims Functions Keep nervous system functioning properly Necessary in the formation of blood Involved in metabolism of every cell but especially affecting DNA synthesis and regulation Daily absorption of B12 is about 5 mcg Liver stores 2000-5000mcg Can take up to 3 years to deplete Very unusual to develop B12 deficiency due to diet Exception = strict vegan Lab Findings: Moderate to severe anemia MCV usually very high (110 – 140 fL) MHC - normal Peripheral blood smear Anisocytosis , poikilocytosis, macro-ovalocyte (characteristic of this), hypersegmented neutrophils Low reticulocyte count initially. Reticulocyte count is up after supplementation occurs Can see pancytopenia if severe BM: Marked erythroid hyperplasia, megaloblastic changes, Elevated LDH and slight increase in indirect bili. (d/t intramedullary destruction) Abnormally low serum B12 Normal >240 pg/mL Borderline B12 deficiency 170-240 Symptomatic <100 Serum B12 can be normal in up to 5% of patients with B12 Deficiency. So can’t always rely on serum B12 alone, also check antibodies, and urine methylmalonic acid (MMA) Antibodies = anti parietal and anti-intrinsic factor (IF) antibody; will be elevated MMA will be elevated Pernicious Anemia Most common macrocytic anemia. Caused by a vitamin B12 deficiency. Lacks intrinsic factor from the gastric parietal cells. Required for vitamin B12 absorption May be a congenital or autoimmune disorder. Autoantibodies against intrinsic factor which is released from the parietal cells in the fundus of the stomach (antiparietal antibodies) Conditions that increase risk include: Past infection with Helicobacter pylori Gastrectomy Proton-pump inhibitors Clinical manifestations Weakness, fatigue Paresthesias of the feet and fingers Loss of appetite, abdominal pains, weight loss Sore tongue that is smooth and beefy red, secondary to atrophic glossitis “Lemon yellow” (sallow) skin as a result of a combination of pallor and icterus Neurologic symptoms from nerve demyelination Ataxia, decreased or lack of DTRs, pathological reflexes; babinski’s, severe paresis Not reversible, even with treatment Schilling Test – not as commonly used nowadays. This localizes the site of pathology of the B12 deficiency A pt gets intramuscular injection of nonradioactive B12 This saturates the pt’s B12 receptors Pt then ingest radioactive B12 In “normal” patient will find vitamin B12 in the urine Why? in normal person the IM B12 already binds to all B12 receptors so when they ingest B12 there is no where for it to bind so the excess will be excreted in the urine In pt with pernicious anemia there is no intrinsic factor, so the ingested B12 or radioactive B12 is never absorbed so it never gets into the blood, to the kidneys, and thus never appears in the urine. Can be some other problem with absorption of vitamin B12 Can differentiate between the 2 because there is a second phase to the test. In phase 2 everything in stage 1 is repeated but now the pt is also given an intrinsic factor. If the problem is pernicious anemia exogenous intrinsic factor should correct it and radioactive B12 will now appear in the urine Folate (folic acid) Deficiency Anemia Folate is an essential vitamin for RNA and DNA synthesis. Absorption of folate occurs in the upper small intestine; it is not dependent on any other facilitating factors. Common in alcoholics and individuals with chronic malnourishment. Associated with neural tube defects of the fetus Folic acid found in most fruits and vegetables Particularly citrus fruits and green leafy veggies) Daily requirement 50-100 mcg Body stores are about 5000 mcg 2-3 month requirement Most common cause of deficiency – DIET Alcoholics, anorectics, overcooked food, diet that exclude fruit/veg Clinical manifestations Severe cheilosis – scales and fissures of the lips and corners of the mouth Stomatitis – mouth inflammation Painful ulcerations of the buccal mucosa and tongue – characteristic of burning mouth syndrome Dysphagia (difficulty swallowing), flatulence, and watery diarrhea Neurologic symptoms – usually NOT seen Some similar to B12 minus neurological Lab findings: Moderate to severe anemia MCV usually very high (110 – 140 fL) MHC normal Peripheral blood smear Anisocytosis , poikilocytosis, macroovalocyte (characteristic of this), hypersegmented neutrophils Megaloblastic RBCs Can see pancytopenia if severe BM: Marked erythroid hyperplasia, megaloblastic changes, Elevated LDH and slight increase in indirect bili. (d/t intramedullary destruction) Abnormally low serum Folic Acid – <150 ng/mL Serum B12 is normal Alcohol Induced Anemia from several factors: Interferes with absorption of folic acid (megaloblastic) Interferes with Hgb synthesis (sideroblastic anemia) Interferes with erythropoiesis (Macrocytosis) The anemia reverses with abstinence from alcohol within weeks Normocytic-Normochromic Anemias Are characterized by RBCs that are relatively normal in size and hemoglobin content but insufficient in number. No common cause, pathologic mechanisms, or morphologic characteristics exist. Are less frequent than macrocytic-normochromic and microcytic-hypochromic anemias. Aplastic Anemia Pancytopenia – reduction or absence of all three types of blood cells Most aplastic anemias are autoimmune disorders some are due to chemical exposure (benzene, arsenic, chemotherapy drugs) Pure RBC aplasia – only RBCs are affected Fanconi anemia – rare genetic anemia from defects in DNA repair Pathophysiology – hypocellular bone marrow that has been replaced with fat Clinical manifestations Hypoxemia, pallor (occasionally with a brownish pigmentation of the skin) Weakness along with fever and dyspnea with rapidly developing signs of hemorrhaging if platelets are affected Evaluation Bone marrow biopsy Posthemorrhagic Anemia Acute blood loss from the vascular space Clinical manifestations Depends on the severity of the blood loss Hemolytic Anemia Accelerated destruction of RBCs Congenital versus acquired Classified as Intrinsic (d/t components of cell, usually hereditary) Caused by Intracopuscular defects Extrinsic (immune, infection; drugs; hyperactive spleen, or intravascular trauma from a prosthetic heart valve or a microangiopathic hemolytic syndrome like DIC) Caused by Extracorpuscular defects Autoimmune hemolytic anemias Warm reactive antibody type Cold agglutinin type Cold hemolysin type (paroxysmal cold hemoglobinuria) Based on the optimal temperature at which the antibody binds to the erythrocytes Drug-induced hemolytic anemia Form of immune hemolytic anemia that is usually the result of an allergic reaction against foreign antigens Called the hapten model Penicillin, cephalosporins (more than 90%), hydrocortisone Clinical manifestations May be asymptomatic Jaundice (icterus) Splenomegaly Hemolytic Anemia – G6PD (Glucose-6- Phosphate Dehydrogenase) Deficiency Hereditary enzyme defect (X-linked recessive) Most common enzyme related hemolytic anemia Inability of the NADPH in the pentose pathway Lack of NADPH leads to the cells anti-oxidant protection or normally it protects cell against oxidants Episodic hemolytic anemia With oxidative stresses When Hgb is oxidized it denatures and forms a precipitant – Heinz bodies Heinz bodies damage the cell membrane Many variants of disorder that have varying severity Signs & Symptoms Usually healthy Hemolysis only with oxidative stress (infection or drug exposure) Common causative drugs – dapsone, primaquine, quinidine, quinine, sulfonamides, macrodantin Episodes are self limiting Lab Findings: Normal between episodes During episodes Reticulocytosis Increased indirect bilirubin (jaundice) Blood smear nondiagnostic but may show bite cells or blister cells Heinz bodies G6PD assay May be low, but misleading at or directly after episode when the enzyme deficient group of cells has been removed. Should be repeated several weeks after hemolysis resolves (6-8 weeks) Hemolytic Anemia – Sickle Cell Anemia Autosomal recessive Mutation of the β globin chain of Hgb. Designated HgbS (α2β2s) Those homozygous for mutation have sickle cell anemia (also noted as HbSS)t Those heterozygous for mutation have sickle cell trait (also noted as HbAS) 1 in 10 American black will have the trait 1:500 will American blacks will have the actual sickle cell; 1 in 100 Hispanic will have the trait 1:36,000 Hispanic American will have actual sickle cell HgbS is unstable and when exposed to acidosis or oxidative stress (hypoxia) the cell sickles The sickling is permanent These cells cannot change their shape which prevents them from passing through narrow capillaries. Sickled cells survive between 10–20 days Laboratory test is Hemoglobin Electrophoresis Laboratory Findings: Hct 20-30%, Hgb 8-10 Peripheral smear Sickled cells Target cells Howell-Jolly bodies Usually the DNA is expelled from the erythrocyte before it gets into circulation, but if there is a basophilic DNA remnant it will stain differently on peripheral smear and those cells are Howell Jolly Bodies Usually the spleen will remove these cells but in a dysfunctional spleen they remain in the circulation. Reticulocytosis Nucleated RBC WBC elevated (12-15K) Dx confirmed by Hgb electrophoresis In homozygous: Hgb S will be predominant, no HgbA, Hgb F varies Signs & Symptoms Painful attacks Brought on by Infection, dehydration, hypoxia Jaundice ((hemolysis) Pigment gallstones Splenomegaly/infarcted spleen Poorly healing ulcers over lower tibia Severe anemia Hemolytic – aplastic crisis Episodes last hours to days Vaso-occlusion CVA (some silent), organ damage (heart, lung, liver), osteonecrosis, renal tubular concentrating defect, Retinopathy that can progress to blindness Pulmonary hypertension (poor prognosis) Acute Chest Crisis Splenic sequestration crisis Sudden pooling of blood in spleen Hypovolemia / hard bloated abdomen Circulatory collapse Paroxysmal Nocturnal Hematuria (PNH) An acquired stem cell disorder Red blood cells become sensitive to complement which causes lysis Patients have episodic hematuria, typically brown tinged urine in am Also prone to thrombosis Can progress to aplastic anemia, myelodysplasia or AML (acute myeloid leukemia) Anemia varies in severity May or may not see reticulocytosis Urine hemosiderin is useful LDH may be elevated May see iron deficiency Best test is flow cytometry CD59 and CD55 will be deficient on RBC Anemia of Chronic Disease (ACD) Most common anemia in elderly Begins as a normocytic anemia and progresses to Microcytic when advanced Usually patients have mild to moderate anemia Severity of Anemia corresponds to severity of underlying disease Erythrocytes typically normocytic, normochromic 1/3 of patients will have microcytic anemia Pathophysiology: Likely secondary to chronic inflammatory response Inflammatory response: Release cytokines, Interleukin (IL-6) Stimulates hepcidin release from liver (key regulator to entry of iron into circulation) Iron is therefore trapped in macrophages and liver cells and decreased gut absorption of iron Results in low access of iron in circulation Decreased erythropoiesis – decreased RBC & decreased availability of iron Diagnostic Manifestations Impaired release of Iron Often a normocytic anemia (MCV normal) However if severe can have Microcytic Ferritin should be normal or high TIBC should be low or normal Transferrin saturation can be very low (misleading to dx of IDA. Not good indicator) RBC morphology nondiagnostic Bone marrow can distinguish between IDA and ACD Mild-to-moderate anemia from decreased erythropoiesis Acquired immunodeficiency syndrome (AIDS), malaria, rheumatoid arthritis, lupus, erythematosus, hepatitis, renal failure, and malignancies Pathologic mechanisms Decreased erythrocyte lifespan Suppressed production of erythropoietin Ineffective bone marrow response to erythropoietin Altered iron metabolism S/S Related to the causative disease Similar to IDA Mild (Hgb 10-12) – likely no symptoms Moderate (Hgb 7-11) – palpitations, dyspnea, exercise intolerance, angular stomatitis, glossitis, pallor, koilonychia Severe (Hgb < 7) – postural hypotension, dizziness, weak, gastritis, paresthesia, lethargy Blood Coag Tests test of bone marrow function – bone marrow aspiration from sternum or pelvis or bone marrow biopsy (provides most reliable and complete info; painful and expensive); bone marrow iron stores can be measured; can determine differential cell count blood tests provide info about absolute and relative numbers of blood cells and their structural and functional characteristics usually provide initial justification for performing a bone marrow aspiration large variety of blood tests available intrinsic pathway (injury inside blood vessel or blood cells themselves) blood tests whole blood clotting time measures the time it takes for blood to clot in glass test tube normally 9-15 minutes PTT (partial thromboplastin time) clotting in test tube is initially prevented by removing calcium measures time for recalcified citrated plasma to clot in test tube extrinsic pathway blood tests PT (prothrombin time) time needed for recalcified citrated plasma to clot in the presence of tissue thromboplastin “protime” adds the critical tissue ingredient (tissue thromboplastin) that is necessary to start off extrinsic pathway normal PT is 11-15 seconds INR (international normalized ratio) is PT test (nominator) divided by PT normal (denominator) 0.9-1.33 for normal people 2-3 for those on anticoag therapy such as warfarin blood tests for both pathways PTT and PT tests are useful to distinguish extrinsic from intrinsic coag disorders in liver failure coumadin or heparin therapy both the PT and PTT will be abnormal both can be elevated in vit k deficiency platelet function tests – assesses the number of platelets bleeding time assesses plt function – BP cuff on at 40 mmHg normal (depends on method) 2-7 min tends to be normal in coag disorders of extrinsic and intrinsic pathways if prolonged usually suggests a defect in plt function Homeostasis the arrest of bleeding; purpose to decrease blood loss components: vasculature, platelets, blood proteins (clotting factors) sequence: vascular injury leads to vasoconstriction → formation of platelet plug → tissue factor activates coagulation cascade → formation of blood clot (secondary hemostasis) → clot retraction and clot dissolution (fibrinolysis) function of the platelets help regulate blood flow into a damaged site by inducing vasoconstriction initiate platelet-to-platelet interactions resulting in the formation of a platelet plug initiate repair processes including clot retraction and clot dissolution (fibrinolysis) four step process: local constriction, formation of pure platelet plug (typically sufficient for sm wounds or injury), formation of blood clot (lg wound or injury), wound repair with formation of fibrous tissue platelet plug (primary hemostasis) important biochemicals released from platelet granules Thromboxane A2 - prothrombotic properties produced by activated platelets stimulates activation of new platelets increases platelet aggregation (attracting platelets) vasoconstriction ADP - prothrombotic platelet activation stimulate shape change Von Willebrand Factor - anchor endothelial cells attached to collagen acts as bridging molecule at sites of vascular injury for normal platelet adhesion under high shear conditions – promotes platelet aggregation carries factor VIII in circulation vascular contraction…after injury intravascular smooth muscle contracts reducing blood flow (vascular spasm) platelets are responsible for a lot of the vasoconstriction because of thromboxane A2 constriction can last minutes to hours allowing for platelet plug and formation of blood clot formation of platelet plug adhesion: mediated by the binding of platelet surface receptor glycoprotein-Ib (GPIb) to von Willebrand factor (vWF) activation: smooth spheres change to spiny projections and degranulation (called platelet-release reaction) resulting in release of various potent biochemicals aggregation: facilitated by fibrogen bridges between receptors on platelets; clot retraction – fibrin strands shorten and become denser and stronger to approximate edges clotting factors factor IV = calcium required throughout entire clotting sequence factor V = stuart synthesized in liver in presence of vit k; common pathway factor VIII = antihemophilic factor A vWF is the carrier; required during intrinsic pathway function of clotting factors fibrin production intrinsic (injury inside of blood vessel) pathway (factors XII, XI, IX, and VIII) longer pathway activated when the Hageman factor (XII) contacts subendothelial substances exposed by vascular injury extrinsic (injury outside of blood vessel) pathway (factor VII) the most dominant activated when the tissue factor (tissue thromboplastin) is released by damaged endothelial cells both pathways lead to a common pathway (factors X, V, II) prothrombin to thrombin fibrinogen to fibrin where clot is ultimately formed What is really important in clotting? Calcium – required in multiple steps in the process to activate clotting factors Vit K – essential in the synthesis (creation) of certain clotting factors in the liver Blood clot – begins in seconds (about 15) if trauma is severe or 1-2 minutes for minor injury injury to the blood vessel wall or blood induces formation of prothrombin activator prothrombin activator changes prothrombin to thrombin dependent on adequate calcium prothrombin attaches platelets adherent to injured areas thrombin changes fibrinogen to fibrin (fibrin is centerpiece of clot) fibrin meshes with blood cells, platelets and plasma to form the clot clot retraction, assisted by platelets, expresses serum remember serum is plasma minus clotting factors, such as fibrinogen plasma can clot, serum cannot Control of Hemostatic Mechanisms major regulatory factors are located on endothelial cell surface endothelium prevents formation of spontaneous clots in normal vessels by several anticoagulant mechanisms: production of nitric oxide (NO) and prostacyclin I2 (PGI2), thrombin inhibitors (antithrombin III), tissue factor inhibitors (tissue factor pathway inhibitors), and degrading activated clotting factors (thrombomodulin-protein C) fibrin in clot absorbs excess thrombin antithrombin III inactivates excess thrombin heparin is produced by mast cells and basophils – enhances activity of antithrombin III coumadin acts by competing with vit K and inhibits production in the liver of prothrombin and other clotting factors; can take several days to reach therapeutic levels plasminogen (profibrinolysin) is activated and becomes plasmin (fibrinolysin) – activator is released by damaged tissues which then activates plasmin; plasminogen activators are used clinically to dissolve coronary artery clots in pts with acute MI Pediatrics and the Hematologic System blood cell counts increase above adult levels at birth; they slowly decline during childhood increase blood cell count d/t trauma of birth and cutting of umbilical cord hypoxic intrauterine environment stimulates erythropoietin production; result is polycythemia of newborn lg number of immature erythrocytes (reticulocytes) in full-term neonates in full-term and premature infants the erythrocyte lifespan is 60-80 days (FT) and 20-30 days (P) differences in clotting factors result in decreased risk for thrombotic diseases and complications children have more atypical WBC (result of more frequent viral infections) neutrophil count is high at birth and rises during the first days of life after 2 wks neutrophil count falls within or below normal adult range by approximately 4yo the neutrophil count is the same as adult eosinophil count high in the first year of life and higher in children than in teenagers or adults monocytes high in first year of life but then decrease to adult levels platelets count in full-term neonates are comparable with that of an adult and remain so throughout infancy and childhood Hematopoiesis, Erythropoiesis, and Erythropoietin Hematopoiesis process of blood cell production in adult bone marrow or liver/spleen of fetus humans need 100 billion new blood cells per day bone marrow or myeloid tissue confined to cavity of bones primary site of residence of hematopoietic stem cells red (produces RBC) and yellow (no production of RBC) pelvic, vertebrae, cranium, mandible, sternum, ribs, humerus, and femur have active bone marrow in adults two stages mitosis (proliferation) - cells beginning to divide maturation (differentiation) continues throughout life to replace blood cells that grow old and die, killed by disease, or lost through bleeding (ex. accelerated in times like hemorrhage or hemolytic anemia) occurs in 2 separate pools stem cell pool: maintains number of pluripotential cells and progenitor cells bone marrow pool: contains cells actually proliferating and differentiating (maturing) once matured stored in peripheral blood in storage (50%) or functional (50%) stored in walls around blood vessel; mainly granulocytes (neutrophils) rapid movement into tissues when needed thrombocytes most are functional; 30% stored all RBC in peripheral blood are functional factors that increase hematopoiesis conversion of yellow bone marrow to red marrow by actions of erythropoietin faster differentiation (maturing) of progenitor cells faster proliferation (dividing) of stem cells into progenitor cells Erythropoiesis development of RBCs erythrocytes derived from erythroblasts maturation (differentiate) stimulated by erythropoietin stimulates stem cells to form proerythroblasts, which are committed into producing erythroid cells this promotes release of reticulocytes sequence: in each step the quantity of hemoglobin increases and the nucleus decreases in size erythroid progenitor → committed proerythroblast → normoblast (nucleus shrinks and is reabsorbed) → reticulocyte (cell leaves marrow and enters blood stream; last immature form) → erythrocyte (cell achieves final size and shape: hemoglobin synthesis ceases) reticulocytes: last immature form of erythroblast contains polyribosomes (globin synthesis) & mitochondria (heme synthesis) 24-48h after leaving marrow for circulation it matures into an erythrocyte loses polyribosomes and mitochondria make up about 1-2% of total RBC circulating in blood lasts about 2 days in marrow and 1 day in blood continuing to fully mature during time of low Hct the time in the marrow decreased to as little as 1 day retic count when elevated indicates new RBCs are being produced elevations: good indicator of erythropoiesis 25 mg Fe is required daily for erythropoiesis; 1-2 mg is dietary and remainder is obtained from Fe recycling Erythropoietin hormone released from kidney in response to low renal oxygenation NOT number of RBC but rather oxygen delivery produced in peritubular interstitial cells of kidney produced in the liver as well but only 10% RBC production increases w/i 24h life span is 4-12h (short ½ life) causes an increase in RBC number in 5 days always present in the plasma - you can always draw a lab to measure it give to dialysis and chemo patients - these pts are often times are anemic so we give this to help production of RBC; can increase Hgb by 33% Coag Disorders Coagulation system has 2 components Platelets Coagulation factors Both interact together to plug sites of bleeding Deficiencies in either can lead to Excess bleeding or clotting Excessive bleeding = hypocoaguable state If platelets or coagulation factors are low then the ability to form a clot is diminished Arise from either deceased coagulation factors , decreased platelet function, or decreased platelet number (thrombocytopenia) Leads to excessive bleeding/bruising from minor trauma, nosebleeds (epistaxis), blood in urine (hematuria), bleeding into joints (hemarthrosis), excessive bleeding during a menstrual period (menorrhagia), and/or bleeding between periods (metrorrhagia). Platelet problem P, P, P = petechiae, platelet dysfunction, low platelets Coagulation factor disorder – deep bleeding Excessive clotting = hypercoagulable state Clots can lodge in various areas leading to different problems. PE, Stroke, mesenteric ischemia Protein C, S, And antithrombin III, serve as checks and balances in clotting system Normally anticoagulants Mutation leads to deficiency = tendency to clot Antiphospholipid antibodies – predispose to hypercoagulability Other predisposing factors Pregnancy, malignancy, oral contraceptives, turbulent flow (atrial fib), heart failure, stasis Occurs with immobility Leads to DVT = PE Excess of platelets or deficiency of anti-thrombotic proteins (protein C, S, Antithrombin III) Alterations of Coagulation Vitamin K deficiency Vitamin K is necessary for synthesis and regulation of prothrombin, the prothrombin factors (II, VII, XI, X), and proteins C and S (anticoagulants) Liver disease Liver disease causes a broad range of hemostasis disorders: Defects in coagulation Fibrinolysis Platelet number and function Decreased Coagulation Factors Clotting factors are proteins synthesized mostly in the liver (II, VII, IX, and X) They need vitamin K for synthesis Deficiency in clotting factors results from: liver failure, vitamin K deficiency, or genetic mutation Hemophilia is X-linked genetic disease that leads ton clotting factor deficiency. Hemophilia A (Classic) is deficiency of factor VIII Hemophilia B (Christmas disease) is deficiency of factor IX Decreased Platelet Function or Numbers Normal platelet count 150,000 -400,000/mm3 Pathology can occur at any step in the function of platelets Von Willebrand’s disease there is decrease in, or absence of vWF Results in decrease in ability of platelets to bind to vessel wall Bernard-Soulier syndrome There is defect in GP Ib-IX (the link to vWF) Results in decreased ability of platelet to bind to blood vessel wall Storage pool diseases There is decrease in storage pool of signaling molecules normally released by platelets Thrombocytopenia Platelet count <150,000/mm3 <50,000/mm3: hemorrhage from minor trauma <15,000/mm3: spontaneous bleeding <10,000/mm3: severe bleeding Result of either decreased production of platelets or platelets are destroyed Decreased production = marrow failure (ie: malignancy, radiation, drugs, infection) Platelet loss/destruction = infection, drugs, autoimmunity, TTP, DIC Hypercoagulable States Thrombotic Thrombocytopenic Purpura (TTP) A thrombotic microangiopathy (damage to microvasculature) Platelets aggregate, form microthrombi, and cause occlusion of arterioles and capillaries Genetic mutation of ADAMTS13 gene with inherited form Acquired form due to triggers that cause antibodies that block activity of ADAMTS13 enzyme Manifestations Classic fever, purpura, altered mental status, neuro signs, renal dysfunction, thrombocytopenia, hemolytic anemia Hemolytic uremic syndrome (HUS) Same underlying pathophysiology as TTP But HUS is generally related to syndrome that occurs following a diarrheal illness (E. coli, Shigella); and is more common in children Laboratory signs of TTP Thrombocytopenia Hemolytic anemia (increased red cells, increased reticulocytes, schistocytes on smear, elevated LDH) Coagulation factors are not affected PT and PTT will be normal TTP can be fatal if plasmapheresis is not initiated immediately and continued until symptoms and signs improve Immune (idiopathic) Thrombocytopenic Purpura (ITP) IgG antibody that targets platelet glycoproteins Antibody-coated platelets are sequestered and removed from the circulation The acute form of ITP that often develops after a viral infection is one of the most common childhood bleeding disorders Manifestations: Petechiae and purpura Progressing to major hemorrhage Essential/Primary Thrombocythemia (thrombocytosis) (ET) Thrombocythemia is characterized by platelet counts >600,000/mm3 Myeloproliferative disorder of platelet precursor cells Megakaryocytes in the bone marrow are produced in excess Microvasculature thrombosis occurs Manifestations = often asymptomatic Often occurs in tandem with inflammatory disease Can occur with polycythemia vera Disseminated Intravascular Coagulation (DIC) Complex, acquired disorder in which clotting and hemorrhage simultaneously occur Does not occur by itself Infections, Massive trauma or surgery, neoplastic disease, chronic inflammatory diseases, complication of childbirth DIC is the result of increased protease activity in the blood caused by unregulated release of thrombin with subsequent fibrin formation and accelerated fibrinolysis. Clotting factors become depleted. Significant Endothelial damage is the primary initiator of DIC Critically ill patient By activating the fibrinolytic system (plasmin), the patient’s fibrin degradation product (FDP) and D-dimer levels will increase The amount of activated thrombin exceeds the body’s antithrombins and the thrombin does not remain localized The widespread thromboses created cause widespread ischemia, infarction, and organ hypoperfusion Because of the patient’s clinical state, the disorder has a high mortality rate Clinical signs and symptoms demonstrate wide variability: Bleeding from venipuncture sites Bleeding from arterial lines Purpura, petechiae, and hematomas Symmetric cyanosis of the fingers and toes Hypercoagulable States Factor V Leiden Mutation of factor V Autosomal dominant disorder Can exhibit incomplete penetrance May that carry the mutation do not suffer any consequences Displays incomplete dominance Those that are homozygous are at heightened risk for event Causes factor V to be unable to be inactivated by protein C Clotting is encouraged Most commonly hereditary hypercoagulability disorder in European Caucasians. Excessive clotting is almost always restricted to the veins Protein C Deficiency Congenital or acquired condition Type of thrombophilia Increased risk of venous thromboembolism No association with arterial thrombotic disease Deficiency in protein c results in loss of normal cleaving of factors Va and VIIIa, 2 main types of mutation Type I and Type II Purpura fulminans in newborns 2 abnormal copies of gene Leads to absence of functioning protein C in bloodstream Protein S Deficiency Protein S is vitamin K dependent anticoagulant that normally activates protein C in degradation of factor V alpha and Factor VIII alpha Deficiency leads to impaired function/activity of protein S and ultimately decreased degradation of these factors. Thus increased risk of venous thrombosis 3 hereditary types Can be acquired through vitamin K def or trt with warfarin, sex hormone therapy and pregnancy, liver disease, and chronic infections like HIV Systemic vs Secretory Immune System/Responses Systemic Secretory Body’s final response Lymphocytes travel through spleen and most lymph nodes Response occurs systemically Response occurs internally (in blood and tissues) Part of body’s first line defense Lymphocytes travel through breasts, bronchi, intestines, and GU tract Response occurs locally Response occurs externally (in secretions) Phases of the body's defense; first, second, and third lines of defense. Main function is protection from foreign organisms. Key strategy is to distinguish self from non-self, and to eliminate that which is foreign First line of defense Innate (natural) (native) immunity Monocytes – precursors to macrophages Formed in the blood Tissue Phagocytic cells Macrophages Microglia Dendritic cells Langerhans cells Kupffer cells Alveolar macrophages Granulocytes (BEN) – visible granules Basophils Eosinophils Neutrophils Platelets Interferons – group of glycoproteins that kill viruses and in general activates macrophages Important cellular defense Lysozyme – natural antibiotic against bacteria Is produced by macrophages and neutrophils Complement – enzyme precursors when activated, undergo cascading chain reaction conversions C reactive protein- serum globulin that increases during acute tissue injury or inflammation Prostaglandins and leukotrienes – fatty acids that may be released by damaged cells Kinins – serum proteins that stimulate vascular dilation and permeability Interleukins – stimulate the proliferation and maturation of lymphocytes Tumor Necrosis factors (TNF) – can help to simulate acute inflammation TGF-beta – help to simulate wound healing Cytokine – general term to signify a protein hormone that affects the function of cells lying near the cell of origin Natural barriers: Skin and mucous membranes Skin Linings of the gastrointestinal, genitourinary, and respiratory tracts These are composed of tightly associated epithelial cells Mechanical cleansing Sloughing off of cells Mucus and cilia Coughing and sneezing Flushing Vomiting Urination Biochemical barriers Synthesized and secreted saliva, tears, ear wax, sweat, and mucus Antimicrobial peptides Small molecular weight particles secreted by epithelial cells. Cathelicidins and Defensin Both toxic to bacteria, viruses, and fungi Normal bacterial flora Spectrum of bacteria that cover many of the body’s surfaces which do not normally cause disease Protect against attachment of pathogens to epithelium Release chemicals that inhibit colonization ex) Ammonia Second line of defense Inflammatory response (first immune response to injury) Caused by a variety of materials Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Depends on cellular and chemical component activity Nonspecific Local manifestations – cardinal signs Redness, heat, swelling, pain, loss of function Effects of inflammation are visible within seconds Vascular response Blood vessel dilation Increased vascular permeability and leakage White blood cell adherence to the inner walls of the vessels and Goals – once in the tissues, the cells and chemicals associated with the inflammatory response Limit and control the inflammatory process Prevent and limit infection and further damage Initiate adaptive immune response Prepare the area of injury for healing Third line of defense Adaptive (acquired) immunity Purposes: Destruction of infectious microorganisms that are resistant to inflammation Long-term highly effective protection against future exposure to the same microorganism Inducible Specific Products Immunoglobulins (antibodies) Lymphocytes (T cells, B cells) B lymphocytes are responsible for humoral immunity that is mediated by circulating antibodies T lymphocytes are responsible for cell-mediated immunity Components: Humoral immunity – control of freely circulating pathogens Produce immunoglobulins (antibodies) by activating B cells and creating plasma cells Bind to antigens on bacteria and viruses Cellular immunity – T cells (control of intracellular pathogens) Subpopulations (effector T cells) Kill target directly Stimulate other leukocytes Both produce memory cells Interaction of both is essential to the function of the acquired immune response Antigens Bind with antibodies,or receptors on T and B cells Not necessarily immunogens; most are though Antigenic determinant (epitope) – precise recognition portion Antigenic binding site (paratope) – matching portion Self-antigen – don’t fulfill foreignness Do not elicit an immune response Tolerance Central and peripheral tolerance Molecular size Haptens – antigens too small to induce immune response but can in combo with larger molecules that function as carries Allergens –antigens that induce allergic response Antigens in high or low extreme quantities can induce tolerance rather than immunity Antigen Presentation – both very important in graft rejection Major histocompatibility complex (MHC) Glycoproteins on the surface of all human cells (except RBCs) Also referred to as human leukocyte antigens (HLAs) Antigen presentation is primary role of MHC 2 types MHC I Found more diffusely on many kinds of cells Present foreign antigens to cytotoxic T cells (CD8 markers) MHC II More common in normal immune response on APC Type II mainly found on macrophages and B Lymphocytes, dendritic cells and Langerhans cells Present foreign antigens to T helper cells (CD4 markers) Superantigens (SAGs) Molecules produced by infectious agents Activates a large population of T-lymphocytes regardless of antigen specificity Produce excessive cytokines Results in systemic inflammatory symptoms; fever, low blood pressure, and potentially fatal shock Immunogens Induce production of antibodies, or T cells All are antigens Also called immunoglobulins Produced by plasma cells (which come from B lymphocytes) Classes of antibody IgG, IgA, IgM, IgE, and IgD Characterized by antigenic, structural, and functional differences Key function of host protection Direct or indirect protection Factors that influence the degree of immunogenicity of the antigen Being foreign to the host Being the appropriate size Having an adequate chemical complexity Being present in a sufficient quantity Active immunity – longer process Natural exposure to antigen Immunization Passive immunity – quicker Occurs when preformed antibodies or T cells are administered from a donor to a host Example: Maternal antibodies passed through placenta to fetus Unvaccinated individual exposed to particular infections give immunoglobulins from individuals who already have antibodies again that particular pathogen Immune Complexes Antigen + Antibody = Immune complex Complexes normally undergo phagocytosis and are removed If not removed they may precipitate damage to normal tissues Immunoglobulins Immunoglobulin A (IgA) Two classes: IgA1 molecules are found predominantly in the blood IgA2 molecules are found predominantly in normal body secretions IgAs found in body secretions – dominate Ig in secretory (mucosal) immune system Secretory piece may function to protect IgAs against enzyme degradation in the secretions Defends against pathogens on body surfaces Immunoglobulin D (IgD) Limited information on IgD function Low concentration in the blood Located primarily on the surface of developing B lymphocytes Function as one type of B cell antigen receptor Present in plasma Easily broken down Immunoglobulin E (IgE) Least concentrated of the immunoglobulin classes in the circulation Mediator of many common allergic responses When produced against innocuous environmental antigens, they are a common cause of allergies Portions of IgEs are bound to mast cells Defender against parasites Provides protection from large parasites Initiates an inflammatory reaction to attract eosinophils Immunoglobulin G (IgG) Most abundant class (80%-85%) Accounts for most of the protective activity against infections Transported across the placenta Four classes: IgG1 IgG2 IgG3 IgG4 Immunoglobulin M (IgM) Largest of the immunoglobulins First antibody produced during the primary response to an antigen Synthesized during fetal life Its synthesis may be increased as a response to infection in utero Tips to Remember Ig IgA- (areola) can be passed through breast milk, found in secretions IgD- (director) involved in regulating cell activity IgE- (emergency) involved with immediate responses, initiates inflammatory reaction IgG- (gestation) passive immunity given to newborns, primary antibody in immune response B cell and T cell B cells are produced in the bone marrow then migrate to the lymph nodes Plasma cells - produce antibodies The thymus is located in mediastinal area; secretes group of hormones that enable lymphocytes to develop into mature T cells B cell Activation – Humoral Immune Response When an immunocompetent B cell encounters an antigen for the first time, B cells with specific BCRs are stimulated to differentiate and proliferate A differentiated B cell becomes a plasma cell A plasma cell is a factory for antibody production Dedicated to the secretion of a single class or subclass of antibody T cell activation – Cellular Mediated Immunity Binding antigen to specific T cell receptors Allows: Direct killing of foreign or abnormal cells (Tc cells) Assistance or activation of other cells (eg. Macrophages) – carried out by Th cells T regulatory cells (Tregs) Regulate the immune response to avoid attacking “self” Memory T cells also produced Primary vs. Secondary Responses Primary response Initial exposure leads to lag or latent phase B-cell differentiation occurs during this phase Time necessary for clonal selection After 5-7 days IgM is detected in circulation Primary is the initial response IgM produced first followed by IgG against specific antigen Primer of the individual’s immune system Secondary response More rapid Larger amounts of antibody are produced Rapidity is caused by the presence of memory cells that do not have to differentiate IgM is produced in similar quantities to the primary response, but IgG is produced in considerably greater numbers Clonal Diversity and Clonal Selection. Clonal diversity Production of T and B lymphocytes Antigen recognition Lymphocyte specificity All necessary receptor specificities are produced Takes place in the primary (central) lymphoid organs (thymus, bone marrow) Driven by hormones Does not require foreign antigen Results in immature but immunocompetent T and B cells Primarily occurs in the fetus Continues to some degree throughout life B Cell Development: Production, proliferation, differentiation in bone marrow Travel to lymphoid tissue and reside there as immunocompetent cells Each cell responds to only one specific antigen T Cell Development: The thymus is the central lymphoid organ of T cell development Development of antigen-specific T cell receptors (TCRs) Leave thymus, travel to and reside in secondary lymphoid tissue as immunocompetent cells Clonal selection Antigen processing and presentation Complex cellular interactions Initiated when T and B cells interact with an antigen Must first be processed and then presented by antigen-processing (antigen-presenting) cells (APCs) Professionals are dendritic cells, macrophages, and B lymphocytes Both B and T cells are immunocompetent before they have “seen” an antigen on the surface of an APC Considered naïve Processing and presentation of antigens to naïve lymphocytes results in activation of the acquired immune response only if The antigen is the appropriate type The antigen is presented appropriately Phagocytosis Phagocytes – Granulocytes Neutrophils Granulocytic cell Also referred to as polymorphonuclear neutrophils (PMNs) Predominate in early inflammatory responses Attracted by neutrophil chemotactic factor released in mast cell degranulation Ingest bacteria, dead cells, and cellular debris Cells are short lived and become a component of the purulent exudate Primary role of removal of debris in sterile lesions (burns), and phagocytosis of bacteria in non sterile lesions Monocytes and macrophages Agranulocytic cell Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages Macrophages typically arrive at the inflammatory site 24 hours or later after neutrophils The monocyte/macrophage are the predominant phagocytes in late inflammatory response. Highly phagocytic Responsive to cytokines Promote wound healing Neutrophils Monocytes & Macrophages Arrive first Shorter life span Attracted by different chemotactic factors Different enzymatic content lysosomes Not involved in adaptive immunity Not involved in wound repair Arrive later Longer lifespan Attracted by different chemotactic factors Different enzymatic content of lysosomes Involved in activation of adaptive immunity Primary cells involved in wound repair Plasma Protein Systems Protein systems that provide a biochemical barrier against invading pathogens are the: Complement system Can destroy pathogens directly Activates or collaborates with every other component of the inflammatory response Functions Anaphylatoxic activity resulting in mast cell degranulation; leukocyte chemotaxis; opsonization; cell lysis Coagulation (clotting) system Forms a fibrinous meshwork at an injured or inflamed site Prevents the spread of infection Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity Forms a clot that stops bleeding Provides a framework for repair and healing Main substance is an insoluble protein called fibrin Kinin system Functions to activate and assist inflammatory cells Primary kinin is bradykinin Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis Kinases degrade kinins All contain inactive enzymes (proenzymes) Sequentially activated- cascade First proenzyme is converted to an active enzyme. The activation of the first component of a system results in sequential activation of other components. Interactions among the three plasma protein systems are finely regulated to prevent injury to the host tissue and to guarantee activation when needed. Multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems. Mast cells and Inflammation Not a blood cell Are cellular bags of granules located in the loose connective tissues close to blood vessels Skin, digestive lining, and respiratory tract Contain histamine and chemotaxic factor Activation Physical injury, chemical agents, immunologic processes, and toll-like receptors Chemical release in two ways Degranulation and synthesis of lipid-derived chemical mediators Mast Cell Synthesis Mediators Leukotrienes Product of arachidonic acid from mast cell membranes Similar effects to histamine in later stages Namely smooth muscle contraction, increased vascular permeability Longer and slower response than histamines Prostaglandins Similar effects to leukotrienes; they also induce pain Aspirin and some other NSAIDs block the synthesis of prostaglandins, thereby inhibiting inflammation Platelet-activating factor Produced by removal of fatty acid from plasma membrane Similar effect to leukotrienes and platelet activation Causes endothelial cell retraction to increase vascular permeability, leukocyte adhesion to endothelial cells, and platelet activation Mast Cell Degranulation Histamine Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Retraction of endothelial cells lining the capillaries Receptors: H1 receptor (proinflammatory) Located on smooth muscle cells Especially in the bronchi and causes bronchoconstriction when stimulated H2 receptor (anti-inflammatory) Abundant on parietal cells of stomach mucosa Induces secretion of gastric acid Acute vs. Chronic Inflammation Acute Inflammation Fever Caused by endogenous pyrogens (fever-causing cytokines). Act directly on the hypothalamus Leukocytosis Increased numbers of circulating leukocytes “left shift” –ratio of immature to mature neutrophils Increased levels in circulating plasma proteins = acute-phase reactants Mostly product of the liver cells IL 1 and IL 6 Chronic Inflammation Inflammation lasting 2 weeks or longer Often related to an unsuccessful acute inflammatory response Chronic inflammation is characterized by the persistence of many of the processes of acute inflammation Dense infiltration of lymphocytes and macrophages Body may wall off and isolate the infection to protect against tissue damage Forms a granuloma. Decay of cells occurs in the granuloma Cellular debris is broken down leaving a clear fluid (liquefaction necrosis) This fluid diffuses out and leave hollow, thick-walled structure Exudative Fluids. Serous exudate – watery exudate indicates early inflammation Fibrinous exudate – thick, clotted exudate indicates more advanced inflammation Purulent exudate (suppurative) – pus indicates a bacterial infection Hemorrhagic exudate – exudate contains blood indicates bleeding Immune Changes with Geriatric and Pediatric Population. Geriatric Impaired function of innate immune cells (phagocytes) Loss of natural barriers Fat loss and thinning of the skin lead to increased risk for infection Impaired inflammation is likely a result of chronic illness Diabetes, cardiovascular disease, etc. Chronic medication intake decreases the inflammatory response Healing response is diminished because of skin’s loss of regenerative ability Infections and chronic inflammation are more common in older adults Infections of urinary tract, lungs, and skin Decreased T cell activity Thymic size is only 15% of its maximum size by middle age Thymic hormone production drops, as does the organ's ability to mediate T cell differentiation Decreased antibody response to antigens Increase in circulating antigen-antibody complexes Increase in circulating autoantibodies Decrease in circulating memory B cells Pediatric Neonates have transiently depressed inflammatory and immune function Neutrophils are not capable of efficient chemotaxis Neonates express complement deficiency Deficient oxidative and bacterial responses Develop overwhelming sepsis Fetus has sufficient IgM but deficient IgG, IgA responses Maternal antibodies provide protection within the fetal circulation and during the first months of life Gone by 10 months of age Immunologically immature when born with deficiencies in antibody production, phagocytic activity, and complement activity Neonate begins producing IgG at birth. Child’s antibodies are protective around 6 months of age. Antigens and Antibodies Antigen Any substance that can combine with special receptor on cells called lymphocytes Each lymphocyte antigen receptor is unique; and interacts with FOREIGN antigens stimulates a specific immune response Antibodies Highly specific defense molecules Process of Infection Colonization Infectious microorganisms: Exist in reservoirs (contaminated soil, contaminated water, breast milk), animals, or another human. Are transmitted by: Direct contact Indirect contact – vectors Droplet versus airborne Vertical versus horizontal Microorganisms adhere to tissue through specific surface receptors. Invasion Invade surrounding tissues by evading the host’s defense mechanisms. Multiplication Warm and nutrient-filled environment of human tissue cause most microorganisms to multiply rapidly. Spread May stay localized or enter other body areas; if the immune system is compromised, spreading is quick. Clinical Infectious Disease Incubation Is the period from initial exposure to the onset of the first symptoms; could last from hours to years. Prodromal The occurrence of initial symptoms are often very mild with feelings of discomfort and tiredness. Invasion Invasion is farther and affects other body tissues. Convalescence Recovery occurs and symptoms decline, or the disease is fatal, or has a period of latency. Clinical Manifestations of Infectious Disease. Are variable, depending on the pathogen. Caused directly by the pathogen or indirectly by its products. Manifestations include fatigue, malaise, weakness, loss of concentration, generalized aching, and loss of appetite. Fever The hallmark of infection. Body temperature is regulated at a higher level than normal. Exogenous pyrogens Endogenous pyrogens Fever is thought to be adaptive host-defense response Infectious Disease Classifications Endemic Diseases with relatively high, but constant, rates of infection in a particular population Epidemic Number of new infections in a particular population that greatly exceeds the number usually observed Pandemic An epidemic that spreads over a large area such as a continent or worldwide Capacity of pathogen to cause disease Communicability – ability to spread from person to person Immunogenicity – ability to produce an immune response Entry portal – how disease infects the host Mechanism of action – how disease damages cells Infectivity – ability to enter and replicate Pathogenicity – ability to produce disease Virulence – capacity to cause severe disease; potency Toxigenicity – production of toxins Bacterial, Fungal, Parasitic, and Viral Infections Bacterial “True” bacteria, filamentous, spirochetes, mycoplasma, rickettsia, and chlamydia Gram-negative versus gram-positive bacteria Various transmission routes Attach through pili (fimbriae) Result in direct confrontation with an individual’s defense mechanisms Evasion of these defenses can result in bacteremia and sepsis. Exotoxins: Enzymes released during growth Damages cell membranes, activates second messengers, and inhibits protein synthesis. Endotoxins: Contained in cell walls of gram-negative bacteria and released during lysis of bacteria Is called pyogenic bacteria because they activate inflammation and produce fever. Produce toxins and extracellular enzymes to destroy phagocytic cells. Coat a portion of an individual’s antibody, preventing complement activation or phagocytosis. Degrade immune cells. Bind and neutralize antibodies. Evade complement. Cause immune suppression. Resistant: Alter surface molecules that express antigens. Tissue damage from bacterial products – superantigens Endotoxic shock (septic shock) Increased vascular permeability allows loss of large volumes of plasma Leads to hypotension and CV shock if not corrected. Normally a result of gram-negative bacterial infection Once bacteria in the blood endotoxins and cytokines are released causing vasodilation; hypotension, decreased oxygen delivery, and CV shock. Can lead to DIC Fungal Large microorganisms with thick cell walls Eukaryotes Single-celled yeasts, multi celled molds, or both Disease caused by fungi: Mycosis Disease transmitted by inhalation or contamination of wounds Dermatophytes if infections invades skin, hair, or nails Systemic infection is usually from immunosuppression. Adapt to the host environment. Wide temperature variations, low oxygen, alkaline pH Suppress the immune defenses. Some fungi survive phagocytosis by replicating in the phagosome or inhibiting lysosomal enzymes. Fungi encapsulate, alter antigen expression, and stimulate immunosuppressive cytokines to resist phagocytosis. Tissue damage is from fungal enzymes and indirectly from inflammation. Parasitic and Protozoan Survive intracellularly Coat themselves Gene switch Antigenic variation Degrade IgG and IgA Neutralize antibodies Tissue damage from infestation and toxins Viral Basic structure is the virion (nucleic acid surrounded by the capsid). Is classified by the nucleic acid in the virion (ribonucleic acid [RNA] or deoxyribonucleic acid [DNA]), whether it is single stranded (ss) or double stranded (ds), and whether it uses the enzyme reverse transcriptase for replication. Viral diseases: Are the most common affliction of humans Viruses: Intracellular parasites Life cycle: Completely intracellular Attaches or binds to the host cell via protein receptors. Penetrates the host cell. Releases genetic information into the host cytoplasm.. Translation of mRNA results in the production of viral proteins. For enveloped viruses, new virions are released through budding. Viral DNA is integrated in the host cell and transmitted to daughter cells by mitosis. Bypass immune defenses Rapid division Intracellular survival Coating with self proteins Antigenic variation Neutralization Complement evasion Immune suppression Harmful effects Inhibition of DNA, RNA, or protein synthesis Disruption of lysosomal membranes Promotion of cell apoptosis Fusion of adjacent cells (giant cells) Transformation into cancer cells Alteration of antigenic properties (immune attacks normal cells) Selye GAS Response. Nonspecific response to noxious stimuli GAS three stages Alarm stage Arousal of body defenses – fight or flight Stressor triggers the hypothalamic-pituitary-adrenal (HPA) axis. Activates the sympathetic nervous system (SNS). Stage of resistance or adaptation Mobilization that contributes to fight or flight Begins with the actions of adrenal hormones. Cortisol, epinephrine, and norepinephrine Stage of exhaustion (allostatic overload) Progressive breakdown of compensatory mechanisms May lead to the onset of disease Occurs only if stress continues and adaptation is not successful. Stress Response Is initiated by the central nervous system and the endocrine system. Corticotropin-releasing hormone (CRH) is released from the hypothalamus. CRH is also peripherally released at inflammatory sites. Stressor can be a perceived or real threat. SNS: Is aroused during the stress response. Causes the adrenal gland medulla to release catecholamines. Hypothalamic CRH stimulates the pituitary gland to release a variety of hormones. Anterior pituitary gland: Prolactin, endorphins, growth hormone (GH), and adrenocorticotropic hormone (ACTH), which stimulate the adrenal gland cortex to release cortisol. Cortisol's Role in Stress Response Is activated by ACTH. Stimulates gluconeogenesis. Elevates the blood glucose level. Is a powerful anti-inflammatory or immunosuppressive agent. Causes poor wound healing and an increased susceptibility to infection. How Stress Affects the Immune System Reactive response involves psychological stressors. Anticipatory response – anticipates a disruption in homeostasis. Conditional response – associates a stimulus with danger. May cause post traumatic stress disorder (PTSD) or phobias Can precipitate disease. Cardiac disease Can worsen an existing disease. Irritable bowel disease Asthma Autoimmune diseases Human immunodeficiency virus (HIV) progression Many immune-related conditions and diseases are associated with stress. Stress and negative emotions increase levels of pro-inflammatory cytokines, providing a possible link among stress, immune function, and disease. Stress-induced immune changes affect immune cell functions. Causes decreased natural killer cell and T-cell cytotoxicity and impaired B-cell function. Hypersensitivity Inappropriate immune responses Is an altered immunologic response to an antigen that results in disease or damage to the host. Three variables Original “insult”: Alters immunologic homeostasis, which is the steady state of tolerance to self-antigens or the lack of immune reaction against environmental antigens. Individual’s genetic makeup: Determines the degree of the resultant immune response from the effects of the insult. Immunologic process – causes disease symptoms. Is characterized by the immune mechanism. Type I IgE mediated Anaphylaxis Is against environmental antigens (allergens). IgE binds to crystalline fragment (Fc) receptors on the surface of mast cells; cross linking causes the release of histamine from mast cell degranulation. H1 receptors Manifestations Bronchial constriction Edema Vasodilation H2 receptors Manifestations Increases gastric secretions Decreases the release of histamine from mast cells and basophils Increases chemotactic activity Allergic Rhinitis Inhaled, airborne allergens may trigger an immune response in the upper airway causing 2 problems: Rhinitis and conjunctivitis Type I, IgE- mediated hypersensitivity response to environment allergen in genetically susceptible patient Called hay fever when it occurs seasonally, Spring, summer, and fall caused by pollens from trees, grass, and weeds; in summer and fall precipitated by mold spores as well When it occurs year round called allergic rhinitis Most common in young children and adolescents. Different types Chronic vasomotor rhinitis Infectious rhinitis Rhinitis medicamentosa Anaphylaxis Acute type I allergic reaction Causes sudden, rapidly progressive urticaria, and resp distress Can be systemic or localized Severe reactions can lead to vascular collapse, systemic shock, and even death. Results for systemic exposure to sensitizing drugs or other antigens, including Serums in vaccines, pollen, hormones, antibiotics, and so on After initial exposure to antigen, immune system produces IgE antibodies in the lymph nodes Antibodies will bind to the membrane receptors on mast cells in connective tissues and on basophils On re-exposure to the antigen, the antigen will bind to adjacent IgE antibodies Response to antigen – IgM and IgG recognize and bind to antigen Release of chemical mediators IgE is activated on basophils with promotion of mediator release Histamine, serotonin, and leukotrienes Intensified response – mast cells release more histamine Vasodilation occurs Respiratory distress – in lungs histamine causes endothelial cell destruction and fluid to leak into alveoli Deterioration – mediators increase vascular permeability, causing fluid to leak from vessels Failure of compensatory mechanisms Endothelial cells damage causes basophils and mast cells to release heparin and mediator-neutralizing substances Although now it is irreversible Type II Tissue-specific reactions Specific cell or tissue (tissue-specific antigens) is the target of an immune response. Mediated by IgG and IgM Cytotoxic mediated Five mechanisms Cells are destroyed by antibodies and complement. Cell destruction occurs through phagocytosis. Neutrophils release granules. Antibody-dependent cell-mediated cytotoxicity is present. Causes target cell malfunction. Examples: Graves disease Autoimmune hemolytic anemia Rheumatic fever Serious inflammatory systemic immune process Occurs normally 1 week to 6 months after group A beta-hemolytic streptococcal pharyngitis Remains important cause of death in 5-25 year olds Many older patient’s have valvular disease b/c of RF Jones criteria – guidelines for diagnosis Set of symptoms major and minor that have to have Causes fever, migratory polyarthritis, and most seriously, carditis Patho unclear Rheumatic Heart Disease Chronic Characterized by repeated inflammation with fibrinous repair to the cardiac valves There is leaflet thickening, commissural fusion, an shortening and thickening of tendinous cords Lead to valvular stenosis or regurgitation; and heart failure Increased risk of afib and endocarditis Rheumatic valvulitis is the inflammation to valves by rheumatic fever in childhood. Patho unclear Type III Immune (antigen-antibody) complex mediated Complexes are formed in the circulation and deposited later in vessel walls or extravascular tissues. Is not organ specific. Damage results from complement activation and neutrophil lysosomal enzymes. Immune complex clearance Large – Macrophages Small – Renal clearance Intermediate – Deposited in tissues; causes problems Immune Complex Disease Is characterized by a variety of symptoms. Periods of remission or exacerbation occur. Examples Serum sickness Affected tissues are blood vessels, joints, and kidney. An example is Raynaud phenomenon Cryoglobulins are deposited in the fingers, toes and nose and block circulation Leading to pallor and numbness followed by cyanosis and finally gangrene if not restored Arthus reaction Caused by repeated local exposure to antigen that then binds with an antibody forming immune complexes in the walls of local blood vessels Localized response causes increased vascular permeability, an accumulation of neutrophils, edema, hemorrhage, clotting, and tissue damage. Type IV Is mediated by T lymphocytes or is cell mediated. Destruction of the tissue is usually caused by direct killing by toxins from cytotoxic T (Tc) cells Examples MS, skin test for tuberculosis (TB), contact allergic reactions, DM 1, Hashimoto disease, Crohn’s disease Allergy – an exaggerated response against an environmental antigen (allergen). Type I Pollen, molds, fungi Certain foods: Milk, eggs, fish Animals Certain drugs Cigarette smoke, house dust Type IV are plant resins, metals, acetylates; chemicals in rubber, cosmetics, detergents, and topical antibiotics Mostly haptens that react with normal self-proteins in the skin Result: Allergic contact dermatitis Example: Poison ivy Type II and III are rare but can include antibiotics (PCN, sulfonamides, and soluble antigens produced by infectious agents (Hep B) Haptens that bind to the surface of cells and elicit an IgG or IgM response Example: Drug allergy – type II Example: Arthus reaction type III Involves a sensitizing process Genetic predisposition – atopic Manifestations Conjunctivitis, rhinitis, asthma Vomiting, diarrhea, or abdominal pain Urticaria (hives) Can result in anaphylaxis Control of type I allergic responses Blocking with use of antihistamines #1 control is through the ANS Biochemical mediators (epinephrine; acetylcholine) bind to appropriate receptors on mast cells and target cells of inflammation This controls the release of inflammatory mediators form mast cells and the degree to which target cells respond to inflammatory mediators. Autoimmunity – a misdirected response against the host’s own cells. Is a breakdown of tolerance during which the body’s immune system begins to recognize self-antigens as foreign. Examples: Sequestered antigens, infectious diseases with molecular mimicry, neoantigens, survival of a forbidden clone, or defective peripheral tolerance Genetic factor: Familial association Systemic lupus erythematosus (SLE) Type III hypersensitivity Chronic multisystem inflammatory disease Autoantibodies against: Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, and many others Deposition of circulating immune complexes containing antibody against the host’s deoxyribonucleic acid (DNA) More common in females 20-40 year-old age group Blacks > whites Genetic predisposition based on twin studies Clinical manifestations Arthralgias or arthritis Vasculitis and rash Renal disease Hematologic changes, especially anemia Cardiovascular disease Transient lupus-like syndrome Indistinguishable both clinically and by laboratory work up Develops from prolonged use of medications; particularly hydralazine and procainamide Can be triggered by UV radiation and infectious agents in genetically susceptible individuals Eleven findings are common. Presence of at least four findings indicates SLE. Facial (malar) rash, discoid rash, photosensitivity, oral or nasopharyngeal ulcers, nonerosive arthritis, serositis, renal disorders, neurologic disorders, hematologic disorders, immunologic disorders, and presence of antinuclear antibodies (ANAs) Currently, there is no cure for SLE. UV exposure worsens symptoms Alloimmunity – directed against beneficial foreign tissues (e.g., transfusions, transplants) Individual’s immune system reacting against antigens on the tissues of other members of the same species Transient neonatal alloimmunity Fetus expressing parental antigens not found in the mother Transplant rejection and transfusion reactions Transfusion Reaction Type II hypersensitivity reaction ABO system Two major carbohydrate antigens Are A and B codominant. Individuals have antibodies to the A and B antigens they lack. Anti-A and anti-B antibody production are induced by similar antigens on naturally occurring bacteria in the intestinal tract. Antibodies are usually of the IgM class (isohemagglutinins). O blood type – a universal donor. AB blood type – a universal recipient. Rh system Is primarily expressed on erythrocytes. Rh-positive – expresses the D antigen on the RhD protein. Rh-negative – does not express the D antigen. Approximately 15% of North American white individuals are Rh-negative. Rh-negative individuals can make anti-D if exposed to Rh-positive erythrocytes. Hemolytic disease of the newborn – Rh-negative mother gives birth to a Rh-positive infant. Graft Rejection Matching the human leukocyte antigens (HLA)–DR locus – most critical for graft acceptance. Transplant rejection – classified according to time. Hyperacute – immediate and rare; pre existing antibody to graft antigens Acute –cell-mediated response against unmatched HLA antigens Chronic – months or years; due to a weak cell-mediated reaction against minor HLA antigens Immunodeficiency – immunity is insufficient to protect the host. All responses can be serious or life threatening. Pathogenesis of Common Viral Diseases Virions enter cells Fifth disease (Erythema Infectiosum) Infection by parvovirus B19 Transmitted via droplet Incubation period 4-14 days, up to 21 days Also referred to as slapped cheek syndrome Mild self-limiting viral disease characterized by erythematous and macular rash first appearing on the cheeks and ears Low grade fever, headache, rash, cold like symptoms Rash and joint symptoms can occur 2-3 weeks after acquiring infection. Outbreaks during late winter and early spring Household spread is common Parvovirus B19- specific IgM antibodies possible to confirm dx; in complicated (persists for 2-4 months); detectable 3 days after infection; IgG antibody usually detectable 7 days after infection Positive IgG in absence of IgM indicates previous infection and immunity Herpangina Acute viral illness Enterovirus – Coxsackie A and B Causes fever, ulcerative mouth lesions, cough, coryza, pharyngitis Transmitted by fecal-oral and oral-oral route Incubation is 3-6 days More frequent in lower socioeconomic groups in the summer Associated with high fever and sore throat – fever up to 106 Also with malaise, h/a, backache, anorexia, drooling, vomiting, and diarrhea Lesions 1-2mm in size On ant tonsillar pillars, soft palate, uvula, tonsils, pharyngeal wall, and post buccal surfaces. Perform throat culture to rule out streptococcal pharyngitis Infectious mononucleosis Kissing disease Infectious, widespread viral disease Caused by Epstein-Barr virus (EBV) Symptoms include; fever, fatigue, pharyngitis, and adenopathy; some risk of complications Splenic rupture rarely Transmission is oropharyngeal route (saliva) or blood Incubation is 30-50 days In adolescents and young adults symptoms appear around 4-6 weeks after initial infection Should differentiate from strep throat Monospot is usual screening test Rapid nonspecific test for heterophile antibody agglutination Consider EBV antibody titer (viral capsid antigen, early antigen) if diagnosis is in doubt, especially in older patients. Influenza Highly infectious. Caused by orthomyxovirus (ssRNA virus) that appears in Antigenic types A and B Virions attach to respiratory epithelial cells and enter by endocytosis. May be fatal for the very young and the very old; it is seasonal. Surface proteins undergo change each year Can have antigenic drift or mutation. Mutation of genes that express surface molecules Can have an antigenic shift. Recombination into a new virus from two different species Mild cold like symptoms; fever, chills, malaise, h/a, nausea, muscle aching, nasal stuffiness Nasal or throat swab for identifying influenza antigen Measles (Rubeola) Measles virus (RNA virus, Paramyxovirus family) Acute viral disease with fever (higher than 101), erythematous, maculopapular rash; cough, coryza, conjunctivitis, Characteristic rash of oral mucus membranes known as Koplik spots Transmitted by direct contact with infectious droplets, or less commonly by airborne spread; highly contagious Incubation period is 8-12 days Communicable 1-2 days before symptoms begin 3-5 days before rash to 4 days after rash onset Greater than 99% reduction in reported incidence since vaccination began in 1963 Serum IgM antibodies peak 10 days after onset of rash, disappear after 20-60 days Measles virus detected from nasopharyngeal secretions, conjunctiva, blood, urine Mumps (Parotitis) Acute viral diseaseCaused by paramyxovirus or mumps virus Affects salivary glands, primarily parotid gland Transmitted via respiratory route (direct contact) Communicable 1-2 days before to 5 days after onset of parotid swelling Incubation period 16-18 days, cases may occur 12-25 days after exposure Symptoms: tender swollen parotid glands, typically covering angle of jaw Tenderness persists 1-3 days; swelling 7-10 days Openings of duct of involved salivary glands may be red and swollen Fever up to 104 Virus best collected in saliva Positive IgG titers or + mumps IgM antibody Rubella (German Measles) Mild viral disease also known as 3-day measles Rubella virus (RNA virus, togaviridae family) Transmitted by direct or droplet contact with nasopharyngeal secretions Incubation period 14-23 days Communicable a few days before rash onset and for 5-7 days after rash appears Infants with congenital rubella may shed virus for 1 year or more Maculopapular rash, beginning on face and spreading, typically to trunk Second day, rash begins to disappear in same pattern, usually resolves by 3rd day Virus can be detected on nasal smear Roseola Also known as 6th disease Acute viral disease of infants and young children (under 2 yrs old) Caused by herpesviruses, HHV-6 and HHV-7 Known collectively as roseolovirus Characterized by sig fever for 7-10 days; when resolved, followed by faint, erythematous, maculopapular rash lasting hours to days Transmission is by droplet and fecal-oral route Incubation period is 9-10 days Presence of fever up to 106 F; faint blanching, erythematous; maculopapular rash beginning on day 4 (lasts 1-2 days) ; may have lymphadenopathy (suboccipital, posterior cervical, postaurticular), mild pharyngitis No diagnostic studies indicated. Self limiting and mild Varicella Usually mild acute viral disease, highly contagious Caused by varicella zoster virus (herpes virus family) Characterized by fever and generalized, pruritic, vesicular rash Rarely spread through contact with fluid in vesicles Can be caused by contact with pts with herpes zoster (shingles)I susceptible individuals Communicable 1-2 days before rash until vesicle are crusted, approximately 5 days after onset of rash Incubation period usually 14-16 days but may be 10-21 days No diagnostics indicated Can be detected in vesicular scrapings during the first 3-4 days of eruption West Nile Virus Viral infection causing febrile illness, rash, arthritis, myalgia, weakness, lymphadenopathy, and meningoencephalitis Caused by arbovirus family Flaviviridae Transmission cycle is spread by infected mosquitoes to birds, then from the birds to feeding mosquitoes Infection can spread through blood transfusions, organ transplantation; and prenatal transmission: RARE Incubation period 2-15 days Symptoms may include fever, h/a’s, fatigue, muscle pain, malaise nausea, anorexia, vomiting; and rash CSF with IgM antibody for WNV is confirmative; CSF with pleocytosis (increased number of lymphocytes) Pleocytosis: increased number of lymphocytes in CSF WNV antibody in serum presumptive of recent infection CMV DNA virus; Herpesvirus Transmitted by direct person-person contact Found worldwide in all ages, races, age, ranging from 40-100% Most common congenital infection in the US 5-15% newborns congenitally infected at delivery Incubation period is unknown CMV normally manifests itself in 4-7 weeks but as long as 16-20 weeks after infection Most likely 30-60 days post transplant Remains with person for life Immunocompromised at risk Symptoms: mono like syndrome; fever; overwhelming fatigue; pharyngitis, ulcerative lesions in mouth; loss of vision Most common illness caused by CMV is retinitis HIV/AIDS Acquired immunodeficiency syndrome (AIDS) is caused by the virus, HIV. Depletes the body’s T helper (Th) cells. Is susceptible to life-threatening infections and cancer. Incidence Worldwide Is and remains a major cause of morbidity and mortality. The epicenter of the AIDS pandemic is Sub-Saharan Africa. 2.1 million new cases of HIV in 2013 35 million living with HIV around the world United States In 2013, diagnosed with AIDS was 26, 680 In 2013 diagnosis of HIV infection was 47,352 At end of 2012 estimated 508, 850 persons in US living with HIV infection Bloodborne pathogen is present in body fluids (e.g., blood, vaginal fluid, semen, breast milk). Routes of transmission Blood or blood products, intravenous drug use, heterosexual and homosexual activity, and maternal-child transmission before or during birth Two types: Both are retroviruses HIV-1 HIV-2 – less virulent variant and is found mostly in western Africa RNA virus (retrovirus) Stores genetic material on two copies of RNA rather than the usual dsDNA. Carries an enzyme, reverse transcriptase, that creates a dsDNA version of the virus. Integrase inserts new DNA into the infected cell’s genetic material. May be dormant: No problems develop. May activate: Many problems develop; new DNA becomes part of the cell’s genetic material and accelerates apoptosis and shedding of infectious HIV HIV structure gp120 protein binds to the CD4 molecule found primarily on the surface of Th cells Typically causes a significant decrease of Th. Reverses CD4:CD8 ratio Decreased T cells Decreased thymic production of new T cells Damaged secondary lymphoid organs, especially lymph nodes Clinical manifestations Serologically negative, serologically positive but asymptomatic, early stages of HIV, or AIDS Window period: Infectious but asymptomatic Fatigue, headache, muscle aches, fever May be asymptomatic for years Diagnosis of AIDS is made If individual is serologically positive for antibodies against HIV Have atypical or opportunistic infections and/or cancers Kaposi sarcoma, histoplasmosis, (BOX 10-2; page 327) Have indications of debilitating chronic disease (wasting syndrome, recurrent fevers) CD4 and T cell numbers at or below 200 Pathogenesis Final phase of HIV occurs when sufficient number of CD4 cells are destroyed and when production of new CD4 cells cannot match destruction Pt exhibits fatigue, fever, and wt loss Most AIDS defining conditions are marked by CD4 <200 cells or appearance of 1 or more opportunistic infections Untreated HIV patients >50 years old; show more rapid progression toward AIDS and poor overall survival Pediatric Acquired Immunodeficiency Syndrome and Central Nervous System Involvement Presence of passive maternal antibody limits testing of HIV antibodies in infants up to 18 months. Central nervous system (CNS) is particularly vulnerable. Developmental delays; loss of intellectual abilities Impaired brain growth or acquired microcephaly Motor deficits Pathogenesis of Common Bacterial Diseases Lyme Disease Tick borne infection from a spirochete transmitted via deer tick (Ixodes scapularis) bite; not dog tick (which is larger) Tick is 2-9mm in size Painless bite; usually drop off in 2-4 days; Must be embedded >24 hours to transmit disease Caused by the spirochete Borrelia burgdorferi: most common vector-borne disease in the US Incubation period from bite to appearance or erythema migrans 3-31 days; usually 7-14 days Primarily clinical diagnosis ELISA is preferred (more sensitive and specific) + proceed to Western blot assay to detect both IgM and IgG Stages Symptoms Lab Findings Stage 1: Early localized disease (3-30 days post exposure) Flu-like symptoms; 50-90% pts develop distinctive rash termed erythema migrans within about 1 week of tick bite; Begins as red macule or papular, expands rapidly over several days to annular, erythematous patch with central clearing, >5cm to as large as 30cm. Resolves 3-4 weeks without trt; usually in area of tick bite but may occur anywhere IgM – appears IgG – negative Stage 2: Early disseminated disease (weeks to months post-exposure) Begins rapidly 3-5 weeks after initial infection, as spirochete spreads; wide variety of symptoms, most notably persistent fatigue; migratory arthralgia common; CN palsies (CNVII); most common multiple erythema migrans lesions; usually smaller than initial lesion IgM – peaks IgG – appears Stage 3: Late disease (months to years later) Months to years after initial infection, characterized by recurrent pauciarticular arthritis, usually affecting large joints (knees); CNS and PNS affected, may develop subacute encephalopathy, distal paresthesias; memory, mood, sleep problems may be noted; cardiac involvement IgM – declines to low levels IgG – peaks; remains elevated but at lower levels Pertussis Upper respiratory illness Characterized by progressive cough that can become severe and spasmodic Caused by bordetella pertussis Transmission is respiratory Incubation is 6-20 days Communicable until 5 days after trt initiated Catarrhal stage: mild upper resp symptoms with cough and mild conjunctival injection (most contagious); indistinguishable from common cold Paroxysmal stage: severe burst of cough with inspiratory whoop followed by vomiting; fever absent or low grade at most; cough is forceful; child unable to breath b/t coughing attacks Nasopharyngeal cultures in catarrhal stage or IgA testing for B. pertussis to confirm diagnosis Rheumatic Fever Rocky Mountain Spotted Fever (RMSF) Moderate systemic febrile illness with rash caused by vasculitis of small vessels; systemic symptoms including fever, characteristic rash; risk of severe complications and death Caused by Rickettsia rickettsii; transmitted by bite of infected tick Tick must attach and feed for 4-6 hours to transmit infection No person-person transmission; disease confers immunity Incubation 2-14 days Triad of symptoms: Fever, rash, and history of tick bite Fever sudden > 104, severe h/a, myalgia, n/v, abd pain, lymphadenopathy, cough, confusion Titers; acute and convalescent sera may not rise for 10-14 days Scarlet Fever Acute infection disease usually associated with streptococcal pharyngitis Characterized by vascular response to bacterial endotoxin Toxin produced by group A hemolytic streptococcus (GAS) and occasionally produce by certain strain of staphylococci Transmitted by direct projection of large droplets or physical transfer of resp secretions Incubation 3-5 days Communicable during incubation and clinical illness, 10 days,no longer communicable after 24 hours antibiotics Normally in children 6-12 years Prodrome 1-2 days of fever, sore throat, h/a, also may be abd pain and vomiting Rash appears in 1-5 days Strawberry tongue Pathogenesis of Common Protozoan/Parasitic Diseases Parasites benefit at the expense of the host. Parasites range from unicellular protozoa to large worms. Parasitic worms (helminths) Intestinal and tissue nematodes (e.g., hookworm, roundworm) Flukes (e.g., liver fluke, lung fluke) Tapeworms Are a common cause of infection worldwide. Are rarely transmitted from human to human; are transmitted mainly through vectors. Malaria by mosquito bites Trypanosomes by the tsetse fly Leishmania spp. by sand fleas Others found in contaminated water or food (e.g., Giardia lamblia). Malaria: Is the most common infection worldwide. Is transmitted through the bite of an infected Anopheles mosquito. Parasite enters the bloodstream, survives in the liver, and invades the parenchymal cells. After several rounds of division, the liver cell ruptures, and thousands of parasites enter the blood, infecting the red blood cells. Symptoms: fever, fatigue, vomiting, and h/a’s. Typically begin 10-15 days after bite Toxoplasmosis Caused by intracellular protozoan parasite, Toxoplasma gondii Cats are the primary host Humans are the intermediate host Acquired through contact the feline feces, by eating raw or undercooked meat, and by eating soil-contaminated fruit or vegetables Once person is infected parasite lies dormant in muscle tissue and will never be eliminated Risk to fetus dependent on gestational age of transmission Greatest risk in 1st trimester 1-8 per 1,000 Incubation period avg 7 days (range 4-21) 80-90% asymptomatic Usually subclinical infection Pathogenesis of Common Fungal Infections Candida albicans: Is the most common fungal infection. Resides in skin, gastrointestinal tract, mouth, and vagina. Local defense mechanisms and microbiome produce antifungal agents. Remains localized if the immune system is intact; if the immune system is compromised, then the infection can become systemic. Tinea Often called ringworm Mycoses of the skin Tinea pedis (foot) Athlete’s foot Tinea unguium (nails) Tinea cruris (groin) Tinea corporis (body) Tinea capitis (scalp) Tinea versicolor (various colors) Pityrosporum orbiculare Systemic Disorders Chronic Fatigue Fatigue with multiple associated symptoms for longer than 6 months; and in which these symptoms have profound impact of daily activities Mostly in women, 4x more than men (age 40-59) Sensitive, nonspecific indicator of underlying med or psych pathology C/o lack of energy, listlessness, fatigue that interferes with participation in family, work, or even leisure activities CDC has 2 criteria for chronic fatigue Unexplained, persistent fatigue >6 months; unrelieved by rest 4 or more of the following Impaired memory, post exertional malaise, unrefreshing sleep, muscle pain, joint pain, headaches, sore throat, tender cervical or axillary lymph nodes FUO – Fever