MS2 renal/pulm Flashcards

Question

Nephrotic syndrome - FSGS ``` Clinical presentation Pathogenesis Light microscopy Immunofluoresent microscopy Electron microscopy ```

Answer 1

FSGS - Focal Segmental Glomerulosclerosis Patho; VISCERAL EPITHELIAL DAMAGE Light microscopy, - SCLEROSIS (focal) - Segmental - affected capillary loops collapse - Segmental HYALINOSIS Immunofluorescence - IgM and C3 in Sclerotic areas +/- mesangium Electron microscopy - Diffuse effacement of foot processes - focal detachment of epithelial cells and denudation of GBM Clinical course - POOR RESPONSE TO CORTICOSTEROID TX

Answer 2

MPGN - Membranoproliferative Glomerulonephritis Primary (idiopathic), (type I and II) Secondary is always type I Patho Type I - Immune complexes - activation of classical and alternative complement pathways Type II - activation of alternative complement pathway Light microscopy - Proliferation of mesangial cells - proliferation of capillary endothelium - Glomerular capillary wall has a “TRAM-TRACK” appearance Immunofluorescence - Type I; C3 in granular pattern. IgG, C1q and C4 may also be present - Type II; C3. NO IgG or C1q or C4 Electron microscopy - Type I; Subendothelial electron-dense depositis, may also be mesangial and subepithelial deposits - Type II; Deposition of dense material into GBM . RIBBON LIKE

Answer 3

1. IgA Nephropathy - Patho; Genetic or acquired abnormality of immune regulation - Light microscopy; Mesangial widening due to proliferation and endocapillary proliferation - Immunofluorescence; MESANGIAL DEPOSITION of IgA. C3, properdin, IgG, IgM often. Dense deposits in mesangium - Clinical features; HEMATURIA 2. Alport Syndrome - Patho; abnormal alpha 3, alpha 4, alpha 5 chains of collagen IV. Defective assemble of collagen IV - Electron microscopy; Early lesion - GBM thinking. Fully developed disease - GBM alternating thick and thin. Splitting and layering of lamina densa - clinical features; hematuria, Red cell casts. HEMATURIA with progressive to chronic renal failure. nerve deafness, Eye disorders 3. Thin Basement Membrane Lesion

Answer 4

1. Lupus nephritis; various possible clinical manifestations 2. Henoch-Schoenlein Purpura 3. Diabetic Nephropathy 4. Amyloidosis - deposits of abnormal proteins (amyloid) in the mesangium and glomerular capillary walls - eventually the glomerulus is completely obliterated - also see deposits in renal interstitium and vessel walls - may present with nephrotic syndrome - may die of uremia from destruction of glomeruli

Answer 5

External K+ Balance—Excretion must equal intake - The relationship between dietary K+ intake and K+ excretion determines external K+ balance. The dietary intake of K+ is approximately equal to that of Na+, 80 to 120 mEq/day. This K+ intake is more than the entire K+ content of the ECF, which is only ∼70 mEq/l. For the plasma K+ content to remain constant, the body must excrete K+ through renal and extrarenal mechanisms at the same rate as K+ ingestion. The kidneys excrete 90% to 95% of the daily K+ intake; the colon excretes 5% to 10%. Internal K+ Balance—Buffer the rise of ECF K+ - Maintaining normal intracellular and extracellular [K+] requires not only the external K+ balance just described, but also the appropriate distribution of K+ within the body. Most of the K+ is inside cells-particularly muscle cells, which represent a high faction of body mass-with smaller quantities in liver, bone, and red blood cells.

Answer 6

Cellular K uptake - Distribution of ingested K+: Upon ingestion K is rapidly taken up by cells, primarily the liver and the muscles. Dietary K load momentarily cause hyperkalemia. This increase is rapidly buffered by K uptake by the cells. The kidneys slowly catch up and increase excretion - ***Increased Na/K ATPase activity increases cellular K uptake K excretion Renal tubular sites of potassium reabsorption and secretion. Potassium is reabsorbed in the proximal tubule and in the ascending loop of Henle, so only about 8 percent of the filtered load is delivered to the distal tubule. Secretion of potassium into the late distal tubules and collecting ducts adds to the amount delivered; therefore, the daily excretion is about 12 percent of the potassium filtered at the glomerular capillaries. The percentages indicate how much of the filtered load is reabsorbed or secreted into the different tubular segments.

Answer 7

1. The K+ depleted state (e.g kids) - K+ is reabsorbed ALL along the nephron (PT, TAL, CCTs) - K+ Reabsorption by Intercalated Cells Occurs Through Apical K+ Uptake Mediated by an H-K Pump—which means that ↑K+ uptake will cause H+ loss A. The proximal tubule reabsorbs most of the filtered K+ through two paracellular mechanisms: - Solvent drag- driven by Na reabsorption - Electro-diffusion- in S3 of the PCT luminal positivity drives out K+ B. The TAL of the loop of Henle reabsorbs K+ by both paracellular and transcellular mechanisms: - Transcellular- NKCC2 - Paracellular- luminal positivity C. The CCTs reabsorb K+ in response to K+ depletion: - A transcellular process mediated by the α intercalated cells. This is an active process mediated by an apical ATP-driven H-K pump. The α intercalated cells are also responsible for H+ secretion. K+ depletion is often associated with accelerated secretion of H+ and the development of hypokalemic alkalosis. 2. The K+ repleted state (e.g diet rich in potassium) - K+ excretion is regulated by ALDOSTERONE (increase) and by changes in cell [K+] in Principal cells in the COLLECTING DUCT. A. Na+ transport (stimulated by aldosterone) into the cell—↑↑luminal negativity—K+ loss B.↑ENaC or ↑Na-K-ATPase will ↑K+ loss C.Antidiuretic hormone (ADH) inserts H2O channels in the luminal membra *****ALDOSTERONE PROMOTES K+ SECRETION

Answer 8

- Increase aldosterone secretion and increase cell K+ in principal cells - Increased luminal flow increases K+ secretion (e.g diuretics) - Increasing delivery of Na+ to the collecting duct stimulates Na+ reabsorption, making the lumen more negative. A more negative lumen potential favors K+ secretion Effect on K+ secretion of changes in urine flow to the collecting duct - Increased urine flow that occurs with extracellular volume expansion, osmotic diuresis, or administration of several diuretic agents (e.g., acetazolamide, furosemide, thiazides) leads to enhanced K+ excretion (kaliuresis). - Almost uniformly, increased urinary flow is also associated with increased Na+ excretion (natriuresis), so that both solutes appear in increased amounts in the urine. - When luminal flow is low, then as K+ moves from the principal cell to the lumen, luminal [K+] rises rapidly to a steady-state level, thereby inhibiting further K+ diffusion from the cell. Thus, total K+ secretion is relatively low. When luminal flow is high, it sweeps newly secreted K+ downstream. The resulting fall in luminal [K+] steepens the K+ gradient across the apical membrane and consequently increases passive K+ flux from cell to lumen. - Increased luminal flow also increases the Na+ delivery to tubule cells, thus raising luminal [Na+] and enhancing Na+ uptake. This incremental supply of Na+ to the principal cell stimulates its Na-K pump, increases basolateral K+ uptake, and further increases K+ secretion. Also, increased Na uptake depolarizes the luminal membrane increasing luminal negativity and increasing electrochemical driving force for K+ secretion

Answer 9

- As a rule, acidemia leads to hyperkalemia as tissues release K+. We can think of this K+ release as an "exchange" of intracellular K+ for extracellular H+, although a single transport protein generally does not mediate this "exchange" * **** Acidosis induces hyperkalemia and decreases K secretion, thus compounding the hyperkalemia * *** Alkalosis induces hypokalemia and increases K secretion, thus compounding the hypokalemia

Answer 10

1. Aldosterone: K directly activates adrenal cortex:- a. Stimulates the basolateral Na/K ATPase increasing [K]i b. Stimulate apical ENaC that ↑luminal negativity- promoting K excretion c. Aldo ↑apical membrane K conductivity 2. Luminal flow affects K excretion: increases with increased and vice versa:- a. Increased luminal flow reduces luminal [K] around the principal cells thus promoting K excretion b. Increased luminal flow ↑Na delivery to, and Na reabsorption by, principal cells, thus increasing luminal negativity and promoting K excretion 3. Alkalosis promotes K excretion and acidosis retention:- a. Alkalosis drives up intracellular pH that activates Na/K ATPase in all cells, including principal cells b. High pH ↑conductance of apical K channels c. Thus, alkalosis not only produces systemic hypokalemia but also worsens it by promoting K excretion by the kidneys

Answer 11

1.HYPOKALEMIA:- 1.1. ↑Renal excretion—hyperaldosternosim; K+-wasting diuretics (acetazolamide, osmotics, NKCC2-blockers, thiazides and thiazide-like drugs); Cushings (high corticosteroids will activate mineralocorticoid receptors) 1.2.GI losses of fluids (vomiting, diarrhea)—loose K+ in GI secretions—also volume loss activates RAAS and aldosterone excretes K+ 1.3.Transcellular movement—alkalosis 1.4.Treatment— 1.4.1.K+ and volume replacement (to “switch off” aldosterone) 1.HYPERKAEMIA:- 1.1.↓Renal excretion—renal failure (↓GFR); hypoaldosternosim; K+-sparing diuretics (spironolactone, eplerenone, amiloride) 1.2.Cell lysis (recall, cells have a LOT of K+)—rhabdomyolysis; leukemias and lymphomas; cell- death after cancer chemotherapy; reperfusion after ischemia spills K+ into the blood stream 1.3.Transcellular movement—acidosis 1.4.Treatment— 1.4.1.Glucose with insulin—push K+ into the cells 1.4.2.Na-HCO3—alkalosis pushed K+ into the cells 1.4.3.IV Calcium gluconate—stabilizes the cardiac membrane and can prevent arrhythmias 1.4.4.β2-agonist (albuterol)—push K+ into the cells 1.4.5.Potassium binding resins (Kayexalate)—binds K+ in the small intestines and prevent its reabsorption into the circulation 1.4.6.Dialysis

Answer 12

1. Calcium absorption lead to phosphate excretion 2. 2 things that increase calcium absorption (While preventing phosphate absorption) - parathyroid - vitamin D 3. Hypercalcemia blocks NKCC2 and dissipates luminal positivity in the TAL—↓Ca2+ resorption 4. Renal failure - decrease GFR - Hyperphosphatemia - hypocalcemia (Will activists PTH - activate osteoclasts - renal osteodystrophy) HIGH POINTS Ca2+ and Pi 1. Kidneys resorb majority of Ca++ filtered—resorption is passive in the proximal tubule and the TAL—active in the DCT where its stimulated by parathyroid hormone and activated vitamin D. 1. 1.Hypercalcemia blocks calcium resorption via the basolateral calcium sensing receptor (CaSR) 2. Phosphate, on the other hand, is excreted by the kidney (in large amounts on a Western diet) 2. 1.Phosphate resorption—the proximal tubule reabsorbs most of the filtered phosphate by the transcellular route (NaPi transporters) 2. 2.FGF23 and parathyroid hormone reduce Pi resorption in the proximal tubule What happens in renal failure 1. ↓GFR—↓urine flow, which will allow for more phosphate reabsorption 2.↓GFR—↓phosphate filtration, which will reduce phosphate excretion 3.Kidneys cannot make enough activated vitamin D3 LEAD TO 1.High [Pi]p will ionize with Ca++ and reduce [Ca++]p (double product) 2.Less Ca++ is absorbed (less vitamin D3) 3.Combined (1 and 2) lower serum Ca++ and activate PTH LEAD TO 1.High PTH is bad news for the body and causes renal osteodystrophy 2.This is characterized by bone remodeling (osteoclast activation) and abnormal deposition on the vasculature (altering the structure of the vasculature)

Answer 13

Kidney functions (5) 1. Sodium balance 2. Potassium excretion 3. Acid excretion 4. Calcium/phosphate balance 5. Erythropoiesis CKD (abnormalities) 1. Sodium retention and volume overload 2. Hyperkalemia 3. Metabolic acidosis 4. Increase phosphate and PTH, decrease serum calcium and calcitrol 5. Anemia Treatment 1. Sodium restriction diuretics 2. DIetary restriction. avoid NSAIDs 3. Sodium bicarbonate 4. Phosphate binders and calcimemetics 5. Erythropoiesis-stimulating agents; iron replacement

Answer 14

1. Glomerulus - urea freely filtered; 100% = amount filtered 2. PT - 50% reabsorbed (solvent drag, facilitated diffusion) 3. Ascending/descending Thin loop - 60% secreted from interstitium into loop (UT-A2) 4. Thick ascending limb - No transport of urea 5. DT - 110% present; no transport of urea 6. MCD ; 70% reabsorbed - 60% into interstitium (UT-A1); increased by ADH (AVP), 10% into vasa recta 7. Excreted; 40% of filtered load * ** Urea transport is passive in all nephron segments, following the urea concentration gradient. Urea crosses cell membranes by facilitated diffusion. - As renal disease progresses and GFR declines, serum creatinine increases. Clinicians measure PCr to follow changes in GFR. - Plasma creatinine is a function of GFR—rises linearly with falling GFR - In renal disease, as GFR declines, less creatinine is filtered so the concentration of creatinine in the serum gradually increases. (As creatinine level increase linearly, urea will also increase disproportionately due to decrease in GFR) - Increase serum BUN/creatinine > 20:1 (prerenal azotemia)

Answer 15

Function of the countercurrent mechanism - The function of the countercurrent mechanism is to create urine with an osmolality different from serum osmolality - To conserve water (the usual physiological condition), the countercurrent mechanism generates urine with osmolality greater than plasma (concentrated urine). - To excrete excess water, the countercurrent mechanism generates urine with osmolality less than plasma (dilute urine) - A concentrated urine is produced when ADH is present in the plasma (the usual physiological condition). - In the absence of ADH a dilute urine is produced. Tubule Fluid Is Isosmotic in the Proximal Tubule, Becomes Dilute by the End Loop of Henle, and Then Either Remains Dilute or Becomes Concentrated by the End of the Collecting Duct - The Loop of Henle helps creates urine with an osmolality different from plasma Functions of the loop of Henle that contribute to the countercurrent mechanism: The countercurrent “multiplier” is located in the Henle’s loop:- 1. The descending limb is impermeable to solutes, but freely permeable to water. 2. The ascending limb reabsorbs large quantities of NaCl & is impermeable to water. 3. Reabsorption of NaCl without water creates a dilute urine. 4. The thick ascending limb is called the “diluting segment”. ADH dictates the urine will be dilute or concentrated….but, recall, water needs ΔOsm to cross compartments - The interstitial around Henle’s loop provides the ΔOsm for water to cross compartments - The medullary interstitium in the juxtaglomerular nephrons is hypertonic, with tonicity increasing towards the hairpin loop Hypertonic medullary interstitium & ADH are required for renal water conservation - Medullary Hypertonicity “Draws” Water Out (FORCE) - ADH Provides Water Permeability Dilute urine is a consequence of withdrawal of ADH - In the absence of ADH the IMCD becomes impermeable to water. Importantly, this does not dissipate the medullary hypertonicity. tALH and TAL are impermeable to water (Diluting segment - because water can’t leave where as NaCl leaves - permeable) The maximal effect of NaCl transport in the thick/thin ascending limb is to create a gradient of 200 mOsm/Kg between the urine and the interstitium (B+A) - The NKCC2 (TAL) actively generates this transepithelial gradient of NaCl while the tALH contributes by passive transport. Remember that the tALH and the TAL are impermeable to water. How is this single effect, of generating a 200 mosmole/l gradient, magnified? The answer lies in the properties of the tDLH that is impermeable to salt, but freely permeable to H2O - Urine in descending limb equilibrates osmotically with interstitium - flow of urine moves hyperosmotic urine into ascending limb - urine in descending limb equilibrates osmotically with interstitium, again. ** Repeat the cycle enough number of times and you have hypertonic medulla Urine osmolality rises and then falls along the nephron

Answer 16

Urine is ALWAYS iso-osmolar (300 mOsmoles/l) at the end of PT, hyperosmolar (>300) at tDLH and hypo-osmolar (<300) at the end of TAL Thin descending limb is is freely permeable to water which is drawn out due to progressively increasing interstitial osmotic gradient Thin ascending limb is water impermeable and freely allows passage of NaCl; thus at the end of this segment urine has the same osmolarity as the interstitium at this point, usually ≈ 350-450 mOsmoles/l TAL (NKCC2 channels) avidly reabsorb solutes without much water reabsorption; thus making the urine hypo-osmolar (always)(referred to as the diluting segment) DCT also reabsorbs NaCl and further dilutes the urine

Answer 17

Problem: If NaCl is the only contributor to the interstitial hyperosmolarity, tALH cannot passively transport NaCl out (no diffusion gradient) of the lumen (remember, NaCl is the principal solute in the lumen). Presence of Urea draws water out of the tDLH, concentrating urine with NaCl. Now at the tALH NaCl concentration is much higher than the interstitium and passive diffusion of NaCl from the lumen to the interstitium can happen. Remember, the TAL does not face this conundrum as there NaCl transport is active. Urea, at the tip of the loop augments overall interstitial osmolarity and increases the renal capacity to concentrate urine ADH, concentrates urine directly (by AQP2) but also aids water reabsorption by increasing urea in the medullary interstitium (ADH-UT-A1) - The urea that accumulates in the interstitium is secreted into the tALH and is again reabsorbed at the IMCD, aided by ADH. This is urea recycling - ***ADH increases urea recycling ADH - Over hydration; No ADH - Dehydration; ADH present Segment - TAL; directly diluting segment and indirectly concentrating segment - IMCD; directly concentrating segment

Answer 18

Remember—If urinary osmolality is greater than plasma—free water clearance is said to be negative Remember—If urinary osmolality is less than plasma —free water clearance is said to be positive With loop diuretics; Free water clearance = 0 (patient is peeing plasma) - Generation of either positive or negative free water clearance depends on NaCl reabsorption in thick ascending limb of loop— generates the medullary hypertonicity:- Damage to the renal medulla or administration of loop diuretics diminishes the capacity to concentrate or dilute urine—free water clearances goes toward zero (urine osmolality approaches the value for plasma osmolality). PATIENT PEES PLASMA

Answer 19

AVP (ADH) Increases Water Permeability in All Nephron Segments Beyond the Distal Convoluted Tubule - Arginine vasopressin is the principal regulator of osmolality, which also co-regulates effective circulating volume - Synthesized in the supraoptic & the paraventricular nucleus of the hypothalamus - Secreted from the posterior pituitary Distal Nephronal segments have high water permeability, only in the presence of AVP ADH (AVP) binds to, and activates, V2 receptor on the collecting ducts of the nephrons and increases cAMP →this leads to recycling of AQP2 & UT-A1 to the luminal membrane Through V1 receptor AVP induces vasoconstriction and platelet aggregation Normal control of ADH Secretion is via the osmoreceptors - Osmoreceptors normally control urine water excretion—they are very sensitive to small changes in plasma osmolality. - An increase in plasma osmolality stimulates ADH secretion—ADH travels to the kidney and makes the collecting ducts permeable to water. - Normally ADH is present in the plasma and the kidneys are conserving water (urine osmolality is greater than plasma osmolality) Several Non-osmotic Stimuli Also Enhance Arginine Vasopressin Secretion 1. Reduced Effective Circulating volume - When ECF decrease significantly, ADH is stimulated even if plasma osmolarity is falling - In day to day life plasma osmolarity changes are much more potent stimuli for ADH release; however, after 20% blood loss, falling MAP & volume depletion are stronger stimuli - This is also because apart from retaining water and increasing volume AVP is a vasoconstrictor and can sustain MAP in face of falling CO - Shift the AVP response curve to left or right is dependent on the state of the circulation * *Inresponse to heart failure or hypovolemic shock, the kidney conserves NaCl and water Other non-osmotic regulators of AVP: 2. Pain, nausea, and several drugs:- morphine, nicotine, and high doses of barbiturates stimulate AVP secretion. 3. Alcohol and drugs that block the effect of morphine (opiate antagonists) inhibit AVP secretion and promote diuresis 4. High levels of chorionic gonadotropins sensitize the hypothalamic nuclei to release AVP at lower plasma osmolarity. This leads to mild water retention in pregnancy. Also seen right before the bleeding phase of the menstrual cycle.

Answer 20

1. ADH increases water permeability of ALL nephron segments after distal convoluted tubule (DCT)—action of V2 receptors 1. 1.Primary effect—↑AQP2 channels into the cell membrane 1.2.Additional effects—↑NKCC2 activity in the TAL; ↑urea permeability in the collecting duct 2. ↑Plasma osmolarity and ↓intravascular volume are two key stimulators of ADH release 3. SIADH—too little ADH; Diabetes insipidus—not enough amount, or defective action of ADH 4. Free water clearance (CH2O)—if urine osmolarity > plasma osmolarity, CH2O is NEGATIVE—urine is concentrated (seen with high ADH) 5. Free water clearance (CH2O)—if urine osmolarity < plasma osmolarity, CH2O is POSITIVE—(seen with low ADH) 6. Free water clearance (CH2O)—if urine osmolarity ≈ plasma osmolarity, CH2O is zero (seen with loop diuretics)

Answer 21

• Too little ADH activity – Leads to excessive water loss in urine, excessive urine volume of dilute urine and increase in plasma sodium – DIABETES INSIPIDUS • Too much ADH activity – Leads to too much water reabsorption, hyponatremia and potential hypervolemia -- patients with brain injuries (SIADH) and patients on loop diuretics

Answer 22

Diabetes Insipidus A. failure to reabsorb necessary amounts of water B. Symptoms; 1) large volume 3.5 - 20 L/d of dilute urine are produced 2) blood volume decrease, [Na+] increase and osmolality increase but 3) Consequent extreme thirst, and polydipsia, make net changes in BV and osmolality small - only 1-2% C. 2 causes; 1) Deficient ADH secretion (<85% norm) - CENTRAL (or hypothalamic or pituitary) DI. 2) Decreased sensitivity of kidney to ADH - NEPHROGENIC DI Central Diabetes Insipidus A. Deficiency or absence of ADH B. Treatment; Hormone replacement Lifelong treatment necessary for most patients - Vasopressin (ADH), V1 and V2; NOT USED FOR DI - Desmopressin; V2>>V1. Longer half life - DRUG OF CHOICE Desmopressin - DRUG OF CHOICE - selective for V2 (cAMP) over V1 (Ca2+). Longer half life. IN 2x - Other uses; – Nocturnal enuresis (bed-wetting). – Treatment of von Willebrand disease (type I) and hemophilia A (see blood coagulation lecture) - toxicity; Water intoxication, - must restrict water intake Nephrogenic Diabetes Insipidus • “Nephrogenic” signifies that the DI results from an inability of the kidney to respond to ADH • Results from – Genetic defects in ADH receptor or aquaporin-2 – Drug side effect, e.g. Li+, demeclocycline • Does not respond to DDAVP • TREATMENT: – Paradoxically, both types of diabetes insipidus can be treated with thiazide diuretics!! – Volume of urine produced can be decreased by 50%

Answer 23

How can a diuretic that increases urine production decrease urine production? • Important to recognize that over the long term, the urine volume must parallel fluid intake - Consequently in order to decrease the volume of urine produced one must decrease fluid intake • What would happen if a DI patient stopped drinking? – Would become hypovolemic, BP ↓ and then NE and ATII produced would stimulate Na+/H would decline • Why does a person with DI drink so much? – They become very thirsty • What stimulates thirst? – Increase in plasma [Na+] and hypovolemia – However, a 2-3 % increase in plasma [Na+] has same effect as a 10-15% decrease in blood volume – This high sensitivity to small changes in [Na+], allows blood volume to be maintained in DI Why do thiazides work? - Since the DCT is impermeable to H 2O, the diuretic effect of HCTZ results from more Na+ in the collecting duct, which reduces the gradient for water reabsorption (Na+ holds water in the lumen)- less H2O absorption in the CD (↓gradient). – Since, in DI H2O cannot be absorbed in CD anyway:- HCTZ will not act as a “diuretic”, but as a “natriuretic”. – Its only effect will therefore be to lower plasma [Na+], and this will decrease thirst and water intake VASOPRESSIN/ADH “ANTAGONISTS”: (DRUGS that INDUCE DIABETES INSIPIDUS) • Under certain conditions, ADH activity can be “too high” leading to hyponatremia - SIADH - patients with brain injuries - hypovolemia - Advanced CHF and cirrhosis with ascites patients on loop diuretics (RAAS activated, ADH increase) - Hyponatremia - cells swell, e.g in brain - We need “ADH antagonist” to increase water loss and treat/prevent the hyponatremia VASOPRESSIN/ADH “ANTAGONISTS”: (DRUGS that INDUCE DIABETES INSIPIDUS) • CONIVAPTAN and TOLVAPTAN – “VAPTANS” the first real vasopressin receptor antagonist • Lithium (Li+) (Eskalith®, 1970) and DEMECLOCYCLINE (Declomycin®) – Not true antagonists, but they… – Block adenylate cyclase in CD and thereby block action of ADH/vasopressin - DI

Answer 24

CONIVAPTAN (Vaprisol) - Action; V1A and V2 antagonist - INDICATION – treatment of hyponatremia ~Since it lowers blood volume, only use in euvolemic and hypervolemic patients ~Use is contraindicated in hypovolemic patients, and also in patients with CHF - ADMINISTRATION; Continuous IV infusion for maximum of 4 days, hence only used in hospitalized patients Lithium (Li+) Carbonate (Eskalith) - USE: Off-label use for tx of hyponatremia ~SIADH (e.g. CNS injury) • MAJOR/USUAL INDICATION ~Antimanic drug (see CNS pharm notes) ~Significant toxicity if [Li]plasma >1mM - SIDE EFFECT: 30% patients - diabetes insipidus ~ Renal handling analogous to sodium ~Re-absorbed by CD cells via Na+ channels ~Tx: thiazides, but lower Li+ dose, as reuptake in PT↑ DEMECLOCYCLINE (Declomycin) • Tetracycline antibiotic with unique property • SIDE EFFECT – Diabetes insipidus, mechanism same as Li+ • USE - off-label use for tx of hyponatremia – SIADH (e.g. from CNS injury) – Heart failure, liver disease (cirrhosis) patients with elevated ADH • Less toxic and effects more predictable than Li+

Answer 25

ATI - Acute tubular injury General 1. Most common cause of acute kidney injury (AKI) 2. Accounts for 50% of cases of AKI in hospitalized patients 3. REVERSIBLE; however if it has progressed long enough, it might not be reversible 4. Characterized by acute renal failure and tubular injury 5. Most common etiologies A. ISCHEMIA - due to decreased or interrupted blood flow - vasculitis; microscopic polyangiitis (MPO ANCA) - malignant HTN - Systemic thrombotic conditions ; HUS, TTP, DIC - hypotension, shock - Dehydration B. Direct toxic injury to tubules; exo vs endogenous 1) Exogenous (5) I. Drugs, heavy metals, radiocontrast dyes; Aminoglycerides (gentamicin), NSAIDs, ACEI, cyclosporine, cisplatin, Amphotericin B II. Heavy metals; mercury, lead III. Organic solvents; carbon tetrachloride IV. Ethylene glycol (antifreeze) V. Radiocontrast dye 2) Endogenous (3) I. Hemoglobin (hemolysis) II. Myoglobin (skeletal muscle injury) III. Monoclonal light chains (multiple myeloma)

Answer 26

1. Tubular epithelium injury a. Loss of cell polarity (Na,K+-ATPase delivers Na+ to distal tubule →vasoconstriction b. Recruitment of WBCs which add to injury c. Injured epithelium 1) Detaches from basement membrane and causes luminal obstruction→ ↑tubular pressure, ↓GFR 2) Glomerular filtrate leaks back into interstitium →↑interstitial edema → ↑interstitial pressure → further damage to tubule 2. Persistent, severe disturbances in blood flow - intrarenal vasoconstriction due to; - RAAS - Increased Na+ delivery to DT (tubuloglomerular feedback)

Answer 27

1. Gross - enlarged, swollen kidneys, pale cortex, hyperemic medulla 2. Microscopic A. Focal tubular epithelial necrosis along the nephron, with skip areas. B. Occlusion of lumen by casts I. DT and collecting duct II. Casts; a) pigmented granular b) eosinophilic hyaline - composed of tamm-horsfall protein (normally secreted by cells of ascending thick limb and distal tubule) C. Changes specific to etiology I. Ischemic; a) patchy, short segments of tubular necrosis in straight segment of PT and Thick ascending Lino of loop of henle b) Rupture of basement membrane (tubulorrhexis) c) Interstitial edema d) accumulation of WBCs in dilated vasa recta. II. Toxic; a) continuous tubular necrosis in PT and straight segment of PT b) No tubulorrhexis (BM rupture) c) Distinctive morphologic changes associated with certain toxins - MERCURIC CHLORIDE; large eosinophilic inclusions. Later - calcifications - CARBON TETRACHLORIDE; accumulation of neutral lipids in injured cells - ETHYLENE GLYCOL; ballooning, vacuolar degeneration of PCT; calcium ocalate crystals in tubular lumens - LEAD; large acidophilic nuclear inclusions, little calcification, no crystal formation d) Evidence of epithelial regeneration as condition progresses

Answer 28

1. Initiation - Lasts ~36 hrs - Dominated by medical, surgical or obstetric precipitating event - Slight decrease in urine output and rise in BUN 2. Maintenance - Lasts 5-7 days - Oliguria 40-400 ml/day - salt and water overload, rising BUN, hyperkalemia, metabolic acidosis - may need dialysis 3. Recovery - 10 to 14 days - steady increase in urine volume to a profuse diuresis (up to 3L/day) - Loss of water, sodium, potassium through still injured but recovering tubule epithelium - increased vulnerability to infection - eventually tubular function is restores, concentrating ability improves, BUN and creatinine return to normal levels 4. Prognosis - Nephrotoxic - depends on; 1) Magnitude and duration of injury 2) damage to other organs like liver or heart 3) ~95% recover with appropriate supportive care - Ischemic; in shock, extensive burns, other causes of multi organ failure, mortality rate is >= 50%

Answer 29

General 1. Involves inflammatory injuries of the tubule and interstitium, onset is often insidious, manifested by azotemia (increased BUN/creatinine) 2. May be acute or chronic 3. Distinguished from glomerular diseases by: a. Absence of nephritic or nephrotic syndromes b. Presence of defects in tubular function; 1) Impaired ability to concentrate urine 2) salt wasting 3) Diminished ability to secrete acids (metabolic acidosis) Causes of tubulointerstitial nephritis 1. Infections; acute (E.coli) and chronic pyelonephritis 2. Drug and toxin induced tubulointerstitial nephritis 3. Metabolic diseases causing tubulointerstitial nephritis (urate nephropathy and nephrocalcinosis) 4. Neoplasms (multiple myeloma)

Answer 30

1. Acute pyelonephritis a. Acute inflammation affecting the tubules, interstitium and renal pelvis b. One of the most common diseases of the kidney c. A serious complication of lower urinary tract infection (cystitis) d. Caused by the same microbes as lower UTI 1) 85% are gram-negative bacilli, normal flora of colon a) E. coli (by far most common) b) Proteus spp. c) Klebsiella spp. d) Enterobacter spp. 2) Gram(+): Enterococcus faecalis, Staphylococcus spp. 3) Virtually any bacterial or fungal agent 4) Immunocompromised: viruses Routes of infection 1. Hematogenous - seeding kidneys from localized or systemic infection, less common 2. ASCENDING INFECTION - most common A) Urethra; bladder i) MORE COMMON IN WOMEN BECAUSE OF SHORTER URETHRA II) via instrumentation in either sex (urinary catheter, cystoscope etc) B. Bladder - kidney I) Urinary tract obstruction and urine stasis; outflow obstruction - incomplete emptying - urine stasis - growth of bacteria that have entered the bladder II) Vesicoureteral reflux; a) incompetent vesicoureteral valve b) congenital or acquired c) during micturition, urine empties through urethra and refluxes into ureter III) Intrarenal reflux; most common in upper and lower poles because of flattened tips of papillae IV) Imaging - cystourethrogram

Answer 31

Morphology 1) Patchy, interstitial suppurative inflammation 2) Intratubular aggregates of neutrophils 3) Neutrophilic tubulitis 4) Tubular necrosis 5) Complications a) Papillary necrosis i. Mainly in DM, sickle cell disease ii. Grossly - tips to distal 2/3rds of papillae show grey white to yellow necrosis III. Microscopically - coagulative necrosis B) Pyonephrosis ; Pelvis, calyces and ureter are filled with pus due to partial or complete obstruction high in urinary tract C) Perinephric abcess; extension of suppurative inflammation through the renal capsule into perinephric tissue 6) Healing - acute inflammation is replaced by chronic inflammatory cells (macrophages, plasma cells and lymphocytes) - Then replaced by scar associated with inflammation, fibrosis and deformation of the underlying calyx and pelvis Associated risk factors 1) Urinary tract obstruction (congenital or acquired) 2) Instrumentation of urinary tract (most often catheterization) 3) Vesicoureteral reflux 4) Pregnancy 5) Gender and age - <1 yr, more common in males from congenital abnormalities - 1-40yrs; more common in WOMEN (SHORTER URETHRA) - >40 yrs; increasing in men due to prostatic hyperplasia and instrumentation 6) Preexisting renal lesions 7) Diabetes mellitus 8) Immunosuppresion, Immunodeficiency Presentation 1) Sudden onset of pain at the costovertebral angle 2) Fever, malaise 3) Sx of lower UTI; dysuria, frequency, urgency 4) UA; WBCs, leukocytes (indicates upper UTI) Transplant pts; polyoma virus from reactivation

Answer 32

a. Chronic tubulointerstitial inflammation and scarring involve the calyces and pelvis b. May be unilateral or bilateral c. Important cause of kidney destruction in children with severe lower urinary tract abnormalities d. TWO FORMS 1) Reflux nephropathy ; most common form of pyelonephritis scarring. Occurs early in childhood as a result of UTI and congenital vesicoureteral and intrarenal reflux 2) Chronic obstructive pyelonephritis; recurrent infections and obstructive lesions. Results in recurrent inflammation and scarring. Morphology 1) Irregular scarring; if bilateral then asymmetrically scarred 2) Coarse, discrete, corticomedullary scars overlying dilated, blunted or deformed calyces, and flattening of papillae 3) Most scars in upper and lower poles, same as intrarenal reflux 4) Microscopic: - tubules with areas of atrophy, hypertrophy, dilation - Thyroidization; dilated tubules filled with casts resemble thyroid colloid - Interstitium; inflammation and fibrosis (LYMPHOCYTES) - vessels; i) In scarred areas - show intimal sclerosis. II) If htn is present then show hyaline arteriolosclerosis throughout kidney - Glomeruli; ischemic changes only Clinical features 1. Silent onset or s/s of recurrent acute pyelonephritis (back pain, fever, pyuria, bacteriuria) 2. Gradual onset of renal insufficiency and hypertension 3. Loss of tubular function, concentrating ability, leads to polyuria, nocturia 4. May develop a secondary focal segmental glomerulosclerosis (example of nephrotic syndrome)

Answer 33

Drug and toxin -induced tubulointerstitial nephritis 1. Second most common cause of acute kidney injury (after pyelonephritis) 2. Three ways that toxins & drugs trigger AKI - interstitial immunologic reaction e.g acute hypersensitivity nephritis induced by methicillin - acute tubular injury - subclinical, cumulative injury to tubules, takes years to develop chronic renal insufficiency 3. Acute drug-induced interstitial nephritis A. Triggered by synthetic penicillins (methicillin, ampicillin) and other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs, miscellaneous (allopurinol, cimetidine), analgesic nephropathy (mostly historical significance, due to phenacetin which is now off the market in most countries) B. Pathogenesis - Idiosyncratic immune mechanism - Not dose related - Late phase reaction of an IgE mediated (type I) hypersensitivity OR - T cell-mediated (type IV) delayed hypersensitivity C. Morphology 1) Interstitium; edema, mononuclear infiltrates (lymphocytes, macrophages), eosinophils and neutrophils may be present, maybe nonnecrotizing granulomas 2) Tubules; Lymphocyte infiltration. Necrosis and regeneration - varying degrees 3) Glomeruli - normal except with NSAIDs then minimal change disease and nephrotic syndrome Clinical - Onset is ~15 days after drug exposure - Fever, eosinophilia (may be transient), rash (25% of pts), renal abnormalities (hematuria, mild proteinuria, leukocyturia including eos) - Rising serum creatinine or AKI with oliguria in ~50% of pts, more often older pts - Recovery follows withdrawal of offending drug - Necrotic papillae may be excreted causing hematuria, sx of obstruction NSAID associated nephropathy 1. Renal complications are uncommon 2. Nonselective NSAIDs; renal effects are due to inhibition of cox dependent prostaglandin synthesis 3. Selective COX-2 inhibitors spare GI tract but affect kidneys because COX 2 is expressed in the kidney 4. Renal syndromes include; - acute kidney injury; due to decreased synthesis of vasodilators prostaglandins - ischemia - acute hypersensitivity interstitial nephritis - acute interstitial nephritis and minimal change disease - due to hypersensitivity reaction affecting interstitium - membranous nephropathy with nephrotic syndrome

Answer 34

1. Urate nephropathy - 3 types A. Acute uric acid nephropathy - Caused by precipitation of uric acid crystals in the collecting ducts - obstruction of nephrons - acute renal failure - Often seen in leukemia or lymphoma when first treated with chemotherapy (tumor lysis syndrome); a) drugs kill cancer cells b) nucleic acids are released from dead cells and broken down, producing uric acid B. Chronic urate nephropathy (gouty nephropathy) - monosodium urate crystals precipitate in distal tubules, collecting ducts and interstitium (due to acidic environment) - Crystals stimulate a granulomatous response with giant cells - Crystals obstruct tubules causing cortical atrophy and scarring C. Nephrolithiasis; uric acid stones are present in 22% of gout pts 2. Nephrocalcinosis A. Disorders associated with hypercalcemia induce formation of calcium stones and deposition of calcium in kidney; Hyperparathyroidism, multiple myeloma, Vit D intoxication, metastatic cancer, excess calcium intake (milk alkali syndrome) B. May lead to chronic tubulointerstitial disease and renal insufficiency via; loss of concentrating ability, tubular acidosis, salt losing nephritis

Answer 35

NEOPLASMS ; Light chain cast nephropathy (multiple myeloma) 1. Renal insufficiency occurs in ~50% of pts with multiple myeloma 2. Factors contributing to renal damage A. Bench-Jones proteinuria and cast nephropathy I) Ig light chains are directly toxic to epithelial cells II) Light chain nephropathy; - light chains and tam horsfall proteins lead to laryngeal tubular casts - Obstruct tubular lumens - induce an inflammatory reaction B. Amyloidosis of AL type - formed from free light chains, usually gamma type C. Light chain deposition disease - kappa type deposit in GBMs, mesangium, tubular basement membrane D. Hypercalcemia and hyperuricemia Morphology A. Bence Jones tubular casts - Pink to blue, amorphous - fractured, concentrically laminated, distend the tubular lumens - may be surrounded by multinucleated giant cells, inflammation, fibrosis B. amyloidosis C. Nephrocalcinosis Clinical features A. Chronic kidney disease may develop slowly OR B. Acute kidney injury with oliguria may develop suddenly C. Bence-Jones proteinuria occurs in 70% of multiple myeloma pts

Answer 36

* CKD is staged based on eGFR and albuminuria. * eGFR is assessed by formulae using the SCr (+/- serum Cystatin C), age and gender along with race. * MDRD is probably best. * Patients with CKD experience much more CV disease than those without CKD. * CKD progression occurs with hypertension, proteinuria and progression of underlying disease. * Uremia is a symptom complex involving virtually all organs. The involvement of the CV, bone, and hematopoietic systems have been best characterized. * It is believed that “trade off” explains the inherent nature of CKD to progress as well as cause the uremic syndrome.

Answer 37

Benign Nephrosclerosis Pathogenesis - Medial and intimal thickening ; due to hemodynamic changes (hypertension), aging, genetics - Hyaline deposition in arterioles Microscopic - Narrowed lumens of arterioles and small arteries due to thickening and hyalinization of walls - Scarring, glomerular sclerosis, loss of tubules alternate with preserved parenchyma; causes granular surface appearance - Fibroelastic hyperplasia; medial hypertrophy, reduplication of elastic lamina, myofibroblastic tissue in intima Clinical Features - May be mild proteinuria - Rarely causes renal insufficiency EXCEPT in; pts in African descent, pts with more severe HTN, pts with another underlying disease esp diabetes

Answer 38

Malignant Hypertension Morphology - Gross; “FLEA-BITTEN” appearance of kidney from petechial hemorrhages on cortical surface Clinical features - Punctate hemorrhages - Poor cortical demarcation - swelling, edema Histology (2) 1. Fibrinous necrosis of arterioles - Vessels walls appear eosinophilic, granular - Stain positive for fibrin 2. hyperplastic ArteriOLOsclerosis - “Onion skinning” appearance of walls arteries and arterioles - due to elongation and proliferation of concentrically arranged smooth muscle cells and layers of collagen - luminal narrowing, may be thrombosis

Answer 39

Renal Artery Stenosis Pathogenesis - UNILATERAL constriction decreases intrarenal circulation/ blood pressure - cells of juxtaglomerular apparatus release renin - Angiotensin II (vasoconstrictor) is produced causing HTN - Aldosterone conserves Na+ and subsequently H2O Morphology 1. Atherosclerotic plaque occlusion (70%) - more common in men - advancing age - diabetes 2. Fibromuscular dysplasia of renal artery - women - 3rd and 4th decades 3. Ischemic kidney - reduced in size, crowding of glomeruli, atrophic tubules, interstitial fibrosis - protected from effects of HTN Clinical course - resembles essential HTN - elevated plasma or renal vein renin levels - 70-80% cure rate with intervention

Answer 40

1. HUS - Hemolytic Uremic Syndrome ; typical and atypical 2. TTP - thrombotic thrombocytopenic purpura Pathogenesis HUS; Tissue dysfunction resulting from formation of microthrombi - vascular obstruction - tissue ischemia HUS - ENDOTHELIAL INJURY - platelet activation and thrombosis A. Typical - Endothelial injury triggered by shiva-like toxin - Associated with consumption of contaminated food B. Atypical - Excessive activation of complement from; - Inherited mutation of complement-regulatory proteins - Acquired causes (scleroderma, HTN, chemo, immunosuppressive drugs, radiation) TTP - PLATELET AGGREGATION from very large multimers of vWF A. Deficiency of plasma metalloprotease ADAMTS13 (cleaves multimers of vWF) - AutoAbs to ADAMTS13 (most common) - Inherited deficiency of ADAMTS13

Answer 41

``` Clinical Features Typical HUS - After intestinal infection with E.coli strain 0157-H7 - Most often in children - flu like symptoms or diarrhea - then symptoms of bleeding - severe oliguria and hematuria - microangiopathic hemolytic anemia - thrombocytopenia - +/- neurological symptoms - ~50% with HTN - Manage with dialysis - Renal fxn recovers in weeks ``` Atypical HUS - Adults - >50% have inherited deficiency of complement regulatory proteins - most common; factor H deficiency - ~half have relapsing course progressing to ESRD - conditions occasionally associated with atypical HUS; anti phospholipid Ab syndrome, pregnancy post parturition, vascular renal disease - sclerosis and malignant HTN, chemo and immunosuppresion, irradiation of kidney, +/- neurological symptoms, distinguish from TTP by normal ADAMTS13 plasma levels TTP - Pentad of fever, neurologic symptoms, microangiopathic hemolytic anemia, thrombocytopenia, renal failure - adults >40 yrs, F>M - CNS involvement is dominant feature - Renal involvement ~50% - Mortality <50% with exchange transfusions and immunosuppression

Answer 42

Acute (Typical and atypical HUS, TTP) A. Cortical necrosis, subcapsular petechaie B. Microscopic - Glomerular capillaries occluded by thrombi - Capillary walls thickened by endothelial cell swelling and cell debris - disruption of mesangial matrix - interlobular arteries/arterioles; fibrinoid necrosis and occluding thrombi Chronic (Atypical HUS, TTP) A. Scarring of renal cortex B. Microscopic - thickening of glomerular capillary walls - splitting of GBM (tram-tracking) - thickening of artery and arteriole walls, persistent hypoperfusion, atrophy, renal failure, HTN

Answer 43

Atherosclerotic Ischemic Renal disease - bilateral renal artery disease - common cause of chronic ischemia, renal insufficiency in older adults, +/- HTN - surgical intervention preserves remaining renal function

Answer 44

Atheroembolic Renal disease - Embolization of atherosclerotic plaque fragments into renal vessels esp. arcuate and interlobular arteries - Follows intervention (AAA repair, aortic valve angioplasty) in elderly pts with severe atherosclerotic disease - May cause acute renal failure in pts with already compromised renal function

Answer 45

Cholesterol Emboli - Arterial seeding of fragmented atherosclerotic plaque to small arterioles - Clear clefts of cholesterol seen embolized to small vessels

Answer 46

Sickle cell Disease Nephropathy - Hematuria - Proteinuria - Diminished concentrating ability is common - Seen In homozygotes and heterozygotes

Answer 47

Diffuse cortical necrosis - Uncommon - follows catastrophic conditions such as abruptio placenta, septic shock - cortex only - massive ischemic (coagulative) necrosis - May have intravascular and intraglomerular thromboses - rapidly fatal without supportive treatment - Rare complication of massive hemorrhage - usually results from obstetric emergency - complete bilateral cortical necrosis

Answer 48

Renal Infarct - End organ circulation, very limited collateral circulation - Most infarcts are due to emboli; left heart is a common source - Morphology; typical of infarcts - Mary be single or multiple, wedge shaped, soft pale yellow Well demarcated after 24hr, eventually replace with scar tissue - Clinically silent or positive pain, tenderness, hematuria

Answer 49

Total renal Infarction - entire kidney is Infarct Ed - vascular compromise at main renal artery

Answer 50

General - may be sudden or insidious, partial or complete, unilateral or bilateral - At any level of the urinary tract - Intrinsic or extrinsic Common causes 1. Congenital abnormalities - structures, mental stenosis 2. Urinary calculus 3. BPH 4. Tumors; prostate, bladder. Tumor of contiguous tissues - cervix, uterus 5. Inflammation - prostatitis, uretitis, urethritis 6. Sloughed papillae or blood clots 7. Pregnancy 8. Uterine prolapse 9. Functional d/o’s; e.g neurogenic (SCI, DM)

Answer 51

1. Dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to the obstruction to urine outflow 2. Initial functional alterations are tubular Morphology A. If obstruction is sudden and complete, mild dilation of pelvis and calyces, sometimes atrophy of renal parenchyma B. If partial or intermittent; dilation is progressive C. Early - dilation and significant interstitial inflammation D. Chronic; 1) Cortical tubular atrophy 2) Interstitial fibrosis 3) Blunting of spices of pyramids e. Far advanced - kidney becomes a thin - walled cystic structure Clinical Features 1. Acute obstruction may be painful from dilation of collecting system and renal capsule 2. Unilateral obstruction may remain silent because unaffected kidney can maintain adequate renal function 3. Bilateral partial obstruction; a) concentrating ability affected first b) presents with polyuria and nocturia 4. Bilateral complete obstruction; a) presets with oliguria or anuria b) fatal without intervention 5. Relief of obstruction in the early stages leads to return of normal renal function - may have postobstructive diuresis

Answer 52

General - affects 5-10% of Americans sometime in their lifetime - May occur anywhere in the urinary tract but most often in kidney - M>F, peak age 20-30 yrs - Familial predisposition - All stones have an organic mucoprotein matrix - Most important fact in stone formation; INCREASED URINARY CONCENTRATION OF THE STONE’S CONSTITUENTS SUCH THAT IT EXCEEDS THEIR SOLUBILITY (SUPERSATURATION) 4 Main Types 1. Calcium oxalate and phosphate stones (70% of stones) - Mostly idiopathic hypercalciuria (50%). Others are hypercalciuris and hypercalcemia > hyperoxaluria > enteric (hyperabsorption of calcium in gut) - Hyperuricosuria (20%) - hypercitraturia - no known metabolic abnormality - RADIOPAQUE (picked up on spiral CT) 2. Magnesium ammonium phosphate stones (aka struvite, 15% of stones) - formed secondary to infections by urea splitting bacteria; Proteus, some staphylococci - conversion of urea to ammonia alkaline the urine - magnesium ammonium phosphate salts precipitate at the higher pH - Form some of the largest, “staghorn” stones which occupy the renal pelvis - RADIOPAQUE 3. Uric acid stones (5-10%) - common in pts with hyperuricemia e.g gout and leukemia (high cell turnover) - >50% of these stones occur without hyperuricemia - may be in persons with urine pH <5.5, uric acid is insoluble in acidic urine - RADIOLUCENT 4. Cystine stones (1-2%) - Cystinuria due to genetic defect in renal reabsorption of AA - Precipitate at a low urinary pH

Answer 53

Morphology - unilateral in ~80% of pts - sites; calyces, pelvises, bladder - stones in renal pelvis tend to stay small, 2-3 mm - Progressive accretions may result in a cast of the pelvis and calyces known as a staghorn calculus Clinical features - may be asymptomatic pr cause severe renal colic and abdominal pain - may cause significant renal damage - stone predispose the pt to UTI

Answer 54

1. Renal papillary adenoma - small adenoma arising from the renal tubular epithelium - found commonly, 7-22% at autopsy - histologically the same as low-grade papillary renal cell carcinoma - size is prognostic of metastasis,<3cm rarely metastasize 2. Angiomyolipoma - Arising from perivascular epithelioid cells - consist of vessels, smooth muscle and fat - associated with familial tumor syndrome tuberous sclerosis (25-50% of t.s pts) - susceptible to spontaneous hemorrhage 3. Oncocytoma - large, eosinophilic cells with benign appearing nuclei, large nucleoli - arise from the intercalated cells of the collecting duct - 5-15% of renal neoplasms - Gross; tan to red brown, homogeneous and usually well encapsulated with a CENTRAL SCAR, may be large

Answer 55

1. Renal Cell Carcinoma 2. Urothelial carcinoma of renal pelvis 3. Wilms tumor

Answer 56

Epidemiology - 65k new cases/yr - 13k deaths/yr - 85% renal cancers - older individuals (6-7 decade); M:F - 2: 1 (males smoke more) Risk factors (7) - tobacco; most significant (2x incidence) - obesity - HTN - Unopposed estrogen - exposures; asbestos, petroleum products, heavy metals - renal factors; ESRD, CKD, acquired cystic disease, tuberous sclerosis - familial variants (4@ renal cancers); Von hipped lindau, hereditary leiomyomatosis and renal cell cancer syndrome, hereditary papillary carcinoma, birth Hogg dube syndrome ``` Major types (5) - classier by histology, cytogenetics, genetics 1. Clear cell carcinoma; most common type. Cells have clear or granular cytoplasm. Nonpapillary. 95% sporadic although can be familial. 98% have deletion on 3p, deleted area includes VHL gene (Von Hippel lindau), even in sporadic tumors. 80% show mutations in non deleted VHL allele ``` 2. Papillary carcinoma; 10-15% of RCC. Papillary growth pattern. Not associated with 3p deletions. Sporadic form - trisomies 7 and 17, loss of Y in males. Familial form - associated with MET proto-oncogenes on chromosome 7. Frequently multifocal in origin, unlike clear cell 3. Chromophobe carcinoma; 5% of RCC. Cells have prominent cell membranes, pale eosinophilic cytoplasm, halo around nucleus. Arise from collecting duct intercalated cells, like oncocytoma. Excellent prognosis 4. Xp1 1 translocation carcinoma; Genetically distinct, translocations of the TFE3 gene located at Xp11.2. Young patients, Clear cytoplasm with papillary architecture 5. Collecting duct carcinoma; <= 1% of RCC. Arise from collecting duct cells in medulla. Malignant cells forming glands in a prominent fibrotic stroma

Answer 57

Morphology 1. Most common in poles of kidney 2. Clear cell RCC - usually unilateral and solitary - bright orange-yellow-gray-white, spherical, distorts renal outline - well circumscribed - tumor cells - abundant clear or granular cytoplasm containing glycogen and lipids - Tumor may enlarge and extend into ureter - Tends to invade renal vein and IVC, even extend to right side of heart 3. Papillary RCC - Arise from distal convoluted tubules - May be multifocal and bilateral - cuboidal cells arranged in papillary formation s - interstitial foam cells in papillary cores 4. Chromophobe RCC - pale eosinophilic cells with perinuclear halo in solid sheets - largest cells around blood vessels Clinical features A. Classic triad; costovertebral pain, palpable mass, hematuria (all three present in only ~10% of pts) B. Hematuria - early but may be intermittent, microscopic C. Constitutional sx when tumor reached >= 10cm: fever, malaise, weakness, weight loss D. Often found incidentally (CT or MRI for another indication) E. Syndromes of abnormal hormone production; polycythemia, hypercalcemia, HTN F. 25% of tumors have metastasized at time of diagnosis; Lung (>50%), bone (33%), regional LNs, liver, adrenal, brain G. Prognosis and treatment - 5 yr; 70%, 95% if no distant metastasis, 60% if renal vein invasion or extension into pernephric fat - Radical or partial nephrectomy (to preserve renal function) - TK and VEGF inhibitors for metastatic disease

Answer 58

1. Originates from urothelial of renal pelvis 2. ~5-10% of primary renal tumors 3. Transitional cell tumors 4. Present early with hematuria, possible outflow obstruction 5. Histologically identical to tumors of the urinary bladder urothelial 6. May be multiple, 50% have history of or concomitant urinary bladder tumor 7. ... Commonly infiltrate wall of pelvis and calyces 8. 5 year survival; 50-100% for low grade tumors, 10% for high grade, infiltrating

Answer 59

Wilms tumor General - Most common primary renal malignancy in children - Fourth most common pediatric malignancy - Peak incidence; 2-5 yrs of age, 95% of tumors present 10 yrs of age - large mass, usually unilateral but 5-10% are bilateral - most cases are sporadic (90%), ~ 10% are associated with syndromes; 1. WAGR syndrome - a) wilms, aniridia, genital abnormality, mental retardation. B) Lifetime risk of developing Wilms = 33% c) Deletion of 11p13, location of WT1 (Wilms tumor-associated gene) and PAX6 (Aniridia) 2. Denys-Drash Syndrome; a) gonadal dyspenesis, early onset nephropathy b) ~90% risk for Wilms tumor c) Mutation in WT1 3. Beckwith-Wiedemann syndrome; a) Organomegaly, macroglossia, omphalocele b) mutations in regions of 11p15.5, multiple genes “WT2” Morphology 1. Classic triphasic combination of cells A) Blastermal - small, blue cells B) Stromal - fibrocystic or myxoid C) Epithelial - primitive tubes and glomeruli 2. Anaplasia; large, hyperchromatic, paleo morphia nuclei + abnormal mitoses; a) 5% of tumors b) correlates with the emergence of resistance to chemo Clinical features - large abdominal mass, unilateral or crosses the midline if large enough - presenting symptoms; hematuria, pain in abdomen after trauma, intestinal obstruction , HTN - 2 year survival = 90% survival > 2 yrs implies cure - Important to identify and manage anaplasia

Answer 60

1. Ureters - congenital anomalies - inflammations - tumors and tumor like lesions - obstructive lesions 2. Urinary Bladder - congenital anomalies - inflammations - metaplasia - neoplasia - obstruction 3. Urethra - inflammation - tumor and tumor Iike lesions

Answer 61

Ureters; Normal - Narrowing at; ureteropelvic junction, crossing iliac vessels, where ureters enter bladder - Note; Ureter enters bladder in an oblique manner which allows the enclosing bladder musculature to act like a sphincteric valve, blocking the reflux of urine even in a distended bladder Ureters; Congenital Anomalies 1. Double ureters - usually associated with duplication of renal pelvis - Usually unilateral and are joined in the wall of the bladder - Usually no clinical significance 2. Ureteropelvic junction obstruction - Children, boys more than girls - 20% are bilateral - most common cause of hydronephrosis in infants and children 3. Diverticula - Saccular outpouching of urethral wall - Urinary stasis in the sac may be a reservoir for bacteria causing recurrent infections - But most are asymptomatic Tumors/tumor like lesions 1. Benign - fibroepithelial polyps - leiomyomas 2. Malignant; majority are urothelial (transitional cell) carcinomas) A. Urothelial carcinoma - Rare in the ureter - Resemble transitional cell (urothelial cell) tumors in renal pelvis, calyces, urinary bladder - risk factors; smoking, occupational exposure (aniline dyes), phenacetin Obstruction - causes hydroureter and hydronephrosis - may be acute (calculus) or chronic (tumors, sclerosing retroperitoneal fibrosis) Obstructive lesions 1. Intrinsic; calculus, strictures, tumors, blood clots, neurogenic 2. Extrinsic; pregnancy, periureteral inflammation, endometriosis, tumors, sclerosing retroperitoneal fibrosis Sclerosing retroperitoneal fibrosis - fibrotic proliferative inflammatory process encasing the retroperitoneal structures - causes hydronephrosis - middle to late age, M>F - 70% idiopathic - can be associated with IgG4-related disease - drugs (ergot derivatives), adjacent inflammatory conditions (Crohn’s), malignancy (lymphomas) - microscopy; fibrous tissues, infiltrate of lymphocytes, plasma cells, eosinophils - tx; corticosteroids, urethral stents

Answer 62

Congenital anomalies 1. Vesicoureteral reflux; most common and serious congenital anomaly 2. Diverticula - Evagination of bladder wall - 1cm to 5-10 cm - acquired are most often associated with obstruction due to BPH - asymptomatic or serve as a reservoir for bacteria 3. Exstrophy - developmental failure of anterior wall of abdomen and bladder - bladder communicated with or lies on surface of abdomen 4. Urachal anomalies - Urachus; canal that connects fetal bladder with allantois, obliterated after birth - totally patent/persistent; a fistula connecting the bladder and umbilicus - central portion persists; urachal cyst, carcinoma may arise in cyst

Answer 63

1. Common agents - E.coli, proteus, klebsiella, Enterobacter - TB cystitis - Candida albicans, cryptococcal agents - Schistosomiasis; middle eastern countries - adenovirus, chlamydia, mycoplasma 2, Risk factors; female sex, bladder calculi, urinary obstruction, DM, instrumentation 3. Morphology - acute; neutrophilic infiltrate - chronic; persistent infection, mononuclear infiltrate - hemorrhagic cystitis; chemotherapy, adenovirus - follicular cystitis; not related to infection, presence of lymphoid follicles in mucosa and wall - eosinophilic cystitis; nonspecific subacute inflammation with eosinophils, but may be due to systemic allergic reaction ``` 4. Clinical features A. Triad of symptoms - Frequency (~15-20 min) - Suprapubic pain (lower abdomen) - Dysuria; pain, burning with urination ``` 5. Special forms A. Interstitial cystitis (Chronic Pelvis Pain Syndrome) - women more than men - intermittent, often severe suprapubic pain, frequency, urgency, hematuria, dysuria - cystoscopy; a) Early - fissues, punctate hemorrhages in mucosa b) Late - classic, ulcerative phase, chronic mucosal ulcers (hunner ulcers) - Late; transmural fibrosis, contracted bladder - Biopsy to rile out carcinoma B. Malakoplakia - Morphology A. Gross; Slightly raised, soft, yellow mucosal plaques 3-4 cm in diameter B. microscopic; large foamy macrophages, multinucleated giant cells, lymphocytes C. Laminated mineralized concretions (calcium in lysosomes), michaelis- Gutmann bodies, seen within macrophages

Answer 64

1. Common lesions 2. Brunn nests - Urothelium grows into lamina propia - Urothelial cells in the nest undergo metaplasia 3. Cystitis cystica; Urothelial cells retract to form cystic space lined by urothelium 4. Cystitis Glandularis; urothelial cells undergo metaplasia to cuboidal/columnar/goblet cell epithelium, resembling intestinal metaplasia 5. Squamous metaplasia; response to injury 6. Nephrogenic metaplasia/nephrogenic adenoma; response to injury, cuboidal epithelium and tubular proliferation of luminal propria * ****MAY BE CONFUSED FOR CANCER

Answer 65

General - M>W, 3:1 - developed nations > developing nations - urban > rural - 80% of pts aged 50-80 yrs - 95% epithelial in origin Risk factors A. Cigarette smoking - most important risk factor, increases risk 3-7x, smaller risk with other tobacco products - occupational exposure to Arya amines; dye, rubber and leather industries - schistosomiasis haematobium; Egypt, Sudan, 70% SCC, 30% TCC - long term analgesics - long term exposure to cyclophosphamide; immunosuppressive agent, induces hemorrhagic cystitis - Irradation Bladder tumors 1. urothelial tumors; - urothelial carcinoma in situ - Papillary urothelial carcinoma, low grade - Papillary urothelial carcinoma, high grade - Papillary urothelial neoplasm of low malignant potential (PUNLMP) - urothelial papilloma - inverted urothelial papilloma - urothelial proliferation of uncertain malignant potential (hyperplasia) - urothelial dysplasia/Atypia 2. Other associated cancers - squamous cell carcinoma - mixed carcinoma - adenocarcinoma - small cell carcinoma - sarcoma

Answer 66

Molecular genetics • Gain-of-function mutation in FGFR3: Mutation leads to activation of tyrosine kinase, usually found in low grade papillary carcinomas • Loss-of-function mutations in TP53 and RB tumor suppressor gene: usually high grade, muscle invasive tumors • Activating mutation of HRAS oncogene • Loss of genetic material on chromosome 9 2. Two distinct precursor lesions to invasive urothelial carcinoma A. Noninvasive papillary Tumors - more common B. Flat, noninvasive urothelial carcinoma (aka carcinoma in situ, CIS)

Answer 67

1. Papilloma - Uncommon, young, 0.5-2cm. - exophytic; attached to mucosa by a stalk - consists of papillae with a core covered by normal; appearing urothelium - may recur 2. Inverted papilloma - benign - extend into lamina propia 3. PUNLMP (Papillary urothelial neoplasms of low malignant potential) • Histologically similar to papilloma but with thicker urothelium than papilloma • Larger than papillomas • Rarely progress to a higher grade 4. Low grade papillary urothelial carcinoma • Orderly appearance • Evenly-spaced, cohesive cells • Mild atypia • Scattered hyperchromic nuclei, some mitotic figures • Rarely invade 5. High grade papillary urothelial carcinoma • Architectural disarray and loss of polarity • Discohesive cells • Large hyperchromatic nuclei • Anaplasia • Atypical mitotic figures • Higher incidence of invasion into muscular layer • Higher risk of progression • Significant metastatic potential (after invasion) 6. Carcinoma in situ (CIS, flat urothelial carcinoma) • Cytologically malignant cells within flat urothelium • No invasion of basement membrane • Discohesive cells, shed into urine • 50-75% of cases progress to invasive cancer

Answer 68

* Ta: Noninvasive, papillary * Tis: Carcinoma in situ (noninvasive, flat) * T1: Invasive, into lamina propia * T2: Invasive, into muscularis propia * T3a: Microscopic extravesicle invasion (into perivesical fat) * T3b: Grossly apparent extravesicle invasion * T4: Invasive, into adjacent structures

Answer 69

1. Embryonal rhabdomyosarcoma (Sarcoma botryoides) • Most common sarcoma of infancy or childhood • Grape like, muscle origin • Cambium layer • Deeper hypocelluar and myxoid stroma 2. Leiomyosarcoma • Most common bladder sarcoma in adults • Fascicles of malignant spindle cells Clinical features - painless gross or microscopic hematuria; most frequent sign (70-90%) - may see dysuria, frequency Treatment - Non invasive; a) routine biopsy b) intravascular chemotherapy c) radiotherapy - Invasive; surgical resection

Answer 70

Bladder - Obstruction • BPH/Carcinomas • Cystocele of bladder • Congenital urethral narrowing/stricture • Inflammatory (urethra/bladder) • Bladder tumors • Secondary invasion (cervix/vagina) • Mechanical obstruction: foreign body/stones • Injury to bladder innervations Morphology • Early: Some thickening of bladder wall, normal mucosa. • Late: Individual muscle bundles enlarge, trabeculation of bladder wall.

Answer 71

``` Urethra Inflammation 1. Urethritis • Gonococcal • Non-gonococcal; E. coli, Chlamydia, Mycoplasma • Pain, itching, frequency ``` 2. reactive Arthritis (Reiter Syndrome) - Arthritis, conjunctivitis, urethritis Tumors 1. Urethral caruncle; • Inflammatory • Small, red, painful mass in external urethral meatus, typically in older females • Histology: Vascular, fibroblasts, leukocytes • May ulcerate and bleed • Tx: surgical excision ``` Benign vs Malignant 1. Benign: Papillomas/condylomas 2. Malignant: • Rare • Proximal: Urothelial origin • Distal: Squamous cell origin ```

Answer 72

An acid donates a proton whereas as a base accepts it H2CO3 ⟷ H+ + HCO3- pH is a measure of H+ concentration and is mathematically calculated as pH = -log10 [H+] Body buffers are primarily weak acids (along with their conjugate bases) that have incomplete dissociation. **Buffer system maintain the pH balance by responding to dramatic changes in pH CO2 + H2O ⇋ H2CO3 ⇋ H+ + HCO3- Or, CO2 + H2O ⇋ H+ + HCO3-; K = [H+][HCO3-]/[CO2] [CO2] = 0.03PCO2 K = [H+][HCO3-]/0.03PCO2 **Ignore water in the equation because concentration of water is so high in the body **Henry’s law is when you convert a gas to a solution so [CO2] = 0.03 **PCO2 = 40 Therefore K = [H+][HCO3-]/1.2 - From Henderson-Hasselbach’s equation: - For a solution containing a weak acid- pH = pK + log base/acid - therefore, for CO2 + H2O ⇋ H+ + HCO3- = pH = pK + log [HCO3-]/[CO2] - = pH = 6.10 + log [HCO3-]/0.03PCO2 pH = pK + log [HCO3-] / 0.03PCO2 - pH is maintained by a ratio of bicarb (kidneys) and CO2 (lungs). 20:1 will always keep pH at 7.4 *****IF CO2 ACCUMULATES in a closed system, pH will decrease. However, our body is an open system to we have minimal changes to out pH

Answer 73

1. Kidneys reabsorb almost all of the filtered HCO3- 2. Human body generates:- - Potential volatile acid- CO2 - Non-volatile acid - Non-volatile bases - Dietary acid load - (Dietary acid + metabolic acid)-metabolic bases = 70 mM/day H+ 3. Hco3- Reabsorption Is The Principal Action Through Which Kidneys Maintain Acid-Base Balance. - supplement job of kidney is to regenate the bicarb that was consumed in step 1

Answer 74

1. Sodium hydrogen exchanger transports H+ in the PT and TAL - Na-H-antiport (NHE): Principal mechanism in the PT (80% HCO3- absorbed and the TAL (20% HCO3- absorbed). Also notice the basolateral Na/HCO3 co transport 2. H+ secretory system; alpha intercalated cells in the cortical collecting tubule/duct - H-ATPase: Principal mechanism in the intercalated cells (less so in TAL). Also notice the basolateral Cl/HCO3 exchanger and the H-K- antiport (secondary H+ secretor) 3. Aldosterone has 3 effects A. Directly stimulate H-ATPase B. Increase Na-K- ATPasem which increase Na gradient to enter the cell C. Increase ENaC activity and number - increase luminal negativity - more H+ can be secreted 4. Not ALL H+ secreted are excreted in urine—a vast majority are resorbed (recycled to reclaim bicarb in the body) - Proximal Tubule and the TAL secretes H+ to reclaim all HCO3- No H+ is Excreted at this step

Answer 75

The apical membrane Na/H anti-porter mediates most of HCO3- absorption in the P.T. These anti-porters are inhibited by lithium and amiloride. The Na/H anti-porter is exquisitely sensitive to H+ concentration on the inside (cytoplasmic side) of the vesicle. NHE3 is the Na/H anti-porter subtype predominantly responsible for aforementioned actions. NHE3 activity stimulated by AngII and endothelin; inhibited by PTH and PKA.

Answer 76

The Second Step: Generation of “new bicarbonate” and EXCRETION of H+ needs urinary buffers phosphates and ammonia are those buffers - **Whenever an H+ secreted into the tubular lumen combines with a buffer other than HCO3- the net effect is addition of a new HCO3- to the blood ** - Filtered H2PO4 and creatinine are titrable proton acceptors and that are protonated primarily in the proximal tubule. The H+ is exchanged for Na by the NHE. This step leads to synthesis of one new molecule of HCO3- - Metabolically-derived NH3 is the second (and more important) proton acceptor in the tubular fluid. NHE in the proximal tubule and H+-ATPase in the distal tubular segments (intercalated cells) allow H+ movement into the tubular lumen. Protonation of NH3 also leads to synthesis of one new molecule of HCO3-. - **Combined titrable and non titrable (NH4+) acid secretion equals the amount of new HCO3- synthesized by the kidneys** N.A.E (Net Acid excretion) - N.A.E. = rate of NH 4+ excretion + rate of titratable acid (T.A.) excretion minus rate of HCO3- excretion - N.A.E. = (U NH4+)(V) + (T.A.)(V) - (UHCO3-)(V) (Units for all terms are microEq/min; V = urine flow, ml/min) - The physiological significance of N.A.E. is that it equals the net amount of new HCO 3- generated by the kidney: - For each NH4+ excreted, 1 new HCO3- is added to renal venous blood - For each H+ excreted combined with HPO4- - ( = T.A.) one HCO 3- is addedto the renal venous blood. - Subtracting the amount of HCO3- excreted gives the NET amount of new - HCO3- added to the renal venous blood.

Answer 77

1. Falling pH, cortisol and endothelin stimulate H+ secretion (in tubular cells) and HCO3- reabsorption - this is by increase in NHE activity and increase cell to lumen gradient for H+ secretion 2. Increasing the [H+] gradient from cell to lumen increases H+ secretion. This effect occurs in all nephron segments that secrete H+. 3. The renal response to increased dietary acid intake is increased net acid excretion 4. Increased PaCO stimulates HCO3- reabsorption since CO2 activates H+ secretion that is central to HCO3- reabsorption 1. Elevated PCO2 directly stimulates H+ secretion 1. 1.As acids consume HCO3- and generate H2CO3 and then CO2, this directly activated PT cells to increase NHE activity, in the short term, and expression in the long term. 2. Acid production and consumption of HCO3- ↓ pH & stimulates H+ secretion and glutamine metabolism 2. 1.↓ extracellular pH decreases tubular cell pH and increases NHE activity in the PT cells. This also increases NH3 production in the distal tubules. 2. 2.Also, Na/HCO3- is activated in face of ↓pH. 2. 3.HCO3- consumption by metabolic acid ↑ lumen to interstitium HCO3- gradient, thus ↑ HCO3- reabsorption. 3. Overproduction of a base will have the opposite effects.

Answer 78

1. Hypokalemia causes metabolic alkalosis: 1. 1.Transcellular shift of H+ in “exchange” for K+ 1. 2.Increased activity of H-K-ATPase 1. 3.Increased activity go NHE3 2.Hyperkalemia causes acidosis: 2.1.Transcellular shift of H+ in “exchange” for K+ is the major cause 3.Important—effects of primary acid base disorders on K+ are much more pronounced than the effects of primary K+ homeostatic disorders on acid-base balance. ****By causing intracellular acidosis, hypokalemia increases NH3 activity. Hypokalemia causes metabolic alkalosis. High aldosterone causes alkalosis. Hypovolemia causes metabolic alkalosis

Answer 79

ELECTRONEUTRALITY has to be maintained - Normally measured urinary cations and anions: Na+, K+, Cl- - NH4+ is also present but can’t me measured - Normal anion gap = [Na]u + [K]u - [Cl]u Cations MUST EQUAL Anions - We have an unmeasured cation and thus, URINARY ANION GAP MUST BE A POSITIVE NUMBER - In metabolic acidosis new HCO3 has to be synthesized by the kidneys i.e. NH4+ excretion must increase (the unmeasured cation) - Cl- excretion also increases to maintain electroneutraility - We still cannot measured NH4+ however, [Cl]u has increased - Thus, we now have NEGATIVE URINARY ANION GAP * * Acidemia with normal urinary anion gap could suggest impaired renal NH4+ excretion(type I renal tubular acidosis or hypoaldosteronism) * * In metabolic acidosis if the UAG is positive then it signifies impaired renal NH4+ excretion i.e. renal cause of acidosis

Answer 80

1. Proximal RTA (TYPE 2)—the proximal tubule is dysfunctional and cannot absorb all the HCO3- it is supposed to 1. 1.Normally, the proximal tubule reabsorbs almost ALL HCO3- till the concentration of bicarbonate in the glomerular filtrate and plasma exceeds 26-28 mmol/L (true in euvolemia, not in hypovolemia). After this points, bicarb is NOT reabsorbed and starts to appear in urine. 1. 2.In TYPE 2 RTA, this mechanism is altered and proximal tubule can reabsorb only 16-17 mmol/L of bicarb. Thus, plasma bicarb drops and the system comes to a new equilibrium at a lower plasma [HCO3-]. Thus, self-limiting acidosis. 1. 3.There are one of three possible mechanisms—↓NHE, ↓Carbonic Anhydrase, ↓Na-K- ATPase in the proximal tubule—all three invariably linked to ↓Na+ resorption and activation of RAAS. 2. Proximal RTA (TYPE 2)—causes: 2. 1.Genetic defects in the proximal tubule—Fanconi’s syndrome 2. 2.Multiple myeloma—likely the most common cause 3. Urinary acidification is normal i.e. urine pH is <5.3—this is because distal nephron is still functional and is excreting protons 4. Plasma K+ is low—hypokalemia—due to aldosterone activation as a consequence of Na+ wasting 5. Diagnostic test—infuse Na-HCO3—as soon as plasma concentration of bicarb exceeds the capacity of the proximal tubule to reabsorb bicarb, urine will become alkaline (bicarbonate will start appearing in urine)

Answer 81

1. Distal RTA (TYPE 1)—the distal tubule is dysfunctional and cannot excrete protons 1. 1.Normally, the distal tubule acidifies urine by excreting protons in urine via the H-ATPase transporter. These protons then bind to NH3 and appear in urine. 1. 2.Most common cause of TYPE 1 RTA is defective H-ATPase in the collecting ducts 1. 3.Since H+ cannot be secreted, K+ excretion increases to balance thenluminal negativity created by Na+ reabsorption in the collecting ducts—hypokalemia is the result. 1. 4.Diagnosis—urine pH is >5.3 and Na-HCO3 infusion does not affect it

Answer 82

1. Renal tubular acidosis due to hypoaldosteronism— 1. 1.Aldosterone activates Na+ reabsorption in the collecting duct, thus creating luminal negativity. This then favors K+ and H+ secretion 1. 2.Aldosterone also activates H-ATPase, thus ↑H+ secretion 1.3.Hypoaldosteronism leads to academia and hyperkalemia— 1. 3.1.↓luminal negativity 1. 3.2.↓H-ATPase 1. 3.3.↓K+ channel activity

Answer 83

The kidneys generate 50 – 100 mEq/day of new HCO3- to replace the HCO3- lost by reaction with metabolic H+ . - Plasma HCO 3- is freely filtered; 99% is reabsorbed. - HCO3- reabsorption is coupled to H+ secretion in proximal tubule, thick ascending loop of Henle, & collecting duct. stimulated by increased PCO Increased in hypovolemia. - HCO3- generation derives from glutamine catabolism. is stimulated by a high protein diet and acidosis.

Answer 84

Acid-base balance is important for metabolic activity of the body - pH of arterial blood = 7.35 - 7.45. Alterations have effects on normal cell function - pH <6.8 or >8.0 death occurs

Answer 85

1. Buffers - A buffer has the ability to minimize changes in pH when H+ are added or removed from the system - E.g. H+ + A- ↔ HA - Body buffers are primarily weak acids (along with their conjugate bases) that have incomplete dissociation. By extension, best buffers are those who have pK as close to physiological pH as possible i.e. close to 7.4. - Two physiological buffer systems ensure tight regulation of body pH: between 7.36-7.44 - IT’S AN IMPERFECT SYSTEM AS ACID-BASE PROBLEMS ARE QUITE COMMON IN THE CLINICS *** The Bicarbonate Buffer System Is the Major ECF Buffer System PH = pK + log [HCO3-] / 0.03 PCO2 - To keep the pH of the biological systems near normal the ratio of HCO3-/CO2 has to be kept constant, acutely. Acute regulation of the pH primarily involves a respiratory compensation. Hyperventilation during acidosis to remove excess CO2 and hypoventilation during alkalosis to retain CO2 - For long term pH regulation the kidneys maintain HCO3- concentration and the lungs CO2 2. Non-bicarbonate buffer system 1.Half of the buffering capacity is contributed by non-bicarbonate buffers 1.1.Intracellular and extracellular proteins especially, albumin and Hb 1.2.Phosphate: H2 PO41-↔ H++ +HPO42- 1.3.Bone is basic: is composed of com-pounds such as sodium bicarbonate and calcium carbonate—and thus, dissolution of bone releases base. This release can buffer an acid load, although at the expense of bone density, if it occurs over an extended period. In contrast, bone formation, by consuming base, helps buffer excess base.

Answer 86

1. Reabsorb ALL filtered HCO3- (98% of the job) 2. Excrete protons - make new HCO3- (2% of the job) ***Both are activated in ACIDOSIS by; increased transcellular gradient for H+ secretion, increased cortisol, increase endothelium

Answer 87

1. Hypokalemia Hypokalemia: causes systemic alkalosis AND increase proximal renal tubular HCO3 absorption AND increase distal nephron acidification. 1.1.Transcellular shift of H+ as cells take up protons and extrude K 1.2.This intracellular increase in protons increases NHE Vmax ,thus absorbing more HCO3 in the PT 1.3.Hypokalemia activates H-K ATPase in the distal nephron thus, increasing distal renal tubular acidification 1.4.Hypokalemia is usually secondary to hyperaldosteronism, which increases H-ATPase activity 2. Hyperkalemia Hyperkalemia: causes systemic acidosis AND reduces proximal renal tubular HCO3 absorption AND reduces distal nephron acidification. 1.1.Transcellular shift of H+ as cells take up K and extrude protons 1.2.This intracellular decrease in protons decreases NHE Vmax ,thus absorbing less HCO3 in the PT 1.3.Hyperkalemia suppresses H-K ATPase in the distal nephron thus, decreasing distal renal tubular acidification 1.4.Hyperkalemia is usually secondary to hypoaldosteronism, which decreases H-ATPase activity

Answer 88

Acidosis stimulates renal HCO3- generation and renal H+ secretion . Increased HCO3- generation in mostly due to increased renal glutamine metabolism **Acidosis increases renal tubular H+ secretion by increasing Tubular cell [H+] and the cell to lumen H+ gradient the activity of the Na+, H+ antiport (proximal tubule & loop) the activity of the H+ ATPase (intercalated cells in collecting duct)

Answer 89

Metabolic acidosis is characterized by low arterial pH (normal 7.40, range of 7.35-7.45) and low serum HCO 3- concentration (normal 24 meq/L, range 22-28 meq/L) The low pH and serum HCO 3- concentration result from excess H+ added to the ECF (or by loss of HCO3-) Major causes of metabolic acidosis 1. Increased acid generation; lactic acidosis, ketoacidosis (uncontrolled DM, excess alcohol intake or fasting), ingestion (methanol, ethylene glycol, aspirin, toluene - inhalant abuse) 2. Loss of HCO3-; diarrhea (stool contains HCO3-), proximal tubular acidosis (inability to reabsorb filtered HCO3-) 3. Diminished renal acid excretion; renal failure, distal tubular acidosis (inability to excrete daily acid load) Buffering - It has an immediate (respiratory) and delayed component (renal) - LOWER SERUM BICARB and INCREASE SERUM K+ Compensation - respiratory compensation; <12hrs - Renal compensation; takes 3-5 days for full renal response * *In simple metabolic acidosis, serum pH, [HCO3-] and PCO2 are all reduced =, uncompensated and compensated * * Metabolic acidosis leads to hyperkalemia and intracellular K+ depletion. The total amount of K+ in the body is decreased, but some K+ shifts from cells to ECF causing hyperkalemia or maybe normokalemia in chronic acidosis. Winter’s rule for compensation *** **Expected pCO2 = 1.5 x [HCO3] + 8 Range (+/- 2)** E.g. What is the expected PCO2 in a patient with acidosis and HCO3 of 12 mEq/L? Remember, this is pulmonary compensation, usually occurs rapidly. = 1.5 * 12 = 18 + 8 = 26±2 mmHg Remember - combined disorder; both metabolic and respiratory acidosis or alkalosis - Mixed disorder; metabolic acidosis and respiratory alkalosis presenting at same time and vice versa

Answer 90

Anion gap - useful in diagnosis of metabolic acidosis The concept of the anion gap is based on the fact that there must be equal concentrations of cations and anions in the serum. Anion gap = [Na+] - ([Cl-] + [HCO3-]) Anion gap = 142 – (105 + 25) = 12 Ion concentrations are mEq/L. Normally the anion gap is mostly due to protein, primarily albumin. 1. The anion gap may be increased by Hyperalbuminemia ****When there is loss of volume (HCO3-), body will gain NaCl Think HCO3 loss: 1. Volume loss and kidneys try to retain NaCl (Diarrhea) 2.Renal HCO3 loss and kidneys absorb more chloride to maintain electroneutrality 2. Serum anion gap increases if a measured anion is replaced by an unmeasured one Anion gap positive vs negative - Positive; measured cations (Na+, K+) > measured anions (Cl-) - Negative; measured cations are still the same but the measured anion has increased (Cl) to maintain urinary electroneutrality.

Answer 91

``` 1. High Anion Gap acidemia Lactic acidosis Ketoacidosis Salicylate poisoning Methanol Ethylene glycol ``` 2. Normal Anion Gap acidemia - HCO3- loss: Diarrhea, Renal tubular acidosis - Renal failure - Ammonium chloride

Answer 92

Respiratory acidosis is defined as a disorder that causes an elevation in arterial PCO2 and a reduction in serum pH resulting from retention of CO2 1. Interference with pulmonary CO a. Chronic obstructive pulmonary disease B. Emphysema C. Chronic bronchitis D. Severe asthma ``` 2. Interference with ventilation A. Neuromuscular diseases B. Chest wall disorders such as severe kyphoscoliosis C. Obesity hypoventilation syndrome D. Obstructive sleep apnea E. Central nervous system depression - Drugs (narcotics, barbiturates, etc) - Neurologic disorders (encephalitis, brainstem disease, trauma) ``` Buffers - Assume for a second that no other buffer exists—both, H+ and HCO3- will rise and the reaction will rapidly come to an equilibrium. - If both increase by only 40 nano-moles (thats 10-9 of a mole) it doesn’t even put a dent in the bicarbonate concentration (24 milli-moles/L), but doubles the H+ concentration (40 nano-moles/L). Since pH is ONLY -log10[H+], pH will drop through the floor. - Thus, we will NOT be able to buffer any rise in CO2 - As you increase PCO2 and form carbonic acid (H2CO3), bicarbonate cannot neutralize the H+. ∴ [H] and [HCO3-] rise and pH falls. - However, intracellular buffers and non-bicarbonate buffers can neutralize the carbonic acid and thus prevent large reductions in pH. - HCO3- levels increase slightly as a consequence * ***In respiratory acidosis, there is increase in CO2. This lead to increase in HCO3- but its not enough to satisfy the equation. 1 FOR 10 * **Renal compensation (4 FOR 10) Summary of compensation vs buffering 1. Intracellular buffering of CO 2 increases serum [HCO3-] 1mEq/L per 10 mm Hg increase in PCO2 (1 for 10 rule) 2. When full compensation has happened, expected HCO3- in chronic respiratory acidosis: The [HCO3] will increase by 4 mmol/l for every 10 mmHg elevation in pCO2 above 40mmHg (the 4 for 10 rule)

Answer 93

Causes Metabolic alkalosis is defined as a disorder that causes elevations in the serum HCO 3- concentration and pH. Most frequent cause is loss of H+ ions from the body Types 1. GI Hydrogen loss (vomiting, nasogastric sunction) - Norovirus 2. Renal Hydrogen loss ( hyperaldosteronism, loop/thiazide diuretics) 3. Intracellular shift of H+; hypokalemia Why does the kidney “allow” metabolic alkalosis when it can excrete HCO3- - MA is almost always caused by loss of H+ and Cl loss is a usual accompaniment. MA is almost always hypochloremic. - Perpetuation of MA requires impairment in renal HCO3- excretion. - ↓GFR can can ↑ HCO3- reabsorption and prevent its excretion- volume loss - ↑ HCO3- reabsorption:• Chloride depletion • Hypokalemia • ↑Aldosterone ECF depletion effect: • Activation of the RAS/SNS increases Na reabsorption in the PT through ↑activation of NHE • RAS activates aldosterone that increases secretion of H+ in the cortical collecting tubules (Aldosterone stimulates the H+ ATPase in the intercalated cells of the collecting duct) Cl depletion is more responsible for increase HCO3- reabsorption • ↓Cl reduces the activity of NKCC2 resulting in activation of the RAAS

Answer 94

Expected pCO2 = 40 + 0.7 x [ΔHCO3]of 1 mEq/L E.g. What is the expected PCO2 in a patient with alkalosis and HCO3 of 36 mEq/L? Remember, this is pulmonary compensation, usually occurs rapidly. = 0.7* (36-24) = 0.7x 12 + 40 = 48 mmHg (+/- 2)

Answer 95

Causes - Respiratory alkalosis is defined as a disorder that causes a reduction in arterial PCO2 and an increase in pH Causes ; ***Usually IATROGENIC (caused by ventilator) 1. Hyperventilation Drug induced Neurological conditions that increase ventilation Anxiety, pain, fear 2. Occurs commonly with mechanical ventilation Symptoms may include dizziness, confusion and seizures. **You pass out from a panic attack because there is decreased CO2 which lead to vasoconstriction of cerebral vessels (hypoperfuson) - As you decrease PCO2 and use carbonic acid (H2CO3) [H] falls and pH rises and the system rapidly comes to equilibrium, however at a high pH - However, intracellular buffers and non-bicarbonate buffers can provide H+ to combine with HCO3- and form carbonic acid which can then dissociate to carbon dioxide to provide for excessive loss of CO2 by the lungs. this buffers the rise in pH - As H+ are combining with HCO3- its levels decrease slightly Buffering - Buffering is due to H+ leaving cells - Loss of H+ from cells decreases intracellular [H+]. H+ from cells reacts with serum [HCO 3-] which decreases 2mEq/L per 10 mm Hg decrease in PCO 2. CO2 is excreted by the lungs Compensation ; RENAL - Intracellular buffering of CO 2 decrease serum [HCO3-] 2 mEq/L per 10 mm Hg decrease in PCO2 (2 for 10 rule) - When full compensation has happened, expected HCO3- in chronic respiratory alkalosis: The [HCO3] will decrease by 5 mmol/l for every 10 mmHg fall in pCO2 below 40mmHg (the 5 for 10 rule)

Answer 96

Respiratory compensation is always acute, if the lungs are functional. Thus, if respiratory compensation was expected and didn't happen fully, respiratory acidosis is complicating metabolic acidosis or respiratory alkalosis is accompanying metabolic alkalosis. Renal compensation takes 2-3 days to fully develop. Within this time frame, lower than expected HCO3 in respiratory acidosis, or higher than expected in respiratory alkalosis, can be deemed partial compensation. After this window, however, it's considered a combined acid-base imbalance. Remember, even with full compensation the pH WILL NOT BE NORMALIZED

Answer 97

Clearly the Pt has respiratory acidosis. Now, if this is acute then HCO3 should have been 26 (24 + 1 for 10). If this is chronic then HCO3 should have been 32 (24 + 4 for 10). However, HCO3 is 36. The Pt has mixed acid-base imbalance: She has respiratory acidosis with metabolic alkalosis. E.g. She has long standing COPD and is being treated with thiazides for hypertension. Suspect mixed acid-base disorder (acidosis and alkalosis) if the pH is normal but PCO2 or HCO3- is abnormal. They might appear at normal or expected values but remember, pH RARELY RETURNS TO NORMAL JUST BY COMPENSATION OR BUFFERING.

Answer 98

§ You must know this!! 1. Rhonchi are lower pitched “musical noises”. They are caused by airway obstruction, usually with mucus secretions. (E.G FROM PRODUCTIVE COUGH) 2. Wheezes are higher pitched noises. Also secondary to airway obstruction, usually more from airway swelling (as in asthma). - inspiratory wheezing is upper airway while expiratory wheezing is usually trachea area. 3. Crackles (also called rales) suggest fluid in the lung parenchyma (fluid from heart failure, infection). 4. Fine dry crackles (velcrow like sound) seen with scarring and interstitial processes. Percussion abnormalities – effusion or consolidation causes decreased resonance. Increased air (as in pneumothorax or emphysema) cause increased resonance. Look for abnormalities in other systems. For example - crackles from heart failure will likely be accompanied by abnormal cardiac findings. Clubbing of the fingers can be seen with congenital heart disease, pulmonary fibrosis, lung cancer. **sometimes it can mean nothing Looks for increased AP diameter of the chest, suggesting chronic hyperinflation. (COPD, air trapping)

Answer 99

***MUST KNOW § Rales (wet crackles) suggests infiltrate or edema. § Fine crackles suggest interstitial disease. § Rhonchi suggest secretions in the airway. § Wheezing suggests airway swelling (as in asthma).

Answer 100

NORMAL ANATOMY A. Right lung with 3 lobes; (heavier, more problems occur here) B. Left lung with 2 lobes (including the lingula) C. Main function- exchange different gases between inspired air and blood D. Trachea branches out to right and left main stem bronchi (more likely to aspirate into the right main stem bronchus) E. Bronchi (HAVE CARTILAGE AND SUBMUCOSAL GLANDS) lead to bronchioles which do not have cartilage or submucosal glands F. Bronchioles lead to terminal bronchioles G. Terminal bronchioles lead to the acinus H. Acinus (terminal respiratory unit) 1. Contains respiratory bronchioles which lead to alveolar ducts 2. Alveolar ducts lead to alveolar sacs (alveoli) I. General histology 1. Respiratory tree lined by ciliated pseudostratified columnar epithelium. ***exception - vocal cord lines by stratified squamous epithelium 2. Cartilaginous airways with mucus-secreting goblet cells and submucosal glands J. Alveolar histology 1. Capillary endothelium 2. Basement membrane 3. Interstitium 4. Alveolar epithelium; a) Type I pneumocytes (flat epithelial cells); cover 95% of alveolar surface and b) Type II pneumocytes (cuboidal epithelial cells) - produce surfactant and repair 5. Alveolar macrophages - esp smokers K. Dual circulation with pulmonary and bronchial arteries - blood vessels are lined by endothelial cells - airways lined by epithelial cells - pleural is lined by mesotheliom cells

Answer 101

1. Pulmonary tract defense mechanisms A. Nasal clearance - sneezing or blowing B. Tracheobronchial clearance by cilia; epithelial mucociliary action C. Alveolar clearance by macrophage; phagocytosis 2. Factors affects our pulmonary defense mechanism A. Loss or suppression of cough reflex (coma, drugs, pain) B. Injury to mucociliary apparatus (ciliary dysfunction, smoking, viruses) C. Interference with alveolar macrophages (alcohol, smoking) D. Pulmonary congestion and edema E. Accumulation of lung secretions (cystic fibrosis)

Answer 102

General 1. Disorders with inflammation and fibrosis of the alveolar wall interstitium leading to restrictive lung disease 2. Dyspnea, tachypnea and eventual cyanosis without wheezing (obstruction) 3. Classic features are reduced carbon monoxide diffusing capacity, lung volume and compliance 4. Chest X-rays show bilateral infiltrative small nodules, irregular lines or ground-glass shadows 5. Advanced disease leads to secondary pulmonary hypertension, cor pulmonale (right sided failure) and end-stage lung or honeycomb lung

Answer 103

IPF - Idiopathic Pulmonary Fibrosis a. Clinicopathologic syndrome with characteristic radiologic, pathologic and clinical features b. Histologic pattern that of usual interstitial pneumonia (UIP) also seen in connective tissue diseases, hypersensitivity pneumonia & asbestosis c. Pathogenesis 1. Etiology unknown but most likely caused by repeated cycles of epithelial activation/injury by certain agents 2. Inflammation causes abnormal epithelial repair leading to fibroblastic/myofibroblastic proliferation (“FIBROBLASTIC FOCI”) 3. Abnormal repair due to fibrogenic TGF-beta, which is released by Type I alveolar epithelial cells 4. TGF-beta1 negatively regulates telomerase activity - increased epithelial cell apoptosis - cycles of cell death and repair 5. Caveolin-1, which is an inhibitor of TGF-beta, is decreased in epithelial cells and fibroblasts in IPF D. Morphology/Histology 1. Cobblestone pleural surface with firm rubbery cut surfaces 2. Mostly involves lower lobes near subpleural regions and along interlobular septae 3. Early stage with fibroblastic foci with temporal heterogeneity (layers of normal and abnormal lung) 4. Late stages with dense fibrosis and cystic spaces lined by hyperplastic Type II pneumocytes (honeycomb lung) 5. Usually see coexistence of both early and late lesions 6. May see mild/moderate inflammation, squamous metaplasia, smooth muscle hyperplasia and pulmonary HTN E. Clinical (1) Insidious onset of dyspnea on exertion and dry cough (2) Later see hypoxemia, cyanosis and clubbing (3) Most patients between 40-70 years of age at diagnosis (4) Unpredictable course with median survival of about 3 years

Answer 104

Nonspecific Interstitial Pneumonia (NSIP) a. Also with characteristic radiologic, pathologic and clinical features b. Etiology unknown c. Morphology/Histology (1) Cellular pattern; (a) Uniform/patchy mild to moderate chronic inflammation (b) Better prognosis than with fibrosing pattern (2) Fibrosing pattern; (a) Diffuse/patchy interstitial fibrosis WITHOUT temporal heterogeneity in UIP (b) NO fibroblastic foci and honeycomb lung d. Clinical (1) Months of dyspnea and cough (2) Most patients between 46-55 years of age (younger than IPF/UIP) (3) Much better prognosis than in patients with UIP * ***RESPONDS TO STEROID

Answer 105

Cryptogenic Organizing Pneumonia (previously known as BOOP) a. Etiology unknown b. Common response to various infections or inflammatory lung injury (e.g. viral/bacterial pneumonias, inhaled toxins, drugs, etc.) c. Morphology/Histology (1) Patchy subpleural or peribronchial airspace consolidation (2) See intra-alveolar polypoid plugs of loose organizing connective tissue (Masson bodies) WITHOUT temporal heterogeneity (3) NO interstitial fibrosis or honeycomb lung d. Clinical (1) Acute onset of cough and dyspnea (2) Most need steroid treatment for > 6 months

Answer 106

Pulmonary involvement in connective tissue diseases a. Include rheumatoid arthritis, scleroderma and systemic lupus erythematosus b. Can occur in many different patterns (UIP, NSIP, organizing pneumonia, bronchiolitis) c. May occur in 30-40% of rheumatoid arthritis patients

Answer 107

Pneumoconioses a. Diseases caused by organic and inorganic particulates as well as chemical fumes and vapors b. Pathogenesis (1) Disease development depends on various physical factors (a) Amount of dust retained determined by concentration in ambient air, duration of exposure and effectiveness of clearing mechanisms (b) Size, shape and buoyancy of particles (c) Particle solubility and physiochemical reactivity (d) Possible additional effects of other irritants (2) Remember- most dangerous particles measure 1-5 um (a) Smaller particles more readily enter pulmonary fluids rapidly reaching toxic levels causing acute lung injury (b) Larger particles persist longer causing fibrosis (silicosis) c. Coal Workers’ Pneumoconiosis (1) Asymptomatic anthracosis (a) Accumulation of carbon pigment in macrophages along lymphatics and lymphoid tissue in miners, tobacco smokers and urban dwellers (b) Does not produce a cellular reaction (2) Simple CWP with little/no pulmonary dysfunction (a) See coal macules (1-2 mm) with carbon-laden macrophages and larger coal nodules with collagen (b) Macules and nodules along the respiratory bronchioles (c) Upper lobes & upper zones of lower lobes more affected (d) Leads to centrilobular emphysema (3) Complicated CWP (progressive massive fibrosis) (a) In a background of simple CWP developing over years (b) See multiple blackened scars > 1 cm (up to 10 cm) in lung parenchyma (c) Composed of dense collagen, carbon pigment & necrotic centers (4) Clinical (a) Usually a benign disease course (b) Mild forms of complicated CWP without loss of function exist (only 10% of simple CWP progress to complicated CWP) (c) More advanced forms of CWP lead to pulmonary hypertension and cor pulmonale even WITHOUT further exposure

Answer 108

Silicosis (1) Caused by inhalation of crystalline silicon dioxide (silica) (2) Most prevalent chronic occupational disease worldwide (3) Seen in sandblasters and mine workers years after exposure (4) Pathogenesis (a) Silica in crystalline and amorphous forms (b) Crystalline form much more fibrogenic (incl. quartz) (c) Silica causes macrophage to release various mediators (e. g. IL-1, TNF, O2-derived free radicals, fibrogenic cytokines) (5) Morphology/Histology (a) Early stage barely palpable nodules in upper lung zones (b) Later stage see nodules coalescing to form hard collagenous scars made of concentric layers of hyalinized collagen with a dense capsule (c) Lesions may involve hilar lymph nodes and pleura with thin calcifications (eggshell calcifications) (6) Clinical (a) X-ray: fine nodularity in upper lung areas (b) Dyspnea occurs after development of massive fibrosis (c) Associated with increased incidence of tuberculosi

Answer 109

(1) Asbestos exposure linked to fibrous pleural plaques, pleural effusions, interstitial fibrosis, lung and laryngeal carcinoma, mesothelioma (2) Pathogenesis (a) Depends on concentration and physical properties (size, shape, solubility) of the fibers (b) 2 types of fibers- serpentine (chrysotile) and amphibole (c) Serpentine form: most prevalent form; curly flexible soluble fibers; removed by upper respiratory mucociliary apparatus (d) Amphibole form: least prevalent form but more pathogenic; stiff and brittle fibers; penetrate deep into the lung interstitium (e) Both fibrogenic but only the amphibole form is associated with mesothelioma (f) Inhaled fibers cause initial injury at the bifurcations of small airways where they penetrate macrophage (g) Macrophage are activated releasing chemotactic factors and fibrogenic mediators leading to widespread fibrosis 3) Epidemiology (a) Exposure leads to 5 fold increase in lung carcinoma (b) Exposure + smoking leads to 55 fold increase in lung ca (c) Exposure leads to 1000 fold increase in mesothelioma (4) Morphology/Histology (a) See diffuse interstitial fibrosis similar to UIP (b) Asbestos bodies- golden-brown elongated asbestos fibers coated with iron-containing protein from macrophage (c) Initial fibrosis around respiratory bronchioles and alveolar ducts extending airspaces extending to alveolar sacs and alveoli (D) Finally creates enlarged airspaces with fibrous walls (honeycomb pattern) (E) Disease begins in the lower lobes with the middle and upper lobes possibly affected later F) Pleural plaques are the most common manifestation of asbestos exposure; dense collagen with calcium mostly on anterior & posterolateral parietal pleura & diaphragm G) Pleural plaques DO NOT contain asbestos bodies 5. Clinical (a) Dyspnea with productive cough (b) Symptoms usually > 20 years after asbestos exposure (c) Chest x-ray: irregular linear densities (d) Asbestosis + lung or pleural cancer = grim prognosis

Answer 110

Therapy-induced lung disease - **certain drugs cause bronchospasm, pulmonary edema, DAD (diffuse alveolar damage), organizing pneumonia and INTERSTITIAL FIBROSIS a. Bleomycin (antineoplastic drug) can cause lung damage and fibrosis b. Amiodarone (anti-arrhythmic drug) causes pneumonitis in 5-15% c. Acute radiation pneumonitis occurs in 10-20% of patients 1-6 months later (fever, profound dyspnea, pleural effusion) d. Chronic radiation pneumonitis (diffuse alveolar damage with epithelial cell atypia and pulmonary fibrosis) can also occur

Answer 111

Caplan syndrome a. CW Pneumoconiosis + rheumatoid arthritis b. See lung nodules with possible central necrosis c. Syndrome can also occur in asbestosis and silicosis

Answer 112

Difference between acute vs chronic infections 1. Acute; neutrophils (60%). Neutrophils perform PHAGOCYTOSIS to kill bacteria, and die by APOPTOSIS 2. Macs; monocyte 9%. Macrophage control when to transition from acute to chronic infections A. M1; - kills ingested and intracellular bacteria (CD40 bind CD40L Th1 effector to produce INTERFERON GAMMA TO KILL THE CELL). - “Angry macrophages” activated by interferon gamma. - Also produce cytokines like IL1, IL12, IL23 to stimulate inflammation. B. M2; - not efficient in killing intracellular bacteria. - Produce IL10 and TGF-beta which are anti-inflammatory cytokines 3. Chronic; Lymphocyte 30% . Lymphocytes, recirculate back to lymphatics and blood if they don’t encounter the cognate antigens (much longer lifespan than neutrophils)

Answer 113

Physiology - cystic fibrosis chloride ion channel • Cystic fibrosis transmembrane conductance regulator (CFTR) (chromosome 7) • Chloride channel transports Cl- in and out of cells. • Basic defect is due to the mutations in CFTR that cause difficulty to move Cl- across the membrane. • Increased Cl ion outside the cells, increased the Na ion reabsorption. • A thin layer of mucus on top of the airway, small intestine (meconium ileus), and pancreatic duct become dehydrated and sticky due to CFTR mutation. Pathology - Cystic fibrosis lung disease ● Thick dehydrated mucus production in airways ● Chronic obstructive pulmonary disease ● Bronchiectasis with pulmonary exacerbations ● Recurrent lung infections ● Bronchopneumonia ● Gradual lung function deterioration (FEV1) Microbiology - BAL (bronchoalveolar lavage) fluid from a patient with CF ***REPEATED ACUTE INFECTION - Inflammatory cells (neutrophils) - IL-8, LTB4, C5a, IL-17, PGP, bacterial products - TNF-a, IL-1b and GM-CSF - Decreased cough clearance - Impaired apoptosis and efferocytosis - Neutrophil elastase and oxidants in BAL - IL-10 downregulated in BAL Pathogens associated with CF (cystic fibrosis) 1. CGD (NADPH oxidase defect) - Catalase positive bacteria - Staphylococcus aureus - Burkholderia (Pseudomonas) cepacia - Serratia marcescens - Nocardia - Aspergillus 2. CF (Cl ion transport defect) - Pseudomonas aeruginosa - Staphylococcus aureus incl. MRSA - Nontypable Haemophilus influenzae - Burkholderia cepacia (poor prognosis for lung transplant) - S. maltophilia - Achromobacter

Answer 114

1. Describe entry (2) - Build a physical barrier by limiting the diffusion of antibiotics through a viscous layer of polysaccharide (biofilms). Decrease entry - Alterations that affect permeability (ie, decrease the intracellular concentration of antibiotic) are used by a variety of antibiotics. This can involve a decreased influx or an increased efflux from the bacterial cell. Decrease entry. 2. Destroy antibiotics - Inactivation of the antibiotic through hydrolysis (eg, β-lactamases that cleave the β-lactam ring of penicillins, cephalosporins and carbapenems)-Destroy antibiotics 3. Altered target (3) - Synthesis of modified LPS that resists action of peptide antibiotics-Altered target. - Chemical modification of the antibiotic through acetylation, phosphorylation, or adenylylation (eg, chloramphenicol acetyl transferase that transfers an acetyl group from acetyl CoA to chloramphenicol, resulting in its inactivation). Altered target. - Alteration of antibiotic targets through mutation (eg, the alteration of a single amino acid in ribosomal protein S12, which prevents streptomycin binding to the 30S ribosome subunit without affecting protein synthesis). Altered target

Answer 115

Beta - lactamase 1. Major mechanism in Gram-negative pathogens 2. May be plasmid- or chromosomally-mediated - Most are plasmid-mediated - “AmpC” β-lactamases may be encoded on chromosome of “SPACE” organisms (Serratia marcescens, Pseudomonas aeruginosa/Proteus spp., Acinetobacter spp., Citrobacter spp., Enterobacter spp.) 3. Main types of β-lactamases: (3) A. Penicillinases inactivate penicillins B. “Extended-spectrum β-lactamases” (ESBLs) inactivate most β- lactams except for carbapenems C. Carbapenemases (e.g., OXA, KPC, metallo-β-lactamases) inactivate carbapenems CF antibacterial therapy • P. aeruginosa is naturally resistant to many antibiotics. *** • Resistant strains often emerge during therapy. • Combination therapy (double coverage) with different mechanisms of action: Intravenous administration of anti-Pseudomonas penicillin, ticarcillin or piperacillin (b-lactam), plus an aminoglycoside, eg. gentamicin or amikacin (acute pulmonary exacerbations). • Inhaled tobramycin and oral azithrommycin. Immunodeficiency in CF • Innate immunity: complement, macrophages, and neutrophils (mucociliary clearance defect). • Antigen presentation by APC (dendritic, macrophages and B cells) (possible). • Adaptive immunity: T and B cells. Th2-Th17 axis. Elevated levels of IgG1-4, IgM, and IgA, indicating that the germinal center of LN is functional with isotype switching. Fc portion of antibodies are fine. • Reduced opsonic phagocytosis with CF sera indicates that affinity maturation due to somatic hypermutation (AID) may not be functional. • Clonal expansion is not an issue. The issue is clonal expansion with not produce good antibodies. CF clinical trials ● Gene therapy ● Broad anti-inflammatory modulator ● Antibacterials with anti-inflammatory properties ● Modulators of intracellular signaling (IL-10, INF-g) ● Inhibitors of neutrophils influx (Anti-IL-8 and anti-IL-17) ● Inhibitors of neutrophil products (DNase) ● Anti-oxidants ● Anti-proteases Summary of CF lung disease - CF lung disease is characterized by repeated acute inflammation with excessive neutrophils in the interstitial space. - Biofilm formation reduces efficacy of both antimicrobial therapy and immune responses, and also causes the chronic presence of bacteria. - Acute inflammation is part of innate immunity which as limited specificity. Uncontrolled acute inflammation eventually leads to structural damage resulting in bronchiectasis and lung abscess. - The key to cure the CF lung disease lies in the production of antibodies with improved specificity (more effective binding). Immunotherapy, CAR-T, chimeric antigen receptor of T cells; CTLA-4 and PD-1 *** TO PRODUCE LIFELONG IMMUNITY

Answer 116

Primary TB • Tuberculosis is caused by inhalation of aerosolized Mycobacterium spp including M. tuberculosis. • Initial exposure causes the primary TB with the formation of focal caseating necrosis in the lower lobe of lung and hilar lymph nodes. • Foci undergo fibrosis and calcification forming Gohn complex. • Generally asymptomatic and PPD positive. Secondary TB due to the reactivation • HIV and aging are two major risk factors. • Occurs at the apex of lung and can spread to any tissue. • Forms cavitary foci of caseous necrosis; May also lead to miliary pulmonary TB or TB bronchopneumonia. • Fevers and night sweats • Cough with hemotypsis • Weight loss • Biopsy-granuloma and AFB positive bacilli Adaptive responses to Intracellular bacteria (2) 1. Prototypical response to intracellular bacteria is TH1 - IFN- g activates macrophages to destroy phagocytosed microbes - MAC-produced IL-12 activates NK cell which produces IFN-g - IL-12 causes the differentiation of T cell o TH1 cell which produces IFN-g - TH1 cell CD40L activates macrophages (APC) via CD40 - GC-LN: TH1 cell CD28 binds to B7 on macrophage (APC) for co- stimulation - GC-LN: TH1 cell CD40L co-stimulates B cells (APC) via CD40 - GC-LN: IFN-g induces opsonizing and complement-binding Ab isotypes via affinity maturation (somatic hypermutation) and isotype switching 2. Phagocytosed bacteria also stimulate CD8+ T cell responses if bacterial Ags are transported from phagosomes into the cytosol - CTLs can kill infected cells

Answer 117

Pathogenesis of granulomas A. Infection before activation of cell mediated immunity B. Initiation and consequences of cell mediated immunity 2 types of granuloma 1. Caseating granulomas • Bacteria: Mycobacterium tuberculosis, Treponema pallidum, Listeria monocytogenes (granulomatosis infantiseptica) • Fungi: Aspergillus, Blastomyces, Coccidioides, Cryptococcus, Candida, and Histoplasma • Helminthic infection: Schistosoma mansoni, S. japonicum, the liver granulomas form around the parasite eggs. 2. Noncaseating granulomas • Reaction to foreign materials • Sarcoidosis (lung, offending antigen unknown) • Beryllium exposure • Crohn disease (offending antigen unknown, contrast to UC) • Cat scratch disease (Bartonella henselae with neutrophils) • Mycobacterium leprae

Answer 118

TB treatment regimen - first Line drugs 1. For pulmonary TB; 3 or 4 drugs for 2 months followed by 2 drugs for 4 months; - RIF, INH, PZA and EMB for 2 months - INH and RIF for 4 months 2. DOT is important to ensure adherence and reduce resistance 3. For extrapulmonary disease or with HIV treatment may be longer 4. For LTBI one drug is used; usually INH for 9 months HIV and TB 1. TB is leading killer of HIV-positive people causing one fourth of all HIV-related deaths 2. HIV-infected; - 30 times more likely to progress to TB disease - 40% develop TB disease 2-3 months after exposure - TB increases risk of HIV progression 3. Associated with multi-drug resistant TB (MDR-TB) MDR and XDR TB 1. Drug resistant Mtb is a result of selection of naturally resistant bacilli from a large population of tubercle bacilli - improper use of TB medications; Non-adherence, inadequate dose of drugs, inappropriate single drug therapy 2. MDR TB; resistant to isoniazid and rifampin 3. XDR TB; resistant to isoniazid and rifampin + a FLUOROQUINOLONES + one injectable second line agent (kanamycin, amikacin, capreomycin) Summary of TB - TB is caused by infections by an intracellular bacterium. The primary infection starts with bacterial colonization in alveolar macrophage via respiratory droplets. - Initial exposure causes the formation of caseating granuloma in the lower lobe of the lung and hilar lymph nodes. - Macrophage will produce IL-12 and TFN-a which causes the naïve T cells to become Th1 which produces IFN-g - IFN-g activated macrophages are called epithelioid histiocytes. - Reactivation of TB can disseminate to other body sites, bone marrow, spleen, kidney, and CNS, all with formation of caseating granulomas

Answer 119

TB diagnosis 1. Immuno-diagnosis: - tuberculin skin test (TST), PPD. Be careful about false positive. Delayed type hypersensitivity (cell-mediated) - In vitro IFN-r release assays. Specific antigen (early secreted antigen target-6 ESAT-6, culture filtrate protein 10 (CFB-10), test true positive. 2. Chest X-ray: primary vs. secondary. 3. Microscopy: Acid fast bacilli (AFB stain of sputum) 4. PCR 5. Culture: gold standard, but takes 3-4 weeks. ``` TB treatment • Anti-TB drugs: 6 MONTHS - Isoniazid (INH). - Rifampin (RIF). - Pyrazinamide (PZA) - Ethambutol (EMB). • Prophylaxis • Vaccination with attenuated M. bovis [bacille Calmette-Guerin (BCG)] ```

Answer 120

Mechanisms of Asthma • Increased numbers of inflammatory cells in the airway: TH2 cells, eosinophils, and B lymphocytes (produce IgE), mast cells • Release more than 100 inflammatory mediators • Inflammatory mediators → induce bronchoconstriction • Cholinergic reflexes → bronchoconstriction • Hypertrophy/hyperplasia of airway smooth muscle cells • Vasodilation, plasma leak → edema • Chronic inflammation leads to structural changes • Subepithelial fibrosis (basement membrane thickening) • Hyperplasia of mucus-secreting cells **AIM OF DRUGS IS TO SUPPRESS BRONCHIOCONSTRICTION

Answer 121

1. Intermittent o Symptoms less than 2 days per week o Nighttime awakenings less than 2 days per month o Interference with normal activity—none o FEV1 greater than 80% of predicted o Albuterol inhaler used less than 2 days per week o Exacerbations requiring systemic corticosteroids (0 to 1 per year) 2. Persistent Mild o Symptoms more than 2 days per week o Nighttime awakenings 3 to 4 times per month o Interference with normal activity—minor limitation o FEV1 greater or equal to 80% of predicted o Albuterol inhaler used more than 2 days per week, but not daily and not more than 1 time per day o Exacerbations requiring systemic corticosteroids (more than 2 per year) 3. Persistent Moderate o Symptoms are daily o Nighttime awakenings more than once per week o Interference with normal activity—some limitation o FEV1 60-80% of predicted o Albuterol inhaler used daily o Exacerbations requiring systemic corticosteroids (more than 2 per year) 4. Persistent Severe o Symptoms are throughout the day o Nighttime awakenings are often (7 times per week) o Interference with normal activity—extremely limited o FEV1 less than 60% o Albuterol inhaler used several times per day o Exacerbations requiring systemic corticosteroids (more than 2 per year)

Answer 122

``` Inhalation therapy: • 10 to 20% of the drug is inhaled • 80 to 90% of the drug is swallowed • Use of large-volume spacer will reduced the amount of drug being deposited on the oropharynx (reduce oral and systemic side effects (this particularly important when it comes to inhaled corticosteroids)) • Metered dose inhalers • Space chambers • Dry powder inhalers ``` • NEBULIZERS (useful for treating extreme exacerbations of asthma or COPD when airway obstruction is extreme). Also useful for delivering drugs to infants and small children • ORAL ROUTE (have to give a much larger dose compared to inhaled dose to get the same effect). Theophylline has be given by the oral route - e.g Some meds may be given as a syrup to children

Answer 123

β2 Adrenergic agonists (sympathomimetics) • Mode of action: Induce β2 receptors, which induces the activation of the Gs-adenylyl cyclase-cAMP-PKA pathway, resulting in phosphorylative events leading to bronchial smooth muscle relaxation Short acting β2-agonists (SABA): albuterol (most common - mixture of R and S isomer), levalbuterol, metaproterenol, terbutaline, pirbuterol (not used anymore). **selective beta 2 agonist • Most effective and widely used bronchodilators in the treatment of asthma (also used in COPD) • Rapid onset (1-5 minutes); relatively short (3-4 hours) duration of action • Effective protection against various asthma triggers: such as exercise, cold air and allergens • They are resistant to enzymatic degradation by COMT and MAO • All are usable by inhalation and orally. • Indicated for all stages of asthma (i.e., albuterol inhaler) as a rescue agent LONG-ACTING INHALED Β2 AGONISTS (LABA): salmeterol, formoterol, indacaterol (indacaterol used in COPD not asthma) • 12 hr bronchodilator activity (used for prophylaxis bronchodilator activity) • salmeterol, formoterol are 2X daily • indacaterol is 1X daily (24h duration of action) • ****In patients with asthma, LABAs should never be used alone because they do not treat the underlying chronic inflammation, and this may increase the risk of life-threatening and fatal asthma exacerbations (***LABA ALONE INCREASE MORTALITY) • ****LABAs should always be used in combination with an inhaled corticosteroid in a fixed-dose combination inhaler.

Answer 124

COMBINATION INHALERS: • Combination inhalers that contain a LABA and a corticosteroid (e.g., fluticasone/salmeterol, budesonide/formoterol) are now widely used in the treatment of persistent asthma. • The combination inhaler is more convenient for patients Β2 RECEPTOR POLYMORPHISMS • Several single-nucleotide polymorphisms of the human ADRβ2, which affect the structure of β2 receptors, have been described. • β2 receptor polymorphisms do not influence patient response to LABA SIDE EFFECTS o Muscle tremor o Tachycardia and palpitations (direct effect on cardiac β2 receptors, high doses stimulate cardiac β1 receptors, also reflex effect from increased peripheral vasodilation via β2 receptors) o Hypokalemia (direct β2 effect on skeletal muscle uptake of K+) o Restlessness o Tolerance (not a major concern) o Tolerance of nonairway β2 receptor–mediated responses occur (tolerance to Muscle tremor) o Airway β2 receptor remains response to SABA and LABA (thus β2 receptor tolerance is not a major issue in the Airway)

Answer 125

Theophylline: • Still widely used in developing countries because it is inexpensive • Add on (alternative) therapy for Asthma and COPD Mechanism of Action: . o Nonselective phosphodiesterase (PDE) inhibitor, *** o Adenosine receptor antagonism. **** o Promotes interleukin 10 release (IL-10 has antiiflammatory activity) o Decreases the expression of proinflammatory genes in airway o Promotes the apoptosis of eosinophils and neutrophils and T lymphocytes (in vitro results) Pharmacokinetics and Metabolism o Metabolized by the liver

Answer 126

Factors affecting clearance 1. Increased clearance A. Enzyme induction (mainly CYP1A2) by co- administered drugs (e.g., rifampicin, barbiturates, ethanol) B. Smoking (tobacco, marijuana) via CYP1A2 induction C. High-protein, low-carbohydrate diet D. Barbecued meat E. Childhood ``` 2. Decreased clearance (increase theophylline levels - toxic) A. CYP inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, fluvoxamine, zileuton, zafirlukast) B. Congestive heart failure C. Liver disease D. Pneumonia E. Viral infection and vaccination F. High-carbohydrate diet G. Old age ``` Prep and route of administration o Not effective via inhalation route o Oral immediate release tablets o IV CLinical use o Patients who fail to respond to, or are intolerant of, β2 agonists o Add on therapy for asthma and COPD Side effects (based off PDE4 and adenosine inhibition 1. Nausea and vomiting - PDE4 inhibition 2. Headaches - PDE4 inhibition 3. Gastric discomfort - PDE4 inhibition 4. Diuresis - Adenosine 1 (A1) receptor antagonism 5. Cardiac arrhythmias - PDE3 inhibition, A1 receptor antagonism 6. Epileptic Seizures - A1 receptor antagonism

Answer 127

Mode of action: Act as competitive antagonists of endogenous ACh at muscarinic receptors and therefore inhibit the M3-Gq-PLC-IP3-Ca2+ pathway on airway smooth muscle cells. • The effects of ACh on the respiratory system include bronchoconstriction and tracheobronchial mucus secretion. Thus, antimuscarinic drugs antagonize these effects of ACh, resulting in bronchodilation and reduced mucus secretion. • ACh may also be released from other airway cells, including epithelial cells • Myriad mechanical, chemical, and immunological stimuli elicit reflex bronchoconstriction via vagal pathways • Muscarinic receptor antagonists are not anti-inflammatory agents • *In asthmatic patients, anticholinergic drugs are less effective as bronchodilators than β2 agonists and offer less-efficient protection against bronchial challenges.

Answer 128

Types 1. Ipratropium is available as a powder meter dose inhaler (MDI) and nebulized preparation. • The onset of bronchodilation is relatively slow and is usually maximal 30–60 min after inhalation but may persist for 6–8 h. • Dosing is three or four times daily on a regular basis. 2. Tiotropium: Long-acting anticholinergic drug that is available as a dry powder inhaler (DPI) that is suitable for once-daily dosing. Combination Inhalers: Combination inhalers, such as albuterol/ipratropium are available. • Several studies have demonstrated additive effects of these two drugs, thus providing an advantage over increasing the dose of β2 agonist in patients who have side effects. Adverse effects (TIOTROPIUM IS BETTER) o Systemic side effects are uncommon during normal clinical use because there is little systemic absorption. o Unpleasant bitter taste of inhaled ipratropium. o Nebulized ipratropium may precipitate glaucoma in elderly patients due to a direct effect of the nebulized drug on the eye. o Paradoxical bronchoconstriction with ipratropium (due to antibacterial additives, such as benzalkonium chloride and EDTA) o Dryness of the mouth in 10%–15% of patients, but this usually disappears during continued therapy. o Urinary retention is occasionally seen in elderly patients.

Answer 129

* *Inhaled corticosteroids (ICS) are first-line therapy for all stages of persistent asthma * Beclomethasone and ciclesonide are prodrugs that release the active corticosteroid after the ester group is cleaved by esterases in the lung. * Budesonide and fluticasone exhibit first-pass metabolism and therefore less likely to produce systemic effects at high inhaled doses. * Effects of ICS: * * Anti-inflammatory activity in the airway * Reductions in the levels of pro-inflammatory cytokines and decreases in the number of inflammatory cells * Reductions in airway edema * Full suppression of airway inflammation by ICS may weeks to months * Corticosteroids potentiate the effects of β agonists on bronchial smooth muscle and prevent and reverse β receptor desensitization in airways in vitro and in vivo. Systemic corticosteroids • Intravenous (IV) steroids are indicated for acute asthma if lung function is less than 30% predicted and in patients who show no significant improvement with nebulized β2 agonist. • IV Hydrocortisone is the steroid of choice because it has the most rapid onset (5–6 h after administration), compared with 8 h with prednisolone. • Prednisone and prednisolone are the most commonly used oral steroids. • Short courses of oral prednisolone indicated for exacerbations of asthma; the dose may be tapered over 1 week after the exacerbation is resolved. Local side effects - Dysphonia - Oropharyngeal - candidiasis - Cough Systemic side effects - Adrenal suppression and insufficiency - Growth suppression - Bruising - Osteoporosis - Cataracts & Glaucoma - Metabolic abnormalities (glucose, insulin, triglycerides) - Psychiatric disturbances (euphoria, depression) - Pneumonia

Answer 130

* Cromolyn and nedocromil * Inhaled (MDI) anti-inflammatory agents * Suppress mast cell degranulation * Good safety profile * Rarely used, because ICS are much more effective * Discontinued

Answer 131

H1 antihistamines • There is little evidence that histamine H1 receptor antagonists provide any useful clinical benefit • Antihistamines are not recommended in the routine management of asthma. Anti-leukotrienes - MONTELUKAST IS SAFEST • Cysteinyl leukotrienes (CT) are produced during asthma and they cause bronchoconstriction, airway hyper-responsiveness, and they are pro- inflammatory in airway • Zafirlukast, Montelukast are cys-LT1 receptor antagonist • Zileuton inhibits 5-lipoxygenase, which is the rate limiting enzyme in leukotriene biosynthesis. • Reduce the occurrence of bronchospasms in response to allergens, aspirin, cold air and exercise • Anti-LTs are considerably less effective than ICSs in the treatment of asthma and cannot be considered the treatment of first choice Benefits - Available in tablet form, which could improve patient compliance (particularly in children). • Montelukast is once per day, Zafirlukast is twice per day, and Zileuton is 4X per day. All given in tablet form ``` Adverse effects • All can cause hepatic toxicity • Headache (Zafirlukast) • Fever and Chills (Zileuton) • Several cases of Churg-Strauss syndrome (rare vasculitis that may affect the heart, peripheral nerves, and kidney) have been associated with the use of zafirlukast and montelukast ```

Answer 132

* Anti-IgE Receptor Therapy * Increased levels of IgE is a fundamental feature of allergic asthma. * Omalizumab is a humanized monoclonal antibody * It blocks the binding of IgE to high-affinity IgE receptors (FcεR1) on mast cells and thus prevents their activation by allergens * Omalizumab also reduces levels of circulating IgE * *Omalizumab is used to treat severe asthma * Administered by subcutaneous injection every 2–4 weeks, and the dose is determined by the titer of circulating total IgE. * Omalizumab reduces the requirement for oral and ICSs and reduces asthma exacerbations. * Not all patients respond, and there are no clear clinical predictors of clinical response, necessitating a trial of therapy (usually over 4 months). * *Generally used only in patients with very severe asthma who are poorly controlled even on oral corticosteroids and in patients with very severe concomitant allergic rhinitis • Adverse effect: anaphylaxis*****

Answer 133

Step 1 Preferred and alternative - SABA (as needed) Step 2 A. Preferred; low dose ICS B. Alternative; LTRA or theophylline Step 3 A. Preferred; Medium dose ICS or Low dose ICS + LABA B. Alternative; low dose ICS + either LTRA, theophylline, or zileuton Step 4 A. Preferred; Medium dose; ICS + LABA B. Alternative; Medium doer ICS + either LTRA, theophylline or zileuton Step 5 Preferred; High dose ICS + LABA and consider omalizumab for pts with allergies Step 6 Preferred; High dose ICS + LABA + Oral corticosteroid AND consider omalizumab for pts with allergies ***SABA as needed for all stages of persistent asthma

Answer 134

• FEV1 Greater than 40% (mild-to-moderate) o Oxygen to achieve SaO2 90% or greater o Inhaled SABA by nebulizer or MDI—up to three doses in first hour o Oral systemic corticosteroids if no immediate response ``` • FEV1 less than 40% (severe) o Oxygen to achieve SaO2 90% or greater o High-dose inhaled SABA plus ipratropium by nebulizer or MDI every 20 minutes for 1 hour o Oral systemic corticosteroids ``` • Impending or actual respiratory arrest o Intubation with mechanical ventilation with 100% oxygen o Nebulized SABA and ipratropium o Intravenous corticosteroids

Answer 135

Mechanism • Cigarette smoke and other irritants activate epithelial cells and macrophages in the lung. • Increased levels of mediators attract circulating inflammatory cells, including monocytes (which differentiate to macrophages within the lung) • Increased in Neutrophils, and T lymphocytes (cytotoxic T cells) • Epithelial cells and macrophages release fibrosis promoting factors • Increased fibrosis of small airways. • Proteases (released from neutrophils) results in alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis) Risk factors 1. Host factors; genetic, alpha 1 proteinase inhibitor deficiency, gender, IgE, asthma 2. Exposures and environmental factors; tobacco smoke, SES, occupation, environmental pollution (cooking/fuel smokes), perinatal events and childhood illness, recurrent bronchopulmonary infections

Answer 136

Stage 1: Mild - Avoidance of risk factor(s); influenza vaccination, pneumococcal vacine - Add short-acting bronchodilator to use as needed Stage II: Moderate - Add regulator treatment with one or more long-acting bronchodilators - Add rehabilitation Stage III: Severe Stage - Add inhaled corticosteroids if repeated exacerbations IV: Very Severe - Add long-term oxygen if chronic respiratory fai lure

Answer 137

* The cys-LT1 receptor antagonists have no role in the therapy of COPD. * In COPD, LABAs are effective bronchodilators that may be used alone or in combination with anticholinergics or ICSs. • LABAs improve symptoms and exercise tolerance by reducing both air trapping and exacerbations. * In COPD, theophylline still remains a useful drug as an add-on therapy * In COPD, anticholinergic drugs may be as effective as or even superior to β2 agonists * ICS are less effective in COPD than asthma. * ICSs reduce the number of exacerbations in patients with severe COPD * Phosphodiesterase 4 (PDE4) Inhibitor for COPD * Roflumilast (once daily oral dose) approved for COPD * Selectively inhibits phosphodiesterase 4 (PDE4), a major cyclic-AMP-metabolizing enzyme in lung tissue. * Roflumilast Side Effects (diarrhea, headaches, and nausea) * * Alpha-1 proteinase inhibitor (alpha-1 PI) deficiency (also known as alpha 1-antitrypsin deficiency) leads to early onset COPD * Patients with severe alpha-1 PI deficiency have increased levels of neutrophil elastase in lung epithelial lining fluid. * Alpha-1 PI (human) IV infusion therapy (once weekly) restores alpa-1 PI deficiency and protects the lung from excessive neutrophil elastase.

Answer 138

1. Antihistamines 2. IPRATROPIUM • Administered as a nasal spray 3. ADRENERGIC AGONISTS • Oxymetazoline, Phenylephrine, Pseudoephedrine • Decongestants (MOA: α1-mediated vasoconstriction in nasal mucosa). - Adverse effects: • Rebound nasal congestion • CV effects (sympathomimetic activity): hypertension 4. MONTELUKAST 5. Inhaled Corticosteroids (ICS) (i.e., Beclomethasone)

Answer 139

OPIOIDS • Agonists of the mu (µ)-opioid receptor. • Central mechanism of action on μ-opioid receptors in medullary cough center to suppress cough • Codeine commonly used to suppress cough • Adverse effects: sedation, constipation, opioid-induced respiratory depression could be especially troublesome in asthma DEXTROMETHORPHAN • Centrally active N-methyl-D-aspartate (NMDA) antagonist • Acts in medullary cough center to suppress cough • Adverse effects: Hallucinations at high concentrations (significant abuse potential) BENZONATATE • Suppresses cough through a peripheral action. • Inhibits stretch or cough receptors of vagal afferent fibers, which are located in the respiratory passages, lungs, and pleura • May also ac through a central mechanism, at the level of the medulla • Tablet or syrup • Adverse effects: Dizziness EXPECTORANT • GUAIFENESIN • Reduces the viscosity of mucus in airway • Adverse effect: Nausea MUCOLYTICS (2) 1. N-acetylcysteine • Acetylcysteine has a free sulfhydryl group that interacts with disulfide bonds in mucus proteins (“opens up” mucus proteins—reduces Airway mucus viscosity) • Indicated for acetaminophen overdose, chronic respiratory disease, cystic fibrosis, and COPD 2. Dornase Alpha • Is a DNase that reduces Airway mucus viscosity in patients with cystic fibrosis by breaking the long extracellular DNA molecules in mucus into smaller DNA fragments • Indicated for cystic fibrosis • Adverse effects: Dyspnea

Answer 140

Normal lung development stages 1. Embryonic stage • Occurs from 3rd to 7th week of gestation • 28 days PCA – R and L mainstem bronchi are present • By 44 days pulmonary arteries arise from the 6th pair of aortic arches • Failure to complete separation from esophagus results in a TE fistula (tracheoesophageal fistula) *** Initial branching occurs in this stage resulting in the familiar 5 lobes seen in the adult lung 2. Pseudoglandular stage • Glandular appearance • Occurs from 5th to 17th week of gestation • Period of rapid branching of the pulmonary tree • Another 17 to 23 branchings occur to reach the terminal acinar units • Mucus glands develop with mucus production present by 14th week of gestation *** All the branching results in the convoluted pathway leading to the terminal bronchioles where gas exchange occurs 3. Canalicular stage • “Canal” like appearance • Occurs between 16th and 24th week of gestation • Capillary bed expands and endothelium thins • Near end of this stage endothelium is thin enough to allow gas exchange (support extrauterine life) • Surfactant and other pulmonary chemicals begin production • Tissue thinning and surfactant production are accelerated by glucocorticoids • Alveolar Capillary Dysplasia occurs if capillary beds fail to form properly 4. Saccular stage • Occurs from 24 to 38 wks PCA • Cell proliferation slows mesenchymal tissue • Type II cell maturation surfactant & surfactant proteins • External factors may lead to surfactant production (maternal diabetes) 5. Alveolar stage • Occurs from 36 wks to 2 yrs PCA • Marked epithelial cells – 2/3 are Type II pneumocytes –1/3 are Type I Pneumocytes (covers 93% of alveolar surface) • Marked changes in the pulmonary vasculature - smooth muscle - pulmonary vascular resistance - Failure to change at this level leads to PPHN

Answer 141

1. Glucocorticoids and Lung development A. Betamethasone - Surfactant Production in Type II Cells - Alveolar division (Willet et al, 1999) - bronchial length B. Administration to the mother - fetal body and lung growth (Adamson et al, 1988) - Effect worsens with number of doses C. Administration to the fetus - Improves lung maturation (Boland et al, 1997) - No effect on fetal lung or body growth 2. Factor that play role in lung development A. VEGF (Vascular endothelial growth factor) - promotes angiogenesis - when blocked, alveolar size (similar to emphysema) - plays an important role in development of BPD and ROP

Answer 142

1. Surfactant components • 40% dipalmitoylphosphatidylcholine (DPPC) • 40% other phospholipids (PC) • 10% protein of which half (or 5%) are surfactant associated proteins (SP-A, B, C and D) • Cholesterol (neutral lipids) • Traces of other substances

Answer 143

1. Surfactant protein A • Most abundant • Recycled by the Type II Pneumocyte • Opsonin: important in binding, phagocytosis, and killing of certain bacteria and fungi –GBS, H. flu, Staph aureus, and Pseudomonas • Deficiency is compatible with life 2. Surfactant protein B • Small but very fusogenic – Enhances spread and stability of surfactant mono layer • Required for extra-uterine life - Term newborns with SP-B deficiency develop RDS within hours of birth - Fail to respond to exogenous surfactant - 15 known mutation in the SP-B gene - Vast majority die ``` 3. Surfactant protein C • Most hydrophobic surfactant protein • Must be activated by SP – B • Main function is to recruit phospholipids to the lipid layer • Deficiency is: – Autosomal dominant – Compatible with life – Develop interstitial pneumonitis / emphysema later ``` 4. Surfactant protein D • Largest of the surfactant proteins • Unlike SP-A, SP-B, and SP-C: - Is not involved in stabilizing or recycling of surfactant - Is found in other organs: GI tract, pancreas, bile ducts, and cervical glands • Main function is for innate immunity: - Bacterial: E. coli, Salmonella, Pseudomonas - Viral: Flu A, Adeno, and RSV - Fungal

Answer 144

``` Surfactant Secretion • Complex regulatory system that is not well understood • Increased by: – Glucocorticoids (stress!!) – Estrogen – Thyroid hormone • Decreased by: –High levels of circulating insulin ``` Surfactant Inactivation • After delivery, any available surfactant can be “used” up in certain disease states • Examples: - Aspiration: BM, Formula, Sterile water - Meconium - Swallowed Blood - Pneumonia

Answer 145

``` 1. Signs of resp distress • Tachypnea (>60 RR per minute) • Grunting • Nasal Flaring • Retractions • Cyanosis (blueness around mouth) ``` 2. Differential • Transient Tachypnea of the Newborn • Respiratory Distress Syndrome • Pneumothorax • Pneumonia • Congenital Heart Disease • Diaphragmatic Hernia • Metabolic Disease • Meconium Aspiration Syndrome 3. Initial evaluation • History • Physical • Glucose • CBC • CXR; check for RIPS - rotation; can affect shape of heart - inspiration; make sure it’s good inspiratory film by showing atleast 8 ribs - penetration; see vertebral bodies behind the heart in baby - soft tissues; check for tubes, clavicular fracture, free air spaces)

Answer 146

TRANSIENT TACHYPNEA OF THE NEWBORN aka Retained Fetal Lung fluid • Failure of fetal lung fluid to be reabsorbed at the time of delivery • Hormonal changes associated with labor cause a reversal of Na channels in the lung tissue • Failure of channel reversal leads to retained fluid in the lung increased respiratory effort to maintain adequate gas exchange • Occurs in 11 of 1000 term births • Associated with: - Males (whimpy white boy syndrome) - C Section (without labor) - Perinatal asphyxia - Umbilical Cord Prolapse - Depressed Newborn (sedation) • CXR is the diagnostic test of choice • Symptoms develop minutes after delivery and resolve over 12 to 48 hrs • Treatment is just supportive (Oxygen and Nasal CPAP) – Diuretics and Surfactant are not beneficial

Answer 147

RESPIRATORY DISTRESS SYNDROME aka Hyaline Membrane Disease * Surfactant Deficiency * Lack of surfactant - alveolar collapse - protein accumulation - hyaline membrane formation * Impaired gas exchange * Surfactant begins to be released by the Type II Pneumocyte around 24 weeks gestation * Most infants > 35 wks make adequate surfactant * 1/3 of infants 32 to 35 wks gestation are surfactant deficient Risk factors for RDS • Prematurity • Caucasian & Male • Previous baby with RDS • Perinatal Asphyxia/Cold Stress • Perinatal Infection • Multiple Gestation • Infant of Diabetic Mother • Patent Ductus Arteriosus Clinical course for RDS • Start out OK then develop respiratory distress a few hours after delivery • Untreated symptoms worsen for the first 3 days of life • Type II Pneumocytes start to make adequate surfactant and symptoms resolve by 7 days of life ``` Treatment for RDS • Surfactant – Natural Surfactant; Porcine, Bovine – Artificial; Lack some of the functional protein. Not as beneficial as natural surfactants • NCPAP/Mechanical Ventilation ```

Answer 148

CONGENITAL PNEUMONIA • Symptom onset in the first 24 hours of life • Usually isolated to the pulmonary system • Not associated with other systemic symptoms (eg. hypotension) • Only 10% of patients with Congenital Pneumonia will have a positive blood culture • Frequency of 5 per 1000 live births • Infectious - E.coli - Group B strep - Others are rare U. Urealyticum • Non-infectious (chemical pneumonitis) - aspiration of blood - aspiration of meconium ``` Risk Factors for congenital pneumonia • Prolonged rupture of membranes (<12 hours) • Maternal fever • Uterine tenderness • Foul smelling amniotic fluid ``` Treatment • Antibiotics (Amp & Gent @ CHH) • Oxygen if needed • NCPAP/Mechanical Ventilation • Surfactant therapy? - surfactant inactivated by; infection, blood, meconium Clinical course • 5 to 10 % mortality rate –Higher if blood culture is positive • Majority improve in 5 to 7 days

Answer 149

SPONTANEOUS PNEUMOTHORAX ``` • Occurs in 1% of newborns • Probably related to alveoli with defective formation during development • Some are small and asymptomatic –undiagnosed ``` RISK FACTORS • Large for Gestational Age ; Infants of diabetic mother • Positive Pressure Ventilation during resuscitation • Connective Tissue Diseases Treatment for pneumothorax • Avoid positive pressure (NCPAP/Mech Ventilation) • Needle the chest • About ½ of those symptomatic require placement of a chest tube CHEST TUBE PLACED • We use a pig tail catheter • Placed over a guidewire • Left in place until leak resolves (no bubbles) Clinical course • Pneumothorax resolves in usually 3 to 4 days • No long term problems or complications • Not at increased risk for pneumothorax later

Answer 150

CONGENITAL DIAPHRAGMATIC HERNIA • Occurs in < 5 per 10,000 live births • Probably related to abnormal diaphragm formation formation during development • Some are small and asymptomatic – undiagnosed ``` Treatment • Supportive initially – Mechanical ventilation – Replogle to LIS • Surgery is potentially curative • Large CDH cause pulmonary hypoplasia with is main cause of mortality ```

Answer 151

A. Pneumonia – any infection of the lung parenchyma B. Epidemiology 1. Respiratory infections are more frequent than infections of any other organ system 2. Account for the largest number of workdays lost in the general population 3. 8th leading cause of death 4. Viruses are the most common etiologic agent 5. Other infectious agents: bacteria, mycoplasma, fungi C. Pneumonia results when local defense mechanisms are impaired 1. Loss/suppression of cough reflex (coma, anesthesia, neuromuscular d/o’s, drugs, chest pain) 2. Injury to mucociliary apparatus (cigarette smoke, inhalation of hot or corrosive gases, viral dz, genetic defects) 3. Accumulation of secretions (cf, bronchial obstruction) 4. Interference with the phagocytic or bacteriocidal action of alveolar macrophages (alcohol, tobacco smoke, anoxia, oxygen intoxication) 5. Pulmonary congestion and edema

Answer 152

Immunologic defects 1. Innate immunity and humoral immunodef’cy – increased infection with pyogenic bacteria 2. Cell-mediated immune defects – increased infection with intracellular microbes (mycobacteria, herpesvirus) and low virulence microbes (Pneumocystis jiroveci) Other points 1. May be a secondary infection - superimposed on an underlying viral infection (e.g. influenza a) 2. May arise from hematogenous seeding from another infected organ 3. May be the terminal event in hospitalized patients with chronic disease 4. Pneumonias are classified by the etiologic agent or by the setting in which it was acquired

Answer 153

A. General 1. Lung infection in otherwise healthy individuals, acquired from the normal environment 2. May be bacterial or viral B. Bacterial 1. C-reactive protein and procalcitonin – a. Markers of inflammation b. More elevated in bacterial pneumonias (over viral pneumonias) 2. Often follows an upper respiratory viral infection 3. Predisposing conditions a. Extremes of age b. Chronic disease (e.g. CHF, COPD, DM) c. Immunodeficiencies d. Absent splenic function - risk of infection from encapsulated organisms (e.g. sickle cell disease, post-splenectomy) Types of bacteria; strep pneumo, H.flu, moraxella catarrhalis, staph aureus, klebsiella pneumo, Pseudomonas aeruginosa, legionella pneumophila, mycoplasma pneumoniae

Answer 154

Streptococcus pneumoniae

Answer 155

Hemophilus influenzae 1. Gram-negative rod; encapsulated (6 serotypes) and unencapsulated forms 2. Vaccine is against encapsulated types so infections by unencapsulated are increasing 3. Neonates and children – risk increased by prematurity, malignancy, immunodef’cy 4. Causes upper respiratory infections (otitis media, sinusitis) as well as bronchopneumonia 5. Pneumonia is a pediatric emergency with a high mortality rate a. Plugs of fibrin-rich exudates with neutrophils cause airway obstruction b. Pulmonary consolidation is usually lobular and patchy 6. Other infections in children – meningitis (dramatically decreased because of vaccine), conjunctivitis

Answer 156

1. Moraxella Catarrhalis | 2. Staphylococcus aureus

Answer 157

1. Klebsiella pneumoniae 2. Pseudomonas aeruginosa 3. Legionella pneumophila ; Gram-negative rod - Legionnaires’ disease - Grows in artificial aquatic environments: water-cooling towers, tubing systems of domestic (potable) water supplies - Mode of transmission: inhalation or aspiration of drinking water - Patients often have predisposing conditions: cardiac, renal, immunologic (particularly organ transplant patients), hematologic - Mortality rate up to 50% in immunosuppressed patients - Diagnosis by Legionella urine antigens, culture 4. Mycoplasma pneumoniae; Children and young adults - Interstitial (atypical) pneumonia - Sporadic cases and epidemics in closed communities: schools, military camps, prisons - Usually mild pneumonia, “walking pneumonia”

Answer 158

Two patterns of anatomic distribution: lobular bronchopneumonia and lobar pneumonia – with overlap A. Lobular bronchopneumonia 1) Patchy consolidation of the lung by foci of acute suppurative inflammation extending from the bronchioles into adjacent alveoli 2) May be confined to one lobe, be multilobar and/or bilateral and basal 3) Gross: dry, granular, slightly-raised, gray-red to yellow lesions 4) Microscopic: neutrophil-rich exudate filling bronchi, bronchioles, adjacent alveolar spaces 5) May become confluent B. Lobar pneumonia 1) Consolidation of a large portion or of an entire lobe 2) Four stages 1. Congestion a) Lung is red, heavy, boggy b) Lots of bacteria, few neutrophils 2. Red hepatization a) Gross: lobe is red, firm, airless with liver-like consistency b) Microscopic: massive exudate of neutrophils, red cells, fibrin filling the alveoli 3. Gray hepatization a) Progressive disintegration of red cells b) Persistence of fibrinosuppurative exudate 4. Resolution a) Exudate in alveoli is broken down by enzymes b) Produces granular debris c) Resorbed, ingested by macrophages, expectorated, or organized by FIBROBLASTS

Answer 159

a. Diffuse, patchy b. Inflammation localized to interstitial areas of alveolar walls c. Alveoli usually free of exudate d. No consolidation on x-ray e. Mycoplasma pneumoniae and viruses

Answer 160

a. Abscess: tissue destruction and necrosis 1) Typically anaerobic organisms or mixed infections 2) Debilitated patients after aspiration of oral flora b. Empyema: spread of infection to pleural cavity c. Bacteremic dissemination: to heart valves, pericardium, brain, kidneys, spleen or joints ***Most important to identify the causative agent and determine the extent of the disease

Answer 161

1. Abrupt onset of high fever, rigors, chills, productive cough 2. May have pleuritic pain and pleural friction rub if the pleura overlying the consolidation becomes inflamed 3. CXR: a. Lobar pneumonia – whole lobe may be radiopaque b. Bronchopneumonia – focal opacities 4. S/s dissipate 48-72 hours after start of abx treatment 5. Isolation and identification of causative agent and determination of antibiotic susceptibilities are important for appropriate therapy 6. < 10% mortality in hospitalized pts, usually from a complication and/or in a debilitated patient

Answer 162

1. Common: influenza virus types A & B, respiratory syncytial virus (RSV), human metapneumovirus, adenovirus, rhinoviruses, rubeola and varicella viruses 2. Can cause upper respiratory infection (“common cold”) or extend to the lower respiratory tract to cause pneumonia 3. Risk factors for developing lower respiratory infection a. Extremes of age b. Malnutrition c. Alcoholism d. Underlying debilitating illness 4. Pathogenesis a. Tropisms which promote attachment to and entry into lower respiratory lining cells b. Viral replication → cell death → secondary inflammation c. Predisposes host to more serious secondary bacterial infection

Answer 163

1. Infects humans, pigs, horses and birds 2. The major cause of influenza epidemics and pandemics 3. Two important virulence factors – both components of viral envelope, both are targets of host antibodies a. Hemagglutinin 1) Three major subtypes (H1, H2, H3) 2) Attachment to and entry of viral RNA into host cell b. Neuraminidase 1) Two major subtypes (N1, N2) 2) Budding of new virions from host cell membrane 4. Bacterial superinfection is often the cause of severe, even fatal pulmonary disease a. S. aureus is most common cause b. Risk increased by comorbidities - DM, heart disease, lung disease

Answer 164

Human metapneumovirus 1. Paramyxovirus discovered in 2001 2. Severe infections such as bronchiolitis and pneumonia 3. Most often in young children, elderly, immunocompromised 4. 12-20% of outpatient visits by children with acute respiratory infections 5. 5-10% of hospitalizations of children with respiratory infections Severe acute respiratory syndrome (SARS) 1. Coronavirus that infects lower respiratory tract and spreads systemically 2. First appeared in China in 2002, spread to many Asian countries and Canada 3. Last case in 2004

Answer 165

Morphology 1. Lung involvement may be patchy or involve whole lobes, unilaterally or bilaterally 2. Interstitial pneumonia a. Inflammatory reaction involving interstitial areas of walls of the alveoli b. Walls are widened and edematous with c. Infiltrate of lymphocytes, macrophages, plasma cells, neutrophils (early) d. Alveoli usually free of exudate 3. Clearing of infection → restoration of normal lung architecture 4. Bacterial superinfection causes ulcerative bronchitis, bronchiolitis and bacterial pneumonia

Answer 166

1. Extremely varied 2. Fever, headache, muscle aches, +/– cough 3. Usually mild and resolve spontaneously 4. In epidemics, even a low complication rate may result in significant morbidity and mortality

Answer 167

A. Distinct entity associated with risk factors 1. Recent hospitalization > 2 days 2. Presentation from long-term care facility 3. Attending a hospital or hemodialysis clinic 4. Recent IV abx therapy 5. Chemotherapy 6. Wound care B. Most common organisms: S. aureus, Pseudomonas aeruginosa C. Higher mortality than community-acquired pneumonia

Answer 168

1. Hospital - acquired pneumonia A. Pulmonary infection acquired during a hospital stay, often serious, may be life- threatening B. Risk factors 1. Severe underlying disease 2. Immunosuppression 3. Prolonged antibiotic therapy 4. Invasive access devices e.g. intravascular catheters 5. Mechanical ventilation C. Most common organisms: Gram-positive: S. aureus, S. pneumoniae; Gram- negative: Enterobacteriaceae, Pseudomonas spp. 2. Aspiration pneumonia A. Patients with abnormal gag and swallowing reflexes: 1. Debilitated patients 2. Unconscious patients 3. Patients who have trouble handling secretions (e.g. post-stroke) 4. Repeated vomiting B. Pneumonia is partly chemical due to irritating effects of gastric secretions and partly bacterial from oral flora 1. Typically recover more than one organism 2. Aerobes > anaerobes 3. Necrotizing with a fulminant clinical course 4. High mortality 5. Lung abscess is frequent complication in survivors 3. Microaspiration 1. Common – occurs in most people 2. Often associated with GERD 3. Find nonnecrotizing granulomas 4. Usually clinically insignificant but may exacerbate lung disease such as asthma or interstitial fibrosis

Answer 169

A. General 1. Local suppurative process that produces necrosis of lung tissue 2. Oropharyngeal surgical or dental procedures, sinobronchial infections and bronchiectasis play a role B. Etiology 1. Streptococci – aerobic and anaerobic 2. S. aureus 3. Gram-negative organisms 4. Mixed infections 5. Anaerobes in oral cavity: Bacteroides, Fusobacterium, Peptococcus (~60% of cases)

Answer 170

Pathogenesis 1. Aspiration of infected material (most frequent cause) – complicating factors: a. Acute alcoholism b. Coma c. Anesthesia d. Sinusitis e. Gingivodental sepsis f. Depressed cough reflex – various causes g. Pneumonia first → abscess 2. After primary lung infection a. S. aureus b. Klebsiella pneumoniae c. ST3 S. pneumoniae d. Immunosuppressed patients at increased risk 3. Septic embolism – from thrombophlebitis or right-sided endocarditis 4. Neoplasia – postobstructive pneumonia → abscess 5. Miscellaneous – traumatic penetration of lung, spread of infection from adjacent organ, hematogenous seeding

Answer 171

Morphology 1. Range from a few millimeters to several centimeters in size 2. Single or multiple, in any part of lung 3. Abscesses due to aspiration a. More common on right because R bronchus is more vertical b. Usually single 4. Postpneumonia - multiple, basal, diffusely scattered 5. Septic emboli and pyemic – multiple, any part of lung 6. Histologic in all abscesses a. Suppurative destruction of the lung parenchyma within a central area of cavitation b. Cavity may contain necrotic debris or, if it communicates with a bronchus, may be partially drained and contain air Clinical course 1. Cough, fever, lots of nasty smelling, purulent sputum, may be with blood 2. May also have chest pain, weight loss, clubbing of fingers and toes 3. Confirm diagnosis with imaging 4. Rule out malignancy in older patients (10-15% of cases) 5. May resolve with antibiotic therapy and leave a scar 6. Complications a. Spread infection into pleural cavity b. Hemorrhage c. Brain abscess or meningitis

Answer 172

General – 1. In an immunocompetent patient it is typically a localized lesion 2. Typically granulomatous 3. Mycobacterium tuberculosis or fungi (below) Fungal infections 1. Histoplasmosis 2. Blastomycosis 3. Coccidiomycosis

Answer 173

1. Inhalation of soil contaminated with bird or bat droppings containing small spores (microconidia) 2. Endemic in the Ohio and Mississippi river valleys and Caribbean, also Mexico, Central and South America, eastern and southern Europe, Africa, eastern Asia and Australia 3. Intracellular pathogen found in phagocytes 4. Presentations (similar to tuberculosis): a. Self-limited, often latent pulmonary involvement, results in coin lesions on CXR OR b. Chronic, progressive, secondary lung disease, in apices, with cough, fever and night sweats c. Spread to extrapulmonary locations: mediastinum, adrenals, liver or meninges d. Widely disseminated disease in immunocompromised patients 5. Morphology a. Immunocompetent patients 1) Granulomas which undergo caseation necrosis 2) Coalesce to form large areas of consolidation 3) Resolution – either spontaneous or after treatment, results in fibrosis and concentric calcification (tree-bark appearance) b. Immunosuppressed patients 1) Fulminant disseminated histoplasmosis 2) No granulomas 3) Focal accumulations of mononuclear phagocytes filled with fungal yeasts throughout the body 6. Diagnosis – a. Culture or identify the fungus in tissue lesions b. Early – detect antigen in body fluids c. 2-6 weeks after infection – detect antibodies in serum

Answer 174

1. Dimorphic, soil fungus 2. Central and southeastern United States also Canada, Mexico, Middle East, Africa, India 3. Three clinical forms: pulmonary blastomycosis, disseminated blastomycosis, primary cutaneous form - rare, direct inoculation of the skin a. Pulmonary blastomycosis 1) Abrupt illness 2) Productive cough, headache, chest pain, wt loss, fever, abdominal pain, night sweats, chills, anorexia 3) CXR – lobar consolidations, upper lobes, multilobar and perihilar infiltrates, multiple nodules or military infiltrates 4) Most often resolves spontaneously 5) Morphology a) Suppurative granulomas b) Persistent yeast attract neutrophils c) Yeast cell with broad-based budding d) Thick, double cell wall with prominent nucleus

Answer 175

1. Spores in the soil/dust 2. Southwestern and western United states and Mexico 3. High infectivity a. Inhalation of the spores results in a delayed-type hypersensitivity rxn b. 80% of people in endemic areas have a positive skin test 4. Most primary infections are asymptomatic a. 10% of infected people develop lung lesions, fever, cough, pleuritic pains + erythema nodosum or erythema multiforme (San Joaquin Valley fever complex) b. < 1% develop disseminated disease involving lungs, skin, meninges, bones, adrenals, lymph nodes, spleen, liver – immunosuppressed, African American and Filipinos are more susceptible 5. Morphology a. Granulomatous lesions with C. immitis present in macrophages and giant cells as thick-walled, non-budding SPHERULES, often filled with endospores b. Rupture of the spherule releases spores, causes pyogenic rxn

Answer 176

A. Appearance of a pulmonary infiltrate +/ – fever is a common and serious complication in these patients B. Opportunistic infectious agents which may not cause disease in immunocompetent persons: 1. Bacteria: P. aeruginosa, Mycobacterium spp., L. pneumophila, Listeria monocytogenes 2. Viruses: cmv, herpesvirus 3. Fungi: P. jiroveci, Candida spp., - Aspergillus spp; fruiting body and narrow angles branching septate hyphae. Aspergilloma - fungus ball (visible on Xray). Invade vessels. - Phycomycetes, - Cryptococcus neoformans (budding yeast with narrow-based buds. Found in pigeon excreta sprung buildings, outside office windows and under bridges. Primary lung disease - granulomatous inflammation with caseation)

Answer 177

A. Accounts for 30-40% of hospitalizations in HIV patients B. Bacterial lower respiratory infections caused by the “usual” pathogens are more common, more severe and more likely to develop bacteremia in HIV patients C. Not all pulmonary infiltrates are infectious. Other options: Kaposi sarcoma, non-Hodgkin lymphoma, lung cancer D. CD4+ counts determine risk of infection with specific organisms: 1. CD4+ > 200: bacterial and tubercular infections 2. CD4+ < 200: Pneumocystis pneumonia 3. CD4+ < 50: Mycobacterium avium complex E. Even common pathogens may have atypical presentations

Answer 178

Multisystem Processes & Disorders: fungal: - blastomycosis (Blastomyces dermatitidis); candidiasis (Candida albicans); coccidioidomycosis (Coccidioides immitis/posadasii); histoplasmosis (Histoplasma capsulatum) Respiratory System: Lower: - fungal infection (aspergillosis, including allergic bronchopulmonary aspergillosis and aspergilloma, histoplasmosis, coccidioidomycosis, Pneumocystis jirovecii); - fungal infection (aspergillosis, including allergic bronchopulmonary aspergillosis and aspergilloma, histoplasmosis, coccidioidomycosis, Pneumocystis jirovecii) Skin & Subcutaneous Tissue - fungal (deep and superficial): candidiasis, skin; dermatophytosis, tinea corporis;dermatomycoses; diaper rash; onychomycosis Nervous System & Special Senses - Fungal (Blastomycosis dermatitidis, Cryptococcus neoformans/gattii); spirochetal Infectious, immunologic, and inflammatory disorders: - Fungal: Blastomycosis dermatitidis, Cryptococcus neoformans/gattii)

Answer 179

Conditions that mimic symptoms of fungal pneumonia - Acute Respiratory Distress Syndrome (ARDS) - Chlamydial pneumonias - Coal workers pneumoconiosis - Bacterial pneumonia - Viral pneumonia - Idiopathic pulmonary fibrosis - Interstitial pulmonary fibrosis(nonidiopathic) - Tuberculosis Clinical symptoms - Flu-like symptoms - Fever,Cough,Night sweats - Muscle aches or joint pain, - Weight loss, Chest pain, Fatigue (extreme tiredness)

Answer 180

Systemic Fungi (RESPIRATORY FUNGI INFECTIONS) - B.dermatitidis - H.capsulatum - C. immitis, C.posadasii. - P. brasiliensis. - Penicillium marneffei* Opportunistic fungi - Aspergillilus :Mold with septate hyphae - Pneumocystis jirovecii :Cup shaped fungus (protozoan look like) Microbiology - Dimorphic (Mold 25c- yeast 37c) - Endemic :Confined to specific geographical location

Answer 181

- Ohio & Mississippi River valleys, the Great Lakes, and in the southeastern region of the United States***endemic adjacent to areas overlapping those where histoplasmosis is found too - DIMORPHIC (mold- hyphae 25c and yeast - 37c) Flu-like symptoms - Fever,Cough,Night sweats, Muscle aches or joint pain,Weight loss,Chest pain, Fatigue (extreme tiredness) Acute pulmonary: lobar segmental consolidation, - Mimics bacterial pneumonia. Chronic pulmonary lobar infiltrates - Mimics tuberculosis or lung cancer Can disseminate to skin & bone in immunocompromised patients acquired by inhaling spores: dissemination Suppurative granulomatous; ***CAN OFTEN BE MISDIAGNOSED AS CARCINOMA; Usually has suppurative or granulomatous lesions in the upper lob

Answer 182

Diagnosis - KOH preparation: - Sputum, BAL, lung tissue, skin biopsy,; Yeast form is large (8-12 micrometer), round, thick-walled and hyaline Treatment - ITRACONAZOLE is typically used to treat mild to moderate blastomycosis. Amphotericin B is usually recommended for severe blastomycosis in the lungs or infections that have spread to other parts of the body.

Answer 183

Location; Ohio and Mississippi river valleys in the USA. - soil rich with a high nitrogen content ***CLOSE MIMIC OF TB; elicits granulomas Clinical presentation - Variable: usually asymptomatic in healthy people (heals & calcifies); can disseminate in immunosuppressed patients - In rare instances: - Acute respiratory distress syndrome a) 10% inflammatory sequelae, such as persistent lymphadenopathy with bronchial obstruction, arthritis, arthralgias, or pericarditis, may be seen. B) Mediastinal fibrosis: Persistent host response to the organism may result in massive fibrosis and constriction of mediastinal structures, including the heart and great vessels.

Answer 184

- Direct microscopy, Culture of blood, bone marrow, or other clinical material, and by enzyme immunoassay. - The yeast phase of the organism can be detected in: - Sputum, BAL, fluid, peripheral blood films, bone marrow, and tissue stained with Giemsa, GMS, or PAS stains Clinical specimens : - Sputum or Bronchial alveolar lavage. - Bone marrow is an excellent source of the fungus

Answer 185

C. posadasii accounts for the majority of infections outside of California. * Endemic in southwest; San Joaquin valley fever - Arid, alkaline soils, hot summers. - Outbreaks---- dust storm and earthquakes HALLMARK - SPHERULES - Can be mistaken for Toxoplasma gondii tissue cysts (a coccidian parasite) Clinical presentation - Variable; usually self-limited; can be life-threatening; “great imitator” like syphilis & typhoid; fever, cough, chills, pleurisy; arthralgia; - Extrapulmonary sites of infection include skin, soft tissues, bones, joints, and meninges. - Risk factor: A. Ethnicity: (e.g., Filipino, African American, Native American, and Hispanic) B. Gender: (males (9:1), C. Condition: women in the third trimester of pregnancy, individuals with depressed cell-mediated immunity (AIDS, chemotherapy, steroid treatment etc.) Pathology: Necrotizing granulomatous inflammation; pneumonitis; huge (20-60 µm) round thick-walled spherule under microscope, full of smaller endospores

Answer 186

Diagnosis - Clinical specimens include sputum, pus from skin lesions, gastric washings, CSF, and biopsy material from skin lesions. * **SPHERULES (30-60 microns) filled with endospores Treatment - Amphotericin B - Maintence therapy: either fluconazole, itraconazole, posaconazole, or voriconazole

Answer 187

- Granulomatous disease of mucous membranes, skin, and pulmonary system. - 25% patients exhibit, pulmonary manifestations of the disease, which can disseminate to extrapulmonary sites in the absence of diagnosis and treatment. ** Extrapulmonary mucosal lesions of Paracoccidioidomycosis Diagnosis - Paracoccidioidomycosis - Examination of sputum, BAL, scrapings or biopsy of ulcers, pus draining from lymph nodes, cerebrospinal fluid, or tissue - Histopathology ; Histologically, one sees multiple buds forming a "Captain's wheel.“ “Pilot’s wheel”

Answer 188

Penicillin marneffei

Answer 189

Pulmonary infiltrate & signs of infection (fever); many agents can cause pneumonia Mortality high Infectious agents include: bacteria (Pseudomonas, Mycobacteria, Legionella); viruses (CMV, herpes virus); fungi (Candida, Aspergillus, Pneumocystis jiroveci Cryptococcus)

Answer 190

1. C. Neoformans - Capsule - rich in pigeon dropping 2. Aspergillilus - Mold with septate hyphae 3. Pneumocystis jirovecii - Cup shaped fungus

Answer 191

1. Coccidiomycosis- spherules 2. Histoplasma capsulatum - Oval budding yeast inside macrophages 3. Histoplasma - prevalent in OHIO and MISSISSIPPI RIVER VALLEYS 4. Cryptococcus neoformans 5. Coccidiomycosis 6. Blastomyces dermatitidis

Answer 192

1. Granulomatous disease; **Granuloma is organized collection of macrophages. There is necrotizing (infection) vs nonnecrotizing. Caseating vs non-caseating a) sarcoidosis - non necrotizing (NON CASEATING) b) hypersensitivity pneumonitis 2. Pulmonary eosinophilia 3. Smoking-related interstitial diseases 4. Pulmonary alveolar proteinosis (PAP)

Answer 193

General/Epidemiology (1) Systemic disease with a higher prevalence in women (2) Unknown etiology (3) Ten times more common in African-Americans and in the southeast US (4) Diagnosis of exclusion Pathogenesis 1. Evidence suggests immunologic, genetic and environmental factors contribute to disease 2. Immunologic factors noted (a) Increased CD4+ (helper) T cells in lung tissue (b) Elevated IL-2 and interferon-gamma levels (c) Elevated levels of IL-8, TNF and macrophage inflammatory protein (d) Anergy to certain skin test antigens (Candida, PPD) 3. Genetic factors include racial clustering and association with certain HLA genotypes

Answer 194

Morphology/Histology (1) See NONCASEATING granulomas with epithelioid cells, giant cells, SCHAUMANN bodies and ASTEROID bodies involving many organs (2) Histologic findings are characteristic but NOT pathognomonic (3) Lungs (90% cases with bilateral hilar lymphadenopathy or lung involvement) (a) Granulomas along lymphatics, bronchi & blood vessels (b) See stages of interstitial fibrosis and hyalinization (4) Lymph nodes (usually hilar and mediastinal nodes) (5) Spleen involved with or without enlargement (6) Liver involved with granulomas more in the portal tracts (7) Skin & mucous membranes with nodules, plaques or flat lesions (8) Bone marrow of the phalangeal bones in the hands and feet (9) Eyes and salivary glands (a) Iritis with lacrimal gland inflammation (dacroadenitis) (b) Dacroadenitis + bilateral involvement of parotid, submaxillary & sublingual glands = MIKULICZ SYNDROME

Answer 195

Clinical (1) May present with peripheral lymphadenopathy, skin lesions, eye involvement or enlarged spleen or liver (2) Most with insidious onset of respiratory symptoms or with Constitutional features (fever, weight loss, night sweats) (3) Variable clinical course with 65-70% of patients with minimal Or no residual impairment (4) About 20% have permanent impairment in vision (5) About 10-15% die of cardiac or CNS disease (6) Most die of progressive pulmonary fibrosis or cor pulmonale (7) Best prognosis with hilar adenopathy alone (8) Worst prognosis with pulmonary involvement alone

Answer 196

a. General (1) Immunologically mediated interstitial lung disorders attributed to prolonged exposure to inhaled organic antigens (2) Chronic disease can be prevented by removal of the antigen b. Pathogenesis (1) Due to increased reactivity to a particular antigen (2) Most likely involves both Type III immune complex and Type IV delayed-type hypersensitivity reactions (3) Hypersensitivity to spores of fungi, animal proteins & bacteria (a)

Answer 197

General a. 5 disease categories (1) Acute eosinophilic pneumonia with respiratory failure (2) Simple pulmonary eosinophilia (

Answer 198

Smoking-related Interstitial Diseases 1. Desquamative Interstitial Pneumonitis a. Morphology/Histology (1) Large numbers of intra-alveolar macrophage containing brown pigment (“smokers’ macrophage”) (2) Thickened alveolar septa with sparse chronic inflammation b. Clinical (1) More common in men usually around the 4th or 5th decade (2) Almost all patients are cigarette smokers (3) Insidious onset of dry cough and dyspnea (4) Associated with clubbing of the digits (5) 100% response to steroid therapy and cessation of smoking 2. Respiratory Bronchiolitis-associated Interstitial Lung Disease a. Patients with significant pulmonary symptoms, abnormal lung function and abnormal radiographic features b. Morphology/Histology (1) Large numbers of “smokers’ macrophage” within respirator

Answer 199

Pulmonary Alveolar Proteinosis (PAP) 1. Pathogenesis a. Three classes of disease (1) Acquired PAP (90% of cases)- due to anti-GM-CSF antibodies (2) Congenital PAP- due to mutations (3) Secondary PAP (very uncommon)- secondary to silicosis, immunodeficiency syndromes & different malignancies b. Deficiency of GM-CSF leads to impaired clearance of surfactant c. Congenital leads to immediate-onset of neonatal respiratory distress 2. Morphology/Histology a. Large heavy lungs b. Dense intraalveolar granular precipitate that is PAS-positive and contains cholesterol clefts c. MINIMAL inflammatory infiltrate 3. Clinical a. Mostly in adults presenting with a productive cough containing chunks of gelatinous material b. Variable disease course with some progressing to severe respiratory failure and some with subsequent disease resolution c. Bronchoalveolar lavage (BAL) used to treat the disease d. GM-CSF therapy effective in 50% of patients e. Congenital PAP is usually fatal without lung transplantation f. 1, 5 and 10 year survival rates are 78%, 50% and 26%, respectively

Answer 200

Pulmonary Langerhans Cell Histiocytosis - langerhan cells; groves, Brubeck granules - numerous eosinophils (pink cytoplasm) * **Pink cytoplasm with groves and a smoker - pulmonary langerhan cell histiocytosis

Answer 201

Caused by mutation in genes encoding proteins involved in surfactant trafficking or secretion • ATP-binding cassette protein member 3(ABCA3) • Surfactant protein C • Surfactant protein B ** Infant with known surfactant protein C deficiency Diffuse interstitial thickening with type II pneumocyte hyperplasia

Answer 202

Synthesis of Histamine ; **Histidine - (HDC - histidine decarbocylase) - histamine - stored - Histamine release - metabolites - urine - Histamine is a biologically active amine and a natural constituent of many mammalian tissues. (<1 to >100 ug/g). Plasma and other body fluids generally have lower levels, but human CSF contains significant amounts. Consist of AN IMIDAZOLE RING, AN AMNO GROUP CONNECTED BY 2 METHYLENE GROUPS 1) synthesized from histidine (HDC enzyme) 2) synthesized/stored predominantly in MAST CELLS (skin, intestinal mucosa, lung - bronchial tree mucosa, around blood vessels and nerves). **Released via allergen, curare, morphine, venoms, inflammatory mediators (bradykinin, cytokines) 3) synthesized/stored in BASOPHILS (in blood) 4) synthesized/stored in non-mast cell states; ECL cells (gastric enterochromaffin like), epidermis, CNS neurons (act as neurotransmitter). **Released from ECL cells by Ach and gastrin 5) stored in complex with; heparin, chondroitin sulfate, eosinophilic chemotactic factor, neutrophilic factor, proteases. Metabolism 1) Histamine - (histamine N methyltransferase) - N-methylhistamine - (MAO) - N-methylmidaxoleacetic acid OR 2) Histamine - (oxidative deamination via diamond oxidase) - imidazole acetic acid - imidazole Actions of Histamine 1) H1; smooth muscle, endothelium, brain. Gq, IP3, increase DAG - H1 agonist ; 2-CH3-histamine - H1 antagonist; chlorpheniramine * *H1 actions on blood vessels (vasodilation, flushing, indirectly release NO and PGI2), increase capillary permeability (edema), lungs (bronchoconstriction), cutaneous sensory nerve endings (pruritis of epidermis, pain and itching of dermis), CNS (NT - increase wakefulness and inhibit appetite), triple response (RED SPOT - vasodilation, WHEAL - increase capillary permeability, FLARE - axon reflec - vasodilation) 2) H2; Gastric mucosa, cardiac muscle, mast cells, brain. Gs >cAMP - H2 agonist; Dimaprit - H2 antagonist; ranitidine * *H2 action on gastric mucosa - INCREASE ASIC SECRETION IN PARIETAL CELLS

Answer 203

***REVERSIBLE COMPETITIVE ANTAGONIST OF H1 RECEPTORS MoA of First gen antihistamine 1. Chlorpheniramine; CNS sedation +/++, antimuscarinic ++, GI + 2. Diphenhydramine; CNS sedation +++, Antimuscarinic +++, GI + 3. Hydroxyzine; CNS sedation +/++, antimuscarinic ++, GI + 4. Promethazine; CNS sedation ++++, antimuscarinic ++++, GI + 2nd gen antihistamine 1. Cetirizine; CNS sedation ++, antimuscarinic 0, GI 0 2. Loratadine; CNS sedation 0, antimuscarinic 0, GI 0 3. Fexofenadine; CNS sedation 0, antimuscarinic 0, GI 0 ***Actions of reversible competitive H1 receptor A. Inhibits vasodilation B. Strongly block capillary permeability C. Partially block increase in HR D. Reduce bronchoconstriction a little if at all E. Do not suppress acid secretion F. Some relief to pruritus G. Suppress both flare and itching **Other actions 1) Antimuscarinic effects: Many of the first-generation H1 antagonists tend to inhibit responses to acetylcholine that are mediated by muscarinic receptors. –Promethazine has perhaps the strongest muscarinic-blocking among these agents. –Second-generation H1 antagonists have no effect on muscarinic receptors. 2) Motion Sickness: An interesting and useful property of certain H1 antagonists is the capacity to countermotion sickness. Promethazine is among the most effective of the H1 antagonists in combating motion sickness. (dimenhydrinate)

Answer 204

Pharmacokinetics • 2nd generation POORLY DISTRIBUTED TO CNS **** whereas first gen enter CNS rapidly • 2nd generation have prolonged duration of action (days) and are excreted unchanged. - very high affinity for H1 receptors - active metabolites of older drugs • Several second generation agents (loratadine) are metabolized by the Cyp3A4 Adverse effects 1) CNS stimulation - Conventional doses - certain individuals – especially children - (restless, nervous, unable to sleep) - seen in H1 antagonist poisoning 2) CNS depression - 1st generation & cetirizine, NOT other 2nd generation - Therapeutic doses - Diminished alertness sedation or somnolence - potentiated by alcohol & CNS depressants 3) Antimuscarinic effects – 1st generation - dry mouth, urinary retention, etc 4) GI (1st generation) - anorexia, nausea, vomiting, diarrhea or constipation

Answer 205

Therapeutic indications 1. Treat acute exudative allergy (e.g. hay fever, pollinosis) - rhinitis, urticaria, conjunctivitis 2. Bronchial Asthma - limited efficacy (not sole therapy) 3. Systemic anaphylaxis - autocoids other than histamine play major roles - mainstay of therapy is epinephrine (H1 antagonists – adjuvant role) 4. 1st generation – CNS effects - prevent motion sickness (promethazine, dimenhydrinate) - induce sedation

Answer 206

Action - Competitive antagonist at H2 receptor Examples (3) - Cimetidine - Ranitidine - Famotidine Effects - DECREASE GASTRIC ACID SECRETION from parietal cells (inhibit H2 receptors) Adverse effects 1. Most common; Headache, GI, fatigue and drowsiness 2. Rare; CNS, cytopenias Pharmacokinetics • Significant renal excretion - reduce dose in renal disease • Significant drug interactions especially with Cimetidine - Cimetidine inhibits cytochrome P450 → ↓ metabolism of other drugs - ↑gastric pH may alter absorption/bioavailability of other drugs. Therapeutic uses • Promote healing of Peptic Ulcer and Duodenal Ulcer • Uncomplicated GERD • Prophylaxis of stress ulcers

Answer 207

1. Arterial blood gases; partial pressures at end of pulmonary capillary PaO2 = 100mmHg PaCO2 = 40mmHg 2. PIP more negative at apex (more overinflated than base so ventilation will be more in base than apex) - Right before inspiration, alveoli at lung apex are larger than those at the base. This is because the PIP is more negative when you go against gravity. - Remember, larger the alveoli greater is their recoil force and more difficult it is to inflate them - Accordingly, the alveolar ventilation is highest at the base and lowest at the apex 3. V/Q - Ventilation is greater at the base. - Blood Flow is greater still at the base. - Thus, V/Q ratio is greater at the apex. - Thus, V/Q ratio is lowest at the base.

Answer 208

1. As the V/Q rises above 0.8 (towards ∞) partial pressure of the alveolar gases reaches that in the inspired air (PAO2=150, PACO2= 0). - you are ventilating alveolus that is not getting perfused - PACO2 is 0 because CO2 only come from blood not inspired air*** so alveolus CO2 is 0 because there is no perfusion 2. The opposite happens when the V/Q ratio is decreasing; In this case in absence of adequate external ventilation the alveolar gases have the same PP as that of mixed venous blood (PAO2= 40, PACO2= 47).

Answer 209

In the normal lung breathing room air (21% O2), the A-a PO2 difference ~ 5-10 mmHg A. Normal diffusion barrier (negligible) B. Normal anatomical shunting of 3-5% of the cardiac output from bronchial veins, pleural veins, and Thebesian veins emptying into the arterial circulation C. Regional differences in V/Q ratios In hypoventilation, A-a is normal becuase you are not changing the diffusion capacity of the lungs

Answer 210

Causes of Hypoxia 1. Hypoxemia = decrease PaO2 2. Anemic = decrease HbO2 content (anemia) 3. Stagnant = decrease blood flow 4. Histotoxic = decrease O2 extraction from tissues (cyanide and CO poisoning) Note: In anemic, stagnant, and histotoxic hypoxia, hypoxia (i.e., low tissue oxygen) is present WITHOUT hypoxemia (low PaO2

Answer 211

1. ↓ alveolar PO 2 a. Hypoventilation b. ↓ inspired O 2 2. Diffusion impairment (Most uncommon..why?) ; because O2 is diffusion limited not perfusion limited 3. R→L Shunt (Venous admixture; V/Q = 0) 4. V/Q mismatch (low V/Q areas, shunt-like states); most severe cause of hypoxemia

Answer 212

``` Examples if you double PACO2 form 40 to 80 mmHg PAO2 = Inspired oxygen - PACO2/R = FiO2 (760 - 47) - (80/0.8) = 150 - 100 = 50 mmHg ``` A simpler way to remember: PAO2 before hypoventilation = 150-40 ≈ 100 PAO2 during hypoventilation = 150-80 ≈ 60 Remember, these simplifications assume R = 1

Answer 213

Hypercapnic - Hypoxemic Respiratory Failure 1. PaO2 decreased (hypoxemia) - hypoxemia causes reflex hyperventilation at high altitude. Compensatory hyperventilation improves PAO2 and PaO2, but hypoxemia persists. - remember at high altitude (decrease inspired air), PaCO2 is normal 2. PaCO2 increase (hypercapnia) 3. A-a PO2 is normal - becuase there is no change in diffusion capacity 4. Frequently drug induced: sedatives, hypnotics, anesthesia. 5.Neuromuscular disorders like myasthenia gravis and the GB syndrome can also cause.

Answer 214

Gas diffusion = A/T x D x (P1 - P2) A. Hypoxemia from diffusion impairment is seldom present at rest because: - Even though the rate of diffusion is decreased by a diffusion impairment, there is often sufficient time for diffusion to occur and for the PO pulmonary capillaries to equilibrate during the ~0.75 sec erythrocyte transit time through the pulmonary capillary. B. Hypoxemia from diffusion impairment may become evident during exercise because: - Pulmonary capillary transit time decreases as the rate of blood flow increases, and thus diffusion is not completed during the erythrocyte’s transit in the pulmonary capillary. - Uncommon at rest as O2 is perfusion-limited gas Conditions causing diffusion impairment 1. Increased thickness of barrier - Interstitial or alveolar edema - interstitial or alveolar fibrosis 2. Decreased surface area for diffusion - Emphysema

Answer 215

1. PaO2 decrease ↓ (generally only seen in severe impairment at rest or moderate diffusion impairment during exercise) 2. PaCO2 ~ to decrease (compensatory hyperventilation) 3. PAO2; normal 4. (A-a) PO2: increase 5. (A-a) rapidly corrected by supplemental O2. 6. Keep in mind, chronic diffusional impairment may be characterized by hypercapnia, for e.g. advanced pulmonary fibrosis (this is usually due to ventilatory failure) **Diffusion impairment - hypocapnic - hypoxemia respiratory failure

Answer 216

Three important causes of diffusion impairment: 1.Emphysema 2. Pulmonary fibrosis 3. Pulmonary edema Emphysema & Pulmonary edema predominantly present as V/Q mismatch instead It is NOT important, clinically, to differentiate diffusion impairment from V/Q mismatch—its really a matter of how uniformly, or not, the d/s is affecting the lungs

Answer 217

1. Anatomic Shunts: Venous Admixture – Veins draining into arterial supply – Venous blood mixing with arterial blood through abnormal anatomical connections 2. Intrapulmonary shunts (V/Q =0) – Alveoli that are perfused but not ventilated * *3-5% cardiac output is normally shunted contributing to normal A-a PO2 - Bronchial veins → Pulmonary veins - Pleural veins → Pulmonary veins - Thebesian veins → Left ventricle * *Venous blood mixing with arterial blood through abnormal anatomical connections, such as in cyanotic congenital heart disease (5 Ts) - Truncus arteriosus - Transposition of the great vessels - Tricuspid atresia - Tetralogy of Fallot - Total anomalous pulmonary venous return * **FIRST SIGN OF RIGHT TO LEFT SHUNTING IS WIDE A-a (100-55 = 45) despite 100% oxygen

Answer 218

1. PaO2 decrease (hypoxemia) 2. PaCO2 decrease (hypocapnia due to reflex stimulation of peripheral chemoreceptors by decrease PaO2) 3. Mixed PAO2 in ventilated regions of the lung is normal (decreas PAO2 in shunted alveoli dose not contribute to mixed PAO2 because those areas are not ventilated. 4. (A-a) PO2 increase 5. (A-a) non responsive to 100% O2, IT IS WIDENED.

Answer 219

1. Uneven resistance to airflow, i.e., variable airway obstruction Mechanisms / Examples: - Bronchoconstriction /Asthma - Airway inflammation / Bronchitis - Mucus obstruction / Chronic bronchitis; cystic fibrosis; bronchiectasis - Airway compression / Tumors; emphysema 2. Nonuniform lung compliance; Mechanisms / Examples: -Elastic Fibers / emphysema -Fibrosis / IPF; Pneumoconioses; ARDS; Collagen diseases -Surfactant production / ARDS -Pulmonary vascular congestion / interstitial edema -Parenchymal compression /Tumors Low V/Q mismatches are frequently seen in lung diseases that will respond to 100% O2, the A-a may still remain relatively wide

Answer 220

1. PaO2 decrease (hypoxemia) - Increasing the number of low units causes hypoxemia because the PO2 of low V/Q units approaches that in mixed venous blood 2. PaCO2 decrease (hypocapnia from stimulation of peripheral chemoreceptors by decrease PaO2, which reflexly increases alveolar ventilation) 3. (A-a) wide at room air; 100% O2 = A-a is still wide and abnormal, but not as wide as R-L shunt

Answer 221

- As lung d/s progresses, work of breathing ↑ses and V/Q mismatch gets worse - Chronic hypoxia depresses the the respiratory neurons of the medulla - Progression of the lung d/s disrupts elastic properties of the lungs - Physiologic dead space continues to rise - Eventually, alveolar hyperventilation fails to compensate for hypoxemia, and hpercapnic-hypoxemia ensues * Disease progresses

Answer 222

V/Q = affinity is dead space ventilation • Anatomic: Conducting airways - No gas exchange occurs in the conducting airways because anatomically they receive blood flow from the bronchial circulation, not the pulmonary circulation. • Alveolar: Alveoli that are ventilated, but not perfused by the pulmonary circulation (V/Q = ∞) - A healthy person has little or no alveolar dead space. • Physiological: Anatomic + Alveolar - Because there is normally no alveolar dead space, physiologic dead space volume approximates anatomic dead space volume in persons with normal lungs. **LARGE SADDLE PE presents like hypoventilation. The difference is that PE has WIDE A-a gradient

Answer 223

ARDS—abrupt onset of diffuse lung injury characterized by severe hypoxemia (shunting) and generalized pulmonary infiltrates on the chest radiograph in the absence of left-sided cardiac failure— previously known as non-non-cardiogenic pulmonary edema. ARDS diagnosed on the basis of a PaO2/FiO2 of less than 300 mmHg **Classically Right to left shunt Etiology (10) 1. Sepsis (gram-positive or gram-negative bacterial, viral, fungal, or parasitic infection) 2. Diffuse pneumonia (bacterial, viral, or fungal) 3. Aspiration of gastric contents 4. Trauma (usually severe) 5. Near-drowning (fresh or salt water) 6. Drug overdose 7. Massive blood transfusion 8. Inhalation of smoke or corrosive gases (usually requires high concentrations) 9. Pancreatitis 10. Fat embolism

Answer 224

In congestive heart failure elevated left-sided cardiac pressures cause hydrostatic pulmonary edema In ARDS, the edema fluid that fills the alveoli is exudative in origin—the alveolar-capillary barrier exhibits increased permeability, allowing for the leakage of protein-rich fluid into the air spaces. Respiratory system compliance is reduced and poor ventilation leads to right-to-left shunting and profound hypoxemia. PaCO2 is generally within the normal range—reflex hyperventilation Pulmonary hypertension is also commonly observed in ARDS, and a number of mechanisms have been proposed including hypoxic vasoconstriction, intravascular fibrin deposition in the pulmonary capillaries, and compression of blood vessels by the positive pressure ventilation used to treat the disorder.

Answer 225

1. Exudative phase (wide spread systemic inflammatory response - type II pneumocytes die - dilution of surfactant) - Inflammatory cells get activated (mainly neutrophils) and alter the alveolar- capillary membrane permeability - Plasma and blood products “flood” the alveoli and impair surfactant - Eventually, type II pneumocytes suffer injury and surfactant production ↓ - Fluid in the alveoli interrupt gas exchange—hyaline membrane is formed by large proteins and with loss of surfactant ↓ lung compliance—↓↓ ventilation and shunting of blood— hypoxemia ensues 2. Proliferative phase ; attempts at recovery - Cellular integrity is restored - Gradual resorption of alveolar fluids - Ion channel activity is recovering - Type II pneumocytes recover, and surfactant production resumes - Pulmonary compliance and oxygenation improve 3. Fibrotic phase ; failure of complete recovery - In a subset of patients—the lungs (including alveoli, blood vessels, and small airways) remodel and scar, with a loss of microvasculature. - In some patients, these changes may lead to pulmonary hypertension and increased pulmonary dead space

Answer 226

Suspect ARDS in a patent with acute onset lung injury, especially following some index events (e.g sepsis) No overt sign of CV dysfunction no peripheral edema, normal or increase CO, normal sized heart on CXR, no change in ECG B/L opacities on CXR, suggestive of Pulmonary edema and infiltrates PCWP <15mmHg

Answer 227

ARDS management is complex and need to be individualized : ***DO NOT FLUID RESUSCITATE and do CAREFUL MECHANICAL VENTILATION Supportive therapy is the cornerstone of therapy—manage the index event Recent evidence indicates that aggressive fluid resuscitation is NOT beneficial MECHANICAL VENTILATION is lifesaving but, when inappropriately applied, can induce or aggravate lung injury. Mortality of ARDS has declined to less than 40% since late nineties—mainly due to ventilatory support NO pharmacological intervention has proven to improve survival

Answer 228

``` 1. V/Q mismatch A. Chronic bronchitis B. Emphysema C. Asthma D. Diffuse emboli ``` 2. Diffusion impairment A. Pulmonary fibrosis ``` 3. Shunt A. Pneumonia +- consolidation B. Atelectasis C. Pulmonary edema D. ARDS ```

Answer 229

Stagnant Hypoxia - decrease tissue O2 delivery = decrease blood flow x arterial oxygen content * PaO2, [Hb], %O2 sat, and arterial oxygen content are all normal * O2 extraction (a-v )2) increases to compensate for reduced delivery - causes A. Local ischemia B. Systemic due to decreased cardiac output

Answer 230

1. Methemoglobinemia (oxidation of iron in Hb from the ferrous (Fe2+) to the ferric (Fe3+) state) A. Congenital (HbM) B. Nitrite poisoning C. Toxic reaction to oxidant drugs 2. CO poisoning A. Hb has 240 x greater affinity for CO than O2 B. As a result, % sat in arterial blood, and thus total oxygen content of the blood are reduced in teh presence of CO

Answer 231

- Hypoxia results from impaired oxygen utilization i.e decreased oxygen extraction (decreased a-v O2), increased PvO2, Increase SvO2 - PaO2, [Hb], % O2 sat (except CO), total arterial oxygen content, blood flow, and tissue O2 delivery are normal Causes of histotoxic hypoxia 1.Cyanide poisoning - binds to and inhibits cytochrome oxidase, blocking oxidative phosphorylation 2.Carbon Monoxide Poisoning – inhibits oxidative phosphorylation 3.Primary mitochondrial respiratory chain disease

Answer 232

a. Most common cause of cancer mortality b. >226,000 new cases in the US (2012) c. 28% of cancer-related deaths d. Common in 40-70 year olds **Very common, diagnosis everyday, smokers

Answer 233

1. Smoking i. 80% of lung cancers in smokers ii. Lung Cancer develops in 11% of heavy smokers iii. Women have a higher susceptibility to carcinogens in tobacco iv. Increase risk in former smoker and second hand smoke ``` 2. Industrial hazards I. Asbestos - lung cancer most frequent malignancy*** - non smokers 5x - smokers 55x (50-90x) ii. Arsenic III. Chromium IV. Uranium; - non smokers 4x - smokers 10x V. Nickel VI. Vinyl chloride VII. Mustard gas Viii. Ionizing radiation ``` 3. Air pollution I. Radon; radioactive gas such as in uranium miners

Answer 234

i. Squamous cell carcinoma 1. Chromosome deletions in tumor suppressor loci a. 3p, 9p (site of CDKN2A gene), 17p (site of TP53 gene) b. Loss of expression of retinoblastoma (RB) tumor suppressor gene 2. Cyclin-dependent kinase inhibitor gene CDKN2A inactivation (protein product p16 is lost) 3. Amplification of FGFR1 (gene coding the fibroblast growth factor receptor tyrosine kinase) ii. Small cell carcinoma 1. Loss of function TP3, RB 2. 3p deletions 3. Amplification of MYC family iii. Adenocarcinoma 1. Gain of function mutation in multiple genes encoding receptor tyrosine kinase (EGFR, ALK, ROS, MET, and RET 2. Tumors without tyrosine kinase gene mutations often have mutations in the KRAS gene

Answer 235

i. 25% of lung cancer ii. Women, adenocarcinoma iii. Most likely EGFR mutation iv. Almost never KRAS mutation

Answer 236

a. Squamous dysplasia b. Atypical adenomatous hyperplasia i. Small (**less than 5 mm**) dysplastic pneumocytes lining the alveoli c. Adenocarcinoma in situ i. Less than 3 cm ii. Dysplastic cells lining the alveolar septae with no invasion d. Neuroendocrine cell hyperplasia **Progression; Metaplasia - dysplasia - carcinoma in situ (severe dysplasia)

Answer 237

a. Hamartoma i. Coin lesion on radiology ii. Solitary, well circumscribed iii. Epithelial and stromal component b. Lymphangioleiomyomatosis i. Young child bearing age women ii. Proliferation of perivascular epithelioid cells and express and melanocytes and smooth muscle markers iii. Loss of function mutation in tumor suppressor TSC2 (tuberous sclerosis gene) iv. Dyspnea and emphysema (spontaneous pneumothorax) v. Lung transplantation is the only definite treatment c. Inflammatory myofibroblastic tumor i. Children ii. Symptoms include fever, cough, chest pain, hemoptysis iii. Usually single well defined mass iv. 3-10 cm v. Fibroblasts, myofibroblasts, lymphocytes, and plasma cells vi. Some have activating rearrangements of the anaplastic lymphoma kinase (ALK) gene located on 2p23 (respond to ALK kinase inhibitor)

Answer 238

Benign tumor HEMARTOMA **look like corn in Xray - incidental finding. They take it out sometimes

Answer 239

Lymphangioleiomyomatosis (benign tumor) ***can have clinical indications - need transplantation most of the time

Answer 240

Inflammatory myofibroblastic tumor **can see in young adult

Answer 241

``` 1. Non small cell carcinoma A. Adenocarcinoma B. Squamous cell carcinoma C. Large cell carcinoma D. Carcinoid tumor (neuroendocrine tumors) ``` 2. Small cell carcinoma (neuroendocrine tumors)

Answer 242

i. Adenocarcinoma 1. Adenocarcinoma in situ (formerly called bronchioloalveloar carcinoma) a. Less than 3 cm b. Mucinous (worse- move form airspace to airspace) vs non-mucinous c. Non-invasive 2. MICROINVASIVE ADENOCARCINOMA a. Invasion less than 5 mm** 3. Histologic subtypes a. Acinar, LEPIDIC**, papillary, micropapillary, solid etc 4. Thyroid transcription factor-1 (TTF-1)*** and Napsin A expression * *Other mutation in PPT ii. Squamous cell carcinoma 1. Smokers 2. Usually centrally located, large mass, necrosis 3. Histology a. Keratin (squamous pearls) b. Intercellular bridges c. P63 and p40 expression iii. Large cell Carcinoma 1. Undifferentiated 2. Could be Squamous cell carcinoma, adenocarcinoma, large cell neuroendocrine carcinoma 3. Immunohistochemical stains important

Answer 243

a. Neuroendocrine cell hyperplasia i. Due to fibrosis, inflammation, or idiopathic b. Carcinoid tumorlet i. Small hyperplastic nests of neuroendocrine cells c. Carcinoid (well differentiated, less than 2 mitosis, no necrosis) i. Less than 5% of all lung tumors ii. Less than 40 year olds iii. 20-40% in non-smokers iv. Histology; less than 2 mitoses per 10 high power fields. No necrosis d. Atypical carcinoid tumor i. 2-10 mitoses per 10 high-power fields ii. May have focal necrosis e. Small cell carcinoma (Poorly differentiated) i. More than 10 mitoses per 10 high-power fields ii. Necrosis * Nuclear molding * **Not candidates for surgery (can only do chemo) f. Large cell neuroendocrine carcinoma

Answer 244

a. SIADH b. Cushing Syndrome c. Hypercalcemia/Hypocalcemia d. Gynecomastia e. Carcinoid Syndrome

Answer 245

Metastatic - lung most common site of Mets (usually from breast cancer to lungs or lymphatics - lymphatic/blood/direct extension - cannonball lesions usually periphery Lung cancer syndromes 1. lambert Eaton myasthenia syndrome 2. superior vena cava syndrome - ultimately CIRCULATORY COMPROMISE 3. horner’s syndrome - PANCOAST TUMORS

Answer 246

1. Pleural effusions: a. Inflammatory pleural effusions b. Noninflammatory pleural effusions 2. Pneumothorax 3. Pleural tumors a. Benign i. Solitary Fibrous Tumor; no asbestos b. Malignant i. Malignant mesothelioma ; Asbestos 1. Epithelioid; most common type. Sheets and nest of polyhedral cells (round cuboidal cells) 2. Sarcomatoid (spindle cell); desmoplastic 3. Mixed (biphasic) 4. Other (small cell, rhabdoid); rare

Answer 247

SOLITARY FIBROUS TUMOR (Pleural Fibroma) [Benign Meso] Gross - dense FIBROUS tissue - occasional cysts with viscous fluid Microscopic - whorls of reticulum and collagen - interspersed spindle cells (resemble fibroblasts) - rarely malignant; size (over 10cm), pleomorphism, mitotic activity, necrosis Staining - CD 34 positive - Keratine negative - NOTE; malignant mesothelioma opposite - NO relationship with asbestos

Answer 248

ADENOCARCINOMA - acini/gland formation - markers; CEA, TTF1 - SURGERY - most common lung malignancy in non smoker female (EGFR mutation - tarsiba (tyrosine kinase inhibitor)) - primary lung tumor with LEPIDIC growth pattern - >3 cm - mucinous (worse prognosis) vs non mucinous (better prognosis)

Answer 249

SQUAMOUS CELL CARCINOMA - HYPERCALCEMIA, necrosis, HILAR MASS - keratin pearls - markers;

Answer 250

SMALL CELL CARCINOMA - smoker, surgery contraindicated (no lobectomy) - mitoses >10, necrosis, poorly differentiated. - slightly larger than lymphocytes

Answer 251

Malignant mesothelioma - pleural mass - spindle and cuboidal cells with invasion * *markers; - smoking does not cause mesothelioma - Not all mesotheliomas are associated with asbestosis. Others are idiopathic **Most common malignancy associated with asbestosis is BRONCHOGENIC CARCINOMA

Answer 252

• Pulmonary neuroendocrine hyperplasia • Benign tumorlets (<5mm) • Carcinoids (<2 mitosis, no necrosis, well differentiated) • Atypical carcinoids (2-10 mitoses, some necrosis) • High grade neuroendocrine carcinoma – Small cell carcinoma – Large cell neuroendocrine carcinoma

Answer 253

• Obstructive lung disease is characterized by Airflow limitation ``` Types of Obstructive Lung Disease: 1. COPD; overlap of chronic bronchitis and emphysema • Chronic Bronchitis • Emphysema 2. Asthma 3. Bronchiectasis ```

Answer 254

• Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. • The main risk factor for COPD is tobacco smoking but other environmental exposures such as biomass fuel exposure and air pollution may contribute. • <5% of patients with COPD can suffer from Alpha 1-antitrpsin deficiency. ATAT (alpha 1 antitrypsin deficiency) - AATD patients are typically < 45 years with Pan-Acinar emphysema - A low concentration (< 20% normal) is highly suggestive of homozygous deficiency. - Patient can also present with liver cirrhosis.

Answer 255

Inflammation - starts with smoking - mediators; IL8 chemokines, TF alpha, LTB4 mediators, proteases - lead to chronic persistent pulmonary inflammation ; 1) progressive lung decline 2) symptoms of airway narrowing, mucus hypersecretion, cough Pathophysiology ► Pathology Ø Chronic inflammation Ø Structural changes ``` ► Pathogenesis Ø Oxidative stress Ø Protease-antiprotease imbalance Ø Inflammatory cells Ø Inflammatory mediators Ø Peri-bronchiolar and interstitial fibrosis ``` ``` ► Pathophysiology Ø Airflow limitation and gas trapping Ø Gas exchange abnormalities Ø Mucus hypersecretion Ø Pulmonary hypertension ``` * * - Blue bloaters; CHRONIC BRONCHITIS, low O2, high CO2, cyanosis, develop pulmonary HTN and cor pulmonale) vs - pink puffers; EMPHYSEMA. Destruction of alveolar wall, not much phlegm, very SOB, lean forward, use of accessory muscles, type 1 resp failure increased risk.

Answer 256

1. Spirometry - normal trace - inhale and exhale as fast as you can - FEV1 (amount you can exhale forcefully in 1 second) - FVC; total amount you can exhale forcibly - Spirometry - obstructive disease (FEV1/FVC <80%) 2. Flow volume loops - scoop like, smaller shape

Answer 257

1. Total Lung Capacity (TLC) • Volume of air contained in the lung at the end of maximal inspiration. 2. Vital Capacity (VC) • Maximum volume which can be ventilated in a single breath 3. Functional Residual Capacity (FRC)= ERV + RV • The amount of air left in the lungs after a tidal breath out, the amount of air that stays in the lungs during normal breathing 4. Inspiratory Capacity (IC) = IRV + TV; REDUCED IN COPD PT • Maximal volume that can be inspired following a normal expiration 5. Inspiratory Reserve Volume (IRV) • Volume, which can be inspired beyond a restful inspiration 6. Tidal Volume (TV) • Volume of a single breath, usually at rest 7. Expiratory Reserve Volume (ERV) • Volume, which can be expired beyond a restful expiration 8. Residual Volume (RV) • Volume remaining in the lungs after a maximum expiration

Answer 258

1. Centrilobular (Centriacinar): • Primarily the upper lobes. • This pattern is most typical for smokers. 2. Panlobular (Panacinar): • Involves all lung fields, particularly the bases. • This pattern is typical for alpha-1-antitrypsin deficiency.

Answer 259

Clinically defined disease • Defined clinically as a persistent productive cough for at least three consecutive months in at least two consecutive years. • Most patients are smokers. • Often, there are features of emphysema as well. Miscoscopic features • Bronchus with increased numbers of CHRONIC INFLAMMATORY CELLS in the submucosa.

Answer 260

Asthma ; no structural damage to airways so responsive to bronchodilators. Obstruction is fully reversible. • A chronic inflammatory disorder of the airways … in susceptible individuals, inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. Obstruction is often fully reversible, either spontaneously or with treatment ``` 2 types 1. Atopic: • Often due to allergic stimuli 2. Non- Atopic: • Exercise induced • Viral infections • Aspirin sensitivity • Occupational exposures. ``` Definition of asthma • Chronic inflammatory disorder of the airways • Mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, epithelial cells . • Causes variable and recurrent episodes of wheezing, breathlessness, chest tightness, cough – especially at night or early morning. • Associated with widespread, but variable airflow obstruction that is often reversible

Answer 261

Early Phase 1. Type I hypersensitivity • Allergens induce TH2 phenotypein CD4+T cells of genetically susceptible individuals. • Th2 cells secrete: - IL-4 ( mediates class switch to IgE) - Il-5 ( attracts eosionphils) - IL-10 ( Stimulates th2 cells) • Re-exposure to allergen: - IgE mediated activation of mast cells. - Release of preformed histamine granules - Generation of Leukotrienes C4, D4, and E4 Late Phase: • Inflammation, especially major basic proteins released from eosinophils , damages cells and perpetuates bronchoconstriction.

Answer 262

Spirometry • Asthma causes variable airflow obstruction. • The variable reduction of FEV1 documents findings consistent with asthma, d • Demonstrates presence and reversibility of airflow obstruction to the patient as objective evidence to encourage adherence to a treatment plan, and aids in monitoring and adjusting medication dosages. Peak expiratory flow (PEF), • Maximum expiratory flow occurring just after the start of a forced expiration from the point of maximum inspiration (total lung capacity). • A morning PEF measurement before administration of a bronchodilator is a guide to drug dosage.

Answer 263

Pathophysiology • Increase mucus production: - Goblet hyperplasia, hypertrophy of mucus glands. • Airway thickening: - Fibrosis of bronchial wall. • Bronchoconstriction: - Smooth muscle hypertrophy. • Three factors contribute to airway narrowing: 1) Bronchial muscle contraction: • Triggered by various stimuli 2) Mucosal swelling / inflammation: • Caused by mast cell and basophil degranulation, resulting in release of inflammatory mediators 3) Increased mucus production and Inflammation: • Mast cell degranulation, Eosinophil infiltration, increase permeability, edema.

Answer 264

EOSINOPHILS ``` - Activated eosinophils produce lipid mediators, such as leukotrienes and platelet activating factor, that mediate smooth muscle contraction. ```

Answer 265

1. Mast cells 2. Th2 lymphocytes 3. Cytokines 4. NKT cells 5. Basophils - While Th2 lymphocytes are a major source of the cytokines thought to participate in asthma, the basophil, in addition to producing histamine and leukotrienes, is a potent producer of IL-4 and IL-13, exceeding levels produced by T cells

Answer 266

1. Smooth muscle • Contraction and relaxation of airway smooth muscle (ASM) accounts for much of the rapid changes in airflow limitation characterizing asthma • Bronchoconstriction may be due to direct effects of contractile agonists released from inflammatory cells or reflex neural mechanisms. As an example, mast cell and eosinophil mediators, such as leukotrienes C4, D4, and E4 and histamine, are potent bronchoconstrictors. 2. bronchial hyperresponsiveness • manifestation of reversible airflow obstruction due to smooth muscle contraction • BHR represents an exaggerated constrictor response to a variety of physical, chemical, or environmental stimuli. 3. airway remodeling • a subset of patients with asthma have irreversible airflow obstruction, which is believed to be caused by airway remodeling • Airway remodeling refers to structural changes in the airways that may cause irreversible airflow limitation, superimposed on the effects of inflammation and smooth muscle contraction described above

Answer 267

Pathology of asthma • Between the bronchial cartilage at the right and the bronchial lumen filled with mucus at the left is a submucosa widened by smooth muscle hypertrophy, edema, and inflammation (mainly eosinophils). • These are changes of bronchial asthma, more specifically extrinsic asthma from type I hypersensitivity to allergens. The peripheral eosinophil count or the sputum eosinophils can be increased during an asthmatic attack. FIndings 1. Curschmann's spirals are a microscopic finding in the sputum of asthmatics. They are spiral-shaped mucus plugs from subepithelial mucous gland ducts of bronchi. 2. Charcot Leyden crystals are hexagonal bipyramidal structures localised in the primary granules of the cytoplasm of eosinophils and basophils. • Formed due to degradation of Eosinophils.

Answer 268

COPD - neutrophils asthma - eosinophils, improves by steroids and bronchodilator **others in PPT

Answer 269

Bronchiectasis • Bronchiectasis is defined by permanent and abnormal widening of the bronchi. • Bronchiectasis is not a specific disease, but a consequence of another disease process that produces a cycle of inflammation, dilation, and destruction with recurrent infection involving the bronchi. • Usually diagnosed using computed tomography scanning to visualize the larger bronchi. • Bronchiectasis is also characterized by mild to moderate airflow obstruction. Etiology - most common is POST INFECTIVE (post pneumonia, whooping cough, measles, Mycobacterial infection) - mucociliary disorder (kartagener, immobile cilia) - obstruction - rheumatic disease - cystic fibrosis in kids

Answer 270

Pathophysiology • Marked inflammation of the bronchial wall, principally in the smaller airways. • Bronchial dilation was characterized by deficiency/loss of elastin and more advance disease by destruction of muscle and cartilage • Variable bronchial wall fibrosis, atelectasis and peri-bronchial pneumonic change. • Spread of the inflammation beyond the airways to cause interstitial pneumonia Inflammatory cells • Neutrophils – Release mediators like protease and elastase. • Causes bronchial dilatation • Cell wall infiltrate – Marcophages and lymphocytes • Emphysema - due to interstitial pneumonia. Distribution • Central Bronchiectasis – Allergic bronhcopulmonary aspergillosis • Right Middle Lobe: Tuberculosis • Localized – Due to previous pneumonia ina lobe or obstruction • Generalized – e.g. Cystic fibrosis

Answer 271

Bacterial infection • Hemophilus Influenzae – 29% -79% • Pseudomonas Aeruginosa (12 - 31% • Moraxella Catarrhalis PFTs • Mild to Moderate Airflow Obstruction • Progressive decline in lung function over time with loss of FEV1. CXR - A posterior-anterior chest radiograph with walls of airways dilated and thickened (arrow) in the right upper lobe as seen in allergic bronchopulmonary aspergillosis. In the left upper lobe are airways filled with mucus and cellular debris. CT chest - High-resolution computerized tomography (HRCT) shows numerous ring shadows representing dilated airways in the right lung, many of which are partially filled with secretions (arrow). ABPA Central bronchiectasis in a patient with allergic bronchopulmonary aspergillosis. Multiple dilated third and fourth generation bronchi are seen. Smaller peripheral bronchi filled with mucus account for the branching linear opacities in the distal lung parenchyma. • Cystic fibrosis and Bronchiectasis - Computerized tomography (CT) of the chest in a patient with cystic fibrosis demonstrates mild cylindrical bronchiectasis, with thickened bronchial walls involving the upper lobes and the superior segments of the lower lobes. Note the sub-segmental atelectasis in the posterior segment of the right upper lobe.

Answer 272

• The bronchus - residual epithelium with necrotizing inflammation with subsequent bronchial destruction. • Inflammation extending into the adjacent lung parenchyma, characteristic of bronchiectasis.

Answer 273

• Characterized by Airway Obstruction. Types of Obstructive Lung diseases: • COPD • Asthma • Bronchiectasis Functionally: • Decrease in FEV1 and FEV1/FVC Ratio. Pathologically: • Inflammation of major and smaller airways. • Destruction of alveolar wall in emphysematous process.

Answer 274

``` Definition • Restrictive lung disease is a term used to describe a set of physiological parameters chiefly characterized by a decrease in TOTAL LUNG CAPACITY. • In restrictive lung diseases, the lungs are prevented from fully expanding because of restriction in: - Lung tissue - Pleura - Chest wall - Diaphragm ``` **restrictive disease that affect the lung; fibrosis, tumor, resection, atelectasis PFT General pathophysiology; cellular events involved in lung injury and fibrosis • Repetitive micro-injury to a susceptible type II alveolar epithelium • Injury induced inflammatory response, including T-cell activation and monocyte/macrophage influx • Increased production / activation of pro-fibrotic mediators, including TGF-B, CTGF, and PDGF. • Accumulation and activation of apoptosis-resistant and contractile (myo)fibroblasts. • Deposition of stiff cross-linked extracellular matrix with tissue destruction. • Failure of type II alveolar epithelial cell reconstitution, leading to bronchiolization with the formation of honeycomb cysts. • Increased pulmonary vascular resistance secondary to hypoxemia and vascular remodeling, leading to arterial hypertension in a subset of patients.

Answer 275

1) Idiopathic interstitial pneumonia - Major prototype ; IPF 2) Granulomatous 3) DPLD of known cause - occupational - environmental - collagen vascular disease - drug induced 4) Other forms of DPLD - LAM - eosinophil pneumonia - histiocytosis

Answer 276

IPF - Idiopathic pulmonary fibrosis • A specific form of chronic, progressive, interstitial fibrosis of unknown etiology. • Occurs primarily in older adults. • Associated with histopathologic and radiographic Patten of Usual Intestinal pneumonitis (UIP). • Exclusion of other forms of interstitial pneumonia & ILD associated with environmental exposure, medication, or systemic disease. • Characterized by progressive worsening of dyspnea, cough and lung function. Genetic predisposition to IPF • Genetic mutations in epithelial cell– associated proteins predispose to the development of lung fibrosis by leading to the development of short telomeres or endoplasmic reticulum (ER) stress. • ER stress may be profibrotic by causing apoptosis or release of TGF-β. Epithelial cells release profibrotic mediators such as PDGF, and TGF-β, which activate fibroblasts, or CXCL12 and CCL2, which recruit fibrocytes to the lung. E • Epithelial cells produce the integrin αvβ6, which activates TGF-P and may thereby cause epithelial cells to undergo epithelial-to-mesenchymal transition.

Answer 277

Gross • Characteristic fibrosis that is distributed along the inferior portions of the lobes with sub-pleural accentuation. • The pleural surface has a bosselated or cobblestone appearance, and on cut section, these regions correspond to areas of airspace enlargement and fibrotic retraction. This pattern of fibrosis has been termed gross honeycombing. Microscopic appearance • SPATIAL HETEROGENEITY (area of normal and abnormal lungs) • Patchy fibrotic reaction with FIBROSIS that is prominent in the PERIPHERAL PORTION of the secondary pulmonary lobule and spares the central portion of the lobule. • Microscopic HONEYCOMBING characterized by irregular airspaces lined by bronchiolar epithelium and surrounded by dense fibrosis. • A characteristic finding of usua interstitial pneumonia is the presence of FIBROBLAST FOCI at the interface between the fibrotic and less involved regions of the lobule

Answer 278

• Interstitial fibrosis due to occupational exposure • Requires chronic exposure to small particles that are fibrogenic. • Alveolar macrophages engulf foreign particles and induce fibrosis. • Examples Include: - Coal Workers’ Pneumoconiosis - Silicosis - Berylliosis - Asbestosis

Answer 279

* Coal worker's pneumoconiosis (CWP) results from inhalation and deposition of coal dust particles. * Inhalation of coal dust particles induces the formation of peribronchovascular coal macules. * pigment and reticulin fibers accumulate in a peribronchiolar location. * Over time, large amorphous black masses develop that occasionally have a liquified center. Simple 1) Gross; upper 2/3rd of lungs. COal macules and sometimes nodules 2) Histology; macules (dust laden macrophages) and nodules (collagen array in delicate network) 3) radiography; small, ill defined, rounded Complicated (A) Chest radiograph from a patient with coal worker's pneumoconiosis shows bilateral upper lobe conglomerate shadows and cephalad retraction of hilar regions. (B) Chest computed tomogram (CT) confirms the dorsal, upper lobe location of conglomerate masses. (C) Needle aspiration biopsy yielded alveolar macrophages filled with black coal dust.

Answer 280

Caplan SYndrome - coal workers pneumoconiosis, nodules, rheumatoid arthritis

Answer 281

Definition • Silicosis refers to a spectrum of pulmonary diseases caused by inhalation of free crystalline silica (silicon dioxide) **Common in; sandblasting, foundry work, mining. **EGG SHELL CALCIFICATION Acute silicosis • Develops after exposure to high concentrations of respirable crystalline silica. • SYmptom ONSET within a few weeks to a few years after the initial exposure. Chronic silicosis (3) 1. Simple silicosis: • Innumerable, sharply marginated, small rounded opacities • Composed of hyalinized, collagenous nodules. • Dorsal aspects of the upper lobes. 2. Progressive massive fibrosis (PMF): • Also known as complicated or conglomerate silicosis, is characterized by • Nodular lung lesions 1 cm or greater in diameter. • Occur predominantly in the upper lung zones of the chest radiograph. • Accelerated silicosis: 3. Associated with high-level exposure to silica. • Develops within 10 years of initial exposure. • Accelerated silicosis is differentiated from chronic disease only by its more rapid development following first exposure.

Answer 282

General • Granulomatous disease caused by exposure to beryllium. • Beryllium is an alkaline earth metal that is used in a number of different industrial applications. • First described in 1946 when 17 fluorescent lamp workers presented with a syndrome of advanced pulmonary granulomatous disease . • Heavy beryllium-using industries: metal and metal alloy (beryllium-copper) machine shops, electronics, defense industry, and beryllium extraction • Other beryllium-using industries: automotive, ceramic, computer, aerospace, metal reclamation, electronics and computer recycling, jewelry making, and dental alloy/appliance Pathogenesis • immunologic response to beryllium exposure - Cell mediated delayed hypersensitivity reaction. - Beryllium sensitization is predominantly a Th1 response involving interferon gamma and interleukin-2 • underlying genetic susceptibility, • HLA-DPB1 gene - Present in 85% of patients • A patient is considered to have CBD if all of the following are present: • A history of any beryllium exposure • A positive blood or broncho-alveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT) • Non-caseating granulomas on lung biopsy and/or mononuclear cell infiltrates on lung biopsy • Increased risk of cancer

Answer 283

General • Asbestosis specifically refers to the pneumoconiosis caused by inhalation of asbestos fibers. • The disease is characterized by slowly progressive, diffuse pulmonaryfibrosis. Forms of asbestos related lung diseases • Asbestos pleural plaques • Benign asbestos pleural effusion • Asbestossi – Fibrosis. • Mesothelioma. • Lung cancer Pathogenesis of asbestos related disease • Direct toxic effects of the fibers on pulmonary parenchymal cells • Release of various mediators (reactive oxygen species, proteases, cytokines, and growth factors) by inflammatory cells • Deleterious reactive oxygen and nitrogen free radicals may be formed either via reactions catalyzed by iron molecules within asbestos bodies. • Free radicals can react with and damage a variety of cellular macromolecules and may disrupt DNA to give rise to malignancy

Answer 284

1. Sarcoidosis | 2. Hypersensitivity pneumonitis

Answer 285

``` General ; African American females • Sarcoidosis is a multisystem Granulomatous disorder of unknown etiology that affects individuals worldwide and is characterized pathologically by the presence of NON-CASEATING granulomas in involved organs. It typically affects young adults, and initially presents with one or more of the following abnormalities: • Bilateral hilar adenopathy • Involves Upper Lobes. • Pulmonary reticular opacities • Skin, joint, and/or eye lesions • Etiology - unknown ``` Pathogenesis • MACROPHAGES AND DENDRITIC CELLS: Activated in the presence of a foreign antigen. Evolve into epitheloid cells. Further fusion leads to giant cells. • As the granuloma matures, macrophages, epitheloid cells and Multinucleated giant cells forma tight central cluster. • Cytokines: IL 2 and IL15 • Interferon Gamma • IL 6 and IL-8 CXR Stage I; bilateral hilar adenopathy II; lung tissues and hilar involvement III-IV; scarring PFT • Stage I – May be Normal (No restriction) • Stage II – IV – Restrictive Pattern (LUNG NOW INVOLVED) - Reduced Vital Capacity - Reduced Total Lung Capacity - Reduced DLCO ``` Microscopic • classic sarcoid granulomas are non-necrotizing, WELL FORMED. • macrophages, • epithelioid cells, • multinucleated giant cells, • T lymphocytes that are CD4 positive ``` Additional findings; - asteroid bodies with stellate arrangement - calcium oxalate crystal

Answer 286

1. Acute HP : • Restrictive Ventilatory defect and may have • Reduced pulse oxygen saturation (SaO2) during symptomatic episodes. • Gas transfer between episodes can be normal. 2. Subacute HP: • Spirometry and lung volumes can demonstrate restriction or a mixed pattern of both obstructive and restrictive Ventilatory abnormalities. • A reduction in diffusing capacity (DLCO). • Mild reduction in resting SaO2 or desaturation on exertion 3. Chronic HP: HONEYCOMBING IN UPPER LOBES • Moderate to severe restrictive defect. • Isolated severe obstructive defect can be seen less commonly. • The DLCO is invariably reduced • Resting or exertional reduction in SaO2 is typical.

Answer 287

1. Acute - Subacute • The classic triad : • Chronic cellular bronchiolitis with a peribronchial infiltration of lymphocytes. • Small, poorly-formed non-caseating granulomas located near respiratory or terminal bronchioles . Well-formed granulomas are not commonly seen, in contrast to their frequent identification in patients with sarcoidosis. • Chronic cellular pneumonitis with a patchy mononuclear cell infiltration (predominantly lymphocytes and plasma cells) of the alveolar walls. 2. Chronic HP ; Fibrotic HP can include features - • UIP • Fibrotic nonspecific interstitial pneumonia (NSIP). • Sometimes features of subacute HP such as lymphocytic infiltrates, poorly-formed granulomas, and multinucleated giant cells (often isolated), are present in patients with chronic HP, although the predominant pattern is fibrosis • Airway-centered fibrotic lesions (peribronchiolar metaplasia) may be present, but are nonspecific.

Answer 288

* Intrapulmonary restriction (e.g., interstitial lung disease) * Extrapulmonary restriction: resulting from diseases of the chest wall (e.g., kyphoscoliosis) or pleura; neuromuscular diseases; obesity; or pregnancy, which may abnormally elevate the diaphragm. * Characterized functionally by: - A reduction of total lung capacity, FRC, VC, expiratory reserve volume, and diffusion capacity. - Preservation of the normal ratio of FEV1 to FVC. • The common features of all these conditions include: - Alveolar thickening due to fibrosis, cellular exudates, or edema. - Increased stiffening of the lungs causing reduced compliance. - Ventilation-perfusion mismatch giving rise to hypoxemia.

Answer 289

1. M. Tuberculosis; night sweats, cough up blood, weight loss. Travel history **Most common spread is via respiratory droplets - Active TB versus Latent TB • Latent TB infections often do not feel sick, do not have any symptoms, and cannot spread TB to others. • However, some patients with latent TB go on to active TB disease. • Most latent TB infections can be treated with prophylaxis to prevent development of active TB. 2. M. Leprae 3. M. Avium complex

Answer 290

• Definition: patients having M. tuberculosis resistant to at least INH and RIF • Higher risk for treatment failure and further acquired drug resistance • Should be referred to ID specialists; state health departments or CDC * Side Note: Patients with strains resistant to RIFAMPIN alone: * Better prognosis than patients with MDR strains in general * However they are at increased risk for treatment failure/additional resistance * Manage by ID specialist * Extensive Drug Resistant (XDR) TB * MDR TB (resistant to INH and RIF) plus Resistance to any FQN AND at least one other of the three injectable drugs (i.e., amikacin, kanamycin, or capreomycin) * Relatively Rare

Answer 291

* Use multiple drugs (Isoniazid drug 4% resistance; 3 vs 4 drugs) * Prolonged treatment is required for successful eradication (don’t stop even if you feel better) • Patients must be followed closely to ensure patient compliance & monitor drug efficacy/toxicity - Non-compliance leads to treatment failure - Recheck sputum cultures at 2 months - Therapeutic failure defined as positive sputum cxs after 4 months of compliant therapy

Answer 292

Intensive Phase followed by Continuation Phase 1. Intensive Phase – 2 months (knocking down the volume); 4 drugs in first 2 months - RIPE or RIPS; Rifampin, Isoniazid, pyrazinamide, ethambutol 2. Continuation Phase – 4 months (de-escalate); 2 drugs for next 4 months - RHODE ISLAND; Rifampin and Isoniazide * *Isoniazide usually for 9 months. Not good for non compliant pt. * *Rifampin is hard to tolerate; (affect liver), extra weight loss from nausea RI (rifampin and Isoniazide) treatment; 6 months for pulmonary TB, 9 months for latent TB

Answer 293

RIFAMPIN MoA A. Inhibits DNA-dependent RNA polymerase •Suppression of initiation of chain formation in RNA synthesis B. Bactericidal: kills slow-growing mycobacteria present within macrophages and in caseating granulomas C. Active against some gram positive and gram negative bacteria. (Reserved for TB, except in very rare cases) D. Combination therapy with INH •Synergism •Shorter courses of therapy Distribution •Widely distributed; excellent tissue distribution •CNS, tuberculosis abscesses, and intracellular sites Metabolism •Primarily metabolized by deacetylation •Autoinduction of metabolism occurs; Maximal induction at ~ 6 doses, whether given daily or twice weekly Adverse effects 1.Transient elevation in serum transaminases 2. Hepatotoxicity (rare) •Risk factors: alcoholics with preexisting liver disease. •Augmented when combined with INH 3. GI upset (frequent) 4. Hypersensitivity (rare) •Flushing, fever, pruritus •Systemic flu-like syndrome •Thrombocytopenia 5. Discoloration of bodily fluids (not necessarily an ADR) •Orange discoloration (sweat, tears, urine) •Contact lenses: permanent discoloration Drug interactions A. Proliferation of the smooth endoplasmic reticulum in hepatocytes 1) Results in an increase in cytochrome p-450 (CP450) activity. 2) Increased metabolism rate of:•Warfarin •Theophylline •Narcotics •Oral Hypoglycemics •Steroids (oral contraceptives) Place in therapy • Treatment of active TB • 2nd line agent for preventative therapy • Dose Adults (maximum): 10 mg/kg (600 mg) once daily, twice weekly, or three times weekly.

Answer 294

ISONIAZID MoA 1. Inhibit synthesis of mycolic acid; important constituent of mycobacterial cell walls 2. Actively transported into bacterium •Kills actively growing organisms in the extracellular environment •Inhibits growth of dormant organisms present within macrophages and in caseating granulomas Pharmacokinetics A. Metabolism •Primarily metabolized by acetylation. •Monoacetyl hydrazine - important metabolite; •Excreted unchanged in the urine -or- •further acetylated to the diacetyl form -or- •hydroxylated to an electrophilic intermediate - responsible for hepatotoxic effects •Rates of acetylation of INH & monoacetyl hydrazine are dependent on an individual’s phenotypic classification as either a slow or rapid acetylator - Slow acetylators may lead to higher blood concentrations higher chance of ADR with more drug around with chronic therapy - Caucasians - equally divided fast and slow - Eskimos and Japanese - rapid, primarily - Egyptians - slow, primarily B. Elimination; depends on acetylator phenotype Adverse effects 1. Transient elevation of serum transaminases (~15%); usually within the first 8-12 weeks of therapy 2. Hepatotoxicity; risk factors; age, preexisting liver disease, 4-8 wks of treatment, use with rifampin 3. Neurotoxicity; •***Pyridoxine (Vitamin B6) will reduce the incidence drastically (some studies state reductions from 20% to less than 1%) •Alcoholics, children, malnourished, slow acetylators 4. Hypersensitivity (rare) Place in therapy •Treatment of active TB •Preventative therapy for patients with (+) PPD

Answer 295

PYRAZINAMIDE MoA; not well documented - Bactericidal toward dormant organisms residing in the acidic environment within macrophages •Metabolism; Hydrolyzed in liver to active pyrazinoic acid •Elimination; 5-hydroxypyrazinoic acid (hydroxylated pyrazinoic acid) is excreted by the kidneys. • t1/2 ~9-10 hours Adverse effects 1. Hepatotoxicity •Documented more frequently with higher doses •Baseline hepatic function should be obtained •Monitor closely for symptoms of hepatitis 2. Hyperuricemia - Decreased renal excretion of uric acid. •Pyrazinoic acid competes with uric acid for elimination •(Bad for GOUT patients) 3. GI upset (frequent) 4. Hypersensitivity; photosensitivity, rash

Answer 296

ETHAMBUTOL 1. OPTIC NEURITIS (Retrobulbar neuritis) •Decreased visual acuity and red-green color blindness. •Usually reversible; time dependent on degree of impairment. •Incidence is dose related •Monitor visual acuity and color perception q 4-6 weeks. •Use with caution in young children **MoA - not well documented.

Answer 297

STREPTOMYCIN MoA •Aminoglycoside antibiotic •Bactericidal through inhibition of protein synthesis. •Inactive against intracellular organisms; limiting it’s activity to suppression. •Used as an alternative to Ethambutol in many regimens. Adverse Effects 1. Nephrotoxicity; less common than other aminoglycosides 2. Impairment of 8th cranial nerve function ; unlike other aminoglycosides, vestibular function (vertigo) more affected than hearing 3. Pain on injection/abcess formation 4. Streptomycin regimen - 8% incidence of ADRs 5. Without streptomycin - 3% incidence of ADRs; Ethambutol better than streptomycin when possible

Answer 298

BEDAQUILINE •MOA: inhibits mycobacterial ATP synthetase which is an enzyme req for generation of energy in M. tuberculosis •First approved since Rifampin in late 60’s •Safety concerns: - QT prolongation - Increased Death potential •Used for MDR TB only - not studied in kids or pregnant patients

Answer 299

* Para-Aminosalicylate (PAS) * Ethionamide * Cycloserine * Capreomycin * Kanamycin * Amikacin ***NEPHROTOXCITY

Answer 300

RIFABUTIN (Mycobutin)

Answer 301

RIFAPENTINE (Priftin) •Advantage: ONCE WEEKLY but watch restrictions above - NO HIV) •ADR: Similar to Rifampin

Answer 302

CLOFAZIMINE (Lamprene) •GI upset •Severe and life-threatening abdominal pain and organ damage caused by crystal deposition •Discoloration of skin and eyes.

Answer 303

•Macrolides • Unlikely to be effective against M. tuberculosis. • Clarithromycin and azithromycin; M. avium complex (MAC) prevention and treatment • Should be used in combination with other agents for MAC tx •Quinolones - Ciprofloxacin and Ofloxacin have been shown to be active against M. tuberculosis.

Answer 304

Treat leprosy with DR. C 1. Dapsone (Adverse Effect - sulfone syndrome); competitive inhibitor of folic acid 2. Rifampin 3. CLOFAZIMINE ***Use for 3-5 years

Answer 305

***C/AE; clarithromycin or azithromycin and embuthamol • Use combination therapy, avoid monotherapy • Clarithromycin is ~4 fold more active than azithromycin against MAC. • Azithromycin’s lower potency may be compensated by greater penetration - Tissue levels may exceed plasma levels by 100 fold • Side note: The quinolones inhibit MAC in vitro (Cipro, Levofloxacin, Moxifloxacin) • Clinical improvement is expected w/in first 1-2 months of treatment with sterilization of blood cultures w/in 3 months of starting therapy

Answer 306

R • GI Upset, Drug-Drug Interactions, Orange discoloration,Hepatotoxicity I • Neurotoxicity, Peripheral Neuropathy, Hepatotoxicity P • GI Upset, Hyperuricemia, Hepatotoxicity E • Optic Neuritis, Children S • Neurotoxicity (8th cranial nerve-Vertigo ), Nephrotoxicity potential

Answer 307

Two major categories (also known as Hansen's disease): 1. Lepromatous (disseminated, multibacillary, with loss of specific cell-mediated immunity) 2. Tuberculoid (localized, paucibacillary, with strong cell- mediated immunity) Transmission requires prolonged contact and occurs directly through intact skin, mucous membranes, or penetrating wounds. Treatment = DR.C (long courses are required ~ 2-5 years) • Dapsone, Rifampin, Clofazimine

Answer 308

MAC Symptoms ; Fever, night sweats, weight loss, and anemia • Usually occurs in advanced HIV (CD4<100/mm3) • In non-HIV ptns, usu. limited to the lungs and presents with a chronic productive cough and CXR of limited , diffuse, and/or cavitary disease. • Primary Prophylaxis recommended when CD4 <50 Prophylaxis (CD4 <50) - Primary prevention of disseminated MAC: • Clarithromycin 500 mg twice daily (BID) -or- • Azithromycin 1200 mg per WEEK • Alternative Rifabutin 300mg QD (if Clarithro or Azithro are not tolerated) Treatment (at least 2 agents, avoid monotherapy) • Clarithromycin 500mg BID –or- Azithromycin 500mg QD plus • Ethambutol (15mg/kg/day) - while considering asking one of the following; CLOFAZIMINE, rifampin, rifabutin or Cipro

Answer 309

Pulmonary hypertension—hemodynamic state in which the pressure in the pulmonary artery is elevated above a mean of 25 mm Hg (n ≈ 15 mm Hg). Two major subcategories: 1. Pulmonary arterial hypertension (PAH)—PCWP < 15 mm Hg. PAH—pathologic increases in pulmonary vascular resistance and, ultimately, to right ventricular failure. 2. Pulmonary hypertension may also be a consequence of many other chronic diseases, including left-sided heart failure, a variety of parenchymal lung diseases, and thromboembolic disease. * *Overtime, Chronic PE may increase PVR * *Finally, increased PVR may be due to remodeling of pulmonary arteries

Answer 310

1. Pulmonary arterial hypertension (PAH) 2. Pulmonary hypertension due to LEFT HEART DISEASE 3. Pulmonary hypertension due to LUNG DISEASES AND/OR HYPOXIA 4. Chronic thromboembolic pulmonary hypertension 5. Pulmonary hypertension with UNCLEAR MULTIFACTORIAL MECHANISM

Answer 311

PAH (Pulmonary arterial Hypertension) 1. Idiopathic PAH 2. Heritable PAH 2. 1.BMPR2 (70% cases of heritable PAH) 2. 2.ALK1, ENG, SMAD9, CAV1, KCNK3 (DO NOT MEMORIZE) ***Remeber, Mutations in the BMPR2 gene have been found in the majority of patients with heritable PAH and some forms of IPAH 3. Drug and toxin-induced (anorexigens, including aminorex, fenfluramine, and dexfenfluramine; amphetamines, methamphetamines, and l-tryptophan; tyrosine kinase inhibitor—dasatinib) ``` **Associated with; A. Connective tissue disease (scleroderma, SLE, RA) B. HIV Infection C. Portal HTN D. COngenital heart disease (VSD, PDA) E. Schistosomiasis ``` **Remember; Eisenmenger syndrome is defined as pulmonary vascular obstructive disease that develops as a consequence of a large preexisting left-to-right shunt such that pulmonary artery pressures approach systemic levels and the direction of the flow becomes bidirectional or right-to-left.

Answer 312

Pulmonary HTN due to left heart d/s (4) 1. Left ventricular systolic dysfunction 2. Left ventricular diastolic dysfunction 3. Valvular disease (MS, MR) 4. Congenital/acquired left heart inflow/outflow tract obstruction (HOCM)

Answer 313

Pulmonary Hypertension due to Lung D/S or Hypoxia 1.1.Chronic obstructive pulmonary disease 1.2.Interstitial lung disease 1.3.Sleep-disordered breathing 1.4.Alveolar hypoventilation disorders 1.5.Chronic exposure to high altitude

Answer 314

Group 4 - Pulmonary HTN due to chronic thromboembolism Group 5 (Multifactorial) 1.Hematologic Disorders: Chronic Hemolytic Anemia, Myeloproliferative Disorders, Splenectomy 2.Systemic Disorders: Sarcoidosis, Pulmonary Histiocytosis, Lymphangioleiomyomatosis 3.Metabolic Disorders: Glycogen Storage Disease, Gaucher Disease, Thyroid Disorders

Answer 315

1.Evolution of PH is complex and eventually involves—endothelial dysfunction, imbalance of pro- and anti-apoptotic pathways, proliferation of all muscular and adventitial layers i.e. vascular remodeling. 2. ↑PVR and right ventricular hypertrophy (to varying extent) and dilation—exertional dyspnea—dyspnea at rest.

Answer 316

1.Pulmonary arterial hypertension (PAH) is now considered to be a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation have a major role 2.A number of proproliferative signaling pathways involving growth factors, cytokines, metabolic signaling, and elastases and proteases have been identified in the pathophysiology of PAH 3.Clinical studies with tyrosine kinase inhibitors, serotonin antagonists, and soluble guanylate cyclase stimulators are underway in patients with PAH

Answer 317

Symptoms 1.Dyspnea—cardinal symptom of idiopathic PAH, described by more than 95% of patients—usually noted first on exertion and gradually with less and less activity. 2. Fatigue and weakness—reported by a majority of patients with idiopathic PAH. 3. Substernal chest pain is also common. In addition to chest pain, hoarseness may result if the enlarged main pulmonary artery compresses the recurrent laryngeal nerve. 4. Syncope, usually with exertion, occurs in some patients with idiopathic PAH and may be its initial manifestation. 5. Late findings in PAH include peripheral edema and ascites related to decompensated right ventricular failure.

Answer 318

1. Hands and feet—cold, the peripheral pulse is diminished, the blood pressure is likely to be low, and the pulse pressure is reduced. 2. Signs of systemic venous hypertension are often present, including a prominent jugular venous a wave, which is exaggerated by abdominal compression (hepatojugular reflux), and prominent c-v waves, which are indicative of tricuspid regurgitation. 3. Palpation of the chest may reveal a right ven-tricular lift at the left sternal border that is sustained throughout the pressure-overloaded cardiac contraction. 4. Second heart sound is closely split with an accentuated pulmonic component. 5.The murmur of tricuspid regurgitation, which is holosystolic, located at the left lower sternal border, and augments with inspiration, is common in patients with moderate to severe pulmonary hypertension.

Answer 319

ECG; RVH (right ventricular hypertrophy) CXR ; PA enlargement Echo; RV/RA enlargement

Answer 320

General measures 1. Supervised exercise training 2. Psycho-social support 3. Avoid strenuous physical activity 4. Avoid pregnancy 5. Avoid high altitudes 6. Influenza and pneumococcal immunization Supportive measure 1. Anticoagulants (Group 1 & 4): 1. 1.Warfarin—1.5-2.0 INR 2. Diuretics (furosemide ± spironolactone) 3. Supplemental oxygen only if SaO2 <90 mmHg at rest Vasodilator therapy 1. For patients with favorable vasodilator response during RV cath 2. Diltiazem or amlodipine preferred 3. AVOID verapamil

Answer 321

1. Ambrisentan (ETa), bosentan (ETa&b) 2. Activation of NO-sGC-cGMP pathway A. PGE5 inhibitors (sidenafil) B. sGC activators - Riociguat 3. Prostacyclin or analogs A. Epoprostenol (first synthetic PGI2) B. Treprostinil (PGI2 analogue) C. ILoprost (PGI2 analog)

Answer 322

Ambrisentan (ETA), bosentan (ETA&B): endothelin receptor-blockers; reduce IP3/DAG signaling—↓ [Ca++]c—vasodilation and antiproliferative. 1.1.Highly teratogenic—monthly pregnancy testing with contraception 1.2.Hepatotoxic—routine LFTs 1.3.Other side effects include lower extremity edema, headache, and nasal congestion

Answer 323

2. 1.PDE5 inhibitors (sildenafil)—Sildenafil and tadalafil are selective inhibitors of cGMP–specific phosphodiesterase-5, an enzyme that promotes the breakdown of cGMP. These should NOT be combined with nitrates. The most common side effects of the inhibitors are headache, flushing, dyspepsia, and epistaxis. 2. 2.sGC activators—Riociguat is a first in class soluble guanylate cyclase stimulator, which directly stimulates soluble guanylate cyclase independent of nitric oxide and increases the sensitivity of sGC to nitric oxide. The most common adverse events included headache, dyspepsia, peripheral edema, and hypotension. Riociguat should not be used concurrently with phosphodiesterase type 5 inhibitors.

Answer 324

3. Prostacyclin or analogs: 3. 1.The first synthetic PGI2, epoprostenol, has dose-dependent inhibitory effects on both SVR and PVR, paired with increases in cardiac output, for patients with PAH. Short hals-life (3-5 mins), light and heat sensitive—must be given by an infusion pump. Very effective in the management of PAH. 3. 2.Treprostinil, a PGI2 analogue, can be given by inhalation. 3. 3.Iloprost—PGI2 analog—inhalation has potent vasodilative effects on the pulmonary circulation, with less systemic vasodilation than intravenous PGI2. 3.4.Common side effects: myalgias and pain in the extremities, jaw pain, nausea, headaches, abdominal discomfort, diarrhea, flushing, dizziness, and systemic hypotension.

Answer 325

ABCDEF • AIRWAY (midline) • BONES AND SOFT TISSUE (good penetration, vertebral bodies behind trachea) • CARDIAC AND MEDIASTINUM (deviation) • DIAPHRAGM AND GASTRIC BUBBLE (is diaphragm pursed up with intrathoracic pressure) • EFFUSIONS (PLEURA) ; fluid build up • FIELDS (LUNGS); air

Answer 326

Spontaneous pneumothorax - blunting of costophrenic angles - Intrathoracic pressure (push up diaphragm a little) - Air in right lung fields - No trachea deviation Tx; High O2, resolves on it’s own.

Answer 327

Tension pneumothorax (medical emergency) - Trachea deviation to the right - Air in left lung fields - Hyperresonant lung fields

Answer 328

Pathophysiology • PNEUMOTHORAX REFERS TO GAS WITHIN THE PLEURAL SPACE. • NORMALLY, THE ALVEOLAR PRESSURE IS GREATER THAN THE INTRAPLEURAL PRESSURE, WHILE THE INTRAPLEURAL PRESSURE IS LESS THAN ATMOSPHERIC PRESSURE. • IF A COMMUNICATION DEVELOPS BETWEEN AN ALVEOLUS AND THE PLEURAL SPACE OR BETWEEN THE ATMOSPHERE AND THE PLEURAL SPACE, GASES WILL FOLLOW THE PRESSURE GRADIENT AND FLOW INTO THE PLEURAL SPACE. • BECAUSE THE THORACIC CAVITY IS NORMALLY BELOW ITS RESTING VOLUME, AND THE LUNG IS ABOVE ITS RESTING VOLUME, THE THORACIC CAVITY ENLARGES AND THE LUNG BECOMES SMALLER WHEN A PNEUMOTHORAX DEVELOPS. [1] • A TENSION PNEUMOTHORAX IS A MEDICAL EMERGENCY AND OCCURS WHEN THE INTRAPLEURAL PRESSURE EXCEEDS ATMOSPHERIC PRESSURE, ESPECIALLY DURING EXPIRATION, AND RESULTS FROM A BALL VALVE MECHANISM THAT PROMOTES INSPIRATORY ACCUMULATION OF PLEURAL GASES. THE BUILDUP OF PRESSURE WITHIN THE PLEURAL SPACE EVENTUALLY RESULTS IN HYPOXEMIA AND RESPIRATORY FAILURE FROM COMPRESSION OF THE LUNG. Treatment • Watchful waiting, with or without supplemental oxygen • Simple aspiration • Tube drainage, with or without medical pleurodesis (chemicals that will go inside pleural space and make pleural stick to thoracic wall so it doesn’t happen again) Management <2; observation >2; needle aspiration Unstable; needle decompression followed by thoracostomy tube insertions

Answer 329

Right middle lobe consolidation (infiltrates) - Pneumonia (Strep pneumonia) * EXTENSIVE INFILTRATE USUALLY ABUTTING PLEURAL SURFACE * PROMINENT AIR BRONCHOGRAMS (DDX: STAPH HAS NO AIR BRONCHOGRAM) * ORGANISM IS ASPIRATED INTO THE LUNGS FROM THE UPPER AIRWAYS SO IT SHOWS A PREDILECTION FOR LOWER LOBES * DOES NOT RESPECT SEGMENTAL BOUNDARIES * RESOLUTION BEGINS PROMPTLY WITH ANTIBIOTICS – FREQUENTLY WITHIN 24 HOURS

Answer 330

Staph pneumonia - start with a flu and then get worse - Xray show fluid buildup in lower lobes and consolidation In both right and left · PATCHY BRONCHOPNEUMONIA OF SEGMENTAL DISTRIBUTION, FREQUENCY BILATERAL · MAY BE ASSOCIATED WITH ATELECTASIS SINCE AIRWAYS ARE FILLED (NOT SO WITH PNEUMOCOCCAL) · PLEURAL EFFUSION (50%)

Answer 331

ASPIRATION PNEUMONIA • RADIOGRAPHIC EVIDENCE OF ASPIRATION PNEUMONIA DEPENDS ON THE POSITION OF THE PATIENT WHEN THE ASPIRATION OCCURRED. • THE RIGHT LOWER LUNG LOBE IS THE MOST COMMON SITE OF INFILTRATE FORMATION DUE TO THE LARGER CALIBER AND MORE VERTICAL ORIENTATION OF THE RIGHT MAINSTEM BRONCHUS. • PATIENTS WHO ASPIRATE WHILE STANDING CAN HAVE BILATERAL LOWER LUNG LOBE INFILTRATES. • PATIENTS LYING IN THE LEFT LATERAL DECUBITUS POSITION ARE MORE LIKELY TO HAVE LEFT-SIDED INFILTRATES . • THE RIGHT UPPER LOBE MAY BE INVOLVED PARTICULARLY IN ALCOHOLICS WHO ASPIRATE WHILE IN THE PRONE POSITION

Answer 332

PULMONARY EMBOLISM CXR - normal CTA (CT angiogram) ; clot in PA (pulmonary artery)

Answer 333

Pleural effusion • THE PRIMARY CAUSE OF A PLEURAL EFFUSION IS SIMPLY AN IMBALANCE BETWEEN THE FLUID PRODUCTION AND FLUID REMOVAL IN THE PLEURAL SPACE. • NORMALLY APPROXIMATELY 15 ML/DAY OF FLUID ENTERS THIS POTENTIAL SPACE • BALANCE IS DISRUPTED WHEN LOCAL OR SYSTEMIC DERANGEMENTS OCCUR. • WHEN LOCAL FACTORS ARE ALTERED, THE FLUID IS PROTEIN- AND LDH-RICH AND IS CALLED AN EXUDATE. • WHEN SYSTEMIC FACTORS ARE ALTERED, THE FLUID HAS LOW PROTEIN AND LDH AND IS CALLED A TRANSUDATE.

Answer 334

SOLITARY LUNG/pulmonary NODULE * PULMONARY NODULE: A SINGLE, WELL-DEFINED LESION, USUALLY ROUNDED OR SLIGHTLY OVOID, SURROUNDED BY NORMAL LUNG TISSUE * DIAMETER MUST BE 3 CM OR LESS * IF DIAMETER GREATER THAN 3 CM, PROCESS IS CALLED A MASS, OF WHICH 90% ARE MALIGNANT * SOLITARY PULMONARY NODULES ARE FOUND IN 1 OF EVERY 500 CHEST RADIOGRAPHS * NODULAR MIMICS: NIPPLE SHADOWS, SKIN MOLES, PROMINENT COSTOCHONDRAL JUNCTION

Answer 335

TB - cavitarial lesion in the right upper lobe - some thickening in the hilar region ``` • “CLASSIC” CHEST X-RAY FINDINGS IN TB - HILAR AND/OR MEDIASTINAL LYMPHADENOPATHY (AS DISEASE SPREADS THROUGH LN) • – PRIMARY TB - UPPER LUNG FIELD INFILTRATE WITH OR WITHOUT CAVITATION • – REACTIVATION TB - LARGE UNILATERAL PLEURAL EFFUSION* - PERICARDIAL EFFUSION* - MILIARY PATTERN* ```

Answer 336

Bronchiectasis - Pathologic dilation of the medium sized airways - Classical clinical triad: chronic cough, excess sputum production and repeated infection

Answer 337

CHF - left sided (backed up into the lungs to become right sided CHF) * Airway right side deviation * Cardiac shadow is enlarged * Costophrenic angle is blunted on left side 5 findings 1. CEPHALIZATION 2. Fluid in between the fissues 3. Interstitial edema (Keller’s B lines 4. Pulmonary edema 5. Cardiac remodeling Treatment - Control the fluid buildup (DIURETICS

Answer 338

ESRD 1. Most common cause of ESRD in USA is diabetic glomerulonephropathy 2. Findings is; waxy casts with oliguria (very low urine flow), Increased ESR

Answer 339

1. Most common cause of AKI in hospitalized patients is ACUTE TUBULAR NECROSIS 2. AKI formerly known as acute renal failure, defined as an abrupt decline in renal function as measured by increased creatinine and increase BUN or by oliguria/Anura 3. 3 types A. Prerenal azotemia; UO >500, UNa <20, FEna <1%, serum BUN/Cr >20 B. Intrinsic renal failure; UO <350, UNa >40, FEna >2%, serum BUN/Cr <15 C. Post renal azotemia; UO <350, UNa varies, FEna varies, serum BUN/Cr varies

Answer 340

2 forms of renal failure: 1. acute (eg, ATN) and 2. chronic (eg, hypertension, diabetes mellitus, congenital anomalies). Consequences of renal failure; MAD HUNGER A. Metabolic Acidosis B. Dyslipidemia (especially triglycerides) C. Hyperkalemia D. Uremia—clinical syndrome marked by: Nausea and anorexia, pericarditis, asterixis, encephalopathy, platelet dysfunction E. Sodium and water retention (HF, pulmonary edema, HTN) F. Growth retardation and developmental delay G. Erythropoietin failure (anemia) H. Renal osteodystrophy; hypocalcemia and hyperphosphatemia

MS2 renal/pulm Flashcards

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