Pbl Exam 8 Case 5

Front 1

1. What are topoisomerases?

Back 1

These enzymes catalyze DNA replication and segregation by breaking, rotating, and religating DNA strands.

The enzymes that have been most successfully targeted by antibiotics are topoisomerases.

Front 2

2. What are the two types of topoisomerases?

Back 2

1. Type 1
-form and reseal single-stranded breaks in DNA to decrease positive supercoiling.

2. Type 2
-performs nuclease and ligase operations on both strands of DNA.

Front 3

3. What are the similarities/differences between types 1 and 2 topoisomerases?

Back 3

Both types of topoisomerases can remove excess DNA supercoils during DNA replication.

However, only type 2 topoisomerases can resolve intertwined copies of double-stranded DNA to permit segregation of the DNA to daughter cells.

Type 2 enzymes are both more complex and more versatile than type 1 topoisomerases, and the type 2 enzyme serves as a more frequent molecular target for chemotherapeutic agents.

Front 4

4. What is the MOA of a type 2 topoisomerase?

Back 4

1. The enzyme binds to a segment of DNA and forms covalent bonds w/phosphates form each strand, thereby nicking both strands.

2. The enzyme causes a second stretch of DNA from the same molecule to pass through the break, relieving supercoilding.

This passage of double-stranded DNA through a double stranded break is what permits separation of intertwined copies of DNA following replication, and thereby, segregation of DNA into progeny cells.

Front 5

5. What are the two main bacterial type 2 topoisomerases?

Back 5

1. DNA gyrase
2. Topoisomerase IV

DNA gyrase is particularly crucial for segregation in some bacteria, while topoisomerase IV is the critical enzyme in other bacteria.

Front 6

6. What enzyme catalyzes transcription?

How is this different in prokaryotes/eukaryotes?

Back 6

RNA polymerase.

In bacteria, one RNA polymerase synthesizes all the RNA in the cell. Furthermore, bacterial RNA polymerase is composed of only five subunits.

In contrast, eukaryotes express three different RNA polymerases, and each enzyme is considerably more complex in its subunit structure than the bacterial counterpart.

Front 7

7. What are inhibitors of toposiomerases called?

Back 7

Quinolones.

Quinolones are a major class of bactericidal antibiotics that act by inhibiting bacterial type II topoisomerases.

Front 8

8. MOA of quinolones

Back 8

Quinolones act by inhibiting one or both fo the two prokaryotic type 2 topoisomerases in sensitive bacteria, DNA gyrase and topoisomerase IV.

Quinolones primarily inhibit DNA gyrase in Gram-negative organisms, and they inhibit topoisomerase IV in Gram-positive organisms such as S. aureus.

Front 9

9. Quinolone activity at low vs. high concentrations

Back 9

At low concentrations, quinolones inhibit type II topoisomerases reversibly, and their action is bacteriostatic.

At higher concentrations, however, quinolone convert the topoisomerases into DNA-damaging agents by stimulating dissociation of the enzyme subunits form the broken DNA.

Doubly-nicked DNA cannot be replicated, and transcription cannot proceed through such breaks. Topoisomerase dissociation from the DNA and/or the bacterial response to the double stranded break lead ultimately to cell death.

Thus, at therapeutic doses, the quinolone antibiotics are bactericidal.

Front 10

10. What are the names of the quinolones?

Back 10

1. Ciprofloxacin
2. Gatifloxacin
3. Levofloxacin
4. Moxifloxacin
5. Norfloxacin
6. Ofloxacin

Front 11

11. What are the quinolones used to treat?

Back 11

They are widely used to treat common urogenital, respiratory, and GI infections caused by E. coli, Klebsiella pneumoniae, Campylobacter jejuni, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Enterobacter, Salmonella, and Shigella species.

Front 12

12. Ciprofloxacin

Back 12

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: *Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Concomitant tizanidine administration and hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 13

13. Gatofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

Back 13

MOA: Inhibits prokaryotic type 2 topoisomerases. At therapeutic doses, it has a bactericidal effect by causing double-stranded DNA breaks and cell death.

PURPOSE: Gram-negative infections

ADVERSE: Cartilage damage, tendon rupture, peripheral neuropathy, increased ICP, seizure, severe hypersensitivity reaction, rash, GI disturbance

CONTRA: Hypersensitivity to quinolones

NOTES: Avoid coadministration of thioridazine due to increased risk of cardiotoxicity.

Front 14

14. How do bacteria evolve resistance to the quinolones?

Back 14

Bacteria evolve resistance through chromosomal mutations in the genes that encode type 2 topoisomerases, or through alterations in the expression of membrane porins and efflux pumps that determine drug levels inside the bacteria.

Front 15

15. What are the inhibitors of transcription called?

Back 15

Rifamycin derivatives, such as:

1. Rifabutin
2. Rifampin

These are semisynthetic derivatives of the naturally occurring antibiotic rifamycin B.

Front 16

16. Rifampin

Back 16

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Prophylaxis of meningococcal disease and for mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, *saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

Front 17

17. Rifampin NOTES

Back 17

NOTES: Particularly effective against phagosome-dwelling mycobaceria b/c it is bactericidal for intracellular as well as extracellular bacteria.

Rifampin increases the in vitro activity of isoniazid

Displays high selectivity for bacteria, so it is generally well tolerated, and the incidence of adverse effects is low.

Rifampin is not used as a single angent b/c of rapid development of resistance

May reduce cyclosporine concentration and efficacy

Front 18

18. Rifabutin

Back 18

MOA: Form a stable complex w/bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. It targets the β-subunit of bacterial RNA polymerase.

PURPOSE: Mycobacterial infections, including tuberculosis

ADVERSE: Thrombocytopenia, hepatotoxicity, saliva, tear, sweat and urine discoloration, influenza like illness, elevated LFTs, GI disturbance

CONTRA: Active Neisseria meningitidis infection

NOTES: Avoid concurrent administration of clarithromycin w/rifabutin, b/c clarithromycin increases plasma concentration of rifabutin and rifabutin reduces plasma concentration of clarithromycin

Front 19

19. What are three general consideration that apply to inhibitors of bacterial translation?

Back 19

1. Translation inhibitors target either the 30S or 50S subunit of the bacterial ribosome.

2. In addition to their inhibitor effects on bacterial ribosomes, protein synthesis inhibitors can affect mammalian mitochondrial ribosomes, cytosolic ribosomes, or both.

3. Complete inhibition of protein synthesis is not sufficient to kill a bacterium.

Front 20

20. What is the most common mechanism by which inhibitors of translation cause adverse effects?

Back 20

Through inhibition of host ribosomes.

Front 21

21. What are the three categories of drugs that target the 30S ribosomal subunit?

Back 21

1. Aminoglycosides
2. Spectinomycin
3. Tetracyclines

Front 22

22. What are aminoglycosides?

What are the names of the aminoglycosides?

Back 22

Aminoglycosides are used mainly to treat infections caused by Gram-negative bacteria. These agents are charged molecules that are not orally bioavailable so they must be administered parenterally.

They include:
1. Streptomycin
2. Amikacin
3. Gentamicin
4. Kanamycin
5. Neomycin
6. Netilmicin
7. Paromomycin
8. Tobramycin

Front 23

23. Aminoglycosides

Back 23

MOA: Bind to 16S rRNA of the 30S subunit and elicit concentration-dependent effects on protein synthesis. Aminoglycosides are bactericidal due to induction of mRNA misreading; misread mRNA causes synthesis of aberrant proteins that insert into membrane, forming pores that eventually lead to cell death.

PURPOSE: Serious Gram-negative infections

ADVERSE: *Ototoxicity, acute renal failure, neuromuscular blockage, respiratory paralysis

CONTRA: Hypersensitivity to aminoglycosides

NOTES: Act synergistically w/β-lactam antibiotics

Front 24

24. What are the 3 mechanisms by which bacteria can become resistant to aminoglycosides?

Back 24

1. Plasmid-encoded production of a transferase enzyme or enzymes that inactivate aminoglycosides.

2. Impaired drug entry, possibly by alteration or elimination of porins or other proteins involved in drug transport.

3. Mutation of the drug target on the 30S ribosomal subunit.

Front 25

25. What is the David model?

Back 25

The David model frames the story of cell death in terms of the concentration dependent effects of aminoglycosides.

When drug first enters the cell, it is poorly transported across bacterial membranes. At these initial low concentrations, misreading occurs, leading to synthesis of aberrant proteins. Some of these proteins insert into membranes and cause the formation of membrane pores, which allow aminoglycosides to flood the cell and halt protein synthesis completely.

As a result, the damage to the membrane cannot be repaired, and leakage of ions and, later, larger molecules leads to cell death.

Front 26

26. What is the single most important factor restricting aminoglycoside use?

Back 26

Ototoxicity (manifesting as either auditory or vestibular damage).

The aminoglycosides are known to accumulate in the perilymph and endolymph of the inner ear and at high concentrations, to damage highly sensitive hair cells.

Aminoglycosides can also cause acute renal failure, apparently as a result of drug accumulation in proximal tubular cells.

Front 27

27. Spectinomycin

Back 27

MOA: Structural relative of the aminoglycosides that also binds to the 16S rRNA of the 30S ribosomal subunit. Spectinomycin permits formation of the 70S complex but inhibits translocation. It is not bactericidal but is bacteriostatic.

PURPOSE: Alternative therapy for gonorrheal infections

ADVERSE: Injection site pain, nausea, dizziness, insomnia

CONTRA: Hypersensitivity to spectinomycin

Front 28

28. What are tetracyclines and what are their names?

Back 28

Tetracyclines are broad-spectrum, bacteriostatic antibiotics that are used widely.

They are:
1. Chlortetracycline
2. Demeclocycline
3. Doxycycline
4. Methacycline
5. Minocycline
6. Oxytetracycline
7. Tetracycline

Front 29

29. MOA of tetracyclines

Back 29

Tetracyclines bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

This action prevents the addition of further AAs to the nascent peptide.

Front 30

30. What is the reason for the high selectivity of tetracyclines in bacteria?

Back 30

The high selectivity derives from active accumulation of these drugs in bacteria but not in mammalian cells.

Tetracyclines enter Gram-negative bacteria by passive diffusion through porin protein in the outer membrane, followed by active transport across the inner cytoplasmic membrane.

In contrast, mammalian cells lack the active transport system found in susceptible bacteria.

Front 31

31. Tetracyclines

Back 31

MOA: Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex.

PURPOSE: Used to treat a variety fo infections, including Corynebacterium acnes, Haemophilus influenze, Vibrio cholerae, spirochetes, Mycoplasma pneumoniae, Chlamydia species, and rickettsial species. Also used for malaria prophylaxis (doxycycline).

ADVERSE: Bulging fontanelle, *discoloration and hypoplasia of teeth and temporary stunting of growth, hepatotoxicity, pseudotumor cerebri, *photosensitivity, rash, GI disturbance, vestibular disturbance (minocycline), candidal infection.

CONTRA: Last half of pregnancy, infancy, < 8 y/o; patients with sever renal impairment should not be treated w/any tetracyclines except for doxycycline.

Front 32

32. How does tetracycline resistance occur?

Back 32

Tetracycline resistance occurs by plasmid-encoded efflux pumps, production of proteins that interfere w/binding of tetracyclines to the ribosome, or enzymatic inactivation of tetracyclines.

Front 33

33. Important pharmacokinetic feature of tetracyclines

What do tetracyclines have to do with acitretin?

Back 33

Interaction of these drugs w/foods high in calcium.

B/c these products and medicines impair the absorption of tetracyclines, the tetracyclines are generally taken on an empty stomach.

Once they are in the circulation, however, the same interaction w/cations, can cause sequestration of the drugs in bone and teeth.

*Also, avoid coadministration with acitretin due to increased risk of elevated ICP

Front 34

34. What are the two most problematic adverse effects of the tetracyclines?

Back 34

Kidney toxicity and GI distress.

Nausea and vomiting are the most common reasons for premature discontinuation of a course of tetracycline.

Front 35

35. What's so special about doxycycline?

Back 35

Compared w/other tetracyclines, a lower fraction of doxycycline is eliminated via the kidney, making this drug safer for use in patients w/renal failure.

Also, doxycycline is excreted in the feces largely in an inactive form, so this agent has the added advantage of minimally altering intestinal flora.

Hence, doxycline use is associated w/a lower incidence of nausea, vomiting, and superinfection w/pathogenic organisms than the other tetracyclines, especially in an immunocompromised patient.

Front 36

36. What are the glycylcyclines?

Back 36

They are a new class of antibiotics.

It includes Tigecycline, which has a broad spectrum of activity and has been approved for IV administration in the treatment of serious skin and abdominal infections.

Front 37

37. Tigecycline

Back 37

MOA: Resembles that of the tetracyclines; Bind reversibly to the 16S rRNA of the 30S subunit and inhibit protein synthesis by blocking the binding of aminoacyl tRNA to the A site on the mRNA ribosome complex. It is bacteriostatic.

PURPOSE: Skin or subcutaneous infection, complicated abdominal infection

ADVERSE: GI disturbance

CONTRA: Hypersensitivity to tigecycine

Front 38

38. What are the five categories of antibiotics that target the 50S ribosomal subunit?

Back 38

1. Macrolides and ketolides
2. Chloramphenicol
3. Lincosamides
4. Streptogramins
5. Oxazolidinones

Front 39

39. What are macrolides?

What is their MOA?

Back 39

Macrolides are named for their large lactone rings. They are especially important in the treatment of pulmonary infections, including Legionnaire's disease.

They are bacteriostatic antibiotics that block the translocation step of protein synthesis by targeting the 23S rRNA of the 50S subunit. Macrolides bind to a specific segment of 23S rRNA and block the exit tunnel form which nascent peptides emerge.

Front 40

40. What are the names of the macrolides and ketolides?

Back 40

1. Azithromycin
2. Clarithromycin
3. Erythromycin
4. Telithromycin

Front 41

41. What is erythromycin used to treat?

Back 41

Erythromycin is used to treat a variety fo infections, notably those due to Corynebacterium acnes, Legionella pneumophila, Treponema pallidum (syphilis), Mycoplasma pneumoniae, and Chlamydia species

Front 42

42. What is clarithromycin used to treat?

Back 42

Clarithromycin has increased activity against H.. influenzae.

Front 43

43. What is azithromycin used to treat?

Back 43

Azithromycin has increased activity against H. influenzae and Moraxella catarrhalis.

Front 44

44. Adverse effects and contraindications of macrolides and ketolides

Back 44

ADVERSE: *Acute cholestatic hepatitis, *ototoxicity, fulminant hepatic necrosis (rare, telithromycin), and GI disturbance

CONTRA: Hepatic dysfunction

Front 45

45. How is resistance accomplished by bacteria against macrolides?

Back 45

Resistance can be onferred by chromosomal mutations leading to alteration of the 50S ribosomal binding site, production of methylases that alter the 50S binding site, or production of esterases that degrade macrolides.

Front 46

46. What is the most frequent reason for discontinuing erythromycin?

Back 46

GI intolerance, as the drug can directly stimulate gut motility and cause nausea, vomiting, diarrhea, and sometimes anorexia.

Azithromycin and clarithromycin are generally well tolerated, although these drugs can also cause liver impairment.

Front 47

47. What are the pharmacological interactions with macrolide use?

Back 47

Macrolides and ketolides inhibit hepatic metabolism of cyclosporine, carbamazepine, warfarin, and theophylline, and can lead to toxic levels of these drugs.

Macrolides eliminate certain species of intestinal flora that inactivate digoxin, thereby leading to greater oral absorption of digoxin in some patients.

Front 48

48. Telithromycin

Back 48

This is the ketolide that has a MOA similar to that of the macrolides, but w/a higher affinity for the 50S ribosomal subunit due to its ability to bind an additional site on 23S rRNA.

This higher affinity allows the use of telithromycin in treating infections due to certain bacterial strains that are resistant to macrolides.

Front 49

49. Chloramphenicol

Back 49

MOA: Binds to 23S rRNA and inhibits peptide bond formation, apparently by occupying a site that interferes w/proper positioning of the aminoacyl moiety of tRNA in the A site.

PURPOSE: Bacteriostatic broad-spectrum antibiotic that is effective against Gram+ and Gram- bacteria (especially anaerobes), and rickettsiae.

ADVERSE: *Hemolytic anemia in patients with low levels of G6PD, aplastic anemia, **gray baby syndrome

CONTRA: Hypersensitivity to chloramphenicol

NOTES: Most adverse effects are due to inhibition of mitochondrial function.

Front 50

50. What are the organisms most highly susceptible to chloramphenicol treatment?

Back 50

1. Haemophilus influenzae
2. Neisseria meningitidis
3. Some strains of Bacteriodes

This drug is still used occasionally in the treatment of typhoid fever, bacterial meningitis, and rickettsial diseases, but only when safer alternatives are not available.

Front 51

51.How have microbes developed resistance to chloramphenicol?

Which two mechanisms are at work here...?

Back 51

1. Low level resistance has emerged by the selection of mutants w/decreased permeability to the drug.

2. More clinically significant is the type of resistance that has arisen from the spread of specific plasmid-encoded acetyltransferases that inactivate the drug.

Front 52

52. What is the gray baby syndrome?

Back 52

Occurs when chloramphenicol is administered at high doses to newborn infants.

B/c newborns lack an effective glucuronic acid conjugation mechanism for the degradation and detox of chloramphenicol, the drug can accumulate to toxic levels and cause vomiting, hypothermia, gray color, respiratory distress, and metabolic acidosis.

Front 53

53. What are the pharmacologic interactions with chloramphenicol?

Back 53

Cloramphenicol antagonizes the bactericidal effects of penicillins and aminoglycosides

Like the macrolides, it also inhibits hepatic metabolism of warfarin, phenytoin, tolbutamide, and chlorpropamide, and thereby potentiates their effects.

Front 54

54. Lincosamides: clindamycin

Back 54

MOA: Clindamycin blocks peptide bond formation, apparently through interactions with both the A site (like chloramphenicol) and the P site.

PURPOSE: Bacterial infections due to anaerobic organisms

ADVERSE: **Psuedomembranous colitis, increased liver function tests, jaundice, GI disturbance, rash

CONTRA: Hypersensitivity to clindamycin

*NOTES: Clindamycin is associated w/overgrowth of C. difficile, which can result in pseudomembranous colitis.

Front 55

55. What are the drugs that are mixed in streoptogramins?

Back 55

1. Dalfopristin, a group A steptogramin

2. Quinupristin, a group B streptogramin

Front 56

56. Streptogramins

Back 56

MOA: Inhibit protein synthesis by binding to the peptidyl transferase center of bacterial 23S rRNA.

PURPOSE: Vancomycin-resistant enterococcus (VRE) infection, skin and subcutaneous infection caused by staphylococcal or streptococcal species.

ADVERSE: Injection site inflammation, GI disturbance, hyperbilirubinemia, arthralgia, myalgia, headache

NOTES: Should not be coadministered w/SSRIs, due to risk of serotonin syndrome. Coadministration with pimozide should be avoided due to increased risk fo cardiotoxicity

Front 57

57. How are streptogramins unusual among the 50S antibiotics?

Back 57

They are bactericidal against many, but not all, susceptible bacterial species.

Current hypothesis is that, unlike other 50S antibiotics, the streptogramins induce a conformational change in the ribosome that is reversible only after subunit dissociation.

Front 58

58. Oxazolidinones: Linezolid

Back 58

MOA: Linezolid appears to act at the 50S ribosomal subunit b/c mutations in 23S rRNA can confer drug resistance.

PURPOSE: Gram+ bacterial infections, especially VRE, MRSA, S. agalactiae, S. pneumoniae (including multi-drug resistant strains) and S. pyogenes, nosocomial pneumonia, complicated diabetic foot infections

ADVERSE: *Myelosuppression, peripheral neuropathy, optic neuropathy

CONTRA: Hypersensitivity to linezolid

NOTES: Available in both oral and IV formulation; precise mechanism of action remains uncertain.

Front 59

59. What is the log cell kill model?

Back 59

The log cell kill model states that the cell destruction caused by cancer chemotherapy is first-order; that is, that each does of chemo kills a constant fraction of cells.

If the tumor starts with 10^12 cells and 99.99% are killed, then 10⁸ malignant cells will remain. The next dose of chemo will then kill 99.99% of the remaining cells, and so on.

Front 60

60. What is the composition of gram-positive bacteria?

Back 60

In Gram-positive bacteria, the cell wall is composed of a thick layer of murein, through which nutrients, waste products, and antibiotics can diffuse. Lipoteichoic acids in the outer leaflet of the cytopasmic membrane intercalate thru the cell wall to the outer surface of Gram-positive bacteria.

The hydrophilic side chains of these molecules are involved in bacterial adherence, feeding, and evasion of the host immune system.

These bacteria appear purple.

Front 61

61. What is the composition of gram-negative bacteria?

Back 61

In gram-negative bacteria, the murein layer is thinner and is surrounded by a second, outer lipid bilayer membrane. Hydrophilic molecules cross this outer membrane through channels, which are formed by a cylindrical arrangement of porins.

Gram-negative bacterial also have LPS in the outer membrane, which is a major antigen for the immune response to Gram-negative organisms.

These bacteria appear pink.

Front 62

62. What is the main difference between Gram-negative bacteria and mycobacteria?

Back 62

Both mycobacteria and Gram-negative bacteria are enclosed by an inner membrane, a murein layer, and an outer membrane.

The main structural different is that in mycobacteria, the two leaflets of the outer membrane are asymmetric in size and composition; the inner leaflet of the outer membrane is composed of arabinogalactan and mycolic acids, whereas the outer leaflet is composed of extractable phospholipids.

Front 63

63. What are the four inhibitors of murein monomer synthesis?

Back 63

1. Fosfomycin
2. Fosmidomycin
3. Cycloserine
4. Bacitracin

Front 64

64. Fosfomycin

Back 64

MOA: Inhibits murein monomers. It is a PEP analogue that inhibits bacterial enol pyruvate transferase by covalent modification of the enzyme's active site. It enters the cells via G-6-P that are normally used by bacteria

Purpose: Gram-negative urinary tract infections: E. coli, Klebsiella, Serratia, Clostridia. ***It is excreted unchanged in the urine***

ADVERSE: Headache, diarrhea, nausea

CONTRA: Hypersensitivity

Front 65

65. Therapeutic considerations for fosfomycin

Back 65

1. Synergistic with beta-lactams, aminoglycosides, and fluoroquinolones
2. Decreased absorption when coadministered with antacids or motility agents such as metoclopramide
3. Less effective against Gram-positive bacteria b/c these bacteria generally lack selective glycerophosphate and G6P transporters.

Front 66

66. Fosmidomycin

Back 66

Fosmidomycin, another PEP analogue, acts by the same mechanism as fosfomycin, and resistance typically arises via mutations in glycerophosphate or G6P transports.

Fosmidomycin also has activity against malaria, but the drug has a different MOA and is not currently in clinical use for that organism.

Front 67

67. Cycloserine

Back 67

MOA: Cycloserine is a structural analogue of D-Ala; it irreversibly inhibits both the alanine racemase and the synthetase that joins together two D-Ala molecules.

PURPOSE: Multidrug resistant tuberculosis infection and M. avium complex

ADVERSE: Seizures, somnolence, peripheral neuropathy, psychosis

CONTRA: Epilepsy, depression, anxiety, psychosis, severe renal insufficiency, alcohol abuse

Front 68

68. Cycloserine therapeutic considerations

Back 68

1. Alcohol, isoniazid, and eithionamide potentiate cycloserine toxicity
2. Pyridoxine may prevent cycloserine-induced peripheral neuropathy
3. Cycloserine inhibits hepatic metabolism of phenytoin

Front 69

69. Bacitracin

Back 69

MOA: Peptide antibiotic that inhibits dephosphorylation by forming a complex with bactoprenol pyrophosphate, rendering this lipid carrier useless for further rounds of murein monomer translocation.

PURPOSE: Cutaneous and eye infections (topical), GI decontamination of C. difficile or VRE (oral)

ADVERSE: If systemic absorption occurs: nephrotoxicity, neurotoxicity, bone marrow suppression; With topical: contact dermatitis, blurred vision, red eye

CONTRA: Coadministration with nephrotoxic agents or neuromuscular blocking agents.

NOTE: Drugs that act as metal chelators could interfere with the activity of bacitracin.

Front 70

70. What are the two inhibitors of murein polymer synthesis?

How do they work?

Back 70

Vancomycin and teicoplanin are glycopeptides with bactericidal activity against Gram-positive rods and cocci.

These agents interrupt cell wall syntehsis by binding tightly to the D-Ala D-Ala terminus of the murein monomer unit, inhibiting transglycosidase and thereby blocking the addition of murein units.

Front 71

71. Vancomycin and teicoplanin

Back 71

MOA: Interrupts cell wall syntehsis by binding tightly to the D-Ala D-Ala terminus of the murein monomer unit, inhibiting transglycosidase and thereby blocking the addition of murein units.

PURPOSE: MRSA (IV), and C. difficile enterocolitis (oral)

ADVERSE: Neurtropenia, ototoxicity, nephrotoxicity, anaphylaxis, *Red man syndrome*

CONTRA: Solutions containing dextrose in patients with known corn allergy

Front 72

72. Vancomycin and teicoplanin therapeutic considerations

Back 72

1. Increased nephrotoxicity w/aminoglycosides
2. Red man syndrome can be avoided by slowing infusion rate or pre-administering antihistamines
3. Resistance occurs thru acquisition of DNA encoding enzymes that catalyze formation of D-Ala D-lactate
4. Teicoplanin is not used clinically in the US.

Front 73

73. What is the "red man syndrome"?

Back 73

Skin flushing or rash caused by fast infusion rates of vancomycin.

Other adverse effects of vancomycin are drug fever, hypersensitivity rash, and anaphylaxis.

These can be prevented by slowing the rate of infusion and by giving antihistamines prophylactically.

Front 74

74. What are the four families of β-lactam agents?

Back 74

1. Penicillins
2. Cephalosporins
3. Monobactams
4. Carbapenems

Front 75

75. What are the two factors that determine a β-lactam's spectrum of action?

Back 75

1. The degree to which it can penetrate the outer membrane and cell wall

2. Its ability to bind to specific transpeptidases once in the periplasmic space.

Front 76

76. What are the broad spectrum β-lactams?

Back 76

Hydrophilic agents such as ampicillin, amoxicillin, and especially, piperacillin, ticarcillin, carbenicillin, and mezolocillin tend to have broader spectrum of action.

Front 77

77. What are the narrow spectrum β-lactams?

Back 77

Hydrophobic agents such as oxacillin, cloxacillin, dicloxacillin, nafcillin, methicillin, and penicillin G tend to have narrow spectrum of action.

Front 78

78. Penicillin G and V

Back 78

MOA: β-lactams inhibit transpeptidase by forming a covalent dead-end acyle enzyme intermediate (Suicide substrate inhibition). Penicillins have a 5-membered accessory ring attached to the β-lactam ring.

PURPOSE: Penicllin-sensitive S. aureus and S. pyogenes, rogal anaerobes, N. meningitidis, Clostridia species; Syphilis, Yaws, Leptospirosis. Prophylaxis of rheumatic fever (penicillin V)

ADVERSE: Seizures, pseudomembranous enterocolitis, drug-induced eosinophilia, hemolytic anemia, acute interstitial nephritis, anaphylaxis, rash, fever, injection site reaction, Jarisch Herxheimer reaction when used to treat syphilis.

CONTRA: Hypersensitivity to penicillins

Front 79

79. Penicillin G and V notes

Back 79

1. Penicillin G is the IV preparation; Penicillin V is the oral preparation
2. Anticoagulant effects of warfarin may be potentiated by concomitant penicillin administration
3. IV penicillin G is preferred to oral penicillin V in hospital settings
4. *β-lactamase sensitive

Front 80

80. What are the common uses for penicillin V?

Back 80

Used mostly to treat mixed aerobic-anaerobic infections of the head and neck, such as dental abscesses.

Additionally, it is used to prevent recurrent rheumatic fever and recurrent streptococcal cellulitis in patients with lymphedema.

Front 81

81. What are the five antistaphylococcal penicillins?

Back 81

1. Oxacillin
2. Cloxacillin
3. Dicloxacillin
4. Nafcillin
5. Methicillin

Front 82

82. Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin, Methicillin

Back 82

MOA: β-lactams inhibit transpeptidase by forming a covalent dead-end acyle enzyme intermediate (Suicide substrate inhibition). Penicillins have a 5-membered accessory ring attached to the β-lactam ring.

PURPOSE: Skin and soft-tissue infections or systemic infection with β-lactamase producing MRSA

ADVERSE: Diarrhea, nausea, vomiting, pseudomembranous colitis (cloxacilling, dicloxacillin), Hepatitis (oxacilling) interstitial nephritis, phlebitis (nafcillin)

CONTRA: Hypersensitivity

NOTES: *β-lactamase resistant! These agents are narrow spectrum.

Front 83

83. What are the names of the four amino penicillins?

Back 83

1. Ampicillin
2. Amoxicillin
3. Amoxicillin/clavulanic acid
4. Ampicillin/sulbactam

These agents have a positively charged amino group on the side chain which enhances diffusion through porin channels but does not confer resistance to β-lactamases.

Front 84

84. What are the uses for IV ampicillin?

Back 84

Invasive enterococcal infections and Listeria meningitis

Front 85

85. What are the uses for oral amoxicillin?

Back 85

Uncomplicated ear nose and throat infections, endocarditis prevention, dental surgery prophylaxis, and component of combination therapy for H pylori infection.

Front 86

86. Adverse, contra, and notes for the amino penicillins

Back 86

ADVERSE: Rash, anusea, vomiting, diarrhea

CONTRA: Hypersensitivity

NOTES:
1. Broad spectrum anti-bacteria activity
2. Ampicillin and amoxicillin are beta-lactamase sensitive as single agents; clavulanic acid and sulbactam are beta-lactamase inhibitors
3. Positively charged amino group on side chain enhances diffusion thru porin channels of Gram-negative bacteria

Front 87

87. What are the two carboxy penicillins?

Back 87

1. Carbenicillin
2. Ticarcillin

These agents are broad spectrum antibiotics that have a side chain carboxyl group that provides a negative charge which confers some resistance to some β-lactamases

Front 88

88. What are the two ureido penicillins?

Back 88

1. Piperacillin
2. Mezlocillin

These drugs have both positive and negative charges on their side chains and are generally more potent than the carboxy penicillins.

Their spectrum of action is similar to that of carboxy penicillins; in addition, they have activity against Klebsiella and enterococci

Front 89

89. Carbenicillin, ticarcillin, piperacillin, mezlocillin

Back 89

PURPOSE: Primarily used as treatment or prophylaxis against P. aeruginosa infection; Hospital acquired pneumonia due to resistant Gram-negative organisms

ADVERSE: Rash, nausea, vomiting, diarrhea

CONTRA: Hypersensitivity to penicillins

NOTES: Broad spectrum activity but primarily used against P. aeruginosa. Generally beta-lactamase sensitive except for carbenicillin and ticarcillin

Front 90

90. What are the cephalosporins?

Back 90

Cephalosporins differ structurally from penicillins by having a six-membered ring rather than a five membered ring attached to the β-lactam ring.

Front 91

91. First generation cephalosporins:

Cefazolin & cephalexin

Back 91

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; relatively good Gram-positive coverage; sensitive to many β-lactamases

PURPOSE: Proteus mirabilis, E. coli, Klebsiella pneumoniae, Skin and soft tissue infections, surgical prophylaxis

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 92

92. Second generation cephalosporins:

Cefuroxime, cefotetan, cefoxitin

Back 92

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; relatively broader Gram-negative coverage than first gen; more resistant to β-lactamases than first gen

PURPOSE: H. influenzae (cefuroxime), Enterobacter spp., Neisseria spp., P. mirabilis, E. coli, K. pneumoniae (cefotetan and cefoxitin)

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Cefotetan may produce disulfiram-like reaction w/alcohol ingestion and block synthesis of vitamin K-dependent coagulation factors

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 93

93. Common uses for cefuroxime, cefotetan and cefoxitin?

Back 93

Cefuroxime is primarily used in community acquired pneumonia

Cefotetan and cefoxitin are primarily used in intra-abdominal and pelvic infections.

Front 94

94. Third generation cephalosporins:

Cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime

Back 94

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; *Highest CNS penetration of the cephalosporins.

PURPOSE: N. gonorrhoeae, Borrelia burgdorferi, H. influenza, most Enterobacteriaceae (ceftriaxone), H. influenzae (cefotaxime), P. aeruginosa (ceftazidime).

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Ceftriaxone may cause cholestatic hepatitis, and cefoperazone may produce disulfiram-like reaction w/alcohol ingestion and block synthesis of vitamin K-dependent coagulation factors

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

NOTE: Resistant to many β-lactamases; highly active against Enterobacteriaceae, but less active against Gram-positive organisms than are first gen cephalosporins

Front 95

95. Fourth generation cephalosporin:

Cefepime

Back 95

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; *resistant to many beta-lactamases

PURPOSE: Enterobacteriaceae, Neisseria, H. influenzae, P. aeruginosa, Gram-positive organisms

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Cefepime may produce erythrocyte autoantibodies w/o significant hemolysis

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 96

96. What are the inhibitors of polymer crosslinking?

Back 96

1. Aztreonam
2. Imipenem/cilastatin
3. Meropenem
4. Ertapenem

Front 97

97. Aztreonam

Back 97

MOA: A monobactam that inhibits transpeptidase by forming a dead-end acyl enzyme intermediate

PURPOSE: Gram-negative bacteria; *used in penicillin allergic patients*

ADVERSE: Same as penicillins

NOTES: No Gram-positive coverage

Front 98

98. Imipenem/cilastatin, Meropenem, Ertapenem

Back 98

MOA: A carbapenem that inhibits transpeptidase by forming a dead-end acyl enzyme intermediate

PURPOSE: Gram-positive and Gram-negative bacteria except MRSA, VRE, and Legionella

ADVERSE: same as penicillins, except *High plasma levels of imipenem and meropenem may cause seizures

Front 99

99. Carbapenem notes

Back 99

NOTES:
1. Cilastin inhibits renal dehydropeptidase I, which would otherwise inactivate imipenem
2. Probenecid may increase meropenem levels
3. All three agents decrease valproate levels
4. Ertapenem can be give one-daily.

Front 100

100. What are the three antimicrobial agents?

Back 100

1. Ethambutol
2. Pyrazinamide
3. Isoniazid (INH)

Front 101

101. Ethambutol

Back 101

MOA: Inhibits the arabinosyl transferase that adds arabinose units to the growing arabinogalactan chain and thus decreases arabinogalactan synthesis.

PURPOSE: Mycobacteriostatic, and used in combo with other antimycobacterials, including rifampin and streptomycin

ADVERSE: Optic neuritis, blindness, peripheral neuropathy, neutropenia, thrombocytopenia, hyperuricemia, mania, nausea, vomiting

CONTRA: Known optic neuritis, patients unable to report visual changes such as young children, *Coadministration with antacids

Front 102

102. Pyrazinamide

Back 102

MOA: Pyrazinamide is a prodrug that must be converted to its active form pyrazinoic acid, which inhibits fatty acid synthestase 1 (FAS1) and thus inhibits mycolic acid synthesis.

PURPOSE: Mycobacterium species; used in combo w/rifampin and streptomycin

ADVERSE: Anemia, hepatotoxicity, arthralgias, hyperuricemia (usually asymptomatic)

CONTRA: Acute gout, severe hepatic dysfunction

Front 103

103. Isoniazid and ethionamide

Back 103

MOA: Targets the FAS2 complex and thus inhibits mycolic acid synthesis.

PURPOSE: Mycobacterium species, and is used in combo with other antimycobacterials

ADVERSE: Hepatitis, *neurotoxicity (paresthesias, peripheral neuropathy, ataxia), SLE, seizure, hematologic abnormalities

CONTRA: Acute liver disease

NOTES: Can inhibit or induce p450 enzymes and thus interacts w/other drugs such as rifampin, antiseizure meds, antifungals, and alcohol; *INH neurotoxicity can be prevented by pyridoxine supplementation

Front 104

104. How does resistance to INH occur?

Back 104

Resistance to INH results from an inactivating mutation in the mycobacterial enzyme catalase-peroxidase, which converts INH to ints antimycobacterial form. Mutations in the INHA gene, which is required for mycolic acid synthesis, also confer resistance to INH.

Front 105

105. How does resistance to ethambutol occur?

Back 105

Results from mutations in the arabinosyl transferase gene, some of which cause overexpression of the target enzyme

Front 106

106. How does resistance to pyrazinamide occur?

Back 106

Due to mutations in the pyrazinamidase gene, which result in the inability to convert the prodrug into its active form.

Front 107

107. What are 7 congenital or development defects of the lung?

Back 107

1. Agenesis or hypoplasia of both lungs, one lung, or single lobes
2. Tracheal and bronchial anomalies (atresia, stenosis, tracheoesophageal fistula)
3. Vascular anomalies
4. Congenital lobar overinflation (emphysema)
5. Foregut cysts
6. Congenital pulmonary airway malformation
7. Pulmonary sequestrations

Front 108

108.What is pulmonary hypoplasia?

Back 108

Pulmonary hypoplasia is the defective development of both lungs resulting in decreased weight, volume, and acini compared to the body weight and gestational age.

It is a common anomaly, seen in 10% of neonatal autopsies, and is most often secondary to space-occupying lesions in the uterus, oligohydraminos, or impaired fetal respiratory movements, as may occur in congenital diaphragmatic hernia, renal cystic disease, renal agenesis, PPROFM, and anencephaly.

Front 109

109. What are foregut cysts?

Back 109

Foregut cysts represent an abnormal detachment of primitive foregut and are most often located in the hilum or middle mediastinum.

Depending on the wall structure, these cysts are classified into bronchogenic (most common), esophageal, or enteric cysts.

Front 110

110. What are bronchogenic cysts?

Back 110

Bronchogenic cysts are rarely connected to the tracheobroncheal tree. It presents in children and young adults as an incidental finding or with symptoms related to mass effect or secondary infection.

Its size varies from 1-4 cm in diameter, but it may be larger in older pts.

*Microscopically, the cyst is lined by ciliated pseudostratified columnar epithelium w/squamous metaplasia occurring in areas of inflammation. The wall contains bronchial glands, cartilage, and smooth muscle.

Front 111

111. What is congenital pulmonary airway malformation (CPAM)?

Back 111

CPAM is a hamartomatous lesion of the lung, with an incidence of about 1 in 5,000 live births. It an be separated into five types based on clinical and pathologic features.

CPAM type 1 is the most common w/large cysts and good prognosis. CPAM type 2, with medium-sized cysts, often has a poor prognosis owing to its frequent association with other significant anomalies.

Front 112

112. What is pulmonary sequestration?

Back 112

Pulmonary sequestration refers to the presence of a discrete mass of lung tissue w/o any normal connection to the airway system. Blood supply to the sequestered area arises not from the pulmonary arteries but from the aorta or its branches

Front 113

113. What are extralobar sequestrations?

Back 113

Extralobar sequestrations are external to the lung and may be found anywhere in the thorax or mediastinum.

Found most commonly in infants as abnormal mass lesions, they may be associated with other congenital anomalies.

Front 114

114. What about intralobar sequestrations?

Back 114

Intralobar sequestrations are found within the lung substance and are usually associated with recurrent localized infection or bronchiectasis.

Although a small percentage of these are clearly congenital in origin, the vast majority are probably acquired lesions formed thru repeated episodes of pneumonia.

Front 115

115. What does atelectasis mean?

What are the three types of acquired atelectasis?

Back 115

Atelectasis refers either to incomplete expansion of the lungs or to the collapse of previously inflated lung, producing areas of relatively airless pulmonary parenchyma.

Acquired atelectasis, encountered principally in adults, may be divided into resorption (or obstruction), compression, and contraction atelectasis.

Front 116

116. What is resorption atelectasis?

Back 116

Resorption atelectasis is the consequence of complete obstruction of an airway, which in time leads to resorption of the oxygen trapped in the dependent alveoli, w/o impairment of blood flow thru the affected alveolar walls. Since lung volume is diminished, the mediastinum shifts toward the atelectatic lung.

Resorption atelectasis is caused principally by excessive secretions (e.g., mucous plugs) or exudates w/in smaller bronchi and is therefore most often found in bronchial asthma, chronic bronchitis, bronchiectasis, and postoperative states and with aspiration of foreign bodies.

Front 117

117. What is compression atelectasis?

Back 117

Compression atelectasis results whenever the pleural cavity is partially or completely filled by fluid exudate, tumor, blood or air (pneumothorax) or tension pneumothorax.

Compression atelectasis is most commonly encountered in pts with neoplastic effusions w/in the pleural cavities. Similarly, abnormal elevation of the diaphragm induces basal atelectasis.

*W/compressive atelectasis, the mediastinum shifts away from the affected lung.

Front 118

118. What is contraction atelectasis?

Back 118

Contraction atelectasis occurs when local or generalized fibrotic changes in the lung or pleura prevent full expansion.

B/c collapsed lung can be re-expanded, atelectasis is a reversible disorder *except that caused by contraction*

Front 119

119. What are the cytokines that mediate acute lung injury?

Back 119

Mediators include cytokines, oxidants, and growth factors, such as TNF, IL-1, IL-6, IL-10, and TGF-beta.

Lung injury may manifest as congestion, edema, surfactant disruption, and atelectasis, and these may progress to acute respiratory distress syndrome or acute interstitial pneumonia.

Front 120

120. What can cause pulmonary edema?

Back 120

Pulmonary edema can result from hemodynamic disturbances (hemodynamic or cardiogenic pulmonary edema) or from direct increases in capillary permeability, owing to microvascular injury.

Front 121

121. What is the most common hemodynamic mechanism of pulmonary edema?

Back 121

Increased hydrostatic pressure, as occurs in left-sided CHF.

Front 122

122. What are the characteristics of hemodynamic pulmonary edema?

Back 122

Whatever the clinincal setting, pulmonary congestion and edema are characterized by heavy, wet lungs. Fluid accumulates initially in the basal regions of the lower lobes b/c hydrostatic pressure is greater in these sites (dependent edema).

Histologically, the alveolar capillaries are engorged, and an intra-alveolar granular pink precipitate is seen. Alveolar microhemorrhages and hemosiderin-laden macrophages ("heart failure" cells) may be present.

Front 123

123. What are the characteristics of the lungs in long-standing pulmonary congestion, such as those seen in mitral stenosis?

Back 123

In long standing cases, hemosiderin-laden macrophages are abundant, and fibrosis and thickening of the alveolar walls cause the soggy lungs to become firm and brown (brown induration).

These changes not only impair respiratory function, but also predispose to infection.

Front 124

124. What is ARDS?

Back 124

ARDS is a clinical syndrome caused by diffuse alveolar capillary damage. It is characterized clinically by the rapid onset of severe life threatening respiratory insufficiency, cyanosis, and severe arterial hypoxemia that is refractory to oxygen therapy and that may progress to extrapulmonary MSOF.

Chest radiographs show diffuse alveolar infiltration. ***Diffuse alveolar damage (DAD) is the histologic manifestation.

Front 125

125. What is the morphology of ARDS?

1/2

Back 125

In the acute stage, the lungs are heavy, firm, red, and boggy. They exhibit congestion, interstitial and intra-alveolar edema, inflammation, and fibrin deposition. The alveolar walls become lined with waxy hyaline membranes that are morphologically similar to those seen in hyaline membrane disease of neonates.

Front 126

126. What is the morphology of ARDS?

2/2

Back 126

Alveolar hyaline membranes consist of fibrin-rich edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithelial cells. In the organizing stage, type II epithelial cells undergo proliferation in an attempt to regenerate the alveolar lining. Resolution is unusual; more commonly, there is organization of the fibrin exudate, with resultant intra-alveolar fibrosis.

Marked thickening of the alveolar septa ensues, caused by proliferation of interstitial cells and deposition of collagen. Fatal cases often have superimposed bronchopneumonia.

Front 127

127. What is the pathogenesis of ARDS?

Back 127

ARDS and DAD are best viewed as the clinical and pathologic end results, respectively, of acute alveolar injury caused by a variety of insults and initiated by different mechanisms.

***Central to the causation of ARDS is diffuse damage to the alveolar capillary walls; this is followed by a relatively non-specific, often predictable series of morphologic and physiologic alterations leading to respiratory failure.

Front 128

128. How is ARDS different from the respiratory distress syndrome of neonates?

Back 128

The mechanism of the respiratory distress syndrome of newborns is a deficiency in pulmonary surfactant.

In contrast, in ARDS, the initial injury is to either capillary endothelium (most frequently) or alveolar epithelium, but eventually both are clearly affected.

Front 129

129. What are the acute consequences of damage to the alveolar capillary membrane?

Back 129

These include increased vascular permeability and alveolar flooding, loss of diffusion capacity, and widespread surfactant abnormalities caused by damage to type II pneumocytes.

Importantly, the exudate and diffuse tissue destruction that occur with ARDS cannot be easily resolved, and generally the result is organization with scarring, producing chronic disease.

Front 130

130. What is a critical component of lung inflammation?

Back 130

An elevated level or pro-inflammatory mediators combined w/a decreased expression of anti-inflammatory molecules is a critical component of lung inflammation.

This includes expression of pro-inflammatory genes, particularly NF-κB, since it is required for maximal expression of many cytokines involved in the pathogenesis of acute lung injury.

Front 131

131. What happens within the first 30 minutes following an acute insult (e.g., acid aspiration, trauma, or exposure to bacterial LPS)?

Back 131

There is increased synthesis of IL-8 by pulmonary macrophages. Release of this and other cytokines like IL-1 and TNF leads to pulmonary microvascular sequestration and activation of neutrophils.

***Neutrophils are thought to play an important role in the pathogenesis of acute lung injury and ARDS.

Activated neutrophils release a variety of products that cause active tissue damage and maintain the inflammatory response.

Front 132

132. ARDS is mainly associated with what four conditions?

Back 132

1. Sepsis
2. Diffuse pulmonary infections (vira, mycoplasma, and pneumocystis pneumonia, and tuberculosis)
3. Mechanical trauma, including head injuries
4. Gastric aspriation

Front 133

133. What is the clinical course of ARDS?

Back 133

Pts who develop ARDS are usually hospitalized for one or the predisposing conditions that cause it.

Profound dyspnea and tachypnea herald ARDS, but the chest radiograph is initially normal. Subsequently, there are increasing cyanosis and hypoxemia, respiratory failure, and the appearance of diffuse bilateral infiltrates on radiographic examination.

Hypoxemia can then become unresponsive to oxygen therapy, and respiratory acidosis can develop.

Front 134

134. What are the functional abnormalities of the lungs in ARDS?

Back 134

The functional abnormalities are not homogeneously distributed throughout the lungs. The lungs are focally stiff and have a decrease in functional volume. In essence, pts lungs can be divided into areas that are infiltrated, consolidated, or collapsed, and regions that have nearly normal levels of compliance and ventilation.

Lungs with ARDS continue to have perfusion of poorly aerated regions, contributing to V/Q mismatching and hypoxemia.

Front 135

135. What is acute interstitial pneumonia?

What causes it?

Back 135

Acute interstitial pneumonia is a clinicopathologic term that is used to describe widespread acute lung injury with a rapidly progressive clinical course similar to that seen in ARDS.

Whereas ARDS is associated with known causes such as sepsis, pulmonary infection, gastric aspiration or trauma, acute interstitial pneumonia is of unknown etiology.

Front 136

136. What are the clinical features of acute interstitial pneumonia?

Back 136

The mean age is 50. Pts present with acute respiratory failure often following an illness of less than 3 weeks duration that resembles and upper respiratory tract infection. The radiographic and pathologic features are identical to that of ARDS.

The mortality rate is about 50% with most deaths occurring within 1-2 months. In the surviving pts, recurrences and chronic interstitial disease may develop.

Front 137

137. What does obstructive lung disease mean?

Back 137

Obstructive disease is characterized by an increase in resistance to airflow owing to partial or complete obstruction at any level, from the trachea and larger bronchi to the terminal and respiratory bronchioles.

Front 138

138. What does restrictive lung disease mean?

Back 138

Restrictive disease is characterized by reduced expansion of lung parenchyma, with decreased total lung capacity.

Front 139

139. What are the four major diffuse obstructive disorders?

Back 139

1. Emphysema
2. Chronic bronchitis
3. Bronchiectasis
4. Asthma

*In pts with these diseases, pulmonary function tests show limitation of max airflow rates during forced expiration.

Front 140

140. What are the two general conditions that cause restrictive diseases?

Back 140

1. Chest wall disorders in the presence of normal lungs (e.g., neuromuscular diseases such as polio, severe obesity, pleural diseases, and kyphoscoliosis)
2. Acute or chronic interstitial and infiltrative diseases (ARDS)

*There is a reduced total lung capacity, while the expiratory flow rate is normal or reduced proportionately.

Front 141

141. What is emphysema?

What are the four major types?

Back 141

Emphysema is a condition of the lung characterized by abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

It is classified according to its anatomic distribution within the lobule. There are four major types:
1. Centriacinar
2. Panacinar
3. Paraseptal
4. Irregular

Front 142

142. What is centriacinar (centrilobular) emphysema?

Back 142

The distinctive feature of this type of emphysema is the pattern of involvement of the lobules; the central or primal parts of the acini, formed by respiratory bronchioles, are affected, whereas distal alveoli are spared. Thus, both emphysematous and normal airspaces exist within the same acinus and lobule.

The lesions are more common and usually more severe in the upper lobes, particularly in the apical segments. The walls of the emphysematous spaces often contain large amts of black pigment. Inflammation around bronchi and bronchioles is common.

Front 143

143. In what population is centriacinar emphysema most common?

Back 143

*Centriacinar emphysema occurs predominantly in heavy smokers, often in association with chronic bronchitis.

Front 144

144. What is panacinar (panlobular) emphysema?

Back 144

In this type, the acini are uniformly enlarged from the level of the respiratory bronchiole to the terminal blind alveoli.

In contrast to centriacinar emphysema, panacinar emphysema tends to occur more commonly i the lower zones and in the anterior margins of the lung, and it is usually most severe at the bases.

*This type of emphysema is associated with alpha-1-antitrypsin deficiency.

Front 145

145. What is distal acinar (paraseptal) emphysema?

Back 145

In this type, proximal portion of the acinus is normal, but the distal part is predominantly involved.

The emphysema is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the lobules. It occurs adjacent to areas of fibrosis, scarring, or atelectasis and is usually more severe in the upper half of the lungs.

Front 146

146. What are the characteristic findings in distal acinar emphysema?

Back 146

The characteristic findings in distal acinar emphysema are of multiple, continuous, enlarged airspaces from less than 0.5 cm to more than 2.0 cm in diameter, sometimes forming cystlike structures.

This type of emphysema probably underlies many of the cases of spontaneous pneumothorax in young adults.

Front 147

147. What is irregular emphysema?

Back 147

AKA airspace enlargement with fibrosis (irregular emphysema). It is so named b/c the acinus is irregularly involved, is almost invariably associated with scarring.

It may be the most common form of emphysema b/c careful search of most lungs at autopsy shows one or more scars from a healed inflammatory process. In most instances, these foci of irregular emphysema are asympatomatic and clinically insignificant.

Front 148

148. What is the incidence of COPD?

Back 148

COPD is a major public health problem. It is the fourth leading cause of morbidity and mortality in the US.

There is a clear-cut association between heavy cigarette smoking and emphysema, and the most severe type occurs in men who smoke heavily.

Front 149

149. What is the most plausible hypothesis to account for the destruction of alveolar walls in emphysema?

Back 149

The protease antiprotease mechanism, aided and abetted by oxidant-antioxidant imbalance.

This theory holds that alveolar wall destruction results from an imbalance between proteases (mainly elastase) and antiproteases in the lung.

Front 150

150. What is the principal antielastase activity in serum and interstitial tissue?

Back 150

Alpha-1-antitrypsin.

Neutrophil elastase is capable of digesting human lung, and this digestion can be inhibited by alpha-1-antitrypsin.

*Thus, emphysema is seen to result from the destructive effect of high protease activity in subjects w/low antiprotease activity.

Front 151

151. How does the protease-antiprotease hypothesis explain the deleterious effect of smoking?

Back 151

In smokers, there is both increased elastase availability and decreased antielastase activity.

Neutrophils and macrophages accumulate in alveoli due to the direct chemoattractant of nicotine as well as the ROS in smoke.

Smoking also enhances elastase activity in macrophages. In addition to elastase, MMPs derived from macrophages and neturophils have a role in tissue destruction.

Front 152

152. How does smoking play a role in the oxidant-antioxidant imbalance in the pathogenesis of emphysema?

Back 152

Normally the lung contains a healthy complement of antioxidants that keep oxidative damage to a minimum. Tobacco smoke contains abundant ROS that deplete these antioxidant mechanism, thereby inciting tissue damage.

A secondary consequence of oxidative injury is inactivation of native antiproteases, resulting in "function" alpha-1-antitrypsin deficiency even in pts w/o enzyme deficiency.

Front 153

153. How do these theories explain centriacinar emphysema?

Back 153

The smoke particles predominately accumulate at the bifurcation of respiratory bronchioles, resulting in influx of neutrophis and macrophages which secrete proteoases.

An increase in protease activity localized in the centriacinar region, together with the smoke induced ROS damage, causes the centriacinar pattern of emphysema that is seen in smokers.

Front 154

154. What is an explanation for the lower lung destruction of panacinar emphysema in alpha-1-antitrypsin deficient pts?

Back 154

The panacinar emphysema reflects a total lack of antiprotease throughout the acinus and susceptibility to chronic low-level proteolysis from neutrophils in transit thru the lung ciruclation.

The predominately lower lung distribution (where perfusion and neutrophil numbers are greatest) of panacinar emphysema is also consistent with this explanation.

Front 155

155. What is the morphology of emphysema?

1/2

Back 155

Panacinar emphysema, when well developed, produces voluminous lungs, often overlapping the heart and hiding it when the anterior chest wall is removed.

The macroscopic features of centriacinar emphysema are less impressive. The lungs might not appear particularly pale or voluminous unless the disease is well advanced. Generally, the upper 2/3rds of the lungs are more severely affected.

Large apical blebs or bullae are more characteristic of irregular emphysema secondary to scarring and distal acinar emphysema.

Front 156

156. What is the morphology of emphysema?

2/2

Back 156

Microscopically, there are abnormally large alveoli separated by thin septa with only focal centriacinar fibrosis. There is loss of attachments of the alveoli to the outer wall of small airways. The pores of Kohn are so large that septa appear to be floating or protrude blinding into alveolar spaces w/a club shaped end.

With advance of the disease, there are even large abnormal airspaces and possibly blebs or bullae. Often, the respiratory bronchioles and vasculature of the lungs are deformed and compressed by the emphysematous distortion of the airspaces, and there is often chronic bronchitis or bronchiolitis.

Front 157

157. What is the clinical course of emphysema?

Back 157

Clinnical manifestations do not occur until at least 1/3 of the lung is damged. Dyspnea is the first symptom. Cough and expectoration can occur. Weight loss is common and can be severe. Classically, the pt is barrel-chested and dyspneic, w/obviously prolonged expiration, sits forward in a hunched over position, and breathes thru pursed lips.

***Expiratory airflow limitation, best measured thru spirometry, is the key to Dx.

Front 158

158. What are pink puffers?

What are blue bloaters?

Back 158

In pts with severe emphysema, cough is slight, overdistention is sever, diffusion capacity is low, and blood gas values are relatively normal at rest. Such patients may over-ventilate and remain well oxygenated. These are the pink puffers.

Pts with chronic bronchitis more often have a history of recurrent infection, abundant purulent sputum, hypercapnia, and severe hypoxemia, promoting the designation blue bloaters.

Front 159

159. What are the three most common causes of death in pts with COPD?

Back 159

1. Respiratory acidosis and coma
2. Right-sided heart failure
3. Massive collapse of the lungs secondary to pneumothorax

Front 160

160. What is compensatory hyperinflation emphysema?

Back 160

This term is sometimes used to designate dilation of alveoli but not destruction of septal walls in response to loss of lung substance elsewhere.

It is best exemplified by the hyperexpansion of the residual lung parenchyma that follows surgical removal of a diseased lung or lobe.

Front 161

161. What is obstructive overinflation emphysema?

Back 161

Obstructive overinflation refers to the condition in which the lung expands b/c air is trapped within it. A common cause is subtotal obstruction by tumor or foreign objects.

It can be a life-threatening emergency b/c the affected portion distends sufficiently to compress the remaining normal lung.

Front 162

162. What is congenital lobar overinflation in infants?

Back 162

congenital lobar overinflation in infants is a good example of obstructive overinflation.

It probably results from hypoplasia of bronchial cartilage and is sometimes associated with other congenital cardiac and lung abnormalities.

Front 163

163. What are the two things that can cause overinflation in obstructive lesions?

Back 163

1. B/c of a ball-valve action of the obstructive agent, so that air enters on inspiration but cannot leave on expiration.

2. B/c the bronchus may be totally obstructed but ventilation thru collateral may bring in air from behind the obstruction.

Front 164

164. What is bullous emphysema?

Back 164

Bullous emphysema refers merely to any form of emphysema that produces large subpleural blebs or bullae (spaces more than 1 cm in diameter in the distended state).

They represent localized accentuations of one of the four forms of emphysema, are most often subpleural, and occur near the apex, sometimes in relation to old tuberculous scarring. On occasion, rupture of the bullae may give rise to pneumothorax.

Front 165

165. What is interstitial emphysema?

Back 165

The entrance of air into the connective tissue stroma of the lung, mediastinum, or subcutaneous tissue is designated interstitial emphysema.

In most instances, alveolar tears in pulmonary emphysema provide the avenue of entrance of air into the stroma of the lung, but rarely a sucking wound in the chest can underlie this disorder.

Front 166

166. What is chronic bronchitis?

Back 166

Chronic bronchitis is defined clinically when any pt has a persistent cough with sputum production for at least 3 months in at least 2 consecutive years, in the absence of any other identifiable cause.

Front 167

167. What is simple chronic bronchitis?

Chronic asthmatic bronchitis?

Obstructive chronic bronchitis?

Back 167

Simple chronic bronchitis occurs when pts have a productive cough by no physiologic evidence of airflow obstruction.

Chronic asthmatic bronchitis occurs when pts have hyperreactive airways with intermittent bronchospasm and wheezing.

Obstructive chronic bronchitis occurs in heavy smokers who have chronic airflow obstruction, usually with evidence of emphysema.

Front 168

168. What are the three long-term consequences of chronic bronchitis?

Back 168

1. May progress to chronic obstructive airway disease
2. Lead to cor pulmonale and heart failure
3. Cause atypical metaplasia and dysplasia of the respiratory epithelium, providing a rich soil for cancerous transformation

Front 169

169. What is the primary or initiating factor in the pathogenesis of chronic bronchitis?

Back 169

Chronic irritation by inhaled substances such as tobacco smoke, and gran, cotton, and silica dust. Bacterial and viral infections are important in triggering acute exacerbation of the disease.

Front 170

170. What is the earliest feature of chronic bronchitis?

Back 170

Hypersecretion of mucus in the large airways, associated with hypertrophy of the submucosal glands in the trachea and bronchi. Proteases and MMPs stimulate this mucus hypersecretion.

Front 171

171. What is the next earliest feature of chronic bronchitis?

Back 171

As chronic bronchitis persists, there is also a marked increase in goblet cells of small airways - small bronchi and bronchioles, leading to excessive mucus production that contributes to airway obstruction.

Many of the respiratory epithelial effects of environmental irritants are believed to be mediated thru the epidermal growth factor (EGF) receptor.

Front 172

172. Although mucus hypersecretion in large airways is the cause of sputum overproduction, what about alterations in the small airways of the lung?

Back 172

It is now though that accompanying alterations in the small airways of the lung (small bronchi and bronchioles, less than 2-3 mm in diameter) can result in physiologically important and early manifestations of chronic airway obstruction.

Front 173

173. What are the four histologic findings in small airways in young smokers?

Back 173

1. Goblet cell metaplasia w/mucus plugging of the lumen
2. Clustering of pigmented alveolar macrophages
3. Inflammatory infiltration
4. Fibrosis of the bronchiolar wall

Smoke and other irritants which cause the hypertrophy of mucous glands, also result in bronchiolitis, or small airway disease.

Front 174

174. When bronchitis is accompanied by moderate to severe airflow obstruction, what is the dominant lesion?

Back 174

Coexistent emphysema is the dominant lesion.

Front 175

175. What is the morphology of chronic bronchitis?

1/2

Back 175

Grossly, there may be hyperemia, swelling, and edema of the mucous membranes, frequently accompanied by excessive mucinous to mucopurulent secretions layering the epithelial surfaces. Sometimes, heavy casts of secretions and pus fill the bronchi and bronchioles.

***The characteristic histologic features of chronic bronchitis are chronic inflammation of the airways (predominantly lymphocytes) and enlargement of the mucus secreting glands of the trachea and bronchi.

Although the numbers of goblet cells increase slightly, the major increase is in the size of the mucous glands. (Use Reid index)

Front 176

176. What is the morphology of chronic bronchitis?

2/2

Back 176

The bornchial epithelium may exhibit squamous metaplasia and dysplasia. There is marked narrowing of bronchioles caused by goblet cell metaplasia, mucus plugging, inflammation, and fibrosis.

In the most severe cases, there may be oliteration of lumen due to fibrosis (bronchiolitis obliterans).

Front 177

177. What is the Reid index?

Back 177

The increase in the size of the mucous glands can be assessed by the ratio of the thickness of the mucous gland layer to the thickness of the wall between the epithelium and the cartilage.

The Reid index (normally 0.4) is increased in chronic bronchitis, usually in proportion to the severity and duration of the disease.

Front 178

178. What are the clinical features of chronic bronchitis?

Back 178

The cardinal symptom of chronic bronchitis is a persistent cough productive of sputum.

With the passage of time, dyspnea on exertion appears and later other elements of COPD may appear, including hypercapnia, hypoxemia, and mild cyanosis.

Front 179

179. What is asthma?

Back 179

Asthma is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and/or in the early morning.

These symptoms are usually associated with widespread but variable bronchoconstriction and airflow limitation that is at least partially reversible, either spontaneously or with treatment.

It is thought that inflammation causes an increase in airway responsiveness (bronchospasm) to a variety of stimuli.

Front 180

180. How is asthma typically categorized?

Back 180

Typically, asthma is categorized into extrinsic (initiated by a type I hypersensitivity reaction induced by exposure to an extrinsic antigen) and intrinsic (initiated by diverse, nonimmune mechanisms, including ingestion of aspiring; pulmonary infections, esp viral, cold; inhaled irritants; stress; and exercise).

Front 181

181. What are the major etiologic factors of asthma?

Back 181

A genetic predisposition to type I hypersensitivity, acute and chronic airway inflammation, and bronchial hyperresponsiveness.

The inflammation involves many cell types and numerous inflammatory cells. TH2 CD4+ cells are prominent components of the bronchial inflammation.

Front 182

182. How do TH1 cells and TH2 cells interact to cause asthma?

Back 182

An imbalance in the reciprocal arrangement between TH1 and TH2 cells may be the key to asthma. It appears that in pts with allergic asthma, T cell differentiation is skewed in the direction of TH2 cells.

Research shows that a transcription factor called T-bet is required for TH1 cell differentiation, and studies on lung tissues from asthmatics reveal absence of T-bet in lung lymphocytes.

Front 183

183. What is the relationship between ADAM-33 and asthma?

Back 183

An abnormal, perhaps genetically determined, microenvironment in the bronchial wall is an essential cofactor in the pathogenesis of asthma. This view has been bolstered by the linkage of teh ADAM-33 gene to asthma.

ADAM-33 belongs to a MMP subfamily such as collagneases. It is known that ADAM-33 is expressed by lung fibroblasts and bronchial smooth muscle cells. It is speculated that ADAM-33 polymorphisms accelerate proliferation of bronchial smooth muscle cells and fibroblasts, thus contributing to bronchial hyperreactivity and subepithelial fibrosis.

Front 184

184. What is atopic asthma?

Back 184

This most common type of asthma usually begins in childhood. The disease is triggered by environmental antigens, such as dusts, pollens, animal dander and foods, but potentially any antigen is implicated.

A positive family history of atopy is common, and asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema.

Front 185

185. What is the pathogenesis of atopic asthma?

Back 185

T-cell differentiation in these pts appears to be skewed to overproduce TH2-type cells which release IL-4 and IL-5, with subsequent IgE and eosinophil dominated immune responses.

In presensitized pts, repeat antigen exposure causes a classic type I (IgE)-mediated hypersensitivity reaction. It is the IgE-mediated reaction to inhaled allergens that elicits an acute response and a late phase reaction.

Front 186

186. What occurs in the acute response in atopic asthma?

Back 186

In the acute phase, antigen binding to IgE-coated mast cells causes primary (e.g., leukotriene) and secondary (e.g., cytokine, neuropeptide) mediator release.

The acute phase mediators cause bronchospasm, edema, mucus secretion, and leukocyte recruitment, along with hypotension in extreme instances.

These inflammatory cells set the stage for the late-phase reaction, which starts 4-8 hours later and may persist for 12-24 hours or more.

Front 187

197. What occurs in the late-phase reaction in atopic asthma?

Back 187

A late-phase reaction is mediated by recruited leukocytes (e.g., eosinophils, lymphocytes, neutrophils, monocytes).

It is characterized by persistent bronchospasm and edema, leukocytic infiltration, and epithelial damage and loss.

Front 188

198. What is eotaxin?

Back 188

Eotaxin, produced by airway epithelial cells, is a potent chemoattractant and activator of eosinophils. The major basic protein of eosinophils, in turn, causes epithelial damage and airway constriction.

Front 189

199. What are the three groups of mediators that are implicated in the asthmatic response?

Back 189

1. This group includes mediators whose role in bronchospasm is clearly supported: leukotrienes C4, D4, and E4; and ACh which also cause smooth muscle constriction
2. These agents present at the scene of the crime with potent asthma-like effects: histamine, prostaglandin D2, and PAF.
3. These are suspects - IL-1, TNF, and IL-6, chemokines (eotaxin), neuropeptides, nitric oxide, bradykinin, and endothelins

Front 190

200. What is nonatopic asthma?

Back 190

This is the nonreaginic variety of asthma and is most frequently triggered by respiratory tract infection. Viruses, (e.g., rhinovirus, parainfluenza virus) rather than bacteria are the most common provokers.

A positive family history is uncommon, serum IgE levels are normal, and there are no other associated allergies.

***It is though that virus induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Inhaled air pollutants, such as sulfur dioxide, ozone, and nitrogen dioxide, may also contribute to the chronic airway inflammation and hyperreactivity.

Front 191

201. What is drug-induced asthma?

Back 191

Several pharmacologic agents cause asthma. Aspirin-sensitive asthma is an uncommon yet fascinating type, occurring in ts with recurrent rhinitis and nasal polyps. These individuals are exquisitely sensitive to small doses of aspirin, and they experience not only asthmatic attacks but also urticaria.

It is probable that aspirin triggers asthma in these pts by inhibiting the COX pathway of arachidonic acid metabolism w/o affecting the lipoxygenase route, thus tipping the balance toward elaboration of the bronchoconstrictor leukotrienes.

Front 192

202. What is occupational asthma?

Back 192

This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toulene), and other chemicals (formadehyde, penicillin products).

Minute quantities are required to induce the attack, which usually occurs after repeated exposure. The underlying mechanisms vary according to stimulus and include type I reactions, direct liberation of bronchoconstrictor substances, and hypersensitivity responses of unknown origin.

Front 193

203. What is the morphologic changes in asthma?

Back 193

Grossly, the lungs are overdistended b/c of overinflation, and there may be small areas of atelectasis.

*The most striking macroscopic finding is occlusion of bronchi and bronchioles by thick, tenacious mucous plugs.

*Histologically, the mucous plugs contain whorls of shed epithelium, which give rise to the well-known Curschmann spirals. Numerous eosinophils and CarcotLeyden crystals are present; the latter are collections of crystalloid made up of eosinophil membrane protein.

Front 194

204. What are four other characteristic histologic findings of asthma that are collectively termed "airway remodeling"?

Back 194

1. Thickening of the basement membrane of the bronchial epithelium
2. Edema and an inflammatory infiltrate in the bronchial walls, w/a prominence of eosinophils and mast cells
3. An increase in size of the submucosal glands
4. Hypertrophy of the bronchial wall muscle

Front 195

205. What is the clinical course of asthma?

Back 195

The classic asthmatic attack lasts up to several hours and is followed by prolonged coughing; the raising of copious mucous secretions provides considerable relief of the respiratory difficulty. In some pts, these symptoms persist at a low level all the time.

The clinical Dx is aided by the demonstration of an elevated eosinophil count in the peripheral blood and the finding of eosinophils, Curschmann spirals, and Charcot-Leyden crystals in the sputum.

Front 196

206. What is status asthmaticus?

Back 196

In its most severe form, status asthmaticus, the severe acute paroxysm persists for days and even weeks, and under these circumstances, ventilatory function might be so impaired as to cause severe cyanosis and even death.

Front 197

207. What is bronchiectasis?

Back 197

Bronchiectasis is a disease characterized by permanent dilation of of bronchi and bronchioles caused by destruction of the muscle and elastic tissue, resulting from or associated with chronic necrotizing infections.

To be considered bronchiectasis, the dilation should be permanent; reversible bronchial dilation often accompanies viral and bacterial pneumonia.

It is manifested clinically by cough, fever, and expectoration of copious amts of foul smelling, purulent sputum.

Front 198

208. What are four types of conditions in in which bronchiectasis develops?

Back 198

1. Congenital or hereditary conditions, including cystic fibrosis, intralobular sequestration of the lung, immunodeficiency states, and primary ciliary dyskinesia and Kartagener syndromes.

2. Postinfectious conditions, including necrotizing pneumonia caused by bacteria (Mycobacterium tuberculosis, Staph aureus, H. influenzae, Psuedomonas), viruses, and fungi (aspergillus).

3. Other conditions, including RA, SLE, IBD, and post-transplantation (chronic lung rejection, and chronic G vs. H disease after bone marrow transplantation).

Front 199

209. What are the two major influences associated with bronchiectasis?

Back 199

Obstruction and infection; it is likely that both are necessary for the development of full-fledged lesions, although either may come first.

*These mechanisms are most readily apparent in the severe form of bronchiectasis associated w/cystic fibrosis.

Front 200

210. What is primary ciliary dyskinesia?

Back 200

This is an autosomal-recessive syndrome with variable penetrance and a freq of 1:15,000 live births. In this disease, poorly functioning cilia contribute to the retention of secretions and recurrent infections that in turn lead to bronchiectasis.

There is an absence or shortening of the dynein arms that are responsible for the coordinated bending of the cilia.

Front 201

211. What is Kartagener syndrome?

Back 201

Approximately half of the pts with primary ciliary dyskinsia have Kartagener syndrome (bronchiectasis, sinusitis, and situs inversus or partial lateralizing abnormality).

The lack of ciliary activity interferes with bacterial clearance, predisposes the sinuses and bronchi to infection, and affects cell motility during embryogenesis, resulting in the situs inversus.

Males with this condition tend to be infertile, owing to ineffective mobility of the sperm tail.

Front 202

212. What is allergic bronchopulmonary aspergillosis (ABPA)?

Back 202

ABPA is a condition that results from a hypersensitivity reaction to the fungus Aspergillus fumigatus.

ABPA is also an important complication of asthma and CF. It is characterized by an intense airway inflammation w/eosinophils and the formation of mucus plugs, which play a primary role in its pathogenesis.

There is evidence that neutrophil-mediated inflammation and the potential deficiency of anti-inflammatory cytokines such as IL-10 may also play a role. Clinically, there are periods of exacerbation and remission that may lead to proximal bronchiectasis and fibrotic lung disease.

Front 203

213. What is the morphology of bronchiectasis?

Back 203

Bronchiectasis usually affects the lower lobes bilaterally, particularly air passages that are vertical, and is most severe in the more distal bronchi and bronchiles. When tumors or aspiration of foreign bodies leads to bronchiectasis, the involvement may be sharply localized to a single segment of the lung.

*The airways are dilated, sometimes up to 4x normal size. These dilations may produce long, tube-like enlargements (cylindrical bronchiectasis), or in other cases, may cause fusiform, or even sharply saccular distention (saccular bronchiectasis).

Front 204

214. What are the characteristic findings of the bronchi and bronchioles in bronchiectasis?

Back 204

Characteristically, the bronchi and bronchioles are sufficiently dilated that they can be followed, on gross exam, directly out to the pleural surfaces. By contrast, in the normal lung, the bronchioles cannot be followed by ordinary gross dissection beyond a point 2-3 cm removed from the pleural surfaces.

On the cut surface of the lung, the transected dilated bronchi appear as cysts filled w/mucopurulent secretions.

Front 205

215. What are the histologic findings in bronchiectasis?

Back 205

The histologic findings vary with the activity and chronicity of the disease. In the full-blown, active case, there is an intense acute and chronic inflammatory exudation within the walls of the bronchi and bronchioles, associated with desquamation of the lining epithelium and extensive areas of necrotizing ulceration. There may be pseudostratification fo the columnar cells or squamous metaplasia of the remaining epithelium.

In some instances, the necrosis completely destroys the bronchial or bronchiolar walls and forms a lung abscess. Fibrosis of the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in the more chronic cases, leading to varying degrees of subtotal or total obliteration of bronchiolar lumina.

Front 206

216. In the usual case of bronchiectasis, what flora can be cultured from the involved bronchi?

Back 206

A mixed flora, including staphlococci, streptococci, pneumococci, enteric organisms, anaerobic and microaerophilic bacteria, and (particularly in children) H. influenzae and Pseudomonas aeruginosa.

In ABPA, a few fungal hyphae can be seen on special stains w/in the mucoinflammatory contents of the cylindrically dilated segmented bronchi. In the late stages, the fungus may infiltrate the bronchial wall.

Front 207

217. What are the clinical features of bronchiectasis?

Back 207

Bronchietasis causes severe, persistent cough; expectoration of foul-smelling, sometimes blood sputum; dyspnea and orthopnea in severe cases; and occasional life-threatening hemoptysis. A systemic febrile reaction may occur when powerful pathogens are present.

These symptoms are often episodic and are precipitated by upper respiratory tract infections or the introduction of new pathogenic agents.

In the full blown case, the cough is paroxysmal in nature due to frequent positional changes in position. Obstructive ventilatory insufficiency can lead to marked dyspnea and cyanosis.

Front 208

218. What are diffuse interstitial diseases?

Back 208

Diffuse interstitial diseases are a heterogeneous group of disorders characterized predominantly by diffuse and usually chronic involvement of the pulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar walls.

The interstitium consists of the basement membrane of the endothelial and epithelial cells, collagen fibers, elastic tissue, proteoglycans, fibroblasts, a few mast cells, and occasional lymphocytes and monocytes.

Front 209

219. In general, what are the clinical and pulmonary functional changes in diffuse interstitial diseases?

Back 209

The clinical and pulmonary functional changes are those of restrictive rather than obstructive lung disease.

Pts have dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis, w/o wheezing or other evidence of airway obstruction.

Front 210

220. What are the classic physiologic and radiographic features of diffuse interstitial diseases?

Back 210

*The classic physiologic features are reductions in carbon monoxide diffusing capacity, lung volume, and compliance.

*Chest radiographs show diffuse infiltration by small nodules, irregular lines, or ground glass shadows. Eventually, secondary pulmonary hypertension and right sided HF with cor pulmonale may result.

*The advanced stages are hard to differentiate b/c they result in scarring and gross destruction of the lung, referred to as end-stage lung or honeycomb lung.

Front 211

221. What are the 5 major categories of chronic interstitial lung disease?

Back 211

1. Fibrosing
2. Granulomatous
3. Eosinophilic
4. Smoking-related
5. Other

Front 212

222. What is the earliest common manifestation of most of the interstitial diseases?

Back 212

Alveolitis, that is, an accumulation fo inflammatory and immune effector cells w/in the alveolar walls and spaces.

The accumulation of leukocytes has two consequences: it distorts the normal alveolar structures, and it results in the release of mediators that can injure parenchymal cells and stimulate fibrosis.

Front 213

223. What is the initial stimuli for alveolitis?

Back 213

Some are related to the inhalation of ROS and some chemicals, which are directly toxic to endothelial cells, epithelial cells, or both.

Beyond direct toxicity, a critical event is the recruitment and activation of inflammatory and immune effector cells.

Also, alveolar macrophages release chemotactic factors for neutrophils (IL-8 and leukotriene B4).

Front 214

224. So, what causes the fibrosis in the later stages of interstitial diseases?

Back 214

It is thought that interactions among lymphocytes and macrophages and the release of lymphokines and monokines are responsible for the slowly progressive pulmonary fibrosis that ensues.

The alveolar macrophage, in particular, plays a central role in the development of fibrosis.

Front 215

225. What is idiopathic pulmonary fibrosis?

Back 215

This disorder with an unknown cause refers to a syndrome with characteristic radiologic, pathologic, and clinical features.

IPF is characterized by progressive pulmonary interstitial fibrosis resulting in hypoxemia.

The histologic pattern of fibrosis is referred to as usual interstitial pneumonia (UIP).

Front 216

226. What is the pathogenesis of IPF?

Back 216

IPF is caused by "repeated cycles" of acute lung injury (alveolitis) by some unidentified agent.

Wound healing at these sites gives rise to exuberant fibroblastic proliferation, giving rise to the "fibroblastic foci" that are so characteristic of IPF.

Mediators of wound healing such as TGF-beta are expressed at these sites.

Front 217

227. What mediators are active in IPF lesions?

Back 217

May be modified by TH2 inflammatory response. Thus, esoinophils, mast cells, and IL-4 and IL-131 are found in the lesions.

Also, there is an abnormal activation of the Wnt-β-catenin signaling pathway withing the mesenchymal cells of the IPF lesions.

Front 218

228. What is the morphology of IPF?

1/2

Back 218

Grossly, the pleural surfaces of the lung are cobblestoned owing to the retraction of scars along the interlobular septa. The cut surface shows fibrosis (firm, rubbery white areas) of the lung parenchyma with lower lobe predominance and a distinctive distribution the subpleural regions and along the interlobular setpa.

***Microscopically, the hallmark of the UIP is patchy interstitial fibrosis, which varies in intensity and with time.

Front 219

229. What is the morphology of IPF?

2/2

Back 219

The earliest lesions contain exhuberent fibroblastic proliferation and appear as fibroblastic foci. W/time these areas become more collagenous and less cellular. Quite typical is the coexistence of both early and late lesions.

The dense fibrosis causes collapse of alveolar walls and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium (honeycomb fibrosis).

Front 220

230. What is the clinical course of IPF?

Back 220

IPF begins insidiously, with gradually increasing DOE and dry cough. Most pts are 40-70 years old at the time of presentation.

Hypoxemia, cyanosis, and clubbing occur late in the course. Most pts have a gradual deterioration of their pulmonary status despite medical treatment.

The mean survival is 3 years or less. Lung transplantation is the only definitive therapy available.

Front 221

231. What is nonspecific interstitial pneumonia?

Back 221

NSIP is a diffuse interstitial lung disease of unknown etiology whose lung biopsies fail to show diagnostic features of any of the other well-characterized interstitial diseases. NSIP is divided into cellular and fibrosing patterns.

Pts present with dyspnea and cough of several mos duration. They are typically between 46-55 y/o.

*These pts have a much better prognosis than do those with UIP.

Front 222

232. What is the morphology of NSIP?

Back 222

The cellular pattern consists primarily of mild to moderate chronic interstitial inflammation, containing lymphocytes and a few plasma cells, in a uniform or patchy distribution.

The fibrosing pattern consists of diffuse or patchy, interstitial fibrosis w/o the temporal heterogeneity that is characteristic of UIP.

Fibroblastic foci are absent, suggesting that NSIP is not caused by alveolitis.

Those having the cellular pattern somewhat younger and they also have a better outcome than those with the fibrosing pattern or UIP.

Front 223

233. What is cryptogenic organizing pneumonia?

Back 223

COP is synonymous w/the term "bronchiolitis obliterans organizing pneunomia".

Pts present w/cough and dyspnea and have subpleural or peribronchial patchy areas of airspace consolidation radiographically. Some pts recover spontaneously but most need treatment with oral steroids for 6 mos or longer for complete recovery.

Front 224

234. What are the histologic characteristics of COP?

Back 224

***Histologically, COP is characterized by the presence of polypoid plugs of loose organizing CT w/in alveolar ducts, alveoli, and often bronchioles.

The CT is all of the same age, and the underlying lung architecture is normal.

There is no interstitial fibrosis or honeycomb lung.

Front 225

235. What is COP with intra-alveolar fibrosis?

Back 225

COP with intra-alveolar fibrosis can be seen as a response to infections or inflammatory injury of the lungs. These include viral and bacterial pneumonia, inhaled toxins, drugs, collagen vasscular disease, and G vs. H disease in bone marrow transplant recipients.

The prognosis is the same for these pts as that for the underlying disorder.

Front 226

236. What is the pulmonary involvement in collagen vascular diseases?

Back 226

Many collagen vascular disease, (e.g., SLE, RA, and scleroderma) can involve the lung.

Patterns include NSIP, UIP, vascular sclerosis, organizing pneumonia, and bronchiolitis.

NSIP pattern occurs classically in scleroderma.

Pulmonary involvement in these disease is usually associated with a poor prognosis.

Front 227

237. What are the 4 forms of pulmonary involvement in RA?

Back 227

1. Chronic pleuritis, w/or w/o effusion
2. Diffuse interstitial pneumonia and fibrosis
3. Intrapulmonary rheumatoid nodules
4. Pulmonary hypertension

*30-40% of pts w/classic RA have abnormalities in lung function.

Front 228

238. What are pneumoconioses?

Back 228

These disorders refer to the non-neoplastic lung reaction to aerosols, including mineral dusts, organic dusts, fumes and vapors. Air particulates also play a role in their formation.

Front 229

239. The development of pneumoconiosis depends on what 4 things?

Back 229

1. The amt of dust retained in the lungs and airways
2. The size, shape, and therefore buoyancy of the particles
3. Particle solubility and physiochemical reactivity
4. The possible additional effects of other irritants such as concommitant cigarette smoking

Front 230

240. Are the most dangerous particles in pneumoconiosis large or small?

Back 230

The most dangerous particles range from 1-5 μm in diameter b/c they may reach the terminal small airways and air sacs and settle in their linings.

Also, in general, the smaller the particles, the more likely it is to appear in the pulmonary fluids and reach toxic levels rapidly; therefore, smaller particles tend to cause acute lung injury.

Front 231

241. Can larger particles cause injury?

Back 231

Larger particles resist dissolution and so may persist w/in the lung parenchyma for years.

These tend to evoke fibrosing collagenous pneumoconioses, such as is characteristic of silicosis.

Front 232

242. What can exacerbate the local reaction of lung injury due to asbestos?

Back 232

Although tobacco smoking worsens the effects of all inhaled mineral dusts, the effects of asbestos are particularly magnified by smoking.

Front 233

243. What is coal worker's pneumoconiosis?

Back 233

These symptoms can range from:
(1) Asymptomatic anthracosis to (2) simple CWP with little to no pulmonary dysfunction to (3) complicated CWP, or progressive massive fibrosis, in which lung function is compromised.

Contaminating silica in the coal dust can favor progressive disease. in most cases, carbon dust itself is the major culprit, and studies have shown that complicated lesions contain considerably more dust than simple lesions do.

Front 234

244. What is anthracosis?

What is the morphology of anthracosis?

Back 234

Anthracosis is the most innocuous coal-induced pulmonary lesion in coal miners and is commonly seen in all urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which ten accumulate in teh CT along the lymphatics, including the pleural lymphatics, or in organized lymphoid tissue along the bronchi or in the lung hilus.

At autopsy, linear streaks and aggregates of anthracotic pigment readily identify pulmonary lymphatics and mark the pulmonary lymph nodes.

Front 235

245. What is the morphology of simple CWP?

Back 235

Simple CWP is characterized by coal macules (1-2 mm in diameter) and the somewhat large coal nodules.

The coal macules consist of carbon-laden macrophages; the nodule also contains small amts of a delicate network of collagen fibers.

These lesions can be scattered throughout the lung, but the upper lobes and upper zones of the lower lobes are more heavily involved. They are located primarily adjacent to respiratory bronchioles, the site of initial dust accumulation. In time it can lead to centrilobular emphysema.

Front 236

246. What is the morphology of complicated CWP?

Back 236

Complicated CWP occurs on a background of simple CWP and generally requires many years to develop. It is characterized by intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter.

They are usually multiple. Microscopically, the lesions consist of dense collagen and pigment. The center of the lesion is often necrotic, resulting most likely from local ischemia.

Front 237

247. What is the clinical course of CWP?

Back 237

CWP is usually a benign disease that causes little decrement in lung function. Even mild forms of complicated CWP fail to demonstrate abnormalities of lung function. In a minority of cases (fewer than 10%), complicated CWP develops, leading to increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale.

Once that develops, it may become progressive even if further exposure to dust is prevented.

Front 238

248. What is silicosis?

Back 238

Silicosis is a lung disease caused by inhalation of crystalline silicon dioxide. Currently, the most preevent chronic occupational disease in the world, silicosis usually presents after decades of expsoure as slowly progressing, nodular, fibrosing pneumoconiosis.

Front 239

249. What is the pathogenesis of silicosis?

Back 239

Silica occurs in both crystalline and amorphous forms, but crystalline forms are much more fibrogenic. Of these, quartz is most commonly implicated.

After inhalation, the particles interact w/epithelial cell and macrophages. Although lung macrophages that ingest the silica particles may ultimately succumb to its toxic effects, silica causes activation and release of mediators by viable macrophages. These mediators include IL-1, TNF, fibronectin, lipid mediators, ROS, and fribrogenic cytokines.

Front 240

250. Interesting note about quartz

Back 240

It has been noted that when mixed with other minerals, quartz has a reduced fibrogenic effect. This is important b/c quartz in the workplace is rarely pure.

Front 241

251. What is the morphology of silicosis?

Back 241

Silicosis is characterized grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the upper zones of the lungs. As the disease progresses, these nodules may coalesce into hard, collagenous scars. Some nodules may undergo central softening and cavitation. This change may be due to superimposed tuberculosis or ischemia.

Fibrotic lesions may also occur in the hilar lymph nodes and pleura. ****Sometimes, thin sheets of calcification occur in the lymph nodes and are seen radiographically as eggshell calcifications.

Histologically, the nodular lesions consist of concentric layers of hyalinized collagen surrounded by a dense capsule of more condensed collagen.

***Examination of the nodules by polarized microscopy reveals the birefringent silica particles.

Front 242

252. What is the clinical course of silicosis?

Back 242

The disease is usually detected when routine chest xray is performed on an asymptomatic worker. The radiographs typically show a fine nodularity in the upper zones of the lung, but pulmonary functions are either normal or only moderately affected.

Most pts do not develop dyspnea until later in the course. At this time, the disease may be progressive even if the pt is no longer exposed.

Front 243

253. Silicosis is associated with increased susceptibility to...?

Back 243

Tuberculosis. It is postulated tha tilicosis results in a depression of cell-mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria.

Nodules of silicotuberculosis often display a central zone of caseation.

Front 244

254. Occupational exposure to asbestos is linked to what 6 things...?

Back 244

1. Localized fibrous plaques or rarely diffuse pleural fibrosis
2. Pleural effusions
3. Parenchymal interstitial fibrosis (asbestosis)
4. Lung CAs
5. Mesotheliomas
6. Laryngeal and perhaps other extrapulmonary neoplasms, including colon CA

Front 245

255. What are the two distinct geometric forms of asbestos?

Back 245

Serpentine (curly and flexible fibers) and amphibole (straight, stiff, and brittle fibers.

The serpentine form accounts for most of the asbestos used in industry.

However, it is the amphibole stiff fibers that are delivered deeper into the lungs, where they can penetrate epithelial cells and cause fibrogenic disease.

*Thus, only amphibole exposure correlates with mesothelioma.

Front 246

256. How is asbestos a tumor initiator/promoter?

Back 246

Some of the oncogenic effects of asbestos are mediated by ROS generated by asbestos fibers, which preferentially localize in the distal lung, close to the mesothelial layers.

In addition, adsorption of carcinogens in tobacco smoke onto asbestos fibers may well be important in the synergy between tobacco smoking and the development of lung CA.

Front 247

267. What is the disease like in asbestosis?

Back 247

Chronic deposition of fibers and persistent release of mediators eventually lead to generalized interstitial pulmonary inflammation and *interstitial fibrosis*

Front 248

268. What is the morphology of the diffuse pulmonary interstitial fibrosis in asbestosis?

Back 248

Indistinguishable from other causes, except for the presence of asbestos bodies.

Asbestos bodies appear as golden brown, fusiform or beaded rods w/a translucent center and consist of asbestos fibers coated with an iron containing proteinaceous material.

They arise when macrophages attempt to phagocytose asbestos fibers; the iron is presumably derived from phagocyte ferritin. Other inorganic particulates may become coated with similar iron protein complexes and are called ferruginous bodies.

Front 249

269. Where does asbestosis begin?

Back 249

In contrast to CWP and silicosis, asbestosis begins in the lower lobes and subpleurally. The middle and upper lobes of the lungs become affected as fibrosis progresses. The scarring may trap and narrow pulmonary arteries and arterioles causing pulmonary hypertension and cor pulmonale.

Front 250

270. What are pleural plaques?

Back 250

Pleural plaques are the most common manifestation of asbestos exposure. They are well-circumscribed plaques of dense collagen, often containing calcium. They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm.

They do not contain asbestos bodies; however, only rarely do they occur in individuals w/o asbestos exposure.

Front 251

271. What is the clinical course of asbestosis?

Back 251

Dyspnea is usually the first manifestation; at first, it is provoked by exertion, but later it is present even at rest. The dyspnea is usually accompanied by a cough associated w/sputum.

These manifestations rarely appear fewer than 10 years after first exposure and are more common after 20 years or more. The disease may remain static or progress to respiratory failure, cor pulmonale, and death.

With advancement of pneumoconiosis, a honeycomb pattern develops. Asbestosis complicated by lung or pleural CA is associated with a particularly grim prognosis.

Front 252

272. What are drug-induced lung disease?

Back 252

Drugs can cause both acute and chronic alterations in respiratory structure and function, including bronchospasm, pulmonary edema, diffuse alveolar damage, organizing pneumonia, interstitial fibrosis, bronchiolitis obliterans, and esoinophilic pneumonia.

For example, cytotoxic drugs used in CA treatment, (e.g., bleomycin) cause pulmonary damage and fibrosis as a result of direct toxicity of the drug and by stimulating the influx of inflammatory cells into the alveoli.

Amiodarone is preferentially concentrated in the lung and causes significant pneumonitis in 5-15% of pts receiving it.

Front 253

273. What about acute radiation pneumonitis?

Back 253

After clinical fractionated irradiation, acute radiation pneumonitis occurs in 1020% of pts, 1-6 mos after therapy, manifested by fever, dyspnea out of proportion to the volume of lung irradiated, pleural effusion, and radiologic infiltrates that usually correspond to an area of previous radiation.

With steroid therapy, these symptoms may resolve completely in some pts without long-term effects.

Front 254

274. What about chronic radiation pneumonitis?

Back 254

There is increasing evidence that irradiation of the lungs initially causes a lymphocytic alveolitis or hypersentivity pneumonitis that can lead to pulmonary fibrosis (chronic radiation pneumonitis). The latter is a consequence of repair, which is initiated by direct tissue injury to endothelial and epithelial cells w/in the radiation portal.

Morphologic changes are those of DAD, including severe atypia of hyperplastic type II cells and fibroblasts. Form cells and epithelial cell atypia within vessel walls are also characteristic of radiation damage.

Front 255

275. What is sarcoidosis?

Back 255

Sarcoidosis is a systemic disease of unknown cause characterized by noncaseating granulomas in many tissues and organs. It presents in many clinical patterns, but bilateral hilar lymphadenopathy or lung involvement is visible on chest xrays in 90% of cases. Eye and skin lesions are next in frequency.

The prevalence of sarcoidosis is higher in women than in men; in the US, the rates are highest in the Southeast; they are 10x higher in blacks than in whites.

Front 256

276. What are 3 local immunologic factors in the pathogenesis of sarcoidosis?

Back 256

1. Intra-alveolar and intersitital accumulation of CD4+ T cells; antigen-driven proliferation
2. Increased levels of TH1 cytokines such as IL-2 and IFN-gamma, resulting in T-cell expansion and macrophage activation
3. Increased levels of several cytokines in the local environment (IL-8, TNF, macrophage inflammatory protein 1-alpha)

Front 257

277. What are 2 systemic immunologic factors in the pathogenesis of sarcoidosis?

Back 257

1. Anergy to common skin test antigens such as Candida or PPD
2. Polyclonal hypergammaglobulinemia, another manifestation of helper-T cell dysregulation

Front 258

278. What are the genetic influences in sarcoidosis?

Back 258

1. Familial and racial clustering of cases
2. Association with certain HLA genotypes (e.g., class I HLA-A1 and HLA-B8)

Front 259

279. What are the environmental factors associated with sarcoidosis?

Back 259

Several putative microbes have been proposed as the inciitng agent for sarcoidosis (e.g., mycobacteria, Propionibacterium acnes, and Rickettsia species).

*To date, there is no unequivocal evidence to suggest that sarcoidosis is caused by an infectious agent.

Front 260

280. What are the histological characteristics of sarcoidosis?

Back 260

Histologically, all involved tissues show the classic noncaseating granulomas, each composed of an aggregate of tightly clustered epithelioid cells, often with Langhans or foreign body type giant cells. Central necrosis is unusual.

With chronicity the granulomas may become enclosed w/in fibrous rims or may eventually be replaced by hyaline fibrous scares.

Front 261

281. What are two microscopic features often present in the granulomas of sarcoidosis?

Back 261

1. Laminated concretions composed of calcium and proteins known as Schaumann bodies

2. Stellate inclusions known as asteroid bodies enclosed within giant cells found in approximately 60% of the granulomas.

*Although characteristic, these microscopic features are not pathognomonic of sarcoidosis b/c asteroid and Schaumann bodies maybe encountered in tuberculosis.

Front 262

282. What is the morphology of the lungs in sarcoidosis?

Back 262

The lungs are common sites of involvement. Macroscopically, there is usually no demonstrable alteration, although at times, the coalescence of granulomas may produce small nodules that are palpable or visible as 1-2 cm noncaseating, noncavitated consolidations.

Histologically, the lesions are distributed primarily along the lymphatics, around bronchi and blood vessels, although alveolar lesions are also seen.

*A CD4/CD8 ratio > 2.5 and the CD3/CD4 ratio < 0.31 is bronchoalveolar lavage lymphocytes is commonly seen in sarcoidosis.

Front 263

283. What is the morphology of the lymph nodes in sarcoidosis?

Back 263

Lymph nodes are involved in almost all cases specifically the hilar and mediastinal nodes, but any other node in the body may be involved.

Nodes are characteristically enlarged, discrete, and sometimes calcified. The tonsils are affected in about 25-33% of cases.

Front 264

284. How are the spleen and liver affected in sarcoidosis?

Back 264

The spleen is affected microscopically in about 75% of cases, but it is enlarged in only one fifth. On occasion, granulomas may coalesce to form small nodules that are barely visible macroscopically. The capsule is not involved.

The liver is affected slightly less often than the spleen. It may also be moderately enlarged and may contain scattered granulomas, more in portal triads than in the lobular parenchyma.

Front 265

285. What about the bone marrow and sarcoidosis?

Back 265

The bone marrow is an additional favored site of localization. Roentgenographic changes can be identified in about one firth of cases of systemic involvement.

The radiologically visible bone lesions have a particular tendency to involve phalangeal bones of the hands and feet, creating small circumscribed areas of bone resorption within the marrow cavity and a diffuse reticulated pattern throughout the cavity, with widening of the bony shafts or new bone formation on the outer surfaces.

Front 266

286. What are the skin lesions in sarcoidosis?

Back 266

Sin lesions are encountered in one third to one half of cases. Sarcoidosis of the skin assumes a variety of macroscopic appearances (e.g., discrete subcutaneous nodules; focal, slightly elevated, erythematous plaques; or flat lesions that are slightly reddened and scaling and resemble those of SLE).

Lesions may also appear on the mucous membranes of the oral cavity, larynx, and upper respiratory tract.

Front 267

287. What are the ocular involvements like in sarcoidosis?

Back 267

The eye, its associated glands, and the salivary glands are involved in one fifth to half of cases.

The ocular involvement takes the form of iritis or iridocyclitis, either bilaterally or unilaterally. Consequently, corneal opacities, glaucoma, and total loss of vision may occur. These ocular lesions are frequently accompanied by inflammation of the lacrimal glands, with suppression of lacrimation.

Front 268

288. What is Mikulicz syndrome?

Back 268

Bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands completes the combined uveoparotid involvement designated as Mikulicz syndrome.

Front 269

289. What are the muscle involvements in sarcoidosis?

Back 269

Muscle involvement is often undiagnosed, since is may be asymptomatic. Symptoms of muscle weakness, aches, tenderness, and fatigue should prompt consideration of occult sarcoid myositis. Sarcoid noncaseating granulomas can be found in muscle biopsies.

Sarcoid granulomas occasionally occur in the heart, kidneys, CNS, and endocrine glands, particularity in the pituitary, as well as in other body tissues.

Front 270

290. What is the clinical course of sarcoidosis?

Back 270

May follow an unpredictable course:
-It can be slowly progressive
-It may pursue a remitting and resolving course (w/ or w/o steroid therapy)
-It can spontaneously resolve
-In 65-70% of pts, there are no or only minimal residual manifestations; 20% have permanent lung or ocular dysfunction; and 10% of pts die, primarily from progressive pulmonary fibrosis

Front 271

291. What is hypersensitivity pneumonitis?

Back 271

This immunologically mediated disorder is caused by intense, often prolonged exposure to inhaled organic dusts and related occupational antigens.

Affected individuals have an abnormal sensitivity or heightened reactivity to the antigen, which in contrast to asthma, involves primarily the alveoli.

***It is important to recognize these diseases early in their course b/c progression to serious chronic fibrotic lung disease can be prevented by removal of the environmental agent.

Front 272

292. What causes the hypersensitivity?

Back 272

It results from the inhalation of organic dust containing antigens made up of spores of thermophilic bacteria, true fungi, animal proteins, or bacterial products. Uses type III and type IV hypersensitivity reactions.

Examples:
1. Farmer's lung from exposure to dusts from hay that permits actinomycetes sports
2. Pigeon breeder's lung
3. Humidifier or A/C lung is caused by thermophilic bacteria in heated water reservoirs.

Front 273

293. What are fives lines of evidence supporting that hypersensitivity pneumonitis is an immunologically mediated disease?

Back 273

1. Bronchoalveolar lavage specimens obtained during the acute phase show increased levels of proinflammatory chemokines such as MIP-1alpha and IL-8.
2. Bronchoalveolar lavage specimens also consistently demonstrate increased numbers of T lymphs of both CD4+ and CD8+ phenotypes.
3. Most pts have specific antibodies in their serum, a feature suggestive of type II (immune complex) hypersensitivity
4. Complement and immunoglobulins have been demonstrated w/in vessel walls, also indicating type III hypersensitivity.
5. The presence of noncaseating granulomas in 2/3's of pts suggests the development of a T cell-mediated (type IV) delayed-type hypersensitivity against the implicated antigens.

Front 274

294. What is the morphology of hypersensitivity pneumonitis?

Back 274

Histologic changes in subacute and chronic forms are characteristically centered on bronchioles.

They include (1) interstitial pneumonitis consisting primarily of lymphocytes, plasma cells, and macrophages; (2) noncaseating granulomas in 2/3rds of pts; and (3) interstitial fibrosis and obliterative bronchiolitis (in later stages).

Front 275

295. What are the clinical features of hypersensitivity pneumonitis?

Back 275

The clinical manifestations are varied. Acute attacks, which follow inhalation of antigenic dust in sensitized pts, consist of recurring episodes of fever, dyspnea, cough, and leukocytosis. Diffuse and nodular infiltrates appear in the chest Xray and pulmonary function tests show an acute restrictive disorder.

Symptoms usually appear 4-6 hrs after exposure. If exposure is continuous and protracted, a chronic form of the disease supervenes that no long features the acute exacerbations on antigen re-exposure. Instead, there are signs of progressive respiratory failure, dyspnea, and cyanosis and a decrease in total lung capacity and compliance.

Front 276

296. What is pulmonary esoinophila?

Back 276

Pulmonary eosinophilia refers to diverse clinicopathologic conditions characterized by eosinophil infiltrates in pulmonary interstitial or alveolar spaces.

Front 277

297. What are the five types of pulmonary eosinophilia?

Back 277

1. Acute eosinophilic pneumonia w/respiratory failure
2. Simple pulmonary esoinophilia or Loffler sydnrome
3. Tropical esoinophilia, caused by infection with microfilariae
4. Secondary eosinophilia
5. So called idiopathic chronic eosinophilic pneumonia

Front 278

298. What is acute eosinophilic pneumonia w/respiratory failure?

Back 278

This is an acute illness of unknown cause. It has a rapid onset w/fever, dyspnea, and hypoxemic respiratory failure.

The chest X-ray shows diffuse infiltrates and bronchoalveolar lavage fluid contains more than 25% eosinophils.

*There is a prompt response to corticosteroids.

Front 279

299. What is simple pulmonary eosinophilia or Loffler syndrome?

Back 279

Simple pulmonary eosinophilia is characterized by transient pulmonary lesions, eosinophilia in the blood, and a benign clinical course. Roentgenograms are often quite striking, w/shadows of varying size and shape in any of the lobes, suggesting irregular intrapulmonary densities.

They alveolar septa are thickened by an infiltrate composed of eosinophils and occasional interspersed giant cells, but there is no vasculitits, fibrosis, or necrosis. In some cases, the eosinophils are found in a background of DAD.

Front 280

300. What is chronic eosinophilic pneumonia?

Back 280

Chronic eosinophilic pneumonia is characterized by focal areas of cellular consolidation of the lung substance distributed chiefly in the periphery of the lung fields.

Prominent in these lesions are heavy aggregates of lymphocytes and eosinophils w/in both the septal walls and the alveolar spaces.

These pts have high fever, night sweats, and dyspnea, all of which respond to corticosteroid therapy.

Chronic eosinophilic pneumonia is Dx when other causes of chronic pulmonary eosinophilia are excluded.

Front 281

301. What is desquamative interstitial pneumonia (DIP)?

What is the morphology?

Back 281

***Desquamative interstitial pneumonia is characterized by large intra-alveolar collections of macrophages with abundant cytoplasm containing dusty brown pigment (smoker's macrophages) in the airspaces.***

Some of the macrophages contain lammellar bodies (surfactant) w/in phagocytic vacuoles, presumably derived from necrotic type II pneumocytes.

The septa are lined by plump cuboidal pneumocytes. Interstitial fibrosis, when present, is mild. Emphysema is often present.

Front 282

302. What is the clinical course of DIP?

Back 282

DIP usually presents in the 4th or 5th decade of life, and it is more common in men than in women by a ratio of 2:1.

Virtually all pts are cigarette smokers. Presenting symptoms include an insidious onset of dyspnea and dry cough over weeks or months, often associated w/clubbing of digits. Pulmonary functions usually show a mild restrictive abnormality w/a moderate reduction of the diffusing capacity of carbon dioxide.

Pts with DIP typically have a good prognosis with excellent response to steroid therapy and cessation of smoking.

Front 283

303. What is respiratory bronchiolitis-associated interstitial lung disease?

Back 283

Respiratory bronchiolitis is a common histologic lesion found in cigarette smokers. It is characterized by the presence of pigmented itraluminal macrophages within first and second order respiratory bronchioles.

In its mildest form , it is seen most often as an incidental histologic finding in the lungs of smokers or ex-smokers.

Front 284

304. What is the morphology of respiratory bronchiolitis-associated interstitial lung disease?

Back 284

The changes are patchy at low magnification and have a bronchiolocentric distribution. ***Respiratory bronchioles, alveolar ducts, and peribronchiolar spaces containing aggregates of dusty brown macropahges (smoker's macrophages) similar to those seen in DIP.***

There is a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. Mild peribronchiolar fibrosis is also seen, which expands contiguous alveolar septa. Centrilobular emphysema is common but not severe.

Front 285

305. What are the clinical features of respiratory bronchiolitis-associated interstitial lung disease?

Back 285

Symptoms are usually mild, consisting of gradual onset of dyspnea and cough in pts who are typically current smokers in the 4th or 5th decade of life with average exposures of over 30 pack years of cigarette smoking.

There is a 2:1 male predominance. Cessation of smoking usually results in improvement.

Front 286

306. What is pulmonary alveolar proteinosis (PAP)?

Back 286

PAP is a rare disease that is characterized radiologically by bilateral patchy asymmetric pulmonary opacification and histologically by ***accumulation of accelular surfactant in the intra-alveolar and bronchiolar spaces.***

There are three classes of this disease: acquired, congenital, and secondary PAP.

Front 287

307. What is acquired PAP?

Back 287

Acquired PAP accounts for 90% of cases.

Autoimmune anti-GM-CSF antibodies may be pathogenic. These antibodies ultimately lead to impaired surfactant clearance by pulmonary macrophages.

Thus, acquired PAP can be considered an autoimmune disorder.

Front 288

308. What is congenital PAP?

Back 288

Congenital PAP is a rare cause of immediate-onset neonatal respiratory distress. To date, mutation in three genes have been found for congenital PAP: sufactant protein B (SP-B), GM-CSF, and GM receptor beta chain.

SP-B deficiency is transmitted in an autosomal recessive manner and is most often caused by homozygosity for a frameshift mutation in the SP-B gene. This leads to an unstable SP-B mRNA, reduced or absent SP-B, secondary disturbances of SP-C, and intra-alveolar accumulation of SP-A and SP-C.

Front 289

309. What is secondary PAP?

Back 289

Secondary PAP is uncommon. The underlying causes include lysinuric protein intolerance, acute silicosis, and other inhalational syndrome, immunodeficiency disorders, malignancies, and hematopoietic disorders.

Front 290

310. What is the morphology of PAP?

Back 290

The disease is characterized by a peculiar homogeneous, granular precipitate within the alveoli, causing focal-to-confluent consolidation of large areas of the lungs w/minimal inflammatory reaction. On section, turbid fluid exudes from these areas. As a consequence, there is a marked increase in the size and weight of the lung.

The alveolar precipitate is PAS positive and also contains cholesterol clefts. Immunohistochemical stains show the presence of surfactant proteins A and C in congenital SP-B deficiency and all three proteins in the acquired form.

Front 291

311. What are the clinical features of PAP?

Back 291

Adult pts for the most part, present with nonspecific respiratory difficultly of insidious onset, cough, and abundant sputum that often contains chunks of gelatinous material.

Some pts have symptoms lasting for years, often with febrile illnesses. These pts are at risk for developing secondary infections with a variety of organisms. Progressive dyspnea, cyanosis, and respiratory insufficiency may occur, but some pts tend to have a benign course.

Whole-lung lavage remains the standard of care.

Front 292

312. What about congenital PAP?

Back 292

Congenital PAP is a fatal respiratory disorder that is usually apparent in the newborn. Typically, the infant is full term and rapidly develops progressive respiratory distress shortly after birth. W/o lung transplantation, death ensues between 3-6 months of age.

Front 293

313. Blood clots that occlude the large pulmonary arteries are almost always from where?

Back 293

Blood clots that occlude the large pulmonary arteries are almost always emoblic in origin.

The usual source of pulmonary emboli is thrombi in the deep veins of the legs in more than 95% of cases.

Front 294

314. What type of people are predisposed to having pulmonary embolisms?

Back 294

Pulmonary embolism is a complication principally in pts who are already suffering from some underlying disorder, such as cardiac disease or CA, or who are immobilized for several days or weeks, those w/hip fracture being at high risk.

Hypercoagulable states, either primary (e.g. Factor 5 leiden, prothrombin 20210 A, hyperhomocyteinemia, and antiphospholipid syndrome) or secondary (e.g., obesity, recent surgery, CA, oral contraceptive use, pregnancy) are frequent risk factors.

Also indwelling central venous lines can be a nidus for right atrial thrombus, which can be a source of pulmonary embolism.

Front 295

315. The pathophysiologic response and clinical significance of pulmonary embolism depends on...?

Back 295

Depends on the extent to which the pulmonary artery blood flow is obstructed, the size of the occluded vessel(s), the number of emboli, the overall status of the cardiovascular system, and the release of vasoactive factors such as thromboxane A2 from platelets that accumulate at the site of thrombus.

Front 296

316. Emboli result in what 2 main pathophysiologic consequences?

Back 296

1. Respiratory compromise owing to the nonperfused, although ventilated, segment.

2. Hemodynamic compromise owing to increased resistance to pulmonary blood flow engendered by the embolic obstruction. This leads to pulmonary hypertension and can cause acute right-sided heart failure.

Front 297

317. What are the morphologic consequences of embolic occlusion of the pulmonary arteries?

Back 297

This depends on teh size of the embolic mass and the general stae of the circulation. Large emboli may impact in the main pulmonary artery or its major branches or lodge at the bifurcation as a saddle embolus. Sudden death often ensues, owing largely to the blockage of blood flow thru the lungs. Death may also be caused by acute cor pulmonale.

Smaller emboli can travel out into the more peripheral vessels, where they may cause infarction.

Front 298

318. When are infarctions not a serous problem?

What occurs instead?

Back 298

In pts with adequate cardiovascular function, the bronchial arterial supply can often sustain the lung parenchyma despite obstruction to the pulmonary arterial system.

Under these circumstances, hemorrhages may occur, but there is no infarction of the underlying lung parenchyma.

Only about 10% of emboli actually cause infarction. Although the underlying pulmonary architecture may be obscured by the suffusion of blood, ***hemorrhages are distinguished by the preservation of the pulmonary alveolar architecture***; in such cases, resorption of the blood permits reconstitution of the preexisting architecture.

Front 299

319. So, when do pulmonary embolisms cause infarction?

Back 299

PEs usually causes infarction only when the circulation is already inadequate, as in pts with heart or lung disease.

About 3/4 of all infarcts affect the lower lobes, and in more than half, multiple lesions occur. They vary in size from lesions that are barely visible to the naked eye to massive involvement of large parts of an entire lobe.

Characteristically, they extend to the periphery of the lung substances as a wedge with the apex pointing toward the hilus of the lung. In many cases, an occluded vessel can be identified near the apex of the infarct.

Front 300

320. What is the morphology of a pulmonary infarct?

Back 300

The pulmonary infarct is classically hemorrhagic and appears as a raised, red-blue area in the early stages. Often, the apposed pleural surface is covered by a fibrinous exudate.

The red cells begin to lyse w/in 48 hours, and the infarct becomes paler and eventually red brown as hemosiderin is produced. With the passage of time, fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a contracted scar.

Front 301

321. What are the histologic features of pulmonary infarcts?

Back 301

Histologically, the diagnostic feature of acute pulmonary infarction is the ischemic necrosis of the lung substance within the area of hemorrhage, affecting the alveolar walls, bronchioles, and vessels. If the infarct is caused by an infected embolus, it is modified by a more intense neutrophilic exudation and more intense inflammatory reaction.

Such lesions are referred to as septic infarcts, and some convert to abscesses.

Front 302

322. What is one of the few causes of virtually instantaneous death?

Back 302

A large pulmonary embolism.

During CPR resuscitation in such instances, the pt frequently is said to have electromechanical dissociation, in which the EKG has a rhythm but no pulses are palpated b/c of the massive blockage of blood in the systemic venous circulation.

If the pt survives after a sizable pulmonary embolus, however, the clinical syndrome may mimic MI, with severe chest pain, dyspnea, shock, elevation of temperature, and increased levels of serum lactic dehydrogenase.

Front 303

323. What about small emboli?

Back 303

Usually, however, in individuals with normal cardiovascular system small emboli induce only transient chest pain and cough or possibly pulmonary hemorrhages w/o infarction. Only in the predisposed, in whom the bronchial circulation itself is inadequate, do small emboli cause small infarcts. Such pts manifest dyspnea, tachypnea, fever, chest pain, cough, and hemoptysis.

Front 304

324. How are PE's diagnosed?

Back 304

The chest radiograph may disclose a pulmonary infarct, usually 12-36 hours after it has occurred, as a wedge-shaped infiltrate. Emboli can also be detected by spiral CT angiography and D-dimer testing. *Pulmonary angiography is the most definitive diagnostic technique but entails more risk to the pt.

Front 305

325. What happens after the initial acute insult from a PE?

Back 305

The emboli often resolve via contraction and fibrinolysis, particularly in the relatively young. Unresolved, multiple small emboli over the course of time may lead to pulmonary hypertension, pulmonary vascular sclerosis, and chronic cor pulmonale.

*Most important is the fact that a small embolus may presage a large one. In the presence of an underlying predisposing factor, pts with a pulmonary embolus have a 30% chance of developing a second embolus.

Front 306

326. What is pulmonary hypertension?

Back 306

Pulmonary hypertension is when the mean pulmonary pressure reaches one fourth of systemic levels.

It is most frequently secondary to structural cardiopulmonary conditions that increase pulmonary blood flow or pressure (or both), pulmonary vascular resistance, or left heart resistance to blood flow.

Front 307

327. What are these structural cardiopulmonary conditions that can lead to pulmonary hypertension (4 of them)...?

Back 307

1. Chronic obstructive or interstitial lung diseases
2. Antecedent congenital or acquired heart disease (mitral stenosis)
3. Recurrent thromboemboli
4. Autoimmune disorders (*systemic sclerosis*)

Front 308

328. What is primary, or idiopathic, pulmonary hypertension?

Back 308

Uncommonly, pulmonary hypertension is encountered in pts in whom all known causes of increased pulmonary pressure are excluded.

This condition is most commonly sporadic; only 6% of pts have the familial form with autosomal-dominant mode of inheritance. Within these families, there is incomplete penetrance, and only 10% to 20% of the family members actually develop overt disease.

Front 309

329. What are the genetic causes of primary pulmonary hypertension?

Back 309

Studies have revealed that primary pulmonary hypertension is caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling pathway.

BMPR2 is a cell-surface protein which binds a variety of cytokines, including TFG-beta, BMP, activin, and inhibin.

Front 310

330. So, how does a mutation in BMPR2 causes primary pulmonary hypertension?

Back 310

In vascular smooth muscle cells, BMPR2 signaling causes inhibition of proliferation and favors apoptosis.

Thus, in the absence of such signaling, smooth muscle proliferation may be expected.

*Inactivating germ line mutations in the BMPR2 gene are found in 50% of the familial (primary) cases of pulmonary hypertension and 26% of sporadic cases.

Front 311

331. What is the pathogenesis of secondary forms of pulmonary hypertension?

Back 311

In secondary forms of pulmonary hypertension, endothelial cell dysfunction is produced by the process that initiates the disorder, such as the increased shear and mechanical injury associated with left-to-right shunts or the biochemical injury produced by fibrin in thromboembolism.

Deceased elaboration of prostacyclin, decreased production of NO, and increased release of endothelin all promote pulmonary vasoconstriction. Also, decreased elaboration of prostacyclin and NO promotes platelet adhesion and activation.

Front 312

332. What plants or medicines can cause pulmonary hypertension?

Back 312

Ingestion of the leguminous plant Crotalaria spectabilis, which is indigenous to the tropics and used medicinally in bush tea, the appetite depressant agent, aminorex, adulterated olive oil, and Fenfen obesity drug.

It has been suggested that such substances might act thru effect on serotonin transporter expression or activity.

Front 313

333. What is the morphology of the vascular lesions in pulmonary hypertension?

Back 313

The presence of many organizing or recanalized thrombi favors recurrent PE as the cause, and the coexistence of diffuse pulmonary fibrosis, or severe emphysema and chronic bronchitis, points to chronic hypoxia as the initiating event.

The vessel changes can involve the entire arterial tree. In most severe cases, atheromatous deposits form in the pulmonary artery and its major branches, resembling systemic atherosclerosis.

The arterioles and small arteries are most prominently affect, with striking increases in the muscular thickness of the media (medial hypertrophy) and intimal fibrosis. These changes are present in all forms of pulmonary hypertension but are best developed int he primary form.

Front 314

334. What is plexogenic pulmonary arteriopathy?

Back 314

One extreme present most prominently in primary pulmonary hypertesnsion ro congenital heart disease with left-to-right shunts is plexogenic pulmonary arteriopathy.

The characteristic features include tufts of capillary formations is present, producing a network, or web, that spans the lumens of dilated thin-walled, small arteries.

Front 315

335. What is the clinical course of pulmonary hypertension?

Back 315

Primary pulmonary hypertension is uncommon, typically occurring in women 20-40 years old.

Clinical signs and symptoms of both primary and secondary forms become evdient only with advanced arterial disease. In the course of time, the features generally progresses to severe respiratory insufficiency, cor pulmonale, and death over several years, often superimposed with thromboembolissm and pneumonia.

Therapies include vasodilators, antithrombotic medications, and occasionally lung transplantation.

Front 316

336. What are the 3 diffuse pulmonary hemorrhage syndromes?

Back 316

1. Goodpasture syndrome
2. Idiopathic pulmonary hemosiderosis
3. Vasculitis-associated hemorrhage, which is found in conditions such as hypersensitivity angiits, Wegener granulomatosis, and SLE

Front 317

337. What is Goodpasture syndrome?

Back 317

Goodpasture syndrome is an uncommon autoimmune disease characterized by the presence of circulating autoantibodies targeted against the noncollageneous domain of the α-3 chain of collagen IV.

The antibodies initiate an inflammatory destruction of the basement membrane in the kidney glomeruli and lung alveoli, giving rise to proliferative, usually RPGN and a necrotizing hemorrhagic interstitial pneumonitis.

Most cases occur in the teens or twenties, and in contrast to many other autoimmune diseases, there is a preponderance among men, and men that smoke.

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338. What is the morphology of Goodpasture syndrome?

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In the classic case, the lungs are heavy, with areas of red-brown consolidation. Histologically, there is focal necrosis of alveolar walls associated with intra-alveolar hemorrhages. Often, the alveoli contain hemosiderin-laden macrophages.

In later stages there may be fibrous thickening of the septae, hypertrophy of type II pneumoncytes, and organization of blood in alveolar spaces.

The immunofluorescence studies reveal linear deposits of Ig's along the basement membranes.

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339. What are the clinical features of Goodpasture syndrome?

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Most cases begin clinically with respiratory symptoms, principally hemoptysis, and radiographic evidence of focal pulmonary consolidations. Soon, manifestations of glomerulonephritis appear, leading to rapidly progressive renal failure.

The common cause of death is uremia. Plasma exchange is thought to be beneficial by removing circulating antibasement membrane antibodies as well as chemical mediators of immunologic injury.

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340. What is idiopathic pulmonary hemosiderosis?

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It is a rare disorder characterized by intermittent, diffuse alveolar hemorrhage. It usually presents with an insidious onset of productive cough, hemotysis, anemia, and weight loss associated with diffuse pulmonary infiltrations similar to Goodpasture syndrome. Most cases occur in children, although the disease occurs in adults as well.

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341. What is the morphology of idiopathic pulmonary hemosiderosis?

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The lungs are moderately increased in weight, with areas of consolidation that are usually red-brown to red.

*The cardinal histologic features are hemorrhage into the alveolar spaces, and hemosiderosis, both within the alveolar septa and in macrophages lying free within the pulmonary alveoli.

There may also be hyperplasia of type II pneumocytes and varying degrees of interstitial fibrosis.

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342. What are the important features in the lungs in Wegener granulomatosis?

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The diagnostically important features are capillaritis and scattered, poorly formed granulomas (unlike those of sarcoidosis, which are rounded and well-defined).