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Define emphysema

COPD w/ permanently enlarged air sacs distal to terminal bronchioles w/ destruction of their walls and w/o obvious fibrosis

1

What is the main enzyme implicated in emphysema?

Neutrophilic Elastase

2

5 morphological subtypes of emphysema

1. centrilobular - esp. w/ cigarettes
2. panlobular / panacinar - a1-antitrypsin and end-stage centrilobular
3. paraseptal - assoc. w/ pulmonary fibrosis. may -> spontaneous pneumothorax
4. irregular - associated w/ pulmonary scars
5. interstitial - subcutaneous. due to trauma or elevated intraalveolar pressure

3

What type of emphysema is cigarette smoking usually associated with?

Centrilobular
Anthracosis often present

4

What part of respiratory tree is involved in centrilobular emphysema?

Primarily respiratory bronchioles due to high conc. of inhaled irritants
More prominant in upper lung fields

5

Chronic Bronchitis Definition

Productive cough w/o discernible cause for at least 3 months in 2 consecutive years

6

Reid index

Ratio of thickness of mucous glands to total thickness of airway wall.

Elevated in chronic bronchitis

7

status asthmaticus

most severe subtype of asthma - prolonged interval of continual symptoms, unresponsive to treatment

May be life-threatening

8

Common effector pathway of asthma

Stimulus in susceptible host -> release of inflammatory mediators -> increased vascular permeability, edema, neural and cytokine mediated bronchoconstriction, mucus hypersecretion, chemotaxis of additional inflamm. cells -> amplification

9

Major chemical mediators of acute phase of asthma

Histamine
LTC4, D4, E4
PGD2 - mucus prod
PAF
Parasympathetic neural reflexes

10

What happens in late phase of asthma?

Infiltration of white cells (esp. eosinophils) in response to locally released chemotactic factors
LTB4, eotactin
Prolongation and augmentation of disease process

11

2 common drugs that can contribute to asthma

aspirin: decreased prostaglandin production and relative increase in leukotriene

B-antagonists: may precipitate bronchospasm

12

What respiratory disease is assoc. w/ mucus plugs?

asthma

13

Curschmann Spirals and Charcot-Leyden Crystals - what are they and what are they associated with?

Curschmann Spirals: mucoid swirls of epithelial cells
Charcot-Leyden Crystals: extruded eosinophil granules - needle-like crystals

14

What is bronchiectasis

Permanent airway dilation due to recurrent infections w/ necrosis

15

Atelactasis neonatorum

Incomplete expansion of lungs at birth

16

What happens to the mediastinum in obstructive atelactasis?

Mediastinal shift toward atelactic lung

17

What happens to the mediastinum in compression atelactasis?

Mediastinal shift away from atelactic lung

18

Effects of alpha, B1, and B2 agonists

alpha: vasoconstriction and vasopressor -> decongestion
B1: increased myocardial conductivity, increased HR and contractile force
B2: relax bronchial sm. muscle, inhibit inflamm. mediator release, stimulate mucocilliary clearance

19

What receptors do epinepherine, ephederine, and isoproterenol work at?

epinepherine: B1, B2, alpha
ephedrine: B1, B2, alpha
isoproterenol: B1, B2

20

How do selective B2 agonists work?

increase AC -> increased cAMP -> sm. muscle relaxation

21

3 short acting B2 agonists

Albuterol
Levalbuterol
Pirbuterol

22

What is the difference between albuterol and levalbuterol?

Albuterol is a racemix mix of R and S enantiomers
Levalbuterol is only R (active)
considered equal, but levalbuterol is expensive.

23

What is the difference between salmeterol and formoterol?

Both last 12+ hrs
Formoterol is a full B2 agonist and has faster onset
Salmeterol is a partial B2 agonist

24

2 long acting B2 agonists available in 1x daily dosing?

Indacaterol
Vilanterol

Both available as DPI

25

What genetic factor has been associated with increased susceptibility to B2 agonist tolerance?

Gly16 polymorphism of B2 receptor.
-> reduced responsiveness to agonists

26

What is the recommendation regarding use of long acting B2 agonists in treating asthma?

Black box warning: should not be used as monotherapy. increased risk of death

27

What is the primary mechanism of action of anticholinergics in treatment of obstructive respiratory disease?

Reduction of intrinsic vagal tone

28

In what patient population is ipratropium contraindicated?

Those w/ soy lecithin or peanut allergy.
Propellant contains lecithin

29

2 long acting anticholinergic drugs for control of COPD and sites of action.

Tiotropium blocks M1-M3 receptors, but dissociates from M2 quickly. M1 and 3: long duration of action
Aclidinium blocks M1-M5. pharmacological action at M3

30

Zileuton

Blocks 5-LOX preventing leukotriene production.
Used in chronic maintenance of asthma

31

Montelukast and Zafirlukast

Long acting controlers of COPD
Selective and competitive inhibition of Cys LT1 receptor -> prevention of production of LTD4 and E4

32

What would be a good medication for chronic management of asthma for a child under 5?

Montelukast
No drug interactions
Chewable tablet / granule form
Indicated for children >1

33

What is lipocortin?

Induced by corticosteroids
Inhibits PLP A2 -> decreased production of prostaglandins and leukotrienes

34

What is the time of onset for inhaled corticosteroids?

From days up to 2 weeks

35

Adverse reactions to inhaled corticosteroids?

Cough, dysphonia
Oral Thrush (rinse mouth after using inhaler)
Adrenal suppression, osteoporosis, skin thinning (high doses)
Decreased growth velocity in children at low doses - may be transient.

36

What is the mechanism of methylxanthines?

Nonselective inhibition of phosphodiesterase
Increased cAMP -> smooth muscle relaxation
Effects intercellular Calcium
Mild anti-inflammatory

37

2 methylxanthine drugs

Theophilline
Aminophilline

Narrow therapeutic window!

38

What is the main concern w/ theophilline use and what factors must be considered?

Narrow therapeutic window (3rd line agent)
Must consider: caffeine use - additive effect
cigarettes - inhibition of cyp -> increased toxicity

39

Target concentration of theophylline and toxic concentration

5-15 mcg/ml
>20 mcg/ml -> toxicity: tachycardia, restlessness, agitation, emesis, seizure

40

Roflumilast

PDE-4 inhibitor
-> accumulation of cAMP -> smooth muscle relaxation
P450 metabolism

Bronchodilation and anti-inflammatory effect - treatment for COPD

41

Cromolyn - mechanism and time to onset of activity.

Mast cell stabilizer - takes 1week for full effect

Does not have bronchodilatory, anti-histaminic, or corticosteroid effects.

42

Omalizumab - what it is and how administered

humanized monoclonal antibody to IgE
Good for pts. w/ comorbid allergies
Subcutaneous injection - expensive

43

Combivent

Combination MDI
Ipratropium / Albuterol combo - COPD quick relief

44

Advair

Salmeterol / Fluticasone - DPI, MDI
COPD and Asthma controller

45

Symbicort

Formoterol + Budesonide
DPI for asthma and COPD
Controller

46

Dulera

Mometasone + Formoterol
MDI asthma controller

47

Breo Ellipta

Fluticasone + Vilanterol
DPI
COPD controller

48

What racial / ethnic groups have the highest incidence of TB infection?

1. Asian
2. Hispanic
3. African American

49

What toxins are produced by TB?

None
But it does produce niacin - old ID Method

50

What is the most common mycobacterial infection in AIDS?

MAC: mycobacterium avium complex
consists of M. intracellulare and M. avium
risk of infection when CD4 is <50
Disseminated infection

51

What are some Non-Tuburculous Mycobacteria species and associated diseases?

M. scrofulaceum - Lymphadenitis
M. marinum and M. ulcerans - cutaneous disease
MAC - disseminated disease in HIV pts.

52

What NTM pathogen causes pulmonary disease in CF?

M. abscessus
person to person spread in CF centers

53

What NTM is most similar to TB?

M. kansasii
not treated with PZA

54

What is the source of NTM spread?

Water and soil source - no person to person

55

TB infection depends on what 3 factors?

Number of droplet nuclei exposed to
Number of TB organisms in droplet nuclei
Duration of exposure

56

5 measures for preventing TB infection

Ventilation (neg. pressure isolation) >20 air volume changes per hour
UV light
Chemotherapy: 1-2 weeks of therapy prevents infectivity
Covering infected person's mouth
Masks

57

What % of people w/ TB exposure become infected? What % of those develop TB?

1/3 become infected (pos skin test or IGRA)
Of those: 10-15% develop TB
Of those: 50% develop early (w/in 2 years), 50% late

58

How long does it take to develop a positive skin test after TB exposure?

3-8 weeks

59

Describe the course of infection of TB from exposure to disease manifestation

Inhalation -> lung -> lymph -> blood and spread
Macrophage endocytosis -> multiplication, inhibition of phagolysosome formation -> macrophage death and realease
3 weeks: Th1 response: IFN-gamma-> macrophage activation and phagolysosome formation - mycobacteria destruction
Macs release TFN-a: increases monocyte response
relative immunity

60

Describe TB skin testing

Mantoux Method:
Intracutaneous injection of 5 Tuberculin Units (TU) of PPD (Purified Protein Derivative)
Induration measured after 48-72 hours

61

What is a positive TB skin test?

5,10, and 15 mm induration depending on risk

High risk: 5mm (close contact of infected, HIV, immune suppressed, etc)

Low-moderate risk: 10mm (health care workers, skin test conversion, recent immigrants from endemic areas, children <4yrs)

Low risk: 15mm: no risk factors - targeted skin testing not recommended.

62

What should be done if TB is suspected?

3 sputum sample collections at least 8 hrs apart w/ one first morning sample
Order: AFB test and culture for mycobacteria

63

What are the fastest turn-around tests for TB?

AFB: Acid fast bacillus stain can be completed in 24-48 hrs
Direct Nucleic Amplification Test on sputum sample: 24-48 hrs

64

What are the shortcomings of AFB staining?

Low sensitivity and Low specificity: produces both false + and -

65

What is the definitive diagnostic test for TB and how long does it take to complete?

Culture and sensitivity
Very slow: 1-2 weeks. maybe up to 6-8 weeks

66

4 major TB drugs

Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)

67

What is multi-drug resistant TB?

Resistant to AT LEAST Rifampin and Isoniazid

68

What is XDR-TB?

Extremely Drug Resistant TB
MDR-TB (resistant to RIF and INH) resistant to any fluoroquinalone
Plus any one of the following injectibles:
Amikacin, Capreomycin, Kanamycin

69

What is the duration of treatment for TB?

Depends on drugs used, presence of resistance, presence of + cultures after initiation phase, and cavitary or HIV add 3 mos.
If RIF and PZA - treat 6 mos

70

What is initial phase and continuation phase treatment of TB?

Initial: standard 4 drug regimen: INH, RIF PZA, EMB for 2 mos
Continuation: additional 4 months (of RIF / INH) or more if pos culture after initial phase (drugs may differ based on susceptibility)

71

What is the definition of latent TB?

TB infection w/ no indication of disease
Pos skin test or IGRA
Lifelong risk of TB - assumed persistence of organisms somewhere in body

72

What is treatment for latent TB?

1. 9 mos of Isoniazid @ 300mg / day or 900mg 2/wk
or
2. 4 mos of Rifampin @ 600 mg / day

watch for Hepatitis

73

What are risks for disease development in cases of TB infection?

Immune suppression: HIV, transplants, Prednisone (15mg/day for 1month or more, TNF-a agonists (infliximab, etanercept, adalimumab)
Stable x-ray consistent with old healed TB
Children < 4yrs
Silicosis, Diabetes, ESRD, underweight, low dose corticosteroids, cancer of head and neck

74

What is BCG?

Bacillus Calmette and Guerin - TB vaccine of M.bovis
varies in efficacy
does not prevent infection, but prevents dissemination

75

What is IGRA and what tests are used?

IFN-gamma release assay
1. QuantiFERON Gold: ELISA to determine IFN-g production in blood sample when Ag added (Ag: ESAT-6, CFP-10, TB7.7)
+: >/= 0.35 IU/mL
-: < 0.35 IU/mL

2. T-Spot TB: incubation of peripheral blood monocytes with 2 separate mixtures of peptides (ESAT-6 and CFP-10).
ELISpot detects # of IFN-g secreting cells
+: +/= 8 spots
-: <7 spots

76

define pneumonia

Inflammation of gas exchanging areas of lung / lower respiratory tract

77

What is the #1 cause of death from infectious disease?

pneumonia

78

What is rust colored sputum suggestive of?

Pneumococcal pneumonia

79

What is "currant jelly" sputum suggestive of?

Klebsiella pneumoniae pneumonia

80

What is creamy yellow sputum suggestive of?

Staphylococcus pneumonia

81

What is very foul smelling sputum suggestive of?

Aspiration pneumonia - oral anaerobes

82

What pneumonia causing organsisms are not seen in sputum?

Mycoplasma, Legionella, TB, viruses

83

What is treatment for Pneumococcal pneumonia?

Macrolide (azithromycin) or doxycycline
Plus 3rd gen cephalosporin (Cefotaxime, cephtriaxone, cephixime, cefpodoxime

84

What is type 3 serotype S.pneumo?

Highly virulent strain. Poorer prognosis.

85

4 groups of community acquired pneumonia

1. Outpatient w/o comorbidity 60 yoa. (s.pneumo, mycoplasma)
2. Outpatient w/ comorbidity or >60yoa (s.pneumo, virus, h.influ)
3. Hospitalized w/ CAP 5-25% mortality
(S.pneumo, H. influenzae, poly (inc. anaerobe), gram -, legionella)
4. Severe hospitalized - ICU. Up to 50% mortality
(S. pneump, legionella, gram -, resp. viruses)

86

What does Mycoplasma pneumonia cause?

Atypical or "walking" pneumonia in young otherwise healthy people.

87

What are clinical symptoms of Mycoplasma pneumonia?

insidious onset
non-productive cough
fever, headache, chills
No leukocytosis
Blistering of eardrum (Bullous Myringitis)
Rare signs of consolidation - usually patchy rales and crackles

88

How is mycoplasma treated?

Macrolide (azithro, clarithro, erythromycin)
or Tetracycline

89

What are indicators of Legionella infection?

Fever over 102 w/ relative bradycardia, GI involvement w/ diarrhea, hyponatremia, hypophosphatemia

90

How is legionella pneumonia treated?

Macrolides- rifampin

91

What populations are associated with H.influenzae pneumonia?

alcoholics, COPD, healthy adults, sickle cell pts.

Lots of sputum

treat w/ cephalosporin, sulfa

92

What populations are associated with Klebsiella pneumonia?

Diabetics, alcoholics, debilitated

bulging fissure on cxr

treat w/ cephalosporin or aminoglycoside

93

In aspiration pneumonia how long does it take following aspiration for tissue necrosis / liquefaction?

~12 days

94

3 tests for Cocciodiomycosis

Skin test: Positive bet. 3 days and 3 weeks after onset.
**- change to +: new infection
**+ change to -: severe infection or dissemination

IgM titer: latex agglutination: + w/in 2-4 weeks of infection

IgG titer: complement fixation: + w/in 8 weeks after infection
diagnostic and prognostic. high titer - high prob. of disseminated disease

95

2 forms of cocciodiomycosis

arthrospore- in soil, infectious
spherule - tissue form - contains endospores

96

2 forms of histoplasmosis

microconidia: infective form in soil. assoc. w/ bird and bat droppings

narrow-necked budding yeast: tissue form

97

What are 2 forms of blastomycosis?

dumbell shaped yeast
broad based budding yeast (tissue)

98

How is blastomycosis diagnosed?

Serologic testing: not useful - high titer may inappropriately indicate disease
Skin testing: not useful - frequently indicates histoplasmosis
Culture: definitive. fast growing and easy to culture

99

How is blastomycosis treated?

Usually no antifungal needed.
Only in disseminated disease - IV anti-fungal

100

How is aspergillus diagnosed?

Skin testing for acute infection
Serology: IgE in acute and fungus balls. IgG also possible

101

4 types of aspergillus infection and treatments

1. Hypersensitive pneumonitis / Extrinsic Allergic Alveolitis - cough, fever, dyspnea, chills w/in 4-6 hrs of exposure
-treat w/ steroids
2. Allergic Bronchopulmonary Aspergillosis (ABPA) - pts. w/ long standing asthma. + skin, + serology, migratory CXR infiltrates. Cough up brown plugs. Treat w/ steroids
3. Aspergilloma - fungus ball. bleeding due to erosion. Surgical removal
4. Invasive aspergillosis - only in immunocompromised. Culture for Dx. multiple IV antifungals. High mortality.

102

What organisms are associated w/ nosocomial pneumonia?

60% enteric gram (E. coli, Klebsiella, enterobacter, pseudomonas, Serratia, Proteus)
10% S. aureus
Legionalla and other

103

What is the most common viral infection seen in AIDS pts?

CMV

104

In what patients is P.carinii seen?

HIV: slowly progressive, fever, cough, dyspnea, CXR infiltrate
Children w/ leukemia: fulminant downhill course

105

What is treatment for P.carinii?

TMP/SMX
Pentamidine IV or aerosol for those who can't tolerate.

106

How is INH activated, how does it work, how metabolized?

Activated by mycobacterium
mycobacterial catalase-peroxidase (KatG)
Action: interferes w/ mycolic acid synthesis (bactericidal against actively growing organisms, bacteriostatic against non-replicating)
Metabolism: N-acetyltransferase

107

What is Rifampin's MOA?

binds B-subunit of bacterial DNA dependent RNA-pol

108

What lab values are elevated in Rifampin toxicity? What about Isozianid?

Rifampin: elevated bilirubin and alkaline phosphatase
Isoniazid: aminotransferase elevated

109

What options are available if there are concerns about Rifampin and DDI?

Rifapentene and Rifabutin - less likely to cause interactions
Rifabutin is usually used.

Rifampin > Rifapentene > Rifabutin

110

What are some examples of drugs that Rifampin interferes with?

Rifampin induces many CYP450 enzymes
Decreases concentrations of: warfarin, cyclosporine, HIV meds (esp. protease inhibitors), anticonvulsants, oral contraceptives.

111

What is Pyrazinamide's MOA?

Unknown. Prodrug activated by mycobacterial pyrizinamidase -> active pyrazinoic acid.
High activity at acidic pH in lysosomes

112

What is the MOA of Ethambutol?

Inhibits arabinosyl transferases - needed for cell wall components.

113

What was the first drug useful against TB, what class, what MOA?

Streptomycin (Aminoglycoside) binds 30s subunit of bacterial ribosome - oxygen dependent

ototoxicity

114

What limits streptomycin use in TB infections?

Rapid development of resistance - 80% of RIF / INH resistant strains are streptomycin resistant.
Does not work intracellularly

Vestibular toxicity - watch for gait abnormalities

115

What are the differences between Rifampin, Rifabutin and Rifapentene?

Rifabutin: more potent than Rifampin, 50% less CYP450 induction

Rifapentene: long half-life: 1x /week option for HIV - patients. Between Rifabutin and Rifampin in CYP450 induction

116

4 major cell types associated w/ asthma

Mast cells - histamine, LT, PG, PAF
Eosinophils - MBP, eosinophil cationic protein
Macrophage - cytokines, ROS, PAF, act as APC
TH2: IL 4, 5, GM-CSF

117

What systems innervate airway sm. muscle?

Parasympathetic: maintains tone. PS constricts airways.
Sympathetic: relaxes airways. Small role in humans.
Nonadrenergic Noncholinergic Neural pathways: mediate tone
-NO and VIP are inhibitory
- Substance P and neurokinins A and B are excitatory
--nerve injury secondary to inflamm -> increased excitatory input, bronchoconstriction and vascular permeability

118

How long does the early asthmatic response last?

resolves by 2 hours

119

How often does the late phase asthmatic response occur and how long does it last?

Occurs in 50% of asthmatics
Occurs w/in 6-8 hrs and may last up to 24 hours

120

3 causes of airway obstruction in asthma

1. bronchospasm
2. vascular congestion and bronchial edema
3. accumulation of airway secretions, mucus casts, and cellular debris

121

What happens to PFTs during an asthma attack?

Reduced FEV1 and FVC
Reduced FEV1/FVC
Lung volume increase, esp RV and FRC

122

How does the work of breathing change in asthma?

Increases
1. Flattened diaphragm w/ hyperinflation - no longer optimal length/tension relationship
2. Hyperinflated lungs shift on compliance curve -> require more pressure for change in volume
3. V/Q mismatch -> hypoxemia and dead space

123

What is criteria for intermittent asthma?

Rule of 2:
symptoms < / = 2x /week
night time awakenings

124

What are the 3 levels of persistent asthma?

Mild: symptoms >2x week, not daily, awakening 3-4/mo, B2 ag >2x/ week, not more than 1x/ day
Moderate: symptoms daily, awakening >1x/week, b2 daily
Severe: symptoms throughout day, awakening daily, b2 multiple/ day

125

What is the goal of asthma therapy and what are its components?

Goal: control
1. Impairment: prevent symptoms, minimize use (<2/week) of SA B2 agonists
2. Risk: minimize hospital visits and pulmonary function decline, minimize adverse medical effects

126

What is the only major disease in US w/ an increasing death rate?

COPD
4th most common cause of death

127

What % of chronic heavy smokers develop COPD?

10-15%
Genetic component

128

What chromosome is implied in families w/ COPD?
What other polymorphisms have been identified?

2q
IL1, TGF-B (both increasing and decreasing risk), GSTM-1

129

Where is a1-antitrypsin gene found? Is deficiency AD or AR?

on chromosome 14
AR

130

What other organ system is affected in persons w/ a1-antitrypsin deficiency emphysema?

Hepatic cirrhosis is seen in 1-3% of emphysema pts.

131

What is the role of oxidative stress in COPD?

1. activates NFk-B -> transcription of inflammatory proteins (TNF-a)
2. inactivation of anti-proteases

132

What is the role of amplification in COPD?

COPD patients have amplified inflammatory response compared to normal.

133

3 key symptoms for COPD diagnosis

1. chronic cough
2. chronic sputum production
3. dyspnea: starts insidiously and escalates - persistent

134

What is the most common cause of COPD exacerbation?

bacterial or viral infection of airways

135

What is the most common genotype of a1-antitrypsin deficiency? What is normal?

PiZZ (homozygous, disease is AR): in 90-95% of cases
PiMM is normal

136

What chromosome houses the genes associated with a1-antitrypsin deficiency?

14

137

What inflammatory cells are associated with COPD?

Macrophage (critical)
CD8 Lymphocyte
Neutrophil

138

What changes in V/Q are seen in COPD?

Both high and low
High: increased dead space (V/Q -> infinity)
Low: hypoxemia, shunt (V/Q -> 0)

139

What are major considerations for COPD diagnosis?

Chronic cough
Sputum
Recurrent bronchitis
Dyspnea - persistent, progressive, worse w/ exertion
Exposures - smoking

140

When should ABG be checked in COPD evaluation?

FEV1 <40%
signs of Cor Pulmonale / Right sided HF
During exacerbations

141

What is a chronic CO2 retainer?

COPD patient with elevated PCO2 between exacerbations
Blood gas reflects compensated respiratory acidosis (normal pH, high HCO3-

142

Why do people lose weight in COPD?

Loss of skeletal muscle, particularly in limbs
-increased TNF-a, increased metabolism
-seen in 50% w/ severe disease, 10-15% in mild-moderate
-inverse relationship w/ survival

143

5 etiologies of bronchiectasis

1. infection: Pertussis, necrotizing pneumonia, viral pneumonia (measles, influenza), TB
2. Immotile cilia syndrome / Kartagener's
3. Hypogammaglobulinemia
4. Cystic Fibrosis (frequent infections w/ S.aureus and PSA)
5. Allergic bronchopulmonary aspergillosis

144

How is bronchiectesis detected?

CT scan reveals dilated bronchi that do not taper toward periphery.

CXR is not reliable, though increased bronchovascular markings and cystic air spaces are suggestive.

145

Treatment for bronchiectasis?

1. Treat underlying problem
2. Improve clearance of secretions: chest physiotherapy
3. Control infections: vaccinations, daily abx (CF - macrolide 3x/wk)
4. Bronchodilators

146

From what tissue do lungs develop?

Foregut endoderm
buds at ~4weeks

147

3 stages of lung development

Pseudoglandular 5-16 wks
Canalicular 16-26 wks
Alveolar / Viable 26- birth

148

What test is used to asses lung maturity prenataly?

Lecithin: sphingomyelin
Lecithin increases w/ maturation, sphingomyelin stays stable

149

What substances accelerate fetal lung maturation?

cortisone, stress, thyroxine, prolactin, theophylline, sympathomimetics

150

3 factors that decrease rate of fetal lung maturation

Insulin
Metapyrone
Barbiturates

151

At what age are all alveoli formed?

~10
few alveoli at birth
8-10 yrs - intense alveolar prolif
10-20 increase in size

152

What is a tracheal-esophageal fistula and when is it formed?

Failure of separation of esophageal and lung buds from foregut. Abnormal connection between trachea and esophagus.

Insult at ~4th week

153

When would failure of a lung or lobe to develop occur and what are the ramifications?

Insult ~4-8 weeks gestation

Generally asymptomatic (60% reserve at max exercise in normal)
but reduced reserve - sx, trauma, infection

154

What are cysts in terms of lung development? Blood supply? What do they cause?

Abnormal detachment of lung tiss from primitive airway buds. Connected to bronchial tree by defective airway - blood from pulmonary circulation
Insult ~4-12 wks of preg.
Poor mucus clearance -> infections.
May need to be removed - easy due to low pressure circ.

155

What are sequestrations in terms of lung development?

Insult in 1st trimester -> ectopic lung tissue w/ systemic blood supply (high pressure)
Non functional
Clinically similar to cysts, but difficult to remove.

156

What population is at high risk for infant RDS?

High: Born 26-30 wks, Low birth weight

more frequent: diabetic mothers, asphyxia to infant, mother w/ bleeding

157

What occurs in RDS?

Infant born w/ insufficient surfactant. Fibrinogen containing materials deposit on alveolar walls -> fibrosis
Low compliance, atelectasis, increased WOB
Hypoxemia
Respiratory acidosis
Pulmonary HTN
Capillary endothelial damage - leak
Epithelial necrosis

158

3 complications of RDS

1. Oxidative damage: a) lung injury due to high FIO2 b) retrolental fibroplasia (blindness - prevent w/ vit E)
2. Barotrauma
3. Chronic lung disease (fibrosis, pulmonary HTN)

159

What is retrolental fibroplasias? How is it prevented?

Seen in infants w/ RDS who are treated w/ oxygen.
Oxidative damage to developing vasculature of retina can -> blindness

Vitamin E prevents.

160

How is RDS prevented?

1. Prenatal care
2. Corticosteroids at least 24 hrs before delivery accelerates lung maturation

161

What is seen on autopsy of SIDS infant?

signs of chronic asphyxia
subtle brain stem lesions

162

3 SIDS theories

1. poorly developed / abnormal brainstem respiratory controls -> decreased chemoreceptor response to CO2
2. poor control and decreased receptor input from upper airway leads to apnea
3. problems w/ sleep arousal

163

Genetic factors in SIDS

Not strongly familial
Type B blood

164

Peak age for SIDS?

2-4 mos
rare after 6 mos

165

3 immotile cilia syndromes

Type I: Kartagener's - lack of dynein arms
Type II: defect in radial spokes
Type III: transposition of A and B outer tubules

166

Clinical manifestations of Immotile Cilia Syndromes

-Recurrent infections of upper and lower airways.
--sinusitis, nasal polyps, otitis media, bronchitis, bronchiectasis, pneumonia
-Kartageners: situs inversus and dextrocardia
-Immotile sperm

167

What organs are affected by Cystic Fibrosis?

Primary: lungs, sinuses, pancreas
Other: Sweat glands, intestines, liver, male GU tract

168

What pattern of inheritance is cystic fibrosis?

Autosomal Recessive

169

What chromosome carries CF gene?

7

170

What is the main mutation seen in CF?

delta F508
Loss of 3 nucleotides and a phenylalanine

1800 others!

171

What is the relative incidence of CF by race?

White > Hispanic > Native Am > AA > Asian

172

What is estimated median survival in CF (2010)

38.3 yrs

173

What is CFTR?

cAMP dependent Cl- channel found in epithelial tissue of lung, pancreas, gall bladder, salivary and sweat glands, epididymis, etc.

174

What abnormalities can result from CFTR mutation?

Quantity
Processing
Trafficking
Function
Rate of Turnover

175

Class I CFTR mutation

CFTR is not produced due to a DNA defect- premature stop codon

176

Class II CFTR mutation

Defective processing and trafficking
seen w/ delta-F508
mutation -> improper folding -> abnormal interaction w/ chaperone proteins -> degradation in ER

177

Class III CFTR mutation

Defective cAMP Regulation -> defective Cl- transport

178

Class IV CFTR mutation

defective conductive pathway of CFTR

179

Class V mutation of CFTR

Abnormally spliced CFTR -> partial or complete reduction

180

Class VI CFTR mutation

Accelerated turnover at apical membrane

181

3 transport systems in apical airway epithelium

ENAC - controls transepithelial Na and volume absorption
CFTR - tonic Cl- conductance regulates other channels
CaCC - Ca++ activated Cl- channel responds to acute stimuli

182

What is the lumen potential in CF?

More negative due to impermeability of epithelium to Cl- and excessive Na+ transport

basis of nasal potential difference test (diagnostic)

183

What genotype of CF is associated with mild lung disease?

A455E

184

What antibiotics are used prophylactically for CF?

TOBRI, colistin, aztreonam

185

What drugs are used in CF patients to help with mucus?

Dornase Alpha
Hypertonic Saline

change viscosity of mucus

186

What is azythromycin used for in CF?

Improves lung functions and decreases exacerbations. Not used as antibiotic in usual sense.
Anti-inflammatory?
PSA biofilm?

187

What is the peak age range for nasal polyposis in CF?

5-19 w/ high recurrence rate after surgery (58-89%)

188

What process leads to diabetes in CF?

Pancreatic duct occlusion -> self-digestion of pancreas and destruction of endocrine pancreatic cells -> diabetes

189

What GI complaints typically accompany CF?

1. Meconium ileus in newborns
2. Stool fat loss (>7%)
3. Steatorrhea
4. Gastritis, Esophagitis, reflux (low bicarb)
5. Malabsorption of fat sol. vitamins (A,D,E, K)

190

What are 3 therapies for CF related GI disease?

Pancreatic enzyme replacement therapy (Lipase 500-2500 w/ meals, 1/2 dose w/ snacks)
Gastric acid suppression (helps w/ enzyme function)
Osmotic agents (for DIOS (Distal Intestinal Obstruction Syndrome)

191

What is the application of Ursodeoxycholic acid in CF?

Treatment of billiary cirrhosis - destruction of small bile ducts of liver -> cholestasis

192

What is the incidence of Diabetes in CF?

24% at 20 yoa
76% at 30 yoa

193

What is the sweat test in CF?

Pilocarpine ionophoresis - tests salt content of sweat
>= 60mmol/L is abnormal
Infants 6mos: 40-59 intermediate <40 normal

194

Criteria for CF diagnosis:

2 known mutations OR
1) 2 sweat Cl- tests >60 and one of: a) fam. hx b) +newborn scrn c) typical symptoms/findings
2) intermediate sweat Cl- due to CF, non-classic CF, CF related disorder - nasal potential dif. may help

195

What is cigarette "tar" and what does it contain?

Residue of cigarette smoke minus nicotine and water
Contains many carcinogens:
-aromatic hydrocarbons
-radioactive elements (nickel)
-free radicals

196

In addition to lung cancer, what others are smoking associated?

laryngeal
oral
esophageal
pancreas
bladder
cervical

197

How does radon cause cancer?

radioactivity: alpha particles

198

What are the 2 leading causes of lung cancer?

smoking
radon

199

Where does small cell lung cancer originate?

Centrally

200

What is the doubling time for small cell lung cancer?

Fast! 30 days

201

Where does small cell lung cancer spread?

Bone Brain Liver

202

How does small cell lung cancer react to therapy?

Very good initial response, but doesn't last
High rate of recurrence

203

What % of lung cancers does small cell comprise?

20%

204

What is the origin of squamous cell lung cancer? where is it found?

From endobronchial tissue
Central tissue - large

205

What lung cancer is least likely to metastasize?

Squamous

206

What is the growth rate of squamous cell lung cancer?

Medium
Doubling rate: 100days

207

What lung cancers have a tendency to cavitate?

Squamous cell

208

Where does squamous lung cancer generally metastasize?

Hilum
Least distant spread

209

How does squamous lung cancer respond to therapy?

Poorly

210

Where is adenocarcinoma located in the lung?

Peripherally

211

What is the growth rate of adenocarcinoma of the lung?

Medium - slow
Doubling rate 100-180 days

212

Where does adenocarcinoma of the lung tend to metastasize?

Pleura
Chest wall
distant

Squamous

213

In what population is bronchioalveolar cancer usually found?

Elderly
Can occur in non-smokers

214

What is a common misdiagnosis of BACA?

Pneumonia
Failure of infiltrate to resolve w/ chemo may be clue to diagnosis

215

What is the appearance of Large Cell Lung Cancer?

Large, highly undifferentiated cells.
Large mass w/ necrosis and hemmorhage

216

Which of the non-small cell lung cancers has the worst prognosis?

Large cell

217

How must a suspected large cell tumor be biopsied?

Several samples from different locations taken - look for more differentiated cells
Diagnosis of exclusion

218

What is a concern with a COPD patient who experiences sudden weight loss?

Cancer

219

How might a tumor cause elevation of the diaphragm?

Impingement on phrenic nerve

220

What is Pancoast Syndrome?

Apical lung tumor grows, invades chest wall, destroys bone.
Involves C8, T1, T2 of brachial plexus and cervical sympathetic plexus-> shoulder and back pain, weakness and atrophy of arm, ipsilateral horner syndrome

221

What is superior vena cava syndrome?

Tumor compresses/ invades SVC -> obstruction
Edema and venous dilation of face, neck, arms
Headache and dizziness
-Medical emergency. Radiation to shrink tumor.

222

What lung cancer cells are most associated w/ endocrinopathies?What are examples?

Small cell (Oat cell)
ACTH, MSH, ADH
insulin, gonadotropins

223

What cancer type is know for producing PTH?

Squamous cell carcinoma
-> hypercalcemia

224

What tumor type is most associated with neuromuscular paraneoplastic issues?

Oat cell

225

What is Myasthenic syndrome and what is it associated with?

Lambert-Eaton
Associated w/ small cell lung cancer
Autoantibodies (elicited by tumor ion channels) directed toward neuronal Ca++ channel
Proximal muscle weakness - no improvement w/ anticholinesterase - enhanced transmission w/ frequent stim (opposite myasthenia gravis)

226

What is hypertrophic pulmonary osteoarthropathy?

connective tissue disease seen w/ some lung cancers
-> clubbing of fingers
Smoker w/ finger clubbing - look for tumor

227

How is lung cancer diagnosed?

Sputum cytology - usually only squamous (difficult to collect, false + and -)
Bronchoscopy or transthoracic needle aspiration (ct guided), depending on tumor location
Thoracotomy
Pleural tap and biopsy
Tissue or fluid from metastatic site

228

Is radiation therapy curative?

No
Local control - external beam or endobronchial
Palliation

229

Is chemotherapy curative?

Only in small cell, otherwise no
Controls distant disease

230

What is major criteria in evaluating operability of lung cancer?

Will patient tolerate resection and have adequate pulmonary function post-op?
PFT's, ABG, V/Q testing

231

At diagnosis of lung cancer, what % is considered resectable?

30%

232

What is overal 5 year survival for lung cancer and w/ surgery?

Overall 5-year survival: 13%
W/ surgery 30%

233

What is the most common histotype of lung cancer?

Adenocarcinoma (32-37%)
followed by Squamous (28-30%)

234

What lung cancer is most likely to occur in a non-smoker?

Adenocarcinoma
followed by Large Cell

235

What two cancers are most closely associated with smoking?

Squamous and Small cell
Risk persists after cessation

236

Small cell and Squamous cell lung cancers arise from what cell types?

Respiratory mucosa of main or lobar bronchi (bronchial stem cells)

237

Adenocarcinoma most often arises from what cell types?

bronchioles and terminal alveolar units - Clara cells and type II alveolar cells

238

What is BACA?

Bronchioalveolar lung cancer
Slow growing adenocarcinoma

239

What mutations are frequently associated with Small Cell lung Cancer?

increased p53, Cyclin D1 and E, EGFR, telomerase activation
Chromosomal losses at 3p, 9q, 5q w/ loss of CDKi p15 and p16

Increasing genetic abnormalities parallel morphological change

240

What is the pathogenesis of Adenocarcinoma?

Normal terminal bronchioles / alveoli -> atypical adenomatous hyperplasia -> adenocarcinoma CIS -> invasive adenocarcinoma

241

What occurs in atypical adenomatous hyperplasia?

An increase in number and grade (N/C ratio, hyperchromasia) of alveolar lining pneumocytes
Parallel thickening of alveolar septa due to fibrosis

242

What are the size definitions of AAH, AIS, and Aca?

AAH: < or = 5mm
AIS: 5mm-3 cm
Aca: 3cm - becomes more aggressive w/ size increases

243

What mutations are seen in Aca in smokers and non-smokers

smokers: K-Ras
non-smokers: EGFR

244

What cancer type is most likely to have EGFR mutations, what is the frequency of mutation and what happens with the mutation?

Adenocarcinoma, esp. non-smokers
20% of all Aca
Mutation in TK domain -> increased activity, increased cell proliferation and increased sensitivity to TK inhibitors

245

In what type of pattern does squamous cell lung cancer grow?

Nests w/ undifferentiated basal cells at the periphery w/ cells becoming more differentiated toward the center.
Center of accumulating squames mixed w/ apoptotic cells and necrotic debris.
Most likely to cavitate.

246

What secretory products are often made by Aca cells?

Mucins
products normally made by Type II or Clara cells

247

Describe the typical appearance of LC carcinoma cells

Large, undifferentiated, non-squamous, non-glandular
Cells have large nuclei, prominent nucleoli, moderate cytoplasm.
Grow in solid discohesive sheets w/ prominent cell borders.

248

How is large cell lung cancer diagnosed?

Diagnosis of exclusion
Thorough sampling - multiple samples from tumor to look for differentiation.

249

What are the major lung cancer types showing neuroendocrine differentiation?

Large Cell Neuroendocrine Carcinoma
Small Cell
Typical Carcinoid
Atypical Carcinoid

250

What is crush artifact?

Seen in small cell lung cancer
Artifact of preparation - long smears of DNA

251

Describe a Typical Carcinoid tumor

Nested pattern, no necrosis, at least 0.5 cm
Neuroendocrine features
Low proliferative rate (<2 mitoses / 2mm^2)

Cells: low N/C ratio, salt and pepper chromatin, absent or small nucleoli

252

Are carcinoid tumors assoc. w/ smoking?

No association w/ smoking

253

What is the prognosis of typical carcinoid lung cancer?

Excellent - 95% survival at 5 years.

254

What syndrome may carcinoid lung cancer appear with?

Multiple Endocrine Neoplasia 1 (MEN1)

255

What are Synaptophysis and Chromogranin?

neuroendocrine markers that may be used to ID neuroendocrine tumors via immunochemistry.

256

What is atypical carcinoid?

Carcinoid tumor exhibiting either elevated mitotic rate or necrosis

More aggressive, lymph node metastases common, worse prognosis (60-70% at 5 yrs, 35-59% at 10 yrs)

257

What is a suspected atypical carcinoid tumor exhibiting >10 mitoses / 10 hpf (2mm^2)?

Considered Small Cell carcinoma at that point.

258

What mechanisms prevent fluid accumulation in the pleural space?

1) starling forces favor resorption
2) active solute coupled fluid pumps in mesothelium
3) lymphatic drainage has large reserve

259

What is the normal volume of pleural fluid?

0.2-0.2 ml/kg

260

Indications for pleural biopsy and 2 types.

Exudate effusion of unknown etiology or suspected TB or malignancy.
1) Closed: by pulmonologists. Rarely done. Useful for TB
2) Open: by thoracic surgeion. Definitive diagnosis. Malignancy.

261

Criteria for transudative vs. exudative effusion

Exudate:
Pleural fluid protein : Serum protein >0.5
or
Pleural fluid LDH : Serum LDH >0.6
or
Pleural fluid LDH > 2/3 upper limit for normal for serum

All others are Transudate

262

Major causes of transudative effusion

CHF
Nephrosis
Cirrhosis
Peritoneal dialysis

(systemic factors)

263

3 homeostatic sleep mechanisms

a) sleep need accumulates w/ wakefulness
b) sleep need can only be met by sleeping
c) more sleep = less need to sleep

264

3 Stages of sleep

N1: perceive that you are still awake. Transition from wake - sleep
N2: true sleep. thoughts are short, fragmented.
N3: slow wave sleep - little or no mentation.

265

3 categories of insomnia

Transient: adjustment sleep disorder. <1wk. precipitated by anxiety/ emotion
Short-Term: up to several weeks. temporary stressful events or inability to adjust sleep-wake cycle to new needs
Chronic: months - years. many causes.

266

4 causes of chronic insomnia

1. Sleep related disorders: sleep hygiene, disruptive or irregular sleep-wake cycle, obstructive sleep apnea, RLS
2. Medication / drug related: extended use of sleep meds or others that interfere w/ sleep. ETOH and drugs of abuse.
3. Medical disorders: chronic pain, GERD, asthma
4. Psych: esp. mood and anxiety

267

2 categories of symptoms of insomnia

Night-time complaints
Day-time complaints (required for insomnia to be a disorder rather than a complaint)

268

What is the hyperarousal theory of insomnia?

Insomniacs have generalized hyperarousability.
-higher rates of depression and anxiety than gen. pop.
-score higher on scales of arousal
-more night-night variability in sleep
-more beta EEG (memory processing - task performance) at sleep onset

269

What is cognitive theory of insomnia?

Patients prone to rumination
increased problem solving -> insomnia
w/ chronic insomnia, worry about sleep all day

270

What is the behavioral theory of insomnia?

Stimulus control model: normal cues assoc w/ sleep become assoc w/ wakefulness
Predisposing factors for chronic insomnia
Insomnia begins w/ precipitating factor
Chronicity w/ onset of perpetuating factors and conditioned arousals. TARGET OF BEHAVIORAL THERAPY

271

What is psychophysiologic insomnia?

Most common primary insomnia
Disorder of somatized tension and learned sleep preventing associations
-sleepy until bedtime routine
-racing thoughts
-tries to force self to sleep
-sleeps better on couch or away from home

272

What is the difference between physiologic sleep tendency and manifest sleep tendency?

Physiologic: tendency toward sleep in absence of alerting factors
Manifest: changes moment to moment depending on host factors - light, noise, motivation, recumbency.
--reduction in impinging stimuli unmasks physiological sleep tendency, not cause it

273

What are 2 tests used for diagnosis of excessive daytime sleepiness?

1. Multiple Sleep Latency Test: Objective. measures tendency to fall asleep at 4 times throughout the day. Normal sleep latency is >15min in adults.
2. Epworth Sleepiness Scale: questionairre - Subjective. Asks about liklihood to fall asleep in 8 situations
Score < or = 10 is normal

274

What is the apneic threshold?

pCO2 below which a subject becomes apneic during NREM sleep
apnea: higher threshold
Men higher than women

275

What happens to the normal ventilatory pattern during sleep?

N1: can be irregular, periodic
N2 and 3: regular
R: irreg. w/ REM
Overall: decrease in TV and minute ventilation. No change in freq. decreased metabolism. increased PaCO2

276

What is the difference between apnea and hypopnea?

Apnea: complete cessation of airflow for 10 sec.
Hypopnea: 20-50% reduction in airflow assoc. w/ arousal or 2-4% decrease in O2 sat.

277

Apnea-hypopnea index

(# of apneas + hypopneas)/ total sleep time = AHI

30: severe

278

What is OSAS?

Obstructive sleep apnea syndrome

Obstructive sleep apnea with daytime sequelae

2% of women and 4% men age 30-60

279

what cardiovascular risks is OSA associated with?

Hypertension
Heart disease (LVH and diastolic dysfunction)
Metabolic syndrome (esp. insulin resistance)
Cerebrovascular disease

Pulmonary HTN and Right-sided HF uncommon w/o lung disease and/or daytime hypoxia

280

What polymorphisms is narcolepsy associated with?

HLA-DQB1*0602

loss of hypocretin neurons in hypothalamus - control/coordinate other wake centers

281

How are the symptoms of narcolepsy treated?

EDS: stimulants
cataplexy: TCAs or SSRIs
Behavioral: avoidance of triggers, short scheduled naps, maximize sleep hygiene

282

What is pharmacologic management of Restless Leg Syndrome?

Dopamine Agonists: ropirinole, pramipexole, levodopa
Opiates: oxycodone, propoxyphene
Anticonvulsants: gabapentin, enacarbil

283

How is nicotine metabolized?

10-20% unchanged in urine
70-80% metabolized to cotine (inactive)
10% to other metabilites

284

What are the half-lives of nicotine and cotine?

Nicotine: 2 hrs
Cotine: 16 hrs

285

How is nicotine/cotine excreted?

Mostly renally
Also in breast milk

286

What are the effects of nicotine?

Stimulatory: CNS, CV, appetite suppression, increased metabolic rate.

Stim DA reward pathway

287

What is the timeline of nicotine withdrawal?

Onset of withdrawal symptoms: 1-2 days
Peak: 1st week
Subside: 2-4 weeks

288

5 A's of smoking intervention

Ask about use
Advise to quit
Assess readiness to quit
Assist w/ quit attempt
Arrange follow-up care

289

5 stages of readiness to quit smoking

1. precontemplation: not ready to quit in next 6 mos
2. contemplation: considering quitting in next 6 mos, but not next 30 days (5 Rs: Relavence, Risk, Reward, Roadblocks, Repetition)
3. preparation: considering quitting in the next 30 days
4. action: have quit w/in last 6 mos. Goal: 6 mos smoke-free
5. maintenance: quit > 6 mos. ago. still vulnerable to relapse. Goal: smoke-free for life

290

Points to discuss in preparation stage of smoking cessation

Praise decision to quit
Use history and previous quit attempts
Reasons, Confidence in ability to quit, Triggers
Concerns: weight gain, withdrawal

291

2 coping strategies to employ in smoking cessation

Cognitive: retrain way of thought
Behavioral: involve specific actions to reduce relapse risk

292

When should a physician follow up with a patient who has decided to quit smoking?

1: after first week
2: after first month
3: as needed afterward

293

non pharmacologic methods to assist w/ smoking cessation

cold-turkey
fading: reduced nicotine cigs, tapered use, special filters / holders
quit key
formal programs
accupuncture, hypno, massage

294

Who should not use nicotine replacement therapy?

Underlying CV disease (arrhythmia, recent MI, severe/worsening angina) or pregnant/lactating
TMJ: shouldn't use gum

295

Dosing for NRT gum and lozenges

2mg: if you smoke 1st cig more than 30 mins after waking
4mg: if you smoke 1st cig w/in 30 mins of waking
Week 1-6: 1 piece q1-2h
Week 7-9: 1 piece q2-4h
Week 10-12: 1 piece q4-8h

Max: 24/day (gum) 20/day (lozenge)

296

What strength Nic patches are available?

7,14,21 mg

297

How are patches dosed for heavy smokers (generic vs. nicoderm)?

Generic step 1: 21mg / day X 4 wks
Nicoderm step 1: 21mg / day X 6 wks

298

What is the standard nic patch dose schedule?

Step 1 (heavy smokers) 21 mg x 4-6 wks
Step 2 light smoker: 14mg x 6 wks
heavy smoker: 14mg x 2wks
Step 3: 7mg x 2 weeks

299

When using a nic patch, how long should pass between reapplying a patch to a given location?

1 week

300

What is the recommendation for nic patch users in the case of vivid dreams?

try 16 hour application rather than 24

301

What is dosing for nicotine nasal spray?

0.5mg nicotine / 50mcL spray ( 1 dose = 2 sprays)

start: 1-2 dose/ hr, increase prn to max 5doses / hr.
1st 6-8 weeks: recommend at least 8 doses / day
Gradually taper over next 4-6 weeks

302

What is dosing for a nicotine inhaler?

4mg nicotine vapor / cartridge
Start: 6 cartridges/day, increase prn to max of 16/day
Gradual dosage reduction over 3-12 weeks. Extend if needed.

303

What antidepressant may be used as adjunct therapy in smoking cessation?

Bupropion SR
DA/NE reuptake inhibitor
Decreases nic craving / withdrawal symptoms

304

Bupropion dosing for smoking cessation

Start 1-2 weeks prior to quit date
150 mg qAM / 3days then 150 bid for 7-12 weeks

305

What is varenicline?

Partial nicotinic receptor agonist (low-level activity) - competitively inhibits binding of nicotine.
-reduces withdrawal symptoms
-blocks DA stim. responsible for reinforcement / reward

306

How is Varenicline dosed?

start 1 week prior to quit date
day 1-3: 0.5mg qd
day 4-7: 0.5mg bid
weeks 2-12: 1mg bid

307

what are the 2 most effective smoking cessation aids?

Nicotine inhaler
Varenicline

308

Can Varenicline be used w/ a NRT or bupropion?

Safety not established

309

For maximum success, what should smoking intervention consist of?

Counseling + one or more meds

310

Cues to expect ILD

Pt. w/ cough, dyspnea
Abn CXR - diffuse, not necessarily uniform, changes
Crackles on PE - cellophane or velcro

311

What exposures can result in ILD?

Pneumoconiosis: inorganic - silicosis, asbestosis
Toxins - oxides of nitrogen
Drugs - Amiodarone, bleomycin
Radiation
Oxygen
Hypersensitivity (farmer's lung) - organic

312

What ILDs are attributed to unknown causes?

make up 2/3 cases
Idiopathic Interstitial Pneumonias / Idiopathic Pulmonary Fibrosis
Sarcoidosis

313

What is Idiopathic Interstitial Pneumonia? What is the most important diagnosis tool?

Includes: Interstitial Pulmonary Fibrosis (IPF) and Nonspecific Interstitial Pneumonia (NSIP)
Radiologic criteria most important for diagnosis
Consists of 7 entities differentiated by clinical, radiologic, and pathologic criteria

314

7 classifications of IIP

UIP: usual interstitial pneumonia
DIP: desquamative interstitial pneumonia
RB: respiratory bronchiolitis
DAD: diffuse alveolar damage
OP: organizing pneumonia
NSIP: non-specific interstitial pneumonia (cellular and fibrotic)
LIP: lymphoid interstitial pneumonia (smoking related, corticosteroid responsive)

315

What is the most common IIP?

Idiopathic Pulmonary Fibrosis (IPF) - 60% of IIP cases
Chronic, Progressive, Fatal
corresponds to UIP histologic pattern

316

What is the usual age of onset of IPF?

40-70 years w/ 2/3 >60
male > female

317

Risk factors for IIP

Familial
Smoking
possibly: exposure (wood/metal dust), GERD, infection

318

Is familial IPF AR or AD? What gene(s) are involved?

AD
variable penetrance
ELMOD2 on 4q31

319

What mutations have been identified in IPF?

seen in 10% of cases
pulmonary surfactant protein C
TERT -telomerase reverse transcriptase
TERC -telomerase RNA component

320

What are IPFs clinical features?

progressive dyspnea w/ exertion, tachypnea
paroxysmal cough
clubbing (25-50%)
fine bibasilar crackles
**abnormal CXR or HRCT**
**restrictive pulmonary physiology, reduced DLCO, wide A-a O2

321

Diagnostic criteria for IPF

Variation w/in lung - "temporal heterogeneity"
Subpleural distribution
Fibrosis
Honeycombing
Fibroblastic foci
***absence of features of alternative diagnosis***

322

How does NSIP differ from IPF?

More uniform distribution
"ground glass" opacities
cellular and fibrotic types
better prognosis (cellular > fibrotic) - more responsive to corticosteroids

323

What is the treatment for IPF?

None.
Cortiticosteroids - don't work - evidence against underlying inflammatory cause

324

What is the survival rate for patients w/ IPF?

Median survival: 3 yrs from diagnosis
5 yr survival: 20-40%

Poor prognosis

325

In what populations is sarcoidosis most frequent?

Swedes, Danes, Blacks

326

Pathophys of sarcoidosis

Stimulus in susceptible host
Accumulation of CD4 cells and macrophages at site of ongoing inflammation
IFN-g, IL-2, other cytokines

327

Is sarcoidosis restrictive or obstructive?

Restrictive +/- obstructive component

328

What are sites of disease in sarcoidosis?

Lung: restrictive +/- obstructive, abnormal diffusion,
Lymph nodes: enlarged (hilar, mediastinal, peripheral)
Skin: papules, macules, pigment change
Heart: conduction defect, sudden death
GI: liver very common, spleen
Eyes: common - uveitis can -> glaucoma / blindness
Nervous system - base of skull, facial palsies, pituitary lesions, space occupying masses

329

What is the prognosis of sarcoidosis?

spontaneous remission in 60%
chronic/ progressive 10-30%
death in 1-5% - respiratory failure

330

Treatment for sarcoidosis?

corticosteroids

331

In what ILD are bronchoscopic biopsies most useful?

sarcoidosis

332

Desquamated Interstitial Pneumonitis

Rare
strong link to smoking
good prognosis: 90-100% survival - responds to steroids
Lots of alveolar macrophages, lymphocytes, mild fibrosis

333

What is BOOP?

Bronchiolitis Obliterans-Organizing Pneumonia
Associated w/ Hypersensitivity Pneumonitis
Granulation tissue plugs in bronchi and/or alveoli

334

What type of hypersensitivity is involved in Hypersensitivity Pneumonitis?

Combination of type III and IV

335

What is Histiocytosis X?

Involves proliferation and tissue infiltration by Langerhaan's cells

336

Types of Histiocytosis X

Unifocal - lung or bone
-Eosinophilic granuloma of lung (most common 60-80%)
--children and young adults
--lung only
--best prognosis

Multifocal
-Hand-Schuller-Christian disease
--1-3 yoa: lung, bone - may be systemic
-Letterer-Siwe
--0-1: worst prognosis (70% mortality)

337

What is Virchow's Triad?

Risk factors for DVT
Stasis
Endothelial Injury
Hyper-coagulable state

338

Initial patient evaluation for suspected PE

CXR: rule out pneumothorax, pneumonia, other
ECG: rule out acute MI or pericardial effusion
ABG: non-specific, but often present w/ PaO2 <80
-absence of hypoxia strike against PE

339

How is d-dimer useful in evaluation for possible PE?

Product of fibrinolysis - always present when there is a clot.
Not diagnostic
Neg test - PE highly unlikely.
Pos test - further testing

340

What is the current tool of choice for diagnosis of PE?

Spiral CT angiography
High specificity (72%) and sensitivity (95%)
Positive: treat
poor for sub-segmental emboli
requires cooperation and 15-25 sec breath hold
more radiation than V/Q scan
requires IV contrast

341

3 types of heparin

Unfractionated (UFH)
Low Molecular Weight
Fondaparinux

342

Where does heparin work?

Factors IXa, Xa, IIa (thrombin) via antithrombin III

343

What did PIOPED I suggest as the first diagnostic test for suspected PE?

ventilation - perfusion lung scan

344

What is the gold standard for PE diagnosis?

Pulmonary angiogram - will shoe intravascular filling defect in area of clot
Risks - hypotension, arrhythmia, arterial rupture, dye reaction

345

How is a V/Q scan performed?

Nuclear markers introduced to chest and scans done for perfusion and ventilation
Negative: virtually excludes PE
High Probabillity: V/Q mismatch - PE very likely
Most results are indeterminate

346

How does heparin induced thrombocytopenia occur?

Heparin binds PF-4. Complex recognized by Ab -> platelet activation and thrombosis

347

How is HIT managed?

Immediate stop of heparin
Anticoagulation: direct thrombin inhibitors: Agatroban
Fondaparinux: heparin like activity - binds AT-III

348

What coagulation factors are affected by Vitamin K antagonists?

Coumadin, Warfarin work at factors II, VII, IX and X

349

3 characteristics of normal pulmonary circulation

Low pressure
Low resistance
High capacitance

350

Physical exam findings in case of pulmonary HTN

Loud S2 (P2) heart sound
With worsening disease: edema of lower extremities, ascites, hepatomegaly, pulsating liver, JVD, right ventricular heave

351

5 groupings of pulmonary HTN

I: PAH: vasculopathy of PA - treat w/ dilators
II: PVH - pulmonary venous hypertension - due to L. heart disease
III: Hypoxemia related
IV: Chronic thromboembolic disease
V: Miscellaneous

352

What mediators are imbalanced in type I pulmonary hypertension?

Type I: PAH
Increased: Thromboxin A2 (vasoconstrictor, mitogen) and Endothelin (vasoconstrictor and mitogen)
Decreased: Prostacyclin (vasodilator, antiproliferative, anti-platelet activation) and NO synth (vasodilator, antiproliferative)

353

What is the theme of therapy for type I pulmonary hypertension?

Inhibit endothelin, promote NO synthesis, replace prostacyclin

354

What test is needed for a diagnosis of pulmonary hypertension? Diagnostic findings?

Right heart cath- gold standard for diagnosis
PH: mean PA pressure: >=25mmHg, w/ exercise: >=30 mmHg, systolic: >=40 mmHg
PAH: mean PA pressure: >=25 ,30 w/ exercise, PCWP =3mmHgxmin/L

355

Once diagnosed w/ group I pulmonary hypertension, what needs to be ruled out?

autoimmune, CT, collagen vascular disease, ILD, HIV, portal HTN, OSA, R->L shunt due to ASD or VSD.

356

Therapeutic approach to pulmonary hypertension

Treat underlying condition
general treatment beneficial to most:
supplemental O2 (keep O2 sat >90), diuretic, inotropic therapy (digoxin)

357

4 therapies for group I pulmonary HTN

Calcium channel blockers - must pass vasodilator test (only ~5%)
Endothelin agonistss: Bosentan, Ambrisentan: Functional class II and III - vasodilator, antiproliferative
PDE5 inhibitor: Sildenafil, Tadalafil: Functional class II and III - increase duration of cGMP -> increased NO production
Prostacyclin derivatives: Epoprostenol, Treprostinil, Iloprost: pulmonary vasodilator, anti-proliferative - class III and IV
NO (acute)
Anticoag -

358

How are class II, III, and IV symptomologies of pulmonary HTN treated?

II: CaCB - if no help add PDE5i or ERA(oral)
III: ERA and/or PDE5i + sq or inhaled prostacyclin analog
IV: IV or sq prostacyclin analog. If needed add ERA / PDE5i - if not already using

359

What anticoagulant is monitored w/ PTT?

Unfractionated Heparin

360

How are UFH and LMWH excreted?

Renally
LMWH much moreso than UFH
LMWH must be adjusted for renal function

361

Can warfarin be used during pregnancy?

No - vit K
-> bone growth issues
Use LMWH instead for anticoag

362

What is the most common clinical presentation of patients w/ HIT?

thrombocytopenia

363

Mortality rate of HIT

5-10%

364

Treatment principles when HIT is suspected

1. stop heparin
2. give non-heparin alternative
3. postpone warfarin pending platelet count (give vit K if warfarin already being taken)
4. test for HIT Ab
5. investigate for LL DVT
6. avoid prophylactic platelet infusion

365

What is the target of warfarin? Effect?

Vitamin K Epoxide Reductase (VKOR)
Prevention of reduction of Vitamin K epoxide -> no gamma carboxylation of factors II, VII, IX, X

Also inhibits carboxylation of C and S -> procoagulant activity

366

How long does it take for warfarin to have therapeutic effect?

~5 days needed for depletion of clotting factors

367

What polymorphisms affect warfarin activity?

polymorphisms of CYP2C9
CYP2C9*2 and CYP2C9*3 -> decreased metabolism -> increased S warfarin half life

VKOR polymorphisms -> usually increased sensitivity

368

What is is the target INR value for warfarin pts?

usually 2-3
w/ mechanical mitral valve replacement - 2.5 - 3.5

369

Options for immediate warfarin reversal

fresh frozen plasma (must be thawed, heated)
prothrombin complex concentrate - ready to go

370

What is Rivaroxaban?

Direct factor Xa inhibitor for reduction of stroke risk and systemic embolism in pts with nonvalvular Afib, treatment of DVT or PE, and VTE prophylaxis (pre-procedural)

371

Silicoproteinosis

Acute massive exposure to silica
Progressive and often fatal - rare w/ protective
Lung rxn is outpouring of proteinaceous material
hypoxia, resp. failure, pulm. edema
"ground glass" CXR - esp. upper lung

372

Chronic "simple" silicosis

silicotic nodules <1-1.5cm
egg-shell calcifications of hilar lymph nodes
few symptoms, minimal to no changes in PFTs

373

Complicated silicosis

Progressive
Simple nodules coalesce -> large densities
restrictive and obstructive characteristics
autoimmune markers may be present

374

Caplan's syndrome

complex silicosis + RA
large nodules, but more benign than typical complex silicosis

375

Effect of silicosis on TB

silica poisons macrophages -> 4-6x increased risk
silicotuberculosis: TB in person w/ silicosis

376

2 diseases caused by asbestos exposure

1. asbestos pleural disease: thickening of pleura -> exudative, bloody pleural effusion
2. asbestosis: interstitial disease - lung bases, "shaggy heart" on cxr. dry cough and crackles. restrictive. -> clubbing, cor pulmonale, respiratory failure

377

Malignant mesothelioma

malignant tumor of pleural mesothelial cells
very poor prognosis
usually non-resectable, not very responsive to chemo or radiation

378

When do farmer's lung symptoms occur related to exposure?

4-8 mos later

379

Course of farmer's lung

usually spontaneously resolves w/in 24 hours. Repeat exposures may -> restrictive disease

380

symptoms of farmer's lung

fever, chills, sweating, cough dyspnea ( mirrors acute pneumonia)

crackles on exam
CXR: bilateral reticulonodular infiltrates

381

How can occupational asthma be diagnosed?

spirometery before and after work

382

Treatment for occupational asthma?

bronchodilators help
removal from exposure is key. Continued exposure may -> COPD

383

Silo Filler's disease

Oxides of nitrogen form over freshly cut hay -> toxic lung injury
Immediate effects or gradually over 18-24 hours depending on exposure.
ARDS type clinical picture / DADS / Bronchial Obliterans
Treat - O2, respiratory support, corticosteroids

384

2 categories of respiratory failure

hypoxia w/ hypercarbia: caused by inadequate ventilation (high PaCO2) and oxygenation.
problems: CNS, chest wall, airway
hypoxia predominating: low PaO2, CO2 normal until the end. inability to get O2 through pulmonary system -> tissues
Problems: circulatory, hemoglobin, intrinsic lung disease, ARDS