Flashcards in Resp. path Deck (385):
COPD w/ permanently enlarged air sacs distal to terminal bronchioles w/ destruction of their walls and w/o obvious fibrosis
What is the main enzyme implicated in emphysema?
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
What type of emphysema is cigarette smoking usually associated with?
Anthracosis often present
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
Chronic Bronchitis Definition
Productive cough w/o discernible cause for at least 3 months in 2 consecutive years
Ratio of thickness of mucous glands to total thickness of airway wall.
Elevated in chronic bronchitis
most severe subtype of asthma - prolonged interval of continual symptoms, unresponsive to treatment
May be life-threatening
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
Major chemical mediators of acute phase of asthma
LTC4, D4, E4
PGD2 - mucus prod
Parasympathetic neural reflexes
What happens in late phase of asthma?
Infiltration of white cells (esp. eosinophils) in response to locally released chemotactic factors
Prolongation and augmentation of disease process
2 common drugs that can contribute to asthma
aspirin: decreased prostaglandin production and relative increase in leukotriene
B-antagonists: may precipitate bronchospasm
What respiratory disease is assoc. w/ mucus plugs?
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
What is bronchiectasis
Permanent airway dilation due to recurrent infections w/ necrosis
Incomplete expansion of lungs at birth
What happens to the mediastinum in obstructive atelactasis?
Mediastinal shift toward atelactic lung
What happens to the mediastinum in compression atelactasis?
Mediastinal shift away from atelactic lung
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
What receptors do epinepherine, ephederine, and isoproterenol work at?
epinepherine: B1, B2, alpha
ephedrine: B1, B2, alpha
isoproterenol: B1, B2
How do selective B2 agonists work?
increase AC -> increased cAMP -> sm. muscle relaxation
3 short acting B2 agonists
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.
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
2 long acting B2 agonists available in 1x daily dosing?
Both available as DPI
What genetic factor has been associated with increased susceptibility to B2 agonist tolerance?
Gly16 polymorphism of B2 receptor.
-> reduced responsiveness to agonists
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
What is the primary mechanism of action of anticholinergics in treatment of obstructive respiratory disease?
Reduction of intrinsic vagal tone
In what patient population is ipratropium contraindicated?
Those w/ soy lecithin or peanut allergy.
Propellant contains lecithin
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
Blocks 5-LOX preventing leukotriene production.
Used in chronic maintenance of asthma
Montelukast and Zafirlukast
Long acting controlers of COPD
Selective and competitive inhibition of Cys LT1 receptor -> prevention of production of LTD4 and E4
What would be a good medication for chronic management of asthma for a child under 5?
No drug interactions
Chewable tablet / granule form
Indicated for children >1
What is lipocortin?
Induced by corticosteroids
Inhibits PLP A2 -> decreased production of prostaglandins and leukotrienes
What is the time of onset for inhaled corticosteroids?
From days up to 2 weeks
Adverse reactions to inhaled corticosteroids?
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.
What is the mechanism of methylxanthines?
Nonselective inhibition of phosphodiesterase
Increased cAMP -> smooth muscle relaxation
Effects intercellular Calcium
2 methylxanthine drugs
Narrow therapeutic window!
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
Target concentration of theophylline and toxic concentration
>20 mcg/ml -> toxicity: tachycardia, restlessness, agitation, emesis, seizure
-> accumulation of cAMP -> smooth muscle relaxation
Bronchodilation and anti-inflammatory effect - treatment for COPD
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.
Omalizumab - what it is and how administered
humanized monoclonal antibody to IgE
Good for pts. w/ comorbid allergies
Subcutaneous injection - expensive
Ipratropium / Albuterol combo - COPD quick relief
Salmeterol / Fluticasone - DPI, MDI
COPD and Asthma controller
Formoterol + Budesonide
DPI for asthma and COPD
Mometasone + Formoterol
MDI asthma controller
Fluticasone + Vilanterol
What racial / ethnic groups have the highest incidence of TB infection?
3. African American
What toxins are produced by TB?
But it does produce niacin - old ID Method
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
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.
What NTM pathogen causes pulmonary disease in CF?
person to person spread in CF centers
What NTM is most similar to TB?
not treated with PZA
What is the source of NTM spread?
Water and soil source - no person to person
TB infection depends on what 3 factors?
Number of droplet nuclei exposed to
Number of TB organisms in droplet nuclei
Duration of exposure
5 measures for preventing TB infection
Ventilation (neg. pressure isolation) >20 air volume changes per hour
Chemotherapy: 1-2 weeks of therapy prevents infectivity
Covering infected person's mouth
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
How long does it take to develop a positive skin test after TB exposure?
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
Describe TB skin testing
Intracutaneous injection of 5 Tuberculin Units (TU) of PPD (Purified Protein Derivative)
Induration measured after 48-72 hours
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.
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
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
What are the shortcomings of AFB staining?
Low sensitivity and Low specificity: produces both false + and -
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
4 major TB drugs
What is multi-drug resistant TB?
Resistant to AT LEAST Rifampin and Isoniazid
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
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
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)
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
What is treatment for latent TB?
1. 9 mos of Isoniazid @ 300mg / day or 900mg 2/wk
2. 4 mos of Rifampin @ 600 mg / day
watch for Hepatitis
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
What is BCG?
Bacillus Calmette and Guerin - TB vaccine of M.bovis
varies in efficacy
does not prevent infection, but prevents dissemination
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
Inflammation of gas exchanging areas of lung / lower respiratory tract
What is the #1 cause of death from infectious disease?
What is rust colored sputum suggestive of?
What is "currant jelly" sputum suggestive of?
Klebsiella pneumoniae pneumonia
What is creamy yellow sputum suggestive of?
What is very foul smelling sputum suggestive of?
Aspiration pneumonia - oral anaerobes
What pneumonia causing organsisms are not seen in sputum?
Mycoplasma, Legionella, TB, viruses
What is treatment for Pneumococcal pneumonia?
Macrolide (azithromycin) or doxycycline
Plus 3rd gen cephalosporin (Cefotaxime, cephtriaxone, cephixime, cefpodoxime
What is type 3 serotype S.pneumo?
Highly virulent strain. Poorer prognosis.
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)
What does Mycoplasma pneumonia cause?
Atypical or "walking" pneumonia in young otherwise healthy people.
What are clinical symptoms of Mycoplasma pneumonia?
fever, headache, chills
Blistering of eardrum (Bullous Myringitis)
Rare signs of consolidation - usually patchy rales and crackles
How is mycoplasma treated?
Macrolide (azithro, clarithro, erythromycin)
What are indicators of Legionella infection?
Fever over 102 w/ relative bradycardia, GI involvement w/ diarrhea, hyponatremia, hypophosphatemia
How is legionella pneumonia treated?
What populations are associated with H.influenzae pneumonia?
alcoholics, COPD, healthy adults, sickle cell pts.
Lots of sputum
treat w/ cephalosporin, sulfa
What populations are associated with Klebsiella pneumonia?
Diabetics, alcoholics, debilitated
bulging fissure on cxr
treat w/ cephalosporin or aminoglycoside
In aspiration pneumonia how long does it take following aspiration for tissue necrosis / liquefaction?
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
2 forms of cocciodiomycosis
arthrospore- in soil, infectious
spherule - tissue form - contains endospores
2 forms of histoplasmosis
microconidia: infective form in soil. assoc. w/ bird and bat droppings
narrow-necked budding yeast: tissue form
What are 2 forms of blastomycosis?
dumbell shaped yeast
broad based budding yeast (tissue)
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
How is blastomycosis treated?
Usually no antifungal needed.
Only in disseminated disease - IV anti-fungal
How is aspergillus diagnosed?
Skin testing for acute infection
Serology: IgE in acute and fungus balls. IgG also possible
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.
What organisms are associated w/ nosocomial pneumonia?
60% enteric gram (E. coli, Klebsiella, enterobacter, pseudomonas, Serratia, Proteus)
10% S. aureus
Legionalla and other
What is the most common viral infection seen in AIDS pts?
In what patients is P.carinii seen?
HIV: slowly progressive, fever, cough, dyspnea, CXR infiltrate
Children w/ leukemia: fulminant downhill course
What is treatment for P.carinii?
Pentamidine IV or aerosol for those who can't tolerate.
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)
What is Rifampin's MOA?
binds B-subunit of bacterial DNA dependent RNA-pol
What lab values are elevated in Rifampin toxicity? What about Isozianid?
Rifampin: elevated bilirubin and alkaline phosphatase
Isoniazid: aminotransferase elevated
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
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.
What is Pyrazinamide's MOA?
Unknown. Prodrug activated by mycobacterial pyrizinamidase -> active pyrazinoic acid.
High activity at acidic pH in lysosomes
What is the MOA of Ethambutol?
Inhibits arabinosyl transferases - needed for cell wall components.
What was the first drug useful against TB, what class, what MOA?
Streptomycin (Aminoglycoside) binds 30s subunit of bacterial ribosome - oxygen dependent
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
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
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
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
How long does the early asthmatic response last?
resolves by 2 hours
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
3 causes of airway obstruction in asthma
2. vascular congestion and bronchial edema
3. accumulation of airway secretions, mucus casts, and cellular debris
What happens to PFTs during an asthma attack?
Reduced FEV1 and FVC
Lung volume increase, esp RV and FRC
How does the work of breathing change in asthma?
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
What is criteria for intermittent asthma?
Rule of 2:
symptoms < / = 2x /week
night time awakenings = 2 days per week
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
What is the goal of asthma therapy and what are its components?
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
What is the only major disease in US w/ an increasing death rate?
4th most common cause of death
What % of chronic heavy smokers develop COPD?
What chromosome is implied in families w/ COPD?
What other polymorphisms have been identified?
IL1, TGF-B (both increasing and decreasing risk), GSTM-1
Where is a1-antitrypsin gene found? Is deficiency AD or AR?
on chromosome 14
What other organ system is affected in persons w/ a1-antitrypsin deficiency emphysema?
Hepatic cirrhosis is seen in 1-3% of emphysema pts.
What is the role of oxidative stress in COPD?
1. activates NFk-B -> transcription of inflammatory proteins (TNF-a)
2. inactivation of anti-proteases
What is the role of amplification in COPD?
COPD patients have amplified inflammatory response compared to normal.
3 key symptoms for COPD diagnosis
1. chronic cough
2. chronic sputum production
3. dyspnea: starts insidiously and escalates - persistent
What is the most common cause of COPD exacerbation?
bacterial or viral infection of airways
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
What chromosome houses the genes associated with a1-antitrypsin deficiency?
What inflammatory cells are associated with COPD?
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)
What are major considerations for COPD diagnosis?
Dyspnea - persistent, progressive, worse w/ exertion
Exposures - smoking
When should ABG be checked in COPD evaluation?
signs of Cor Pulmonale / Right sided HF
What is a chronic CO2 retainer?
COPD patient with elevated PCO2 between exacerbations
Blood gas reflects compensated respiratory acidosis (normal pH, high HCO3-
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
5 etiologies of bronchiectasis
1. infection: Pertussis, necrotizing pneumonia, viral pneumonia (measles, influenza), TB
2. Immotile cilia syndrome / Kartagener's
4. Cystic Fibrosis (frequent infections w/ S.aureus and PSA)
5. Allergic bronchopulmonary aspergillosis
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.
Treatment for bronchiectasis?
1. Treat underlying problem
2. Improve clearance of secretions: chest physiotherapy
3. Control infections: vaccinations, daily abx (CF - macrolide 3x/wk)
From what tissue do lungs develop?
buds at ~4weeks
3 stages of lung development
Pseudoglandular 5-16 wks
Canalicular 16-26 wks
Alveolar / Viable 26- birth
What test is used to asses lung maturity prenataly?
Lecithin increases w/ maturation, sphingomyelin stays stable
What substances accelerate fetal lung maturation?
cortisone, stress, thyroxine, prolactin, theophylline, sympathomimetics
3 factors that decrease rate of fetal lung maturation
At what age are all alveoli formed?
few alveoli at birth
8-10 yrs - intense alveolar prolif
10-20 increase in size
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
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
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.
What are sequestrations in terms of lung development?
Insult in 1st trimester -> ectopic lung tissue w/ systemic blood supply (high pressure)
Clinically similar to cysts, but difficult to remove.
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
What occurs in RDS?
Infant born w/ insufficient surfactant. Fibrinogen containing materials deposit on alveolar walls -> fibrosis
Low compliance, atelectasis, increased WOB
Capillary endothelial damage - leak
3 complications of RDS
1. Oxidative damage: a) lung injury due to high FIO2 b) retrolental fibroplasia (blindness - prevent w/ vit E)
3. Chronic lung disease (fibrosis, pulmonary HTN)
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.
How is RDS prevented?
1. Prenatal care
2. Corticosteroids at least 24 hrs before delivery accelerates lung maturation
What is seen on autopsy of SIDS infant?
signs of chronic asphyxia
subtle brain stem lesions
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
Genetic factors in SIDS
Not strongly familial
Type B blood
Peak age for SIDS?
rare after 6 mos
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
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
What organs are affected by Cystic Fibrosis?
Primary: lungs, sinuses, pancreas
Other: Sweat glands, intestines, liver, male GU tract
What pattern of inheritance is cystic fibrosis?
What chromosome carries CF gene?
What is the main mutation seen in CF?
Loss of 3 nucleotides and a phenylalanine
What is the relative incidence of CF by race?
White > Hispanic > Native Am > AA > Asian
What is estimated median survival in CF (2010)
What is CFTR?
cAMP dependent Cl- channel found in epithelial tissue of lung, pancreas, gall bladder, salivary and sweat glands, epididymis, etc.
What abnormalities can result from CFTR mutation?
Rate of Turnover
Class I CFTR mutation
CFTR is not produced due to a DNA defect- premature stop codon
Class II CFTR mutation
Defective processing and trafficking
seen w/ delta-F508
mutation -> improper folding -> abnormal interaction w/ chaperone proteins -> degradation in ER
Class III CFTR mutation
Defective cAMP Regulation -> defective Cl- transport
Class IV CFTR mutation
defective conductive pathway of CFTR
Class V mutation of CFTR
Abnormally spliced CFTR -> partial or complete reduction
Class VI CFTR mutation
Accelerated turnover at apical membrane
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
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)
What genotype of CF is associated with mild lung disease?
What antibiotics are used prophylactically for CF?
TOBRI, colistin, aztreonam
What drugs are used in CF patients to help with mucus?
change viscosity of mucus
What is azythromycin used for in CF?
Improves lung functions and decreases exacerbations. Not used as antibiotic in usual sense.
What is the peak age range for nasal polyposis in CF?
5-19 w/ high recurrence rate after surgery (58-89%)
What process leads to diabetes in CF?
Pancreatic duct occlusion -> self-digestion of pancreas and destruction of endocrine pancreatic cells -> diabetes
What GI complaints typically accompany CF?
1. Meconium ileus in newborns
2. Stool fat loss (>7%)
4. Gastritis, Esophagitis, reflux (low bicarb)
5. Malabsorption of fat sol. vitamins (A,D,E, K)
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)
What is the application of Ursodeoxycholic acid in CF?
Treatment of billiary cirrhosis - destruction of small bile ducts of liver -> cholestasis
What is the incidence of Diabetes in CF?
24% at 20 yoa
76% at 30 yoa
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
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
What is cigarette "tar" and what does it contain?
Residue of cigarette smoke minus nicotine and water
Contains many carcinogens:
-radioactive elements (nickel)
In addition to lung cancer, what others are smoking associated?
How does radon cause cancer?
radioactivity: alpha particles
What are the 2 leading causes of lung cancer?
Where does small cell lung cancer originate?
What is the doubling time for small cell lung cancer?
Fast! 30 days
Where does small cell lung cancer spread?
Bone Brain Liver
How does small cell lung cancer react to therapy?
Very good initial response, but doesn't last
High rate of recurrence
What % of lung cancers does small cell comprise?
What is the origin of squamous cell lung cancer? where is it found?
From endobronchial tissue
Central tissue - large
What lung cancer is least likely to metastasize?
What is the growth rate of squamous cell lung cancer?
Doubling rate: 100days
What lung cancers have a tendency to cavitate?
Where does squamous lung cancer generally metastasize?
Least distant spread
How does squamous lung cancer respond to therapy?
Where is adenocarcinoma located in the lung?
What is the growth rate of adenocarcinoma of the lung?
Medium - slow
Doubling rate 100-180 days
Where does adenocarcinoma of the lung tend to metastasize?
In what population is bronchioalveolar cancer usually found?
Can occur in non-smokers
What is a common misdiagnosis of BACA?
Failure of infiltrate to resolve w/ chemo may be clue to diagnosis
What is the appearance of Large Cell Lung Cancer?
Large, highly undifferentiated cells.
Large mass w/ necrosis and hemmorhage
Which of the non-small cell lung cancers has the worst prognosis?
How must a suspected large cell tumor be biopsied?
Several samples from different locations taken - look for more differentiated cells
Diagnosis of exclusion
What is a concern with a COPD patient who experiences sudden weight loss?
How might a tumor cause elevation of the diaphragm?
Impingement on phrenic nerve
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
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.
What lung cancer cells are most associated w/ endocrinopathies?What are examples?
Small cell (Oat cell)
ACTH, MSH, ADH
What cancer type is know for producing PTH?
Squamous cell carcinoma
What tumor type is most associated with neuromuscular paraneoplastic issues?
What is Myasthenic syndrome and what is it associated with?
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)
What is hypertrophic pulmonary osteoarthropathy?
connective tissue disease seen w/ some lung cancers
-> clubbing of fingers
Smoker w/ finger clubbing - look for tumor
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
Pleural tap and biopsy
Tissue or fluid from metastatic site
Is radiation therapy curative?
Local control - external beam or endobronchial
Is chemotherapy curative?
Only in small cell, otherwise no
Controls distant disease
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
At diagnosis of lung cancer, what % is considered resectable?
What is overal 5 year survival for lung cancer and w/ surgery?
Overall 5-year survival: 13%
W/ surgery 30%
What is the most common histotype of lung cancer?
followed by Squamous (28-30%)
What lung cancer is most likely to occur in a non-smoker?
followed by Large Cell
What two cancers are most closely associated with smoking?
Squamous and Small cell
Risk persists after cessation
Small cell and Squamous cell lung cancers arise from what cell types?
Respiratory mucosa of main or lobar bronchi (bronchial stem cells)
Adenocarcinoma most often arises from what cell types?
bronchioles and terminal alveolar units - Clara cells and type II alveolar cells
What is BACA?
Bronchioalveolar lung cancer
Slow growing adenocarcinoma
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
What is the pathogenesis of Adenocarcinoma?
Normal terminal bronchioles / alveoli -> atypical adenomatous hyperplasia -> adenocarcinoma CIS -> invasive adenocarcinoma
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
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
What mutations are seen in Aca in smokers and non-smokers
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
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.
What secretory products are often made by Aca cells?
products normally made by Type II or Clara cells
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.
How is large cell lung cancer diagnosed?
Diagnosis of exclusion
Thorough sampling - multiple samples from tumor to look for differentiation.
What are the major lung cancer types showing neuroendocrine differentiation?
Large Cell Neuroendocrine Carcinoma
What is crush artifact?
Seen in small cell lung cancer
Artifact of preparation - long smears of DNA
Describe a Typical Carcinoid tumor
Nested pattern, no necrosis, at least 0.5 cm
Low proliferative rate (<2 mitoses / 2mm^2)
Cells: low N/C ratio, salt and pepper chromatin, absent or small nucleoli
Are carcinoid tumors assoc. w/ smoking?
No association w/ smoking
What is the prognosis of typical carcinoid lung cancer?
Excellent - 95% survival at 5 years.
What syndrome may carcinoid lung cancer appear with?
Multiple Endocrine Neoplasia 1 (MEN1)
What are Synaptophysis and Chromogranin?
neuroendocrine markers that may be used to ID neuroendocrine tumors via immunochemistry.
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)
What is a suspected atypical carcinoid tumor exhibiting >10 mitoses / 10 hpf (2mm^2)?
Considered Small Cell carcinoma at that point.
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
What is the normal volume of pleural fluid?
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.
Criteria for transudative vs. exudative effusion
Pleural fluid protein : Serum protein >0.5
Pleural fluid LDH : Serum LDH >0.6
Pleural fluid LDH > 2/3 upper limit for normal for serum
All others are Transudate
Major causes of transudative effusion
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
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.
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.
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
2 categories of symptoms of insomnia
Day-time complaints (required for insomnia to be a disorder rather than a complaint)
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
What is cognitive theory of insomnia?
Patients prone to rumination
increased problem solving -> insomnia
w/ chronic insomnia, worry about sleep all day
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
What is psychophysiologic insomnia?
Most common primary insomnia
Disorder of somatized tension and learned sleep preventing associations
-sleepy until bedtime routine
-tries to force self to sleep
-sleeps better on couch or away from home
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
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
What is the apneic threshold?
pCO2 below which a subject becomes apneic during NREM sleep
apnea: higher threshold
Men higher than women
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
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.
(# of apneas + hypopneas)/ total sleep time = AHI
What is OSAS?
Obstructive sleep apnea syndrome
Obstructive sleep apnea with daytime sequelae
2% of women and 4% men age 30-60
what cardiovascular risks is OSA associated with?
Heart disease (LVH and diastolic dysfunction)
Metabolic syndrome (esp. insulin resistance)
Pulmonary HTN and Right-sided HF uncommon w/o lung disease and/or daytime hypoxia
What polymorphisms is narcolepsy associated with?
loss of hypocretin neurons in hypothalamus - control/coordinate other wake centers
How are the symptoms of narcolepsy treated?
cataplexy: TCAs or SSRIs
Behavioral: avoidance of triggers, short scheduled naps, maximize sleep hygiene
What is pharmacologic management of Restless Leg Syndrome?
Dopamine Agonists: ropirinole, pramipexole, levodopa
Opiates: oxycodone, propoxyphene
Anticonvulsants: gabapentin, enacarbil
How is nicotine metabolized?
10-20% unchanged in urine
70-80% metabolized to cotine (inactive)
10% to other metabilites
What are the half-lives of nicotine and cotine?
Nicotine: 2 hrs
Cotine: 16 hrs
How is nicotine/cotine excreted?
Also in breast milk
What are the effects of nicotine?
Stimulatory: CNS, CV, appetite suppression, increased metabolic rate.
Stim DA reward pathway
What is the timeline of nicotine withdrawal?
Onset of withdrawal symptoms: 1-2 days
Peak: 1st week
Subside: 2-4 weeks
5 A's of smoking intervention
Ask about use
Advise to quit
Assess readiness to quit
Assist w/ quit attempt
Arrange follow-up care
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
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
2 coping strategies to employ in smoking cessation
Cognitive: retrain way of thought
Behavioral: involve specific actions to reduce relapse risk
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
non pharmacologic methods to assist w/ smoking cessation
fading: reduced nicotine cigs, tapered use, special filters / holders
accupuncture, hypno, massage
Who should not use nicotine replacement therapy?
Underlying CV disease (arrhythmia, recent MI, severe/worsening angina) or pregnant/lactating
TMJ: shouldn't use gum
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)
What strength Nic patches are available?
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
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
When using a nic patch, how long should pass between reapplying a patch to a given location?
What is the recommendation for nic patch users in the case of vivid dreams?
try 16 hour application rather than 24
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
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.
What antidepressant may be used as adjunct therapy in smoking cessation?
DA/NE reuptake inhibitor
Decreases nic craving / withdrawal symptoms
Bupropion dosing for smoking cessation
Start 1-2 weeks prior to quit date
150 mg qAM / 3days then 150 bid for 7-12 weeks
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
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
what are the 2 most effective smoking cessation aids?
Can Varenicline be used w/ a NRT or bupropion?
Safety not established
For maximum success, what should smoking intervention consist of?
Counseling + one or more meds
Cues to expect ILD
Pt. w/ cough, dyspnea
Abn CXR - diffuse, not necessarily uniform, changes
Crackles on PE - cellophane or velcro
What exposures can result in ILD?
Pneumoconiosis: inorganic - silicosis, asbestosis
Toxins - oxides of nitrogen
Drugs - Amiodarone, bleomycin
Hypersensitivity (farmer's lung) - organic
What ILDs are attributed to unknown causes?
make up 2/3 cases
Idiopathic Interstitial Pneumonias / Idiopathic Pulmonary Fibrosis
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
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)
What is the most common IIP?
Idiopathic Pulmonary Fibrosis (IPF) - 60% of IIP cases
Chronic, Progressive, Fatal
corresponds to UIP histologic pattern
What is the usual age of onset of IPF?
40-70 years w/ 2/3 >60
male > female
Risk factors for IIP
possibly: exposure (wood/metal dust), GERD, infection
Is familial IPF AR or AD? What gene(s) are involved?
ELMOD2 on 4q31
What mutations have been identified in IPF?
seen in 10% of cases
pulmonary surfactant protein C
TERT -telomerase reverse transcriptase
TERC -telomerase RNA component
What are IPFs clinical features?
progressive dyspnea w/ exertion, tachypnea
fine bibasilar crackles
**abnormal CXR or HRCT**
**restrictive pulmonary physiology, reduced DLCO, wide A-a O2
Diagnostic criteria for IPF
Variation w/in lung - "temporal heterogeneity"
***absence of features of alternative diagnosis***
How does NSIP differ from IPF?
More uniform distribution
"ground glass" opacities
cellular and fibrotic types
better prognosis (cellular > fibrotic) - more responsive to corticosteroids
What is the treatment for IPF?
Cortiticosteroids - don't work - evidence against underlying inflammatory cause
What is the survival rate for patients w/ IPF?
Median survival: 3 yrs from diagnosis
5 yr survival: 20-40%
In what populations is sarcoidosis most frequent?
Swedes, Danes, Blacks
Pathophys of sarcoidosis
Stimulus in susceptible host
Accumulation of CD4 cells and macrophages at site of ongoing inflammation
IFN-g, IL-2, other cytokines
Is sarcoidosis restrictive or obstructive?
Restrictive +/- obstructive component
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
What is the prognosis of sarcoidosis?
spontaneous remission in 60%
chronic/ progressive 10-30%
death in 1-5% - respiratory failure
Treatment for sarcoidosis?
In what ILD are bronchoscopic biopsies most useful?
Desquamated Interstitial Pneumonitis
strong link to smoking
good prognosis: 90-100% survival - responds to steroids
Lots of alveolar macrophages, lymphocytes, mild fibrosis
What is BOOP?
Bronchiolitis Obliterans-Organizing Pneumonia
Associated w/ Hypersensitivity Pneumonitis
Granulation tissue plugs in bronchi and/or alveoli
What type of hypersensitivity is involved in Hypersensitivity Pneumonitis?
Combination of type III and IV
What is Histiocytosis X?
Involves proliferation and tissue infiltration by Langerhaan's cells
Types of Histiocytosis X
Unifocal - lung or bone
-Eosinophilic granuloma of lung (most common 60-80%)
--children and young adults
--1-3 yoa: lung, bone - may be systemic
--0-1: worst prognosis (70% mortality)
What is Virchow's Triad?
Risk factors for DVT
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
How is d-dimer useful in evaluation for possible PE?
Product of fibrinolysis - always present when there is a clot.
Neg test - PE highly unlikely.
Pos test - further testing
What is the current tool of choice for diagnosis of PE?
Spiral CT angiography
High specificity (72%) and sensitivity (95%)
poor for sub-segmental emboli
requires cooperation and 15-25 sec breath hold
more radiation than V/Q scan
requires IV contrast
3 types of heparin
Low Molecular Weight
Where does heparin work?
Factors IXa, Xa, IIa (thrombin) via antithrombin III
What did PIOPED I suggest as the first diagnostic test for suspected PE?
ventilation - perfusion lung scan
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
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
How does heparin induced thrombocytopenia occur?
Heparin binds PF-4. Complex recognized by Ab -> platelet activation and thrombosis
How is HIT managed?
Immediate stop of heparin
Anticoagulation: direct thrombin inhibitors: Agatroban
Fondaparinux: heparin like activity - binds AT-III
What coagulation factors are affected by Vitamin K antagonists?
Coumadin, Warfarin work at factors II, VII, IX and X
3 characteristics of normal pulmonary circulation
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
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
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)
What is the theme of therapy for type I pulmonary hypertension?
Inhibit endothelin, promote NO synthesis, replace prostacyclin
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
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.
Therapeutic approach to pulmonary hypertension
Treat underlying condition
general treatment beneficial to most:
supplemental O2 (keep O2 sat >90), diuretic, inotropic therapy (digoxin)
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
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
What anticoagulant is monitored w/ PTT?
How are UFH and LMWH excreted?
LMWH much moreso than UFH
LMWH must be adjusted for renal function
Can warfarin be used during pregnancy?
No - vit K
-> bone growth issues
Use LMWH instead for anticoag
What is the most common clinical presentation of patients w/ HIT?
Mortality rate of HIT
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
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
How long does it take for warfarin to have therapeutic effect?
~5 days needed for depletion of clotting factors
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
What is is the target INR value for warfarin pts?
w/ mechanical mitral valve replacement - 2.5 - 3.5
Options for immediate warfarin reversal
fresh frozen plasma (must be thawed, heated)
prothrombin complex concentrate - ready to go
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)
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
Chronic "simple" silicosis
silicotic nodules <1-1.5cm
egg-shell calcifications of hilar lymph nodes
few symptoms, minimal to no changes in PFTs
Simple nodules coalesce -> large densities
restrictive and obstructive characteristics
autoimmune markers may be present
complex silicosis + RA
large nodules, but more benign than typical complex silicosis
Effect of silicosis on TB
silica poisons macrophages -> 4-6x increased risk
silicotuberculosis: TB in person w/ silicosis
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
malignant tumor of pleural mesothelial cells
very poor prognosis
usually non-resectable, not very responsive to chemo or radiation
When do farmer's lung symptoms occur related to exposure?
4-8 mos later
Course of farmer's lung
usually spontaneously resolves w/in 24 hours. Repeat exposures may -> restrictive disease
symptoms of farmer's lung
fever, chills, sweating, cough dyspnea ( mirrors acute pneumonia)
crackles on exam
CXR: bilateral reticulonodular infiltrates
How can occupational asthma be diagnosed?
spirometery before and after work
Treatment for occupational asthma?
removal from exposure is key. Continued exposure may -> COPD
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