Lecture 4 Chronic Obstructive Pulmonary Disease

8/8/2019 Lecture 4 Chronic Obstructive Pulmonary Disease

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CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Definition of COPD

ATS/ERS

y A preventable and treatable disease state characterized by airflow limitation that isnot fully reversible.

y The airflow limitation is usually progressive and is associated with an abnormalinflammatory response of the lungs to no xious particles or gases, primarily caused by

cigarette smoking.

y Although COPD affects the lungs, it also produces significant systemic consequences.Smoking causes 80-90% of COPD.50% of smokers develop chronic bronchitis15-20% of smokers develop clinical airflow obstructionObstructive Pulmonary Diseases

Any disease affecting the upper or lower airways can be associated with obstruction

of airflow from the lungs.

This presentation will focus on those pathological processes primarily affecting the

lower airways, including:

Emphysema Chronic Bronchitis Asthma Bronchiectasis Bronchiolitis obliterans (constrictive bronchiolitis) Tracheobronchomalacia*

*A deficiency in the cartilaginous wall of the trachea and/or bronchus, can also lead to to

airway obstruction, but will not be addressed further in this presentation.


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Aetiology: Other Risk factors

British hypothesis: frequent lung infections (esp. in childhood)

Dutch hypothesis: atopy and AHR

Occupational/chemicals: coal, cotton, cement dust, cadmium

Environmental pollution: particulate air pollutionDiet low in fish, fruit and antioxidants

Low birth weight

Genetic factors: FH of COPD, E1-antitrypsin

COPD is a growing burden to society and the patient

COPD is a growing cause of morbidity and mortality worldwide

In 2005, COPD caused 5% of all deaths worldwide

More than 3 million people died from COPD in 2005: this is greater than that of lung and

breast cancer combined

COPD is projected to be the third biggest killer by 2020

1990 2020

Ischemic heart disease

CVD disease

Lower respiratory infection

Diarrhoeal disease

Perinatal disorders

COPD

Tuberculosis

Measles

Road traffic accident

Lung cancer

Stomach cancer

HIV

Suicide

3rd

6th


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Clinical Features of COPD

Typically smokers - mean 20 cigs/day for 20 years

Usually present in 5th decade of life with productive cough or acute chest illness

when the disease is far advanced

DOE not usual until 6th or 7th decade Patients who are dyspneic give up activitiesHx of wheezing accompanying dyspnea may lead to erroneous dx of asthma

Sputum production initially only in AM

daily volume rarely exceeds 60 ml usually mucoidAcute exacerbations characterized by increased cough, purulent sputum, wheezing,

dyspnea, sometimes fever

Interval between exacerbations grows shorter with disease progression

Differential Diagnosis: COPD and Asthma

COPD ASTHMA

Onset in mid-life Symptoms slowly progressive Long smoking history Dyspnea during exercise Largely irreversible airflow

limitation

Onset early in life (oftenchildhood)

Symptoms vary from day to day Symptoms at night/early morning Allergy, rhinitis, and/or eczema

also present

Family history of asthma Largely reversible airflow

limitation

Emphysema (The Pink Puffer Phenotype)

A condition of the lung characterized by abnormal, permanent enlargement of airspaces

distal to the terminal bronchiole, accompanied by the destruction of their walls, and

withoutobvious fibrosis


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Three principle types:

A. Centriacinar(centrilobular) y Predominantly in upper lung zones.y Associated with smoking & pneumoconiosis.

B. Panacinar(panlobular) y More progressive, and with more severe symptoms because it involves the lower

lung zones (areas of greater gas exchange).

y Associated with alpha-1-antitrypsin deficiency.C. Distalacinar(paraseptal)

y Focal or multifocal disease.y Involves distal alveolar sacs and ducts, resulting in subpleural blebs and bullae.y More likely to cause spontaneous pneumothorax.

Protease-Anti-protease Theory:

Emphysema results from the destructive effect of high protease activity in subjects

with low anti-protease activity

Chronic Bronchitis (The Blue Bloater Phenotype)

Cough productive of sputum on most days during at least three consecutive monthsfor more than two successive years

More profound hypoxemia at rest

Elevated PaCO2 with chronic respiratory acidosis

Cor pulmonale with right heart failure

ANTIELASTASE

1 - antitrypsin

PMN

ELASTASE

MAC

ELASTIC

DAMAGE

EMPHYSEMA

1 ANTITRYPSIN

DEFICIENCY

SMOKING


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Di

nosis of C

D

Spi o

t

SYMPTOMS

COUGH

S

UTUM

DYS

EXPOSURE TO RISK FA

TORS

TOB CCO

OCCUPATIONS

INDOOR/OUTDOOR POLLUTION

SPIROMETERY


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Spirometry: Normal and Patients with COPD

Classification of COPDS

everity byS

pirometry

Stage I: Mild FEV1/FVC < 0.70

FEV1 > 80% predicted

Stage II: Moderate FEV1/FVC < 0.70

50% < FEV1 < 80% predicted

Stage III: Severe FEV1/FVC < 0.70

30% < FEV1 < 50% predicted

Stage IV: Very Severe FEV1/FVC < 0.70

FEV1 < 30% predicted or

FEV1 < 50% predictedplus chronic

respiratory failure


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Chest radiographic findings:

Poor in evaluating very early disease due to limitations in small airway visualization.

As the disease progresses, CXR can directly demonstrate disease pathology, as well

as indirect signs of increased lung compliance and air -trapping.

Identification of emphysema on CXR:

Signs of hyperinflation

Irregular, asymmetric areas of decreased lung density

Vascular deficiency:

Rapidly attenuating peripheral pulmonary arteries, may be absent peripherally Increased branching angles Smaller-than-expected caliber Signs of pulmonary artery hypertensionBullaeSaber-sheath trachea

CT findings

Relatively well-defined, low attenuation areas with very thin (invisible) walls,

surrounded by normal lung parenchyma.

As disease progresses:

Amount of intervening normal lung decreases. Number and size of the pulmonary vessels decrease. +/- Abnormal vessel branching angles (>90o), with vessel bowing around the

bullae.

Chest radiographic findings

It is difficult to know which radiographic findings are attributable to chronic

bronchitis, rather than to emphysema, because they commonly coexist.

CXR is poor at detecting or excluding chronic bronchitis.

CXR is helpful in excluding diseases that can clinically mimic chronic bronchitis(TB, tumor, bronchiectasis, and abscess).


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Principle CXR abnormalities

Thickening of bronchial walls

Overinflation*

Oligemia*

Signs of pulmonary artery hypertension

*Many argue that the overinflation and oligemia seen in chronic bronchitis may be due to

superimposed emphysema

ChronicBronchitis

CT findings

Limited literature on CT features of chronic bronchitis.

Bronchial wall thickening has been documented in patients with chronic bronchitis,

but has also been observed in patients without respiratory symptoms.

Quantitative CT

Spirometically triggered images at 10% and 90% vital capacity (VC) have been

reported to be able to distinguish patients with chronic bronchitis from those

with emphysema.

Patients with emphysema had significantly lower mean lung attenuation at90% VC than normal subjects or patients with chronic bronchitis.

Attenuation was the same for normal subjects and those with chronicbronchitis.

Manage Stable COPD

Manage Stable COPD: Bronchodilators

Bronchodilator medications are central to the symptomatic management of COPD.

They are given on an as-needed basis or on a regular basis to prevent or reduce

symptoms.

y Alleviate symptomsy Improve exercise tolerancey Improve quality of lifey Decrease the incidence of exacerbationsy Decrease hyperinflation


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Inhaledtherapyis preferred

Beta2-agonists: increase cyclic adenosine monophosphate levels and promote

airway smooth-muscle relaxation

y Short acting: Albuteroly Long acting: Salmeterol (Serevent) and Formoterol fumarate (Foradil)

Anticholinergics : block muscarinic receptors

y Short acting: Ipratropium bromide (Atrovent)y Long acting: Tiotropium bromide (Spiriva)Combination: (Combivent)

Phosphodiesterase Inhibitors: increase intracellular cyclic adenosine

monophosphate levels within airway smooth muscle

y 3rd line agenty Improves respiratory muscle function, stimulates the respiratory center,

decreases dyspnea, and enhances activities of daily living

y

Toxic side effects: tachyarrhythmias, nausea, vomiting, seizuresy Monitoring should include intermittent serum level measurements: target range

8-12mcg/mL

Inhaled Steroids (ICS)

Inhaled Steroids (ICS) in Stable COPD

Glucocorticoids act at multiple points within the inflammatory cascade.

Regular treatment with ICS does notmodifythe long-termdecline in FEV1.

Appropriate for symptomatic COPD patients with an FEV1 < 50% and repeated

exacerbations (Stage IIIandIV).

ICS reduce frequencyof exacerbationsandimprove healthstatus (Evidence A).

ICS combined with long-acting b2-agonist more effective than individual components

Steroids in Stable COPD

GOLD guidelines recommend a trial of 6 weeks to 3 months of ICS to identify subset

of patients who may benefit.

Short course oforalsteroidsisa poor predictor of long-term response to ICS.Long-termtreatmentwithoralsteroidsis NOTrecommended(Evidence A ):

No evidence of long-term benefit Major side effects: skin damage, cataracts, diabetes, osteoporosis, secondary

infection, psychosis, fluid retention.


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Other pharmacologic treatments

Vaccines: Influenza vaccine reduces serious illness and death in COPD patients by

50%. Pneumococcal vaccine is recommended every 5 years although data in COPD

patients is lacking.

Otheranti-inflammatoryagents: Cromolyn, nedocromil, and leukotriene inhibitors

have not been adequately tested in patients with COPD

Alpha-1 Antitrypsin Augmentation Therapy: young patients with severe deficiency

and established emphysema

Antibiotics are not recommended other than in treating infectious exacerbations

(Doxycycline, amoxicillin, macrolide, fluoroquinolones)

Mucolyticagents: not recommended

Antioxidants (N-acetylcysteine)mayreduce the frequencyof exacerbations

Antitussives: contraindicatedin stable COPD because cough is protective

Pulmonary Rehabilitation in Stable COPD

All COPD-patients benefit from exercise training programs, improving with respect to

both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A).

The minimum length of an effective rehab program is 2 months; the longer the

better (Evidence B).

Comprehensive pulmonary rehabilitation program includes exercise training,

nutrition counseling, and education.

Manage Stable COPD: Oxygen

The long-term administration of oxygen (> 15 hours per day) to patients with chronicrespiratory failure (Stage IV) has been shown to increase survival (Evidence A).

Oxygen administration reduces hematocrit, pulmonary artery pressures, dyspnea,and rapid eye movement related hypoxemia during sleep.


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Oxygen therapy

The goal is to prevent tissue hypoxia by maintaining arterial oxygen saturation

(Sa,O2) at >90%.

Main delivery devices include nasal cannula and venturi mask.

Arterial blood gases should be monitored for arterial oxygen tension (Pa,O2),

arterial carbon dioxide tension ( Pa,CO2) and pH.

Arterial oxygen saturation as measured by pulse oximetry (Sp,O2) should be

monitored for trending and adjusting oxygen settings.

If CO2 retention occurs, monitor for acidemia.

If acidaemia occurs, consider mechanical ventilation.

Therapy at Each Stage of COPD

FEV1/FVC 80%

predicted

FEV1/FVC < 70%

50% < FEV1< 80%predicted

FEV1/FVC < 70%

30% < FEV1< 50%

predicted

FEV1/FVC < 70%

FEV1< 30%

predicted Or FEV1< 50% predicted

plus chronic

respiratory failure

I: Mild IV: Very SevereIII: SevereII: Moderate

Active reduction of risk factor(s); influenza vaccination

Addshort-acting bronchodilator (when needed)

Addregular treatment with one or more long-acting bronchodilators (when needed);

Addrehabilitation

Addinhaled glucocorticosteroids if repeated exacerbations

Addlong term oxygenif chronic respiratory failure.

Considersurgical treatments


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Pharmacotherapy in COPD

Surgical Treatments

Bullectomy: In carefully selected patients, this procedure is effective in reducing

dyspnea and improving lung function (Evidence C)

Lung Volume Reduction Surgery

Lung Transplantation: In appropriately selected patients, improves quality of life and

functional capacity (Evidence C). Criteria for referral: FEV1


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COPD Exacerbation

Definition Elements

Worsening dyspnea

Increased sputum purulence

Increase in sputum volume

Severity

Severe - all 3 elements

Moderate - 2 elements

Mild - 1 element plus:

URI in past 5 days

Fever without apparent cause

Increased wheezing or cough

Increase (+20%) of respiratory rate or heart rate

Assessment of severity of exacerbation

Peak flow


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Pathoph

siolo

-Cu

nt Hypoth

sis

Effect

on Lung Function Decline

ChronicInfl

mm

tion

Exacer

ation

Acute

Inflammation

Unknown20

Air

Pollution

5%

B ! cterial

Infection

50%

ViralInfection

25%

109 pt"

(mean FEV1 = 1# 0L over4 year"

Fre$

uentexacer%

ator&

:

faster decline in PEFR and FEV1 more c ' ronic symptoms (dyspnea,

whee(

e)

no differences in PaO2 or PaCO2Conclusion:

Fre0

uentexacer1

ationsaccelerate declinein

lungfunction


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The Clinical Course Of COPD: Consequences ofExacerbatio n

Therapy of COPD Exacerbation (Guidelines)

Variable ACCP-ACP GOLD

Steroids Yes, for up to two weeks Yes, oral or IV for 10-14 days

Oxygen Yes Yes - target PaO2 60 torr or

Sat of 90% with ABG check

ChestPT No Maybe - for atelectasis or

sputum control

Mucokinetics No Not discussed

Exacerbation

2e

3 4ce

3

5ealt

5-

relate3

6 4ality of

life

Increase3

mortality wit

5

exacerbation

5ospitalizations

Accelerate7 7 eclinein FEV1

Increase3

5

ealt5

reso

4

rce

4

tilization an3

3irect costs


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Manage 8 xacerbations: Key Points

RoleofInfectioninC9

PD 8 xacerbation

Up to 60% o@

exa A erbationB

are due to respiratory in@

ections.

Bacteria C In@ ections: H. in@ C eunza, M. catarrha C is, S.pneu D oniae.AcE uisition of new strainsvs.colonization

Viral InF

ections: InF

Guenza,

Harain

F

Guenza,Coronavirus, Rhinovirus.

Coinfection iscommon

Antibiotic Therapy forCI

PD P xacerbation

Place Q o-controlled studies demonstrated that antibioticsimproveclinical outcomein manypatients with COPD e R acerbation.

A recent meta-analysis demonstrated improved Survival in moderate -to-severeCOPD treated with antibioticscompared to placebo (Puhaneta

S

.2007T

Inhaled bronchodilators (Beta2-agonists

and/or anticholinergicsU, and systemic,

preferably oral, glucocortico-steroids are

effective for the treatment of COPD

eV

acerbations (Evidence A).

80% of AECB are infectious. Environmental

factors and medication nonadherence are

20%.


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Indications for Antibiotics in COPD Exacerbation

Increased sputum purulence with increased SOB of sputum volume. Need for hospitalization. Need for mechanical ventilation.

Risk factors for poor outcome:a) Comorbiditiesb) Severe underlying COPD (FEV-1 3/year)d) Recentantibioticuse (within the past3 months)

Antibiotic Treatment for Exacerbation of COPD

Mild

Only 1 of the 3 cardinal

symptoms: Increased dyspnea Increased sputum volume Increased sputum purulence

No antibiotic Increased bronchodilators Symptomatic therapy Instruct patient to report

additional cardinal symptoms

Moderate orSever

At least 2 of the 3 cardial

symptoms:Increased dyspnea

Increased sputum volume

Increased sputum purulence

UncomplicatedCOPD

Noriskfactors

Age 50 percent

< 3 exacerbations / year

No cardiac disease

ComplicatedCOPD

1 ormore riskfactors

Age > 65 years

FEV1 < 50 percent predicted

3 exacerbation / year

Cardiac disease

Advanced macrolide (azithromycin,

clarithromycin)

Cephalosporin (cefuroxime,

cefpodoxime, cefdinir)

Doxycycline

Trimethoprim/sulfamethoxazole

If recent (


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Manage Exacerbations: NIV

y Noninvasive intermittent positive pressure ventilation (NIPPV) in acuteexacerbations improves blood gases and pH, reduces in -hospital mortality, decreases

the need for invasive mechanical ventilation and intubation, and decreases the

length of hospital stay (Evidence A).

Noninvasive intermittent positive pressure ventilation (NIPPV)

y Selection criteria: Moderate to severe dyspnea with use of accessory muscles and paradoxical

abdominal motion

Moderate to severe acidosis and hypercapnia Respiratory frequency >25/min

Aims of NPPV

y Improve gas exchange (decrease CO2 and increase O2)y Rest or improve respiratory musclesy Stabilize the upper airwayy Improve quality of life/exercise tolerancey Prevent cardiovascular consequences of nocturnal hypercapnia and hypoxia

Assisted ventilation

1. Noninvasive positive pressure ventilation (NPPV) should be offered to patients withexacerbations when, after optimal medical therapy and oxygenation, respiratory

acidosis (pH


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NIPPV

Exclusion criteria:

Respiratory arrest

Cardiovascular instability

Somnolence, impaired mental status, uncooperativepatient High aspiration riskViscous or copioussecretions

Recent facial or gastroesophageal surgery

Craniofacial traumaExtreme obesity

Assisted ventilation

Patientsmeeting exclusion criteria should be considered for immediate intubation

and ICU admission.

Auto-PEEP (IntrinsicPEEP)

Example:ifPEEPi = +8W thepatienteffortmustbe>-8tocreateairfloX

y In patients with COPD Rate of lung emptying becomes impaired because of increased expiratory

resistance and expiratory airflow limitation

Therefore, apositive pressure ispresent at end expiration (PEEP)y Patient must overcome a positivepressure before inspiration can begin

Inspiration reY uires negativepressure


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Indications for ICU Admission in COPD Exacerbation

1. Severe dyspnea that responds inadequately to initial emergency therapy2. Confusion lethargy or respiratory muscle fatigue (the last characterized by

paradoxical diaphragmatic motion

3.

Persistent or worsening hypoxemia despite supplemental oxygen or severe /worsening respiratory acidosis (pH < 7.30)

4. Assisted mechanical ventilation is required, whether by means of endotracheal tubeor noninvasive teachnique

Bronchiectasis

A chronic, necrotizing infection of the bronchi & bronchioles, leading to abnormal,

permanent dilatation of the involved airways.

May develop in association with:

Bronchial obstruction: localized (tumor, foreign body) or diffuse (asthma, chronicbronchitis)

Congenital/Hereditary: CF, Kartageners syndrome Necrotizing pneumoniaIncidence markedly decreased, due to the advent of antibiotics and immunizations.

Pathology:

Obstruction and infection are the major influences associated with bronchiectasis.

Bronchial obstruction leads to atelectasis of airways distal to the obstruction.

Bronchial wall inflammation & intraluminal secretions cause dila tation of the patentairways proximal to the obstruction.

Process becomes irreversible if the obstruction persists or if there is added infection.

Vicious cycle of recurrent/chronic infections perpetuates the airway inflammation &

dilatation, leading to extensive endobronchial destruction.

FYI: There are different types of bronchiectasis:

Cylindrical

Airway wall is regularly/uniformly dilated.

Varicose

Greater dilatation with alternating areas of constriction and dilatation.Cystic

Progressive, distal enlargement resulting in sac-like terminations of the airways. Cystic spaces can be several centimeters in diameter and contain air-fluid levels.

Most Severe


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COPD vs. Bronchiectasis

Variable ChronicObstructive

PulmonaryDisease

Bronchiectasis

Cause Cigarette smoking Infection or genetic or

immune defect

Role of infection Secondary Primary

Predominant organism in

sputum

Streptococcus pneumoniae,

Haemophilus influenzae

H.influenzae, pseudomonas

aeruginosa

Airflow obstruction and

hyperresponsiveness

Present Present

Findings on chest imaging Hyperlucency,

hyperinflation, airways

dilatations

Airway dilatation and

thickening, mucous plugs

Quality of sputum

(in the steady state)

Mucoid, clear Purulent, three layered

Pathophysiology

Permanent abnormal dilation and destruction of bronchial walls

Two factors

Infection Impairment of drainage, airway obstruction, and/or defect in host defense

Biomarkers: inflammatory cells or 8-iso-prostaglandin F(2) in sputum

Etiology

Pulmonary infections

viral, mycoplasma, TB, MAC

Airway obstruction

Defective host defenses

ABPA (allergic bronchopulmonary aspergillosis)

Rheumatic and other systemic dz

RA, Sjogrens syndrome

Ulcerative colitisDyskinetic cilia

Cystic fibrosis rare in TW

Cigarette smoking?


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Clinical Manifestations:

Chronic cough and expectoration of copious, purulent sputum.

+/- dyspnea

+/- hemoptysis

+/- fever, weight loss, anemia, clubbing

Chest radiographic findings:

Earliest finding is bronchial wall thickening Curvilinear/reticular opacities With further dilatation & wall thickening, see tram lines & ring shadows Variable areas of atelectasis Generalized hyperinflation of involved lobe Signs of pulmonary artery hypertension

Most frequent CT findings:

Lack of tapering of the bronchial lumen Bronchial wall thickening Bronchial dilatation Visualized peripheral bronchi Mucus plugging

Management

Infection control

bronchial hygiene

Surgical resection in selected patient

Infection Control

Acute exacerbation

viscous, dark sputum, lassitude, SOB, pleurisy Fevers and chills generally absent CXR rarely show new infiltrates H. influen ae and P. aeruginosa FQ is reasonable (eg. ciprofloxacin) for 7~10 days

Less frequent

Mostfrequent


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Prevention

Daily ciprofloxacin (500~1500mg) in 2~3 doses

Macrolide daily or three times weekly

Daily use of a high dose oral antibiotic, such as amoxicillin 3 g/day

Aerosolization of an antibioticIntermittent intravenous antibiotics

Problematic Pathogen

Pseudomonas aeruginosa

Almost impossible to irradicate

Wilson CB et al.

Reduced QoL More extensive bronchiectasis on CT Increased number of hospitalizationsCiprofloxacin quickly develops resistance

Bronchial Hygiene

Oral hydration

Nebulization

Normal saline

Acetylcyteine

Recombinant DNAase

Hypertonic saline, mannitol, dextran, lactose

PhysiotherapyChest percussion

Prone position

Bronchodilator? Steroid? NSAID?

Surgical Intervention

Removal of the most involved segments Most common: middle and lower lobe resecton Hemoptysis: Bronchial a. embolization

Lung transplantation


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Lung Transplantation

Overall 1-year survival : 68% (54-91%)

Overall 5-year survival : 62% (41-83%)

Subgroup

SLTX : 1 yr survival 57% (20%-94%) n=4 Mean FEV1 : 50% predicted (34%-61%), Mean FVC : 53% predicted (46 -63%)2 lungs : 1 yr survival 73% (51 -96%) n = 10

Mean FEV1 : 73% predicted (58%-97%), Mean FVC : 68% predicted (53%-94%)

What is cystic fibrosis (CF)?

A multisystem disease

Autosomal recessive inheritance

Cause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)

chromosome 7 codes for a c-AMP regulated chloride channel

Clinical features of Cystic Fibrosis

Chronic Sino-Pulmonary Disease Nutritional deficiency/GI abnormality Obstructive Azoospermia Electrolyte abnormality CF in a first degree relative

Burden of CF

Most common life-shortening recessive genetic disease in Caucasians

1:3,500 newborns in the US 1 in 10,500 Native Americans 1 in 11,500 Hispanics 1 in 14,000 to 17,000 African Americans 1 in 25,500 AsiansAbout 30,000 people affected in United States

>10,000,000 people carriers of mutant CFTR

80% cases diagnosed by age 3

Almost 10% diagnosed 18 years


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Ca Survival

Overall trend is improved survival

Femalesurvival worse than malebetween 2-20years of age1

35% ofpatients are older than 18years of age2

Median survival 36.8years

3

compared to 1930s when life expectancy was about 6months

2

TypesofmutationsinC b TR

Airway surfaceliquidlow volumehypothesisandCbTR

Normal CFTR inhibits a sodiumchannel (ENaC)

Mutant CFTR----ENaC not inhibited Sodium absorption is increased Water followssodium ASL volume decreases

Normal CFTR will cause Cl- ions to besecreted if the ASL fluid is low

Mutant CFTR Cl- ions not secretedAirway surfaceliquidlow volumehypothesisandconsequences

Cilia do not beat well when PCL volume is depleted

Mucins are not diluted and cannot beeasilyswept up the airway

Mucus becomesconcentrated

Results in increased adhesion to airwaysurface

Promoteschronic infection

Class I Defectiveprotein production

Class II Defects in processing

F508

Class III CFTR reaches cell surface but

regulation is defective (channel

not activated)

Class IV CFTR in membrane with

defectiveconduction

Class V Decreased synthesis of CFTR


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Chronic Sino-Pulmonary Disease

Chronic infection with CF pathogens Endobronchial disease

Cough/sputum production

Air obstruction---wheezing; evidence of obstruction on PFTs Chest x-ray anomalies Digital Clubbing

Sinus disease Nasal Polyps CT or x-ray findings of sinus disease

Nasal Polyps

Benign lesions in nasal airway

If large enough, can be associated with significant nasal obstruction, drainage,

headaches, snoring

Likely associated with chronic inflammation

May need surgical intervention

High recurrence rate

Digital Clubbing

Bulbous swelling at end of fingers

Normal angle between nail and nail bed lost ---Schamroth sign

Can be associated with pulmonary disease, cardiac disease, ulcerative colitis, and

malignancies

Nutritional deficiency

Pancreatic insufficiency

Autopsy of malnourished infants--1938--- cystic fibrosis of the pancreas---mucus plugging of glandular ducts

1

Chloride impermeability affects HCO3- secretion and fluid secretion inpancreatic ducts

2

Pancreatic enzymes stay in ducts and are activated intraductallyAutolysis of pancreas

Inflammation, calcification, plugging of ducts, fibrosis

Malabsorption Failure to thrive Fat soluble vitamin deficiency


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Infertility

Men

Abnormal embryologic development of the epididymal duct and vas deferens---

may be incomplete of absent

Congential bilateral absence of the vas deferens97-98% of men with CFWomen

Lower fertility rate than non-CF women

Viscid mucoid cervical secretions of low volume in women with CF

Pregnancy and CF:

Goss et al, 2003---no significant difference in survival in women who became

pregnant with CF compared to women who did not become pregnant (after

adjusting for disease severity)

Electrolyte abnormality---history

Dr. Paul di Sant Agnese

y 1949 NYC heat wave ----noted CF infants to have a higher rate of heat prostrationthan non-CF

Showed that sodium and chloride concentration in CF patients sweat was

5 times higher than in non-CF

Became basis for sweat chloride testElectrolyte abnormality

Clinically---hypochloremic metabolic alkalosis CFTR on luminal side of sweat duct

Chloride goes in from lumen via CFTR and out to blood by other transporters

Sodium goes in via ENaC

Defective CFTR---Na and Cl- movement and reabsoprtion into lumen impeded

Diagnosis---Sweat chloride

Technique first described by Gibson and Cooke in 1950s

Chemical that stimulates sweating placed under electrode pad; saline underother electrode pad on arm

Mild electric current is passed between electrodes Sweat collected


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Sweat chloride

Positive Sweat chloride: 60-165 meq/L Borderine sweat chloride: 40-60 meq/L Normal sweat chloride: 0-40

False positives:

Hypothyroidism Addison disease Ectodermal dysplasia Glycogen storage disease Edema Malnutrition Lab error (evaporation or contamination of sample)False negatives:

Edema Malnutrition Some CF mutations Sample diluted

Genetic testing

Mutation analysis available Varies from screening for most common mutations to sequencing entire CFTR

gene

Treatment: Nutrition

Follow nutrition parameters closely

Pancreatic enzymes

Vitamin supplementation

Other nutritional supplementation

Tube feedings High calorie supplemental shakes, formulas


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Nutrition parameters

Percent ideal body weight (IBW%)

90-110%: Normal 85-89%: Underweight

80-84%: Mild malnutrition 75-79%: Moderate malnutrition

Lecture 4 Chronic Obstructive Pulmonary Disease

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