CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Definition of COPD

ATS/ERS

 A preventable and treatable disease state characterized by airflow limitation that is

not fully reversible.
 The airflow limitation is usually progressive and is associated with an abnormal
inflammatory response of the lungs to noxious particles or gases, primarily caused by
cigarette smoking.
 Although COPD affects the lungs, it also produces significant systemic consequences.

 Smoking causes 80-90% of COPD.

 50% of smokers develop chronic bronchitis
 15-20% of smokers develop clinical airflow obstruction

Obstructive 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.
 Bronchiolar and Bronchial
injury
Bronchospasm
Infections

Hypersecretion of mucus
Reversible obstruction in
bronchioles and small
bronchi

Continued and repeated

injury (smoking) Continued and repeated
infections

Chronic bronchitis

Pathophysiological Features of COPD

Airflow Limitation Inflammation Structural

Changes

Bronchoconstriction Oxidative stress Alveolar destruction

Mucus hypersecretion Neutrophils Glandular hypertrophy
Loss of elastic recoil Macrophages Airway fibrosis
Airway narrowing CD8+ lymphocytes Blood vessels
Dynamic hyperinflation IL-8 and TNF-a
during exercise Protease/antiprotease
imbalance
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 pollution
Diet low in fish, fruit and antioxidants
Low birth weight
Genetic factors: FH of COPD, a1-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 3rd

Diarrhoeal disease

Perinatal disorders

COPD 6th

Tuberculosis

Measles Stomach cancer

Road traffic accident HIV

Lung cancer Suicide

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 activities
Hx of wheezing accompanying dyspnea may lead to erroneous dx of asthma
Sputum production initially only in AM
 daily volume rarely exceeds 60 ml
 usually mucoid
Acute 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
 Onset in mid-life
 Symptoms slowly progressive
 Long smoking history
 Dyspnea during exercise
 Largely irreversible airflow
limitation
ASTHMA
 Onset early in life (often
childhood)
 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
without obvious fibrosis
Three principle types:

A. Centriacinar (centrilobular)
 Predominantly in upper lung zones.
 Associated with smoking & pneumoconiosis.
B. Panacinar (panlobular)
 More progressive, and with more severe symptoms because it involves the lower
lung zones (areas of greater gas exchange).
 Associated with alpha-1-antitrypsin deficiency.
C. Distal acinar (paraseptal)
 Focal or multifocal disease.
 Involves distal alveolar sacs and ducts, resulting in subpleural blebs and bullae.
 More likely to cause spontaneous pneumothorax.

Protease-Anti-protease Theory:

↓ANTIELASTASE α1 – ANTITRYPSIN
α1 - antitrypsin DEFICIENCY

SMOKING

PMN ELASTIC DAMAGE EMPHYSEMA

↑ ELASTASE
MAC

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 months
for more than two successive years

More profound hypoxemia at rest

Elevated PaCO2 with chronic respiratory acidosis

Cor pulmonale with right heart failure

Diagnosis of COPD

SYMPTOMS EXPOSURE TO RISK FACTORS

TOBACCO
COUGH
OCCUPATIONS
SPUTUM
INDOOR/OUTDOOR POLLUTION
DYSPNEA

SPIROMETERY

Spirometry
Spirometry: Normal and Patients with COPD

Classification of COPD Severity by Spirometry

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% predicted plus chronic
respiratory failure
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 hypertension
Bullae
Saber-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 (>90 o), 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).
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

Chronic Bronchitis

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 at
90% VC than normal subjects or patients with chronic bronchitis.
 Attenuation was the same for normal subjects and those with chronic
bronchitis.

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.
 Alleviate symptoms
 Improve exercise tolerance
 Improve quality of life
 Decrease the incidence of exacerbations
 Decrease hyperinflation
 Inhaled therapy is preferred
Beta2-agonists: increase cyclic adenosine monophosphate levels and promote
airway smooth-muscle relaxation
 Short acting: Albuterol
 Long acting: Salmeterol (Serevent) and Formoterol fumarate (Foradil)
Anticholinergics: block muscarinic receptors
 Short acting: Ipratropium bromide (Atrovent)
 Long acting: Tiotropium bromide (Spiriva)
Combination: (Combivent)
Phosphodiesterase Inhibitors: increase intracellular cyclic adenosine
monophosphate levels within airway smooth muscle
 3rd line agent
 Improves respiratory muscle function, stimulates the respiratory center,
decreases dyspnea, and enhances activities of daily living
 Toxic side effects: tachyarrhythmias, nausea, vomiting, seizures
 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 not modify the long-term decline in FEV1.

Appropriate for symptomatic COPD patients with an FEV1 < 50% and repeated
exacerbations (Stage III and IV).

ICS reduce frequency of exacerbations and improve health status (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 of oral steroids is a poor predictor of long-term response to ICS.
Long-term treatment with oral steroids is NOT recommended (Evidence A):
 No evidence of long-term benefit
 Major side effects: skin damage, cataracts, diabetes, osteoporosis, secondary
infection, psychosis, fluid retention.
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.

Other anti-inflammatory agents: 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)

Mucolytic agents: not recommended

Antioxidants (N-acetylcysteine) may reduce the frequency of exacerbations

Antitussives: contraindicated in 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 chronic
respiratory 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.

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

I: Mild II: Moderate III: Severe IV: Very Severe

FEV1/FVC < 70%

FEV1 < 30%
predicted Or FEV1
FEV1/FVC < 70% < 50% predicted
30% < FEV1 < 50% plus chronic
FEV1/FVC < 70% predicted respiratory failure
50% < FEV1 < 80%
FEV1/FVC< predicted
70%
FEV1 > 80%
predicted

Active reduction of risk factor(s); influenza vaccination

Add short-acting bronchodilator (when needed)

Add regular treatment with one or more long-acting bronchodilators (when needed);
Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Add long term oxygen if chronic respiratory failure.

Consider surgical treatments

Pharmacotherapy in COPD
 COPD Severity

DYSPN
EA &
DISABI  SABD1 prn
MILD
LITY
 Tiotropium or LABA2 + SABD prn

 Tiotropium + LABA + SABA3 prn

MODERATE
 Tiotropium + LABA (+ theophylline) + SABA prn

 Tiotropium + LABA/ICS4 + theophylline + SABA prn

SEVERE

1. SABD : Short-acting bronchodilator (beta2-agonist

or anticholinergic)
1. LABA : Long-acting beta2-agonist (e.g. formoterol
or salmeterol)
2. SABA : Short-acting beta2-agonist (e.g.
salbutamol)
3. LABA/ICS : Long-acting beta2-agonist combined
with inhaled corticosteroid in one preparation

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: FEV 1<35% predicted PaO2<55-
60mm Hg, PaCO2>50 mm Hg, and secondary pulmonary hypertension

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 <100 L/min or FEV1 <1.0 L indicates severe exacerbation

ABG

CXR

EKG

D-dimer, spiral CT

Sputum culture

Pathophysiology - Current Hypothesis

 Chronic Inflammation
Viral Unknown
Infection 20%
25%

Bacterial Acute
Infection Inflammation Air
50% Pollution
5%

Exacerbation

Effects on Lung Function Decline

109 pts (mean FEV1 = 1.0 L over 4

years
Frequent exacerbators:
 faster decline in PEFR and FEV1
 more chronic symptoms (dyspnea,
wheeze)
 no differences in PaO2 or PaCO2

Conclusion:

Frequent exacerbations accelerate decline in

lung function

The Clinical Course Of COPD: Consequences of Exacerbation

 Reduced
health-
related
quality of
life

Increased Increased
health mortality with
resource Exacerbation exacerbation
utilization and hospitalizations
direct costs

Accelerate
d decline
in FEV1

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

Chest PT No Maybe - for atelectasis or

sputum control

Mucokinetics No Not discussed

Manage Exacerbations: Key Points

 Inhaled bronchodilators (Beta 2-agonists and/or
anticholinergics), and systemic, preferably oral,
glucocortico-steroids are effective for the
treatment of COPD exacerbations (Evidence A).

80% of AECB are infectious. Environmental

factors and medication nonadherence are 20%.

Role of Infection in COPD Exacerbation

Up to 60% of exacerbations are due to respiratory infections.

Bacterial Infections: H. infleunza, M. catarrhalis, S. pneumoniae.

Acquisition of new strains vs. colonization

Viral Infections: Influenza, Parainfluenza, Coronavirus, Rhinovirus.

Coinfection is common

Antibiotic Therapy for COPD Exacerbation

 Placebo-controlled studies demonstrated that antibiotics improve clinical outcome

in many patients with COPD exacerbation.
 A recent meta-analysis demonstrated improved Survival in moderate -to-severe
COPD treated with antibiotics compared to placebo (Puhan et al. 2007)

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) Comorbidities
b) Severe underlying COPD (FEV-1<50%)
c) Frequent exacerbations (> 3/year)
d) Recent antibiotic use (within the past 3 months)

Antibiotic Treatment for Exacerbation of COPD

Exacerbation
Mild Moderate or Sever
Only 1 of the 3 cardinal symptoms: At least 2 of the 3 cardial symptoms:
 Increased dyspnea Increased dyspnea
 Increased sputum volume Increased sputum volume
 Increased sputum purulence Increased sputum purulence

 No antibiotic Uncomplicated COPD Complicated COPD

 Increased bronchodilators No risk factors 1 or more risk factors
 Symptomatic therapy Age <65 years Age > 65 years
 Instruct patient to report FEV1 > 50 percent FEV1 < 50 percent predicted
additional cardinal symptoms < 3 exacerbations / year ≥ 3 exacerbation / year
No cardiac disease Cardiac disease

Advanced macrolide (azithromycin, Fluoroquinolone (moxifloxacin.

clarithromycin)
Cephalosporin (cefuroxime,
cefpodoxime, cefdinir)
Doxycycline
Trimethoprim/sulfamethoxazole
 If recent (<3 months) antibiotics
exposure, use alternative class
Gemifloxacin, levofloxacin)
Amoxicillin / clavulanate
If at risk for Pseudomonas, consider
ciprofloxacin and obtain sputum
culture
If recent (< 3 months), antibiotic
exposure, use alternative class

Worsening clinical status or inadequate response in 72 hours

Re-evaluate
Consider sputum culture

Manage Exacerbations: NIV

  Noninvasive intermittent positive pressure ventilation (NIPPV) in acute exacerbations
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)

 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

 Improve gas exchange (decrease CO2 and increase O2)

 Rest or improve respiratory muscles
 Stabilize the upper airway
 Improve quality of life/exercise tolerance
 Prevent cardiovascular consequences of nocturnal hypercapnia and hypoxia

Assisted ventilation

1. Noninvasive positive pressure ventilation (NPPV) should be offered to patients with

exacerbations when, after optimal medical therapy and oxygenation, respiratory
acidosis (pH <7.36) and or excessive breathlessness persist. All patients considered
for mechanical ventilation should have arterial blood gases measured.

2. If pH <7.30, NPPV should be delivered under controlled environments such as

intermediate intensive care units (ICUs) and/or high-dependency units.

3. If pH <7.25, NPPV should be administered in the ICU and intubation should be readily
available.

4. The combination of some continuous positive airway pressure (CPAP) (e.g. 4–8
cmH2O) and pressure support ventilation (PSV) (e.g. 10–15 cmH2O) provides the
most effective mode of NPPV.

NIPPV

Exclusion criteria:
 Respiratory arrest
Cardiovascular instability
Somnolence, impaired mental status, uncooperative patient
High aspiration risk
Viscous or copious secretions
Recent facial or gastroesophageal surgery
Craniofacial trauma
Extreme obesity

Assisted ventilation

Patients meeting exclusion criteria should be considered for immediate intubation

and ICU admission.

Auto-PEEP (Intrinsic PEEP)

-9

+8 0

Diaphra
gm
-9 -1

COPD lung Normal

Lung

Example : if PEEPi = +8, the patient effort must be > -8 to create air flow

 In patients with COPD

 Rate of lung emptying becomes impaired because of increased expiratory
resistance and expiratory airflow limitation
 Therefore, a positive pressure is present at end expiration (PEEP)
 Patient must overcome a positive pressure before inspiration can begin
 Inspiration requires negative pressure
 Indications for ICU Admission in COPD Exacerbation

1. Severe dyspnea that responds inadequately to initial emergency therapy

2. 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 tube
or 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, chronic
bronchitis)
 Congenital/Hereditary: CF, Kartagener’s syndrome
 Necrotizing pneumonia
Incidence 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 dilatation of the patent
airways 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
COPD vs. Bronchiectasis

Variable Chronic Obstructive Bronchiectasis

Pulmonary Disease
Cause Cigarette smoking
Role of infection Secondary
Predominant organism in Streptococcus pneumoniae,
sputum Haemophilus influenzae
Airflow obstruction and Present
hyperresponsiveness
Findings on chest imaging Hyperlucency,
hyperinflation, airways
dilatations
Quality of sputum Mucoid, clear
(in the steady state)
Infection or genetic or
immune defect
Primary
H.influenzae, pseudomonas
aeruginosa
Present
Airway dilatation and
thickening, mucous plugs
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(2α) in sputum

Etiology

Pulmonary infections
viral, mycoplasma, TB, MAC
Airway obstruction
Defective host defenses
ABPA (allergic bronchopulmonary aspergillosis)
Rheumatic and other systemic dz
RA, Sjogren’s syndrome
Ulcerative colitis
Dyskinetic cilia
Cystic fibrosis ← rare in TW
Cigarette smoking?
 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:

Most frequent

 Lack of tapering of the bronchial lumen

 Bronchial wall thickening
 Bronchial dilatation
 Visualized peripheral bronchi
 Mucus plugging

Less frequent

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. influenzae and P. aeruginosa

– FQ is reasonable (eg. ciprofloxacin) for 7~10 days

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 antibiotic
Intermittent intravenous antibiotics

Problematic Pathogen

Pseudomonas aeruginosa
Almost impossible to irradicate
Wilson CB et al.
 Reduced QoL
 More extensive bronchiectasis on CT
 Increased number of hospitalizations
Ciprofloxacin quickly develops resistance

Bronchial Hygiene

Oral hydration
Nebulization
Normal saline
Acetylcyteine
Recombinant DNAase
Hypertonic saline, mannitol, dextran, lactose
Physiotherapy
Chest 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
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 Asians
About 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
CF Survival

Overall trend is improved survival

Female survival worse than male between 2-20 years of age 1
35% of patients are older than 18 years of age 2
Median survival 36.8 years3 compared to 1930s when life expectancy was about 6
months2

Types of mutations in CFTR

 Class I
 Defective protein production
 Class II
 Defects in processing
ΔF508
 Class III
 CFTR reaches cell surface but
regulation is defective (channel not
activated)
 Class IV
 CFTR in membrane with defective
conduction
 Class V
 Decreased synthesis of CFTR

Airway surface liquid low volume hypothesis and CFTR

Normal CFTR inhibits a sodium channel (ENaC)

– Mutant CFTR----ENaC not inhibited
 Sodium absorption is increased
 Water follows sodium
 ASL volume decreases
Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is low
– Mutant CFTR Cl- ions not secreted

Airway surface liquid low volume hypothesis and consequences

Cilia do not beat well when PCL volume is depleted

Mucins are not diluted and cannot be easily swept up the airway
Mucus becomes concentrated
Results in increased adhesion to airway surface
Promotes chronic infection
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 ducts1
 Chloride impermeability affects HCO3- secretion and fluid secretion in pancreatic
ducts2
 Pancreatic enzymes stay in ducts and are activated intraductally
Autolysis of pancreas
Inflammation, calcification, plugging of ducts, fibrosis
 Malabsorption
 Failure to thrive
 Fat soluble vitamin deficiency
GI disease

 Intestinal abnormality
 Meconium ileus
 Distal intestinal obstruction syndrome (DIOS)
 Rectal prolapse
 Hepatobiliary disease
 Focal biliary cirrhosis
 Multilobular cirrhosis
 Pancreatic endocrine dysfunction
 Cystic fibrosis related diabetes

Cystic fibrosis related liver disease

Focal inspissation of bile

– Obstructs biliary ductules
Second leading cause of death in CF1
Prevalence 9-37%1
Spectrum of disease
– increased liver enzymes
– biliary cirrhosis
– portal hypertension

Cystic fibrosis related diabetes mellitus

 Screening
 Oral glucose tolerance test (OGTT)
 Every two years in patients 10-16 years
 Any patient with random plasma glucose >180
 Fasting>=140 mg/dl
 initiate insulin treatment
 Fasting<140 and OGTT at 2 hrs>200 mg/dl
 Home glucose monitoring; consider insulin
 Fasting <140 and 2 hour 140-200
 Impaired glucose tolerance
 OGTT annually
 Fasting and 2 hour <140
 Normal glucose tolerance
Infertility

Men
Abnormal embryologic development of the epididymal duct and vas deferens---
may be incomplete of absent
Congential bilateral absence of the vas deferens—97-98% of men with CF
Women
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

 1949 NYC heat wave----noted CF infants to have a higher rate of heat prostration
than 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 test

Electrolyte 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 under
other electrode pad on arm
– Mild electric current is passed between electrodes
– Sweat collected

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

Nutrition parameters
 Percent ideal body weight (IBW%)
– 90-110%: Normal
– 85-89%: Underweight
– 80-84%: Mild malnutrition
– 75-79%: Moderate malnutrition
– <75%: Severe malnutrition
Height as a percentage of 50 th percentile height for age (height/50 th percentile height
for age )X100.
– 95-100% normal
– 90-94%: mildly stunted
– 85-89%: moderately stunted
– <85%: severely stunted

Treatment: Pancreatic enzymes

 Initiate if have malabsorption history

Fecal fat
Fecal elastase
 May need H2 blocker or PPI to activate enteric coated enzyme
 Fibrosing colonopathy
Strictures in the colon associated with high dose enzyme use (enzyme gets to
colon and causes damage leading to scarring/stricture)

Treatment: Cystic fibrosis related liver disease

 Ursodiol
 Increased bile flow
 Decrease toxicity of bile acids
 Sclerotherapy, portosystemic shunts
 Liver transplantation---only curative treatment for portal hypertension

Treatment: Infertility

Microsurgical epididymal sperm aspiration coupled plus in vitro technology

Percutaneous epididymal sperm aspiration

Testicular sperm extraction

Maternal genetic testing