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Topics in Pulmonary Medicine

I. Pleural disease

A. Features of diagnostic evaluation

1. Criteria for exudative pleural effusion

a. Light's criteria - any of the following:

(1) Pleural fluid/serum protein >0.5

(2) Pleural fluid/serum LDH >0.6

(3) Pleural fluid LDH >2/3 upper normal

b. Other criteria have been proposed but have not generally supplanted Light's criteria

c. Implications: transudate related to change in hydrostatic and oncotic pressure balance; exudate related to change in pleural permeability

2. Bloody pleural fluid

a. Trauma

b. Malignancy

c. Pulmonary infarction

3. Pleural fluid WBC differential

a. Lymphocytes

(1) TB

(2) Lymphoma

(3) Sarcoidosis

(4) Chronic rheumatoid pleurisy

(5) Carcinoma

b. Eosinophils

(1) Following blood or air in pleural space

4. Low pleural fluid glucose

a. Lowest values

(1) Rheumatoid arthritis - decreased glucose transport into pleural space

(2) Empyema - increased utilization of glucose

b. Other causes

(1) TB

(2) Malignancy

(3) Lupus

(4) Esophageal rupture

5. pH

a. Tends to be low in conjunction with low glucose

b. Prognostic implication for development of complications (loculations) in parapneumonic effusion (See Sahn 1993 ref)

6. Pleural fluid lipids

a. Chylothorax

(1) Diagnostic: triglycerides >110 mg/dL

(2) Borderline: triglycerides 50-110 mg/dL (chylomicrons on electrophoresis diagnostic)

b. Chyliform effusion

(1) Cholesterol or lecithin-globulin complexes

B. Radiographic points

1. Features of subpulmonic effusion

a. "Hockey stick" deformity

b. Uniform density of diaphragm contour with failure to see lung markings behind diaphragm

2. Rounded atelectasis

a. Complication of resorption of effusion

b. Mimics pulmonary nodule

c. Typical appearance with "comet tail" on chest CT

3. Post-reexpansion pulmonary edema following large volume thoracentesis

C. Specific causes of pleural effusions

1. Tuberculosis: effusion from either primary or reactivation disease

2. CHF: altered profile with diuresis

3. Cirrhosis: leakage through diaphragmatic defects

4. Pulmonary embolism: any profile possible

5. Drugs: bromocriptine (pleural effusions, thickening, pulmonary infiltrates)

D. Selected aspects of diagnosis and management

1. Pleural biopsy: primarily for tuberculosis

2. Small-bore catheter drainage

3. Sclerosis (pleurodesis): talc, minocycline or doxycycline

4. Pleuroperitoneal shunting

5. Thoracoscopy

E. Pleural disease in AIDS

1. Pleural effusion

a. Most common

(1) Parapneumonic

(2) Kaposi's sarcoma (serosanguinous)

b. Other causes

(1) Tuberculosis

(2) Cryptococcosis

c. Rare: PCP

2. Spontaneous pneumothorax - suspect PCP

II. Genetic disorders

A. Cystic fibrosis

1. Genetics of cystic fibrosis

a. Defect in single gene on chromosome 7 coding for CFTR (cystic fibrosis transmembrane conductance regulator) 

b. CFTR: 1480 amino acid protein

c. Multiple potential genetic defects 

(1) Protein synthesis 

(2) Protein processing 

(3) Protein regulation 

(4) Protein function

d. Most common abnormality: AF508 (3-base deletion ~ loss of phenylalanine residue at position 508)

2. Pathogenesis of cystic fibrosis

a. CFTR = C1- channel; protein abnormality produces:

(1) Defective cAMP-dependent C1- secretion from respiratory epithelium

(2) Increased Na+ absorption from airway lumen

b. Decreased NaC1 in airway lumen means less osmotic force for movement of water into secretions ---> thick secretions

c. Increased C1- in sweat - used for diagnosis

d. Different cellular location of CFTR on sweat duct epithelial cells (basal surface) vs. lung or pancreas cells (apical surface)

3. Clinical manifestations of cystic fibrosis

a. Lower respiratory tract

(1) Chronic bronchitis and airflow obstruction

(2) Bronchiectasis: S. aureus and H. infiuenzae P. aeruginosa

b. Chronic sinus disease

c. Meconium ileus - episodes of SBO ("meconium ileus equivalent") in older children and adults

d. Pancreatic insufficiency

e. Infertility

(1) 95% of men; due to atresia of vas deferens

(2) 20% of women; due to tenacious cervical mucus

4. Recent treatments for cystic fibrosis

a. Aerosolized recombinant human DNase

(1) Decreases viscoelasticity of sputum

(2) Decreases frequency of respiratory exacerbations (by 30-35%)

(3) Slight (6%) improvement in pulmonary function

b. Aerosolized tobramycin

(1) Improved pulmonary function

(2) Decreased density of P. aeruginosa in sputum

5. Gene therapy for cystic fibrosis

a. Need 5-10% of normal CFTR mRNA levels in airway lining cells

b. Possible vectors

(1) Plasmid DNA

(2) Viral vectors - retrovirus, adenovirus

(3) Nonviral vectors - eg, liposome-based

c. Problems

(1) Vector production and low efficiency of delivery

(2) Duration of expression

(3) Inflammatory response

B. Alpha-l-antitrypsin deficiency

1. Pathogenesis of alpha-l-antitrypsin deficiency

a. Genetics

(1) Normal allele = M; normal genotype = MM

(2) Multiple types of abnormal alleles

(3) Most important abnormal allele = Z; most important form of deficiency due to ZZ

b. Impaired transport of ZZ protein out of liver

c. Approximately 15% of normal serum level in ZZ patients

2. Clinical aspects of alpha-l-antitrypsin deficiency

a. Associated with panacinar, predominantly lower lobe emphysema

b. Consider diagnosis with:

(1) Early onset of emphysema

(2) Emphysema without smoking

(3) Family history of emphysema

c. Can be misdiagnosed as "asthma"

d. Liver disease in 10-15% of adults

(1) Cirrhosis

(2) Hepatoma

3. Replacement therapy for alpha-l-antitrypsin deficiency

a. Threshold of serum level for considering treatment: <11 umol/L (80 mg/dL)

b. Alpha-l-antitrypsin from pooled human plasma (Prolastin) by IV infusion ranging from q week to q month

(1) Extremely expensive

c. Can achieve good levels in alveolar lining fluid

d. No controlled trials showing clinical efficacy

(1) Uncontrolled NIH Registry data suggest benefit in patients with intermediate levels of pulmonary impairment

III. Drug-induced lung disease

A. Amiodarone pulmonary toxicity

1. Occurs in -5-10% of patients

2. Risk factors:

a. Dose - at least 400 mg/day b. Duration - usually >2 months c. Older age

3. Pathology notable for foamy macrophages (filled with amiodarone phospholipid complexes)

4. Fever in 33-50%

5. Radiography:

a. CXR - diffuse or localized interstitial, alveolar, or mixed opacities

b. CT - may see increased density in liver, lungs, spleen

6. DLCO not useful as predictive index or diagnostic test for toxicity

7. Treatment

a. D/C amiodarone

b. Steroids for severe disease or when discontinuing therapy is ineffective

c. Note long T 1/2 (45 days)

B. Pulmonary toxicity from anorexic agents

1. Reports of pulmonary hypertension associated with fenfiuramine or derivatives

2. European case-control study:

a. Odds ratio of 23.1 for developing pulmonary hypertension with use of anorexic drugs

b. Associated risk factors - FH of pulmonary hypertension, HW infection, cirrhosis, cocaine or W drug use

c. Overall risk still small - 28 cases per million person-years of use

3. Fenfiuramine and dexfenfiuramine subsequently withdrawn because of valvular heart disease

IV. Lung transplantation

A. Indications for lung transplantation

1. COPD

2. Emphysema due to alpha-l-antitrypsin deficiency

3. Idiopathic pulmonary fibrosis

4. Cystic fibrosis

5. Primary pulmonary hypertension

6. Eisenmenger's syndrome

7. Other - bronchiectasis, sarcoidosis, lymphangioleiomyomatosis, eosinophilic granuloma

B. Common questions re eligibility

1. Age - usually <60-65 years for single lung transplant

2. Problem with previous pleurodesis or pleurectomy; other thoracic surgery usually acceptable

3. Steroids not a contraindication

C. Types of lung transplantation

1. Single lung - the standard for most cases

2. Bilateral lung - for generalized bronchiectasis or other forms of chronic pulmonary infection (including CF)

3. Heart-lung - for Eisenmenger's syndrome or combined severe lung and heart disease

D. Selection from waiting list

1. Priority based on time on waiting list, not severity of illness

2. Median waiting time -550 days

E. Causes of death after transplantation

1. Early - mainly infection and graft failure

2. Late - mainly infection and allograft rejection (bronchiolitis obliterans)

F. Survival after transplant

1. Single and bilateral lung transplants - similar survival rates of approximately 70% at 1 yr., 60% at 2 yrs., and 55% at 3 yrs.

2. Slightly lower survival rates for heart-lung transplant