Emphysema; Causes, Symptoms, Diagnosis, Treatment

Emphysema is defined as a pathological permanent dilatation of distal airways (respiratory bronchioles, alveolar ducts, and alveolar sacs) due to the destruction of the walls of the airways without fibrotic changes. Emphysema destroys the essential ventilatory units and interrupts the gas exchange. Functionally, emphysema causes obstructive ventilatory defect evidenced in the spirometry and is included in the collective diseases of chronic obstructive pulmonary disease, commonly termed as COPD. [rx]

Emphysema is defined as “an anatomic alteration of the lung characterized by an abnormal airspace enlargement distal to the terminal bronchioles accompanied by destructive changes of the alveolar walls”[rx] and is a variable component of the syndrome COPD which is now understood to have also extrapulmonary systemic manifestations.[rx]

Pulmonary emphysema a progressive lung disease, is a form of chronic obstructive pulmonary disease (COPD). Global Initiative has defined COPD for chronic obstructive lung disease (GOLD) as “a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases. [rx][rx][rx]

Pathophysiology

Emphysema involves pathological destruction of alveolar walls and respiratory bronchioles, alveolar ducts, alveolar sacs causing permanent dilatation resulting in a decreased surface area of the ventilatory units. Ventilation or gas exchange requires an intact alveolar wall, interstitium, and capillaries with adequate blood flow. Hence emphysema interferes with gas exchange leading to extreme hypoxia and hypercapnia thus resulting in respiratory failure. Emphysema classifies into three subtypes namely- centriacinar, panacinar, and paraseptal. Paraseptal emphysema can occur in smokers as well as with alpha-1 antitrypsin (AAT) deficiency. Centriacinar is common in smokers, and panacinar is prevalent in AAT deficiency. With the exposure to smoke and other chemicals, inflammatory mediators such as macrophages, T lymphocytes, and neutrophils are activated, releasing cytokines. Also, proteinases are released, destroying the lung parenchymal connective tissue and ventilatory units causing, in advanced cases, severe hypoxia and hypercarbia. Another consequence is excessive mucus production. It is worth noting that AAT is an anti-proteinase that prevents lung destruction by counteracting the proteinase and due to their genetic deficiency, emphysema occurs due to the loss of this protection

Types of Emphysema

Pulmonary emphysema can be classified into three major subtypes based on the disease distribution within secondary pulmonary lobules [rx]:

• Centriacinar emphysema,
• Panacinar emphysema, and
• Distal acinar emphysema [rx]. The relationships among these types of pulmonary emphysema and how each type is formed have yet to be clarified.

The GOLD Emphysema Staging System

Causes of Emphysema

• Injury to the parietal pleura that allows for the passage of air into the pleural and subcutaneous tissues
• Air from the alveolus spreading into the endovascular sheath and lung hilum into the endothoracic fascia
• The air in the mediastinum spreading into the cervical viscera and other connected tissue planes
• Air originating from external sources
• Gas generation locally by infections, specifically, necrotizing infections
• Post infective (post pneumonia, whooping cough, measles, mycobacterial infection)
• Mucociliary disorder (immotile cilia, Kartagener’s syndrome, Young’s syndrome)
• Obstructive (foreign body, mycobacterial infection, obstructing cancer)
• Immune disorder (hypogammaglobulinemia, HIV infection, cancer, allergic bronchopulmonary aspergillosis, transplant rejection)
• Rheumatic/inflammatory disease (rheumatoid arthritis, inflammatory bowel disease)
• Extremes of age
• Malnutrition/socioeconomic disadvantage
• Chronic obstructive pulmonary disease
• Miscellaneous (yellow nail syndrome)
• Alpha1-antitrypsin deficiency

Bacterial Infections

• Mycobacterium: Tuberculosis and atypical
• Haemophilus influenzae
• Pseudomonas aeruginosa
• Staphylococcus aureus
• Mycoplasma and HIV

Viral Infections

• Respiratory syncytial virus and measles

Fungal Infections with Bronchial obstruction

• Foreign body
• Mucus plug
• Tumors
• Hilar lymphadenopathy (right middle lobe syndrome: extrinsic compression from postinfectious adenopathy)

Postinflammatory pneumonitis

• Chronic aspiration/gastroesophageal reflux disorder
• Chronic sinusitis
• Inhalational injury

Congenital/Genetic

• Cystic fibrosis
• Young syndrome
• PCD: primary ciliary dyskinesia (Kartenger Syndrome)
• immunodeficiency (hypogammaglobulinemia)
• Alpha1-antitrypsin deficiency (AAT)
• Mounier-Kuhn syndrome

Inflammatory diseases

• Ulcerative colitis
• Rheumatoid arthritis
• Sjögren syndrome

Pulmonary Diseases

• Asthma
• Bronchomalacia
• Cronic-obstructive pulmonary disease (COPD) (reported in up to 50% of patients with moderate-to-severe COPD)
• Diffuse panbronchiolitis
• Idiopathic pulmonary fibrosis (traction bronchiectasis)

Altered immune response

• Allergic Bronchopulmonary Aspergillosis
• Hypersensitivity pneumonitis

Others

• Yellow nail syndrome (yellow nails, lymphedema, pleural effusion, bronchiectasis 40% first described in 1964)
• Allergic bronchopulmonary aspergillosis (ABPA) is a rare but typical complication in bronchiectasis. The underlying pathophysiology is sensitization to Aspergillus fumigatus, which leads to a CD4+/TH2 mediated inflammatory reaction.
• Typical symptoms include a raised body temperature, weight loss, a drop in FEV1, and pulmonary infiltrates on the radiograph. Bronchiectasis can be a sequela of ABPA, but it can also predispose to ABPA.

Symptoms of Emphysema

• Cough – 98%, sputum: 78% (sputum is typically mucoid and relatively odorless), dyspnea: 62%, haemoptysis: 56% to 92%, and pleuritic chest pain: 20% (secondary to chronic coughing).
• Some people with bronchiectasis – may have a cough productive of frequent green/yellow mucus (sputum), up to 240 ml (8 oz) daily.
• Bronchiectasis – may also present with coughing up blood (hemoptysis) in the absence of sputum, called “dry bronchiectasis”. Sputum production may also occur without coloration. People with bronchiectasis may have bad breath indicative of active infection.
• Frequent bronchial infections – and breathlessness are two possible indicators of bronchiectasis. Crepitations and expiratory rhonchi may be heard on auscultation. Nail clubbing is rare.^[rx]
• Breathing difficulties during physical exercise – and while at rest in advanced COPD
• Shortness of breath, especially during light exercise or climbing steps
• The ongoing feeling of not being able to get enough air
• Long-term cough or smoker’s cough
• Wheezing
• Long-term mucus production
• Ongoing fatigue
• Daily cough over a long period of time
• Sputum (coughed-up phlegm)
• Breathing sounds such as wheezing
• Symptoms that get worse when you have a cold or flu
• Chronic daily cough
• Coughing up blood
• Abnormal sounds or wheezing in the chest with breathing
• Chest pain
• Coughing up large amounts of thick mucus every day
• Weight loss
• Fatigue
• Change in the structure of fingernails and toenails, known as clubbing
• Frequent respiratory infections

Diagnosis of Emphysema

GOLD staging based on the severity of airflow limitation is as follows

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• Mild with FEV1 greater or equal to 80% predicted
• Moderate with FEV1 less than 80%predicted
• Severe with FEV1 less than 50% predicted
• Very severe with FEV1 less than 30 % predicted
• Blood tests – to check how well your immune system is working and check for infectious agents, such as bacteria, viruses, and fungi.
• Blood tests, including a complete blood count (CBC) – to see if you have anemia (when your body doesn’t make enough red blood cells) or infection and other tests to check for a blood clot or fluid in your lungs.
• Phlegm (sputum) test – to check for bacteria or fungi
• a sample of your sweat can be tested to see how much salt is in it – high levels of salt can be caused by cystic fibrosis (if this test is positive, a more detailed genetic test can be carried out.
• Lung function test – a small, handheld device (a spirometer) that you blow into is used to measure how hard and how quickly you can expel air from your lungs; this can assess how well your lungs are working
• Bronchoscopy – a flexible tube with a camera at one end is used to look into your lungs; this is usually only required if you think you have inhaled a foreign object
• A chest x-ray – is only helpful in diagnosis if emphysema is severe, but it is usually the first step when suspecting COPD to rule out other causes. Destruction of alveoli and air trapping causes hyperinflation of lungs with flattening of diaphragm and heart appears elongated and tubular-shaped.
• Arterial blood gases – are usually not required in mild to moderate COPD. It is done when oxygen saturation goes below 92%, or there is severe airflow obstruction to access for hypercapnia.
• Spirometry – A test called spirometry can help show how well your lungs are working. You’ll be asked to breathe into a machine called a spirometer after inhaling a medication called a bronchodilator, which helps widen your airways. The spirometer takes two measurements: the volume of air you can breathe out in one second, and the total amount of air you breathe out. You may be asked to breathe out a few times to get a consistent reading.

Other tests you might have include

• Pulse oximetry  – a device is clipped to your finger or ear lobe, and a light on it measures how much oxygen is in your blood.
• Chest X-ray or a computerized tomography (CT) scan – to see if you have pneumonia, blood clot in your lung, or another lung disease. A CT scan puts several X-rays taken from different angles together to make a more complete picture.
• Electrocardiogram (ECG) –  to measure the electrical signals from your heart to see if you’re having a heart attack and find out how fast your heart is beating and if it has a healthy rhythm.
• Patients should be tested for electrolyte abnormalities – endocrine disorders (specifically hyperthyroid) drug-induced causes, infections, drug or chemical withdrawal, and echocardiography to check for structural heart disease. In patients presenting with ischemic stroke and with no prior history of AF, 72-hour Holter monitoring improves the detection rate of silent paroxysmal.[rx]
• Screening spirometry – Can assess how much air you can breathe
• Complete pulmonary function testing – Can evaluate your breathing capabilities in more detail than screening spirometry by measuring how much air you can breathe in and out, as well as how quickly
• Arterial blood gas measurement – Provides a measure of the oxygen content of your blood, which alerts your doctors if you are becoming low in oxygen
• Echocardiography – May be ordered if your EKG suggests that you have heart disease
• Standard exercise treadmill testing – Evaluates your breathing when you have increased oxygen demands
• Complete cardiopulmonary exercise testing – Evaluates your heart and lung function in detail.

Treatment Emphysema

There is no known, definitive treatment which can modify the disease process. However, risk-factor modification and management of symptoms have been proven effective in slowing the disease progression and optimizing the quality of living.[rx][rx][rx]

Based on the symptoms and number of exacerbations, we can divide the disease into 4 COPD GOLD stages and modify the treatment accordingly.

• Antibiotics – If your doctor or healthcare provider suspects that you have a lung infection, he or she may order antibiotic pills or intravenous (IV), depending on how severe your illness is, and your overall health status. Commonly prescribed antibiotics for bronchitis, pneumonia and respiratory (breathing) problems include azithromycin and levofloxacin. If you are prescribed antibiotic pills, take the full prescription. Do not stop taking pills once you feel better.
• Cough medications/Decongestants – may help you to be more comfortable if you are coughing a lot. Guaifenesin is an active ingredient in many cough medications, may be given alone, but is often combined with other drugs, such as codeine, to help your cough. Guaifenesin may also be combined with pseudoephedrine as a decongestant, or anyone of many medications, depending on your symptoms.  Another common medication you may receive is Hydrocodone Bitartrate-Homatropine Methylbromide. This is a narcotic antitussive (anti-cough medication), which will help relieve your cough.
• Antianxiety medications – If you are experiencing anxiety with your emphysema, depending on the cause, your healthcare provider may prescribe an anti-anxiety medication, called an anxiolytic.  These medications will help you to relax. These may include lorazepam or alprazolam. It is important to take these medications only when you are feeling anxious. Do not operate heavy machinery, or drive an automobile while taking these. These medications must be used very cautiously if you have a severe pneumothorax. Discuss the risks and benefits of taking this medication with your doctor or healthcare provider.
• Beclomethasone –  an inhaled steroid, is useful in the treatment of chronic emphysema. Inhaled steroids act directly on the lung tissue, so there are fewer long-term side effects, compared with a pill or IV form. People who have an outbreak of severe shortness of breath and airway inflammation may be ordered a steroid pill, such as prednisone, for a short period of time. This is usually given with inhaled steroids. Patients with severe asthma may require IV administration of another steroid, methylprednisolone.
• Diuretics – may be known as “water pills” as they work to prevent or treat lung congestion by making you urinate out extra fluid. Some examples of this medication may include furosemide and Hydrochlorothiazide. You may receive this medication alone or in combination with other medications.
• Drugs that open up (dilate) the airways (bronchodilators) These drugs are typically inhaled as a powder to make it easier to breathe. They include beta-2 agonists, anticholinergics, and methylxanthines.
• PDE4 inhibitors – These tablets also have an anti-inflammatory effect.
• Medical therapy – includes using a bronchodilator alone or in combination with anti-inflammatory drugs (corticosteroids and phosphodiesterase four inhibitors).

Bronchodilator

The primary mechanisms of action can be divided into two categories

• Beta2 agonists and anticholinergic medications – They are first-line drugs for COPD and are administered by inhalation. They are known to improve FEV1 by altering the smooth muscle tone of the airways and thus improve exercise tolerance. Bronchodilators are usually given regularly to prevent and to reduce symptoms, exacerbations, and hospitalizations.
• Short-acting beta2 agonists (SABA) – and short-acting muscarinic antagonists (SAMA) are usually prescribed as needed for management of intermittent dyspnea. Long-acting beta2 agonists (LABA) and long-acting muscarinic antagonists (LAMA) are used especially with increasing dyspnea or more than occasional dyspnea. If the symptoms are persistent while on one bronchodilator, another bronchodilator should be added.
• Beta2 agonists – cause relaxation of airway smooth muscles. SABA like albuterol can be used with or without anticholinergics. SABA is the mainstay in COPD exacerbation. LABA includes formoterol, salmeterol, indacaterol, olodaterol, vilanterol, among others. The side effects are arrhythmias, tremors, and hypokalemia. Caution should be taken in heart failure as tachycardia may precipitate heart failure.
• Anti-muscarinic agents –  such as tiotropium, ipratropium, and umeclidinium are beneficial as they dry secretions of goblet cells, decrease bronchoconstriction, and inhibit excessive fluid production in bronchi.
• Long-acting beta-agonists – like salmeterol and formoterol can be added, but should never be monotherapy. Necessary vaccinations for patients include pneumococcal 13-valent conjugate vaccine given initially and pneumococcal vaccine polyvalent given one year later and a yearly inactivated influenza vaccine. Smoking cessation is beneficial to combat the progression of the disease and decrease mortality.
• Anticholinergics inhibit acetyl-choline-  induced bronchoconstriction. SAMA includes ipratropium and tiotropium. LAMA such as tiotropium can be given once daily.
• Inhaled corticosteroid (ICS) is an add-on therapy to bronchodilator in a step-up therapy. ICS includes beclomethasone, budesonide, fluticasone, etc. The common side effects are local infection, cough, and pneumonia. Oral systemic corticosteroids are used for all patients with COPD exacerbation and avoided in stable patients due to more adverse effects.
• Oral Phosphodiesterase-4 inhibitors like Roflumilast act by reducing inflammation and can be added if there is severe airflow obstruction with no improvement with the above medications.
• Triple inhaled therapy – (LABA+ LAMA+ ICS) has been recently approved by the FDA and is taken only once a day.
• Intravenous aloha1 antitrypsin augmentation therapy – for AATD patients. The high cost and lack of availability is the main limitation of this therapy.

Supportive Therapy

Supportive therapy includes oxygen therapy and ventilatory support, pulmonary rehabilitation, and palliative care.

• Routine supplemental oxygen Therapy – does not improve the quality of life or clinical outcomes in stable patients. Continuous long-term, i.e., longer than 15 hours of supplemental oxygen is recommended in COPD patients with PaO2 less than 55 mmHg (or oxygen saturation less than 88%) or PaO2 less than 59 mm Hg in case of cor pulmonale. Oxygen therapy has shown to increase survival for these patients with severe resting hypoxemia. For those who desaturate with exercise, intermittent oxygen will help. The goal is to maintain oxygen saturation greater than 90%. A major cause of hypoxemia in COPD is due to ventilation-perfusion mismatch (V/Q Mismatch), particularly in low V/Q areas.
• Hypoxic vasoconstriction – of pulmonary arteries is to improve overall gas exchange efficiency. Supplemental oxygen can successfully reach the alveoli in these lungs, which prevent this vasoconstriction and thereby increasing perfusion and improving gas exchange thus resulting in improvement of hypoxemia.
• Noninvasive positive pressure ventilation (NPPV) – is known to decrease morbidity and mortality in patients with acute respiratory failure and hospitalized for COPD exacerbation. It should be tried as the first mode of ventilation in patients with COPD exacerbation with respiratory failure who otherwise have no absolute contraindication as it improves gas exchange, decreases hospitalization duration, reduces work of breathing, improves VQ matching, and improves survival. If NPPV doesn’t work in in a COPD patient in a hospital setting, then the patient should be intubated and put on a ventilator.
• Pulmonary rehabilitation – for patients with severe symptoms and multiple exacerbations reduces dyspnea and hospitalizations and is recommended for GOLD stages B, C, and D. Although available from the time the person is diagnosed with COPD, palliative care is typically recommended for GOLD stage D.

Therapy

• Pulmonary rehabilitation. A pulmonary rehabilitation program can teach you breathing exercises and techniques that may help reduce your breathlessness and improve your ability to exercise.
• Nutrition therapy. You’ll also receive advice about proper nutrition. In the early stages of emphysema, many people need to lose weight, while people with late-stage emphysema often need to gain weight.
• Supplemental oxygen. If you have severe emphysema with low blood oxygen levels, using oxygen regularly at home and when you exercise may provide some relief. Many people use oxygen 24 hours a day. It’s usually administered via narrow tubing that fits into your nostrils.
• Vitamin D – There is some evidence that people with emphysema can have insufficient levels of vitamin D, which is needed for healthy bones, teeth, and muscles. Your health care professional might test your vitamin D levels, especially as current government advice is that adults should have 10 micrograms of vitamin D every day.
• Interventional Therapy – Lung volume reduction surgery reduces hyperinflation and improves elastic recoil, Lung transplantation when FEV1 and or DLCO is less than 20%.
• Inhalers – If your COPD is affecting your breathing, you’ll usually be given an inhaler. This is a device that delivers medication directly into your lungs as you breathe in. Your doctor or nurse will advise how to use your inhaler correctly and how often to use it. If you have severe symptoms or experience a particularly bad flare-up, you may sometimes need additional treatment.
• Nebulised medication – Nebulised medication may be used in severe cases of COPD if inhalers haven’t worked. This is where a machine is used to turn liquid medication into a fine mist that you breathe in through a mouthpiece or a face mask. It enables a large dose of medicine to be taken in one go. You’ll usually be given a nebulizer device to use at home after being shown how to use it.
• Long-term oxygen therapy – If your COPD results in a low level of oxygen in your blood, you may be advised to have oxygen at home through nasal tubes or a mask. This can help stop the level of oxygen in your blood becoming dangerously low, although it’s not a treatment for the main symptoms of COPD, such as breathlessness. Long-term oxygen treatment should be used for at least 16 hours a day. The tubes from the machine are long, so you will be able to move around your home while you’re connected. Portable oxygen tanks are available if you need to use oxygen away from home. Don’t smoke when using oxygen. The increased level of oxygen is highly flammable and a lit cigarette could cause a fire or explosion.
•  Some people with COPD will benefit from ambulatory oxygen – oxygen used when you walk or are active in other ways. If your blood oxygen levels are normal while you’re resting but fall when you exercise, you may be able to have ambulatory oxygen therapy rather than long-term oxygen therapy.
• Non-invasive ventilation (NIV) – If you’re taken to hospital because of a bad flare-up, you may have a treatment called non-invasive ventilation (NIV).This is where a portable machine connected to a mask covering your nose or face is used to support your lungs and make breathing easier.

• Postural Drainage (or modified postural drainage) – is an effective treatment that incorporates gravity-assisted techniques to help clear secretions from specific segments of the lungs and often requires tilting the head down to clear secretions from the middle and lower lobes.
• PD is commonly used in conjunction with other techniques like ACBT percussion – coughing or huffing and studies have found using PD with these techniques produced a greater amount of sputum^[rx][rx]. Although PD is effective in secretion clearance it is time-consuming and often found to be less tolerated than techniques that are performed in a sitting^[rx].
• Where tilting the head down is contraindicated – or not tolerated then modified postural drainage (MPD) positions can be used instead and in cases where gastroesophageal reflux disease GORD) is present and exacerbated even when using modified PD then it is suggested to use a technique that can be performed in sitting.
• Autogenic Drainage is a technique – that utilizes breathing control to clear secretions from the airways. The aim is to vary the depth, rate, and location of lung volumes during respiration to move secretions from the smaller airways to the larger airways for easier expectoration. It consists of three phases:

Additional Interventions

• Chronic medical therapy includes several interventions. First, a short-acting beta-agonist such as albuterol is integral for acute shortness of breath and bronchodilation.
• Long-term oxygen is a possible add-on therapy if the pO2 is < 55 or the oxygen saturation is < 88% on a six-minute walk test.
• Identification and reduction of exposure to risk factors. Counseling about smoking cessation, as it is the single most important intervention that slows the progression of the disease Reduce the exposure to open cooking fires and promote efficient ventilation.
• Daily oral opioids for severe COPD symptoms refractory to medical therapy. Nutritional supplementation in malnourished COPD patients
• Pneumococcal vaccine 23 valent every 5 year years for COPD patients older than 65 or with other cardiopulmonary disease and Influenza vaccine for all COPD patients every year
• Readmission rates can be reduced with counseling on the optimal use of metered-dose inhalers (MDI)
• Exercise for all COPD patients

References

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