Obstructive lung diseases: Pathology review

Chapters:

Watch video only

Case Study0:00–0:59

While doing your rounds, you see two individuals. First is Elsa, a 66-year-old with a history of smoking 2 packs a day for the past 35 years.
She came in with progressive shortness of breath and chronic, productive cough, which appeared two and a half years ago but recently got worse.
On examination, she presents with pursed-lip breathing, barrel chest, and diminished breath sounds with wheezing. Spirometry was requested, and it showed signs of moderate respiratory obstruction, including an important reduction in forced expiratory volume in one second.
The other individual is James, a 7-year-old with a history of wheezing and coughing episodes that began 2 years ago. The episodes used to be only during the winter, but in the past 6 months, they increased in frequency and severity.
His father has a history of asthma, and the child himself has eczema. Physical examination and spirometry was normal.Now, both seem to have some type of obstructive lung disease.

Physiology0:59–2:32

But first a bit of physiology. The respiratory tree can be divided into the conducting zone, which consists of large airways like nose, pharynx, larynx, trachea, and bronchi; and the respiratory zone, consisting of respiratory bronchioles, alveolar ducts, and alveoli.
Lining the lumen of the airways you’ve got the epithelium, mostly composed of one layer of ciliated pseudostratified columnar epithelial cells up until the beginning of terminal bronchioles, where it is replaced by cuboidal cells.
The ciliated pseudostratified columnar epithelial cells have hair-like projections called cilia. The cilia are responsible for eliminating larger particles like dust that reach the terminal bronchioles by moving them towards the pharynx, where they are coughed out.
The epithelium also contains the goblet cell which makes the mucus within the airway. Going deeper past that layer you’ve got the basement membrane and loose connective tissue, called the lamina propria, which together with the epithelium makes up the mucosa.
Beyond the mucosa, there is smooth muscle followed by more connective tissue, and together, these two layers make up the submucosa, which is where the bronchial mucinous glands that secrete the majority of the mucus into the lumen of the bronchi live.
Finally, in the bronchi, but not the bronchioles, there is a layer of cartilage below the submucosa which stiffens the bronchus and helps to keep it open.
Ok, so obstructive lung diseases are a group of conditions, characterized by obstruction of airflow, which traps air inside the lungs.

Pathology2:32–3:24

Now, because the airway is narrowed down or severely obstructed, exhaled air comes out more slowly than normal, and at the end of a full exhalation, an abnormally large amount of air still remain in the lungs.
This an obstructive respiratory deficit, and it’s marked by several changes which can be seen on pulmonary function tests or PFTs, like spirometry and plethysmography.
Spirometry is when you breathe into a tube attached to a machine called a spirometer, which measures the amount of air you breathe in and out, and how quick you do it.
Plethysmography is when you are placed inside a sealed chamber and asked to breathe through a mouthpiece, which measures the pressure generated by your breathing to calculate the amount of air inside your lungs.

Pulmonary Function Tests3:24–7:17

Ok, so in obstructive lung diseases, first, there’s an increase in residual volume or RV, which is the amount of air left in the lungs after exhaling as much as you can, and in functional residual capacity or FRC, which is the amount of air remaining in the lungs at the end of a normal exhalation.
Second, there’s a small reduction in forced vital capacity or FVC, which measures the amount of air a person can breathe out forcefully after taking as deep a breath as possible, and a significant reduction in forced expiratory volume in one second or FEV1, which measures the total amount of air that can be forcibly exhaled in the first second of the FVC test.
This is because these individuals have a narrow airway, which hinders how fast air can leave the lungs. Third, there’s a decrease in the ratio of FEV1 to FVC secondary to the disproportionate decrease in FVC and FEV1.
The ratio measures the amount of air a person can forcefully exhale in one second relative to the total amount of air they can exhale.
Ok, so this decrease in the ratio of FEV1 to FVC is considered the hallmark of obstructive lung disease and can also be used to figure out the severity of the obstruction.
Fourth, the total lung capacity is either normal or increased, unlike restrictive lung diseases, where it almost always is decreased.
The reason why TLC may increase is that in some obstructive lung diseases, like emphysema, there’s air trapping and lungs hyperinflate.
TLC is calculated by adding the volume of air left in the lungs after exhalation or the residual volume with the FVC. Fifth, there might also be a V/Q mismatch, where the V stands for ventilation, which is the air you breathe in, and the Q stands for perfusion, which is blood flow.
A V/Q mismatch happens because the blood flow is normal but the lungs don’t receive enough oxygen due to airway obstruction, and this is measured by a test called a pulmonary ventilation/perfusion scan.
Over time, this can lead to hypoxemia, because there’s not enough oxygen in the blood. In order to keep the V/Q ratio constant, as the ventilation decreases, the pulmonary vessels start to constrict in order to reduce perfusion to the areas that do not participate in gas exchange.
This is called hypoxic vasoconstriction, and it leads to pulmonary hypertension. Over time, pulmonary hypertension puts a strain on the right heart, and can lead to right heart failure, or cor pulmonale; which manifests as jugular venous distention, peripheral edema, and hepatomegaly due to congestion.
Finally, it’s important to assess the gas exchange, which varies, depending on the particular disease. This is done by measuring the diffusing capacity of the lungs for carbon monoxide, also known as DLCO.
This test involves asking the individual to inhale a small amount of carbon monoxide and seeing how well it diffuses. Another high yield concept is how obstructive lung disease can change the flow-volume loop which is used to show airflow on the y axis as it relates to lung volume on the x axis.
So imagine taking the deepest breath you can and then exhaling it out as forcefully as possible. The volume you’re gonna exhale is the forced vital capacity, and what will be left after maximal expiration will be the residual volume.
And these two combined give us the total lung capacity. Now since in most cases of obstructive lung disease, the residual volume is increased while the total vital capacity is normal or increased, the loop will typically show a shift to the left.
Okay, now let’s look at each specific disease, starting with chronic obstructive pulmonary disease or COPD. The condition is characterized by obstruction of airflow due to either chronic bronchitis or emphysema.

COPD7:17–9:54

Sometimes patients can have one or the other; however, most patients have elements of both chronic bronchitis and emphysema at the same time.
In addition, the triggers of the inflammation of the airway are often the same, and include environmental triggers, like inhalation of toxic substances such as tobacco smoke, or occupational pollutants like dust and silica.
Now, chronic bronchitis is an inflammation of the tracheobronchial tree that leads to increased mucus production. So what happens is that a trigger, usually smoking, irritates the mucosa of the airways, leading to hypertrophy and hyperplasia of mucinous glands in the main bronchi and goblet cells in the bronchioles.
One test that’s used post-mortem is the Reid index, which measures the ratio of the thickness of the bronchial mucinous glands layer relative to the total thickness of the wall between the epithelium and the glands.
Normally, the ratio should be less than 0.3, but for people with chronic bronchitis it can be over 0.4. Now hyperplasia and hypertrophy of the mucinous glands increases mucus production in both the main bronchi and the bronchioles, which causes airway obstruction.Usually, signs and symptoms of chronic bronchitis include productive cough due to excess mucus secretion, and wheezing from the narrowing of the airways.
Crackles or rales can be heard on auscultation of the lungs, which are caused by the popping open of small airways. There’s also hypoxemia and hypercapnia, both secondary to the mucus plugs blocking air exchange.
Additionally, the obstruction of the airflow can get so bad that deoxygenated blood from the right side of the heart reaches the left side without any participation in gas exchange in the pulmonary capillaries.
This is called a shunt, and it’s the reason why some people develop cyanosis, which is a blue discoloration of the skin.
So a high yield fact is that these individuals are sometimes referred to as “blue bloaters”. And finally, when there’s a mucus plug obstructing the airways, there’s a high risk for pneumonia behind the obstruction.
Classic symptoms of pneumonia include high fever, chills, confusion or irritability, worsening dyspnea and changes in sputum color, thickness or amount.
The other COPD is emphysema, which is the permanent enlargement and loss of elasticity of the alveolar wall secondary to alveolar injury.

Emphysema9:54–16:07

This is caused by irritants like tobacco smoke that triggers inflammation in the alveoli. The way this happens is that neutrophils gather and release destructive proteases like elastase which breaks down the elastin in alveolar walls, making them weaker, so the alveoli collapse during exhalation.
Alveoli also lose their ability to stretch and recoil so they can’t return to their normal shape. The result is alveoli trap a tiny bit of air distal to the point of collapse.
Now, alveoli are organized in clusters, called acini. And depending on which part of the acini are affected, we can have one of three types of emphysema.
The most common one is centriacinar or centrilobular emphysema and it only damages the central or proximal alveoli of the acinus.
This is the pattern seen with cigarette smoking and it typically affects the upper lobes of the lungs. There is also panacinar emphysema, where the entire acinus, usually in the lower lobes, is uniformly affected, and this is often associated with alpha-1 antitrypsin deficiency.
Since the alveolar neutrophils are always releasing proteases to help clear the debris, the body protects itself by releasing alpha-1 antitrypsin, which is a protease inhibitor that prevents excessive collateral damage.
Now, those with alpha-1 antitrypsin deficiency have no way to stop the proteases, so they end up with damaged air sacs earlier in life, especially if they smoke, since it will attract more neutrophils to the area.
And finally we have paraseptal emphysema, in which the distal alveoli of the acinus are most affected, and this type typically affects the lung tissue on the periphery of the lobules, near the interlobular septa that separate each lobule.
When it comes to signs and symptoms, people with emphysema typically experience shortness of breath. To counteract this, patients might exhale slowly through pursed lips, which increases the pressure inside the alveoli to prevent them from collapsing.
A high yield term to describe these individuals is “pink puffers” since in the earlier stages of the disease, the alveoli are still able to participate in gas exchange, and they don’t look cyanotic.
Additionally, due to the air-trapping and hyperinflation of the lungs can also cause individuals to develop a barrel-shaped chest.
Over time, though, as more and more alveoli are damaged, emphysema can lead to hypoxemia.Now, COPD diagnosis is based on history, clinical findings, and a series of tests.
To start with, pulmonary function tests can help detect any changes in lung volumes associated with obstructive lung disease.
Next, if COPD seems likely, an inhaled bronchodilator, like albuterol is given to the person, and pulmonary function tests are measured again to see if the obstruction is reversible.
Reversibility is defined as more than 12% increase in FEV1 after administering the bronchodilator. Ok so note that unlike asthma, COPD is an irreversible disease so giving a bronchodilator should not change the values too much.
This means that if the FEV1 doesn’t increase by more than 12% after the bronchodilator, then COPD is the likely diagnosis.
Next, it’s important to find out if the individual has predominantly chronic bronchitis, emphysema or both. Typically, the diagnosis of chronic bronchitis is clinical and based on a productive cough that lasts for at least 3 months, and over a period of 2 or more years.
Another clue for you is a complete blood count showing polycythemia, which is an increase in the red blood cell number. Individuals with chronic bronchitis develop secondary polycythemia as a response to chronic hypoxemia, which triggers increased production of erythropoietin by the kidneys.
By contrast, emphysema can’t be diagnosed clinically as it is defined by structural changes in the lungs. This means an x-ray or CT scan is needed, which might show enlargement of the air spaces, increased anterior-posterior diameter, a flattened diaphragm, and increased lung field lucency.
Additionally, a DLCO might also show a decrease in the lung’s diffusing capacity secondary to alveolar wall destruction, unlike those with chronic bronchitis.
And finally, alpha-1 antitrypsin deficiency screening is done in those who develop COPD without having any risk factors.Treatment of COPD largely involves reducing risk factors, like stopping smoking, but also managing associated illnesses.
Because infections often trigger COPD exacerbations, people should be given the influenza vaccine annually. If an infectious exacerbation does happen, these individuals may need a course of antibiotics, corticosteroids, inhaled short-acting bronchodilators, including beta-agonists like albuterol and muscarinic agents like ipratropium as well as supplemental oxygen.
Be careful, though, as giving too much oxygen could potentially be harmful in patients with COPD. In healthy individuals, the stimulus of respiratory drive is normally the partial pressure of carbon dioxide or PaCO2, which stimulates the central chemoreceptors in the medulla.
In those with longstanding hypoxemia, this role is attributed assumed by the partial pressure of oxygen or pO2, which stimulates the peripheral chemoreceptors in the carotid and aortic bodies.
So if you give too much oxygen to someone with COPD, their only respiratory stimulus disappears, which leads to respiratory failure.
Long-term treatment of COPD include long-acting agents if short-acting agents can not relieve symptoms. Other options include long-acting beta-agonists like formoterol and long-acting muscarinic agents like tiotropium or umeclidinium.
Now, in some individuals with severe hypoxia, or there’s cor pulmonale, home supplemental oxygen might be also needed.Ok, next is asthma, an episodic disorder caused by inflammation and hyperresponsiveness of the bronchial smooth muscle, leading to reversible bronchoconstriction.

Asthma16:07–23:40

Although the specific causes of asthma are ultimately unknown, it’s thought to be due to a combination of genetic and environmental factors, like air pollution, cigarette smoke, and car exhaust, as well as allergens.
Some worth remembering include dust, animal dander, cockroaches, and mold. For your exam, don’t forget that aspirin has also been known to trigger symptoms in some individuals with asthma.
Aspirin-induced asthma has to do with leukotriene B4 overproduction, which is a compound that results in bronchospasm and increased mucus production.
What’s especially high-yield is that aspirin-induced asthma is often combined with nasal polyps and chronic sinusitis. Ok so, regardless of the trigger’s nature, it causes a Type I hypersensitivity reaction.
It starts when the trigger causes an excessive activation from type 2 helper T cells, or Th2 cells, and causes them to produce cytokines like IL-4.
These cytokines cause B lymphocytes to produce IgE antibodies against the foreign antigens. These then coat mast cells and cause them to release granules containing histamines, leukotrienes, and prostaglandins.
These inflammatory mediators cause bronchoconstriction and edema which leads to airway obstruction. Another cytokine released by Th2 cells is IL-5, which activates eosinophils and these cells release more inflammatory mediators which contribute to the symptoms.
Initially these inflammatory changes are reversible, but over time irreversible changes take place, like scarring and fibrosis in the basement membrane of the airways, causing permanent reduction of airway diameter.
Furthermore, there’s smooth muscle hypertrophy and hyperplasia that worsens the obstruction. The signs and symptoms of asthma come and go, and tend to be more frequent in winter or when exposed to an irritant such as cigarette smoke.
An asthma episode can include coughing and a feeling of chest tightness due to airway irritation, but also tachypnea, dyspnea, and wheezing, due to airway edema.
Okay, the first step of diagnosis is asking for a personal or a family history of asthma, atopic eczema, and allergy Next, it’s important to conduct pulmonary function tests.
Now, because asthma is an episodic obstructive lung disease, these tests show the typical signs of obstructive pulmonary disease only when the individual is having symptoms.
If asthma seems likely, an inhaled bronchodilator is given to the person, just as in COPD. Note that unlike COPD, giving a bronchodilator should reverse the pulmonary function tests measurements back towards normal, confirming the diagnosis.
Now, if they do not have symptoms at the time we can try to induce asthma by performing the “methacholine challenge test”.
Methacholine binds to muscarinic receptors on bronchial smooth muscle, causing mild bronchoconstriction. In a healthy individual who doesn't have asthma, this bronchoconstriction is negligible, and there is no significant change in pulmonary function tests measurements.
But because an asthmatic’s bronchial smooth muscle is hyperresponsive, methacholine causes a 20% decrease in their FEV1 from the baseline.
Now, it’s important to remember that the methacholine challenge test is highly sensitive, meaning that a negative test can rule out the diagnosis, but nonspecific, so a positive test doesn’t confirm the diagnosis.Another thing to be aware of is that DLCO is usually normal or slightly increased in asthma.
The rationale behind this is that in asthma, there is no destruction of the alveolar membrane. Instead, air gets trapped in the alveoli, causing them to stretch out and increasing the surface area available for gas exchange.
Occasionally, sputum analysis can be also done, which often shows the so-called Curschmann spirals. These are shed, elongated epithelial cells that can form whorled mucous plugs.
The plugs can be particularly dangerous because they not only block the exchange of air, but they also block inhaled medications from getting to the site of inflammation.
Another thing you might see in the sputum that will help you think of asthma are Charcot-Leyden crystals, which look like hexagonal, double-pointed crystals formed by the breakdown of eosinophils secondary to IL-5 stimulation.
Other findings might include a decreased inspiration/expiration ratio. In normal spontaneous breathing, the expiratory time is about twice as long as the inspiratory time, which gives an inspiration/expiration ratio of 1 to 2.
In those with asthma, because the airway obstruction leads to prolonged expiration, the ratio can be 1 to 4 or sometimes even 1 to 5.
Those with severe asthma might also develop something called pulsus paradoxus, which is a drop in systolic blood pressure of more than 10 milligrams Mercury during inspiration.
Pulsus paradoxus results from a decrease in cardiac stroke volume with inspiration due to greatly increased left-ventricular afterload.
This is caused by the dramatic increase in negative intrapleural and transmural pressure in someone struggling to breathe against significant airway obstruction.
Finally, chest x-ray which might show signs of hyperinflation like a flattened diaphragm, blood eosinophil count and serum IgE level which might be increased.
A skin reactivity test to various allergens can be also done. But the fact is that they are less sensitive, meaning that normal findings on these tests cannot exclude the diagnosis.
While there is no cure for asthma, there are treatments to help manage the symptoms and prevent an asthma attack. In acute exacerbations, a short acting bronchodilator like albuterol is often administered through an emergency inhaler.
It causes the smooth muscles to relax and dilates the airways, but, as side effects, albuterol can cause tremor and arrhythmias.
Next, keep in mind that in those with chronic asthma, corticosteroids like fluticasone or budesonide, which inhibit the synthesis of cytokines, are considered first-line therapy.
Additionally, a long-acting beta-agonist or a muscarinic antagonist bronchodilator can be added to control symptoms if corticosteroids are not enough.
If this fails, theophylline, a methylxanthine which likely causes bronchodilation by inhibiting phosphodiesterase, can be added to the treatment plan.
However, this drug has limited use due to its cardiotoxicity and neurotoxicity. Alternatively, antileukotrienes like montelukast and zafirlukast, which block leukotriene receptors, or zileuton, a 5-lipoxygenase pathway inhibitor that blocks the conversion of arachidonic acid to leukotrienes, can be given in addition to corticotherapy, especially in those with aspirin-induced and exercise-induced asthma.
Now, there are many other ways to prevent an asthma episode. In general, people with asthma should avoid or minimize contact with triggering substances.
Next, long-acting bronchodilators like salmeterol and formoterol can also be used for prophylaxis. Rarely, chromones like cromolyn, which work by preventing mast cell degranulation, can also be used to prevent acute asthma symptoms.

Bronchiectasis23:40–26:54

And finally, bronchiectasis is characterized by damaged and dilated bronchi and bronchioles secondary to chronic inflammation and mucus obstruction.
There are many causes of chronic inflammation, like primary ciliary dyskinesia, where the cilia don’t move normally and that leaves mucus stuck in the airways.
Bacteria that are trapped in the mucus start to multiply and can cause pneumonia. If that happens repeatedly, it results in chronic inflammation.
Now, if primary ciliary dyskinesia is combined with situs inversus or reversal of the internal organs, chronic sinusitis, and bronchiectasis, it is called by a fancy name, the Kartagener syndrome.
Another example is cystic fibrosis, when the mucus itself is extra-sticky, hard to sweep, and therefore it accumulates, causing obstruction and dilation of the bronchi and bronchioles and thus, bronchiectasis.
Another cause you might find in a test is allergic bronchopulmonary aspergillosis, which is caused by a fungus called Aspergillus that triggers chronic inflammation and damage of the airways, which can progress to bronchiectasis.
And then there is airway obstruction, usually caused by tumors, foreign objects or anything else that can block the bronchus or bronchiole, which subsequently leads to pneumonia and chronic inflammation.
Whatever the cause of the inflammation, immune cells in the bronchi and bronchioles release cytokines that damage the ciliated epithelial cells and destroy the elastin fibers in the walls of the airway.
As a result, the airways become dilated and becomes clogged with mucus. Over time, chronic inflammation leads to scarring and fibrosis which narrows the airways, resulting in airflow obstruction.
And as the ventilation decreases, it leads to hypoxic vasoconstriction, meaning that the pulmonary vessels start to constrict in order to reduce perfusion to the areas that do not participate in gas exchange and keep the V/Q ratio constant.
If that’s widespread, it can lead to pulmonary hypertension and in time, cor pulmonale.Bronchiectasis causes symptoms like wheezing, shortness of breath, and a productive cough with foul smelling, purulent sputum.
If the lungs are severely injured, people might also cough up blood, which is called hemoptysis. Long term hypoxia can lead to digital clubbing, or rounding of the nail beds, and individuals might also present with symptoms of pneumonia and a history of recurrent infections.A diagnosis of bronchiectasis can be made by CT scan showing dilated bronchi and bronchioles in conjunction with pulmonary function testing detecting signs of obstructive lung disease.
Additionally, other tests like genetic testing or a sweat test can be done to look for underlying conditions like primary ciliary dyskinesia and cystic fibrosis.
Treatment is usually aimed at treating the recurrent pneumonias with antibiotics and removing excess mucus with percussion or postural drainage.
Additionally, individuals need to stay hydrated, which helps prevent airway mucus from becoming thick and sticky. If there’s a physical obstruction like a tumor or foreign body, then surgery may be needed to remove them.
obstruction, like a tumor or foreign body, then surgery may be needed to remove. All right, is a quick recap obstructive lung.

Review26:54–28:30

Diseases are characterized by blockages or instructions of the Airways which results in an increase in RV FRC and TLC. A reduction of fvc, fev1 fev1 fvc ratio TLC, and a VQ mismatch, and a normal, or decreased DLC, and a left shift in the flow volume Loop.
Okay. So COPD presence has either chronic bronchitis emphysema or both and it's usually caused by exposure to chemicals in irritants like cigarette smoke.
In chronic bronchitis, the trigger stimulates increase mucus, production in the Airways, which causes a chronic productive, cough, and wheezing people.
With this disorder are often described as blue bloaters in, emphysema exposure, to irritant causes elastin destruction in the small Airways which leads to air trapping.
However, people with this disorder, don't have hipoxemia early on, which is why they are called pink puffer. Asthma is an episodic disorder characterized by chronic inflammation, which leads to smooth muscle, spasms edema and mucus production, resulting in coughing and wheezing that's reversible.
And finally, in bronchiectasis the bronchi and bronchioles are chronically inflamed causing damage to the Cilia and the walls of the Airways which leads to their dilation overtime, excessive fibrosis and mucus.
Cause airflow obstruction symptoms include productive, coughing, wheezing, and shortness of breath. Now, back to our cases, Elsa has a long history of smoking and she came in with Progressive shortness of breath and chronic productive cough, which first appeared, more than two years ago, on examination.

Summary28:30–29:27

She presents pursed lip breathing a barrel chest, diminished breath sounds and wheezing spirometry showed signs of Airway obstruction and given her history of productive cough, for more than two years.
And characteristic presentation, a diagnosis of COPD due to chronic. Bronchitis can be made next.
James has a two-year history of eczema and of episodes, consisting of wheeze and cough which have increased the frequency and severity.
He also has a family history of asthma. All of this points to asthma.
Spirometry was normal, which is why methacholine challenge test was done. Listen to Stan asthma attack along with a 20%, decrease in fev1 from the Baseline, which was reversed by giving bronchodilators confirming the diagnosis of