COPD

Smoker’s lung

Chronic Obstructive Pulmonary Disease (COPD) is a pattern of lung damage seen in smokers. Heavy smokers have a 10% chance of getting lung cancer, but a 100% chance of getting COPD. And COPD is a really crummy disease with no cure. Cigarettes wreak damage all over the lungs, but we break up COPD into two discrete “diseases.”

1. 1. Damage to Alveoli results in Emphysema
  2. Damage to the tubes (bronchi and bronchioles) results in Chronic Bronchitis

They are always short of breath. Once every few months (more often if they still smoke), their COPD will become acutely worse. This is a COPD exacerbation. If the patient also complains of an increasingly productive or colorful cough, it suggests an infection -- usually one of the typical ENT bugs like Strep pneumo, H flu, M catarrhalis or the Rhinovirus.

Both Emphysema and Chronic Bronchitis are obstructive lung diseases. Obstructive lung diseases make it difficult to exhale. You should understand how COPD changes spirometry (see charts below). COPD increases the TLC, RV and FRC. COPD decreases all other lung volumes (ERV, IC, VC, IRV), in addition to the FEV1, FCV, FEV1:FVC ratio and DLCO.

Increased

Decreased

CHRONIC BRONCHITIS

Blue bloaters

Chronic Bronchitis (CB) is one half of COPD. It reflects damage to the bronchi and bronchioles. To oversimplify, CB is when your lungs make too much mucus. Why is there too much mucus? Cigarettes are full of crap. Smoke debris deposits along the walls of the trachea, bronchi and bronchioles. In healthy lungs, debris is caught by the mucus and swept up the mucociliary elevator. But in CB, there is debris > mucus. So cigarette gunk accumulates. The lungs reasonably adapt by making more mucus, which is great for catching the increased debris. But smokers bring more debris into their lungs day after day. The lungs make more and more mucus, but the lungs weren’t designed to handle this much mucus! There is so much mucus that it blocks up the bronchioles (mucus plugs). Mucus plugs prevent fresh air from reaching the alveoli, and as a result, hypoxia occurs (blue). This hypoxia causes pulmonary hypertension, and eventually, heart failure (bloaters).

The CB diagnosis is based on the presence of telltale symptoms. A patient is said to have CB once they have a productive cough for at least 3 months out of the year (during two different years). On exam, look for rhonchi that clears with a cough (the mucus becomes unplugged when they cough). They also like us to know what the histology of CB looks like:

EMPHYSEMA

Pink puffers

Emphysema is the second half of COPD. It reflects the damage to alveoli. There is a loss of elastin and a loss of septae (the walls of the alveoli). Note - the pathophysiology underlying the loss of septae is mysterious to the author. Here’s how the loss of elastin works. Nasty cig debris makes its way down to the alveoli. That induces inflammation inside the alveoli. Neutrophils arrive, and they release lots of damaging substances. Mostly we think of Neutrophils using oxidizing agents (free radicals), but neutrophils also release proteases. Proteases break up connective tissue (chopping up Gram negative cell walls). But these proteases indiscriminately chop up normal connective tissue too. Daily smoking results in daily protease release, which causes daily elastin destruction. More so than any other organ, the lung needs connective tissue to function -- Elastin enables passive exhalation. Additionally, smoking induces Free Radical release, which breaks the natural anti-proteases. So there’s ↑proteases and ↓anti-proteases. Hitting ‘em from both ends! In emphysema, the alveoli turn from “bundles of grapes'' into “big floppy plastic grocery bags.” The loss of elastin leads to obstruction. Here’s why:

Emphysema causes dyspnea. Patients can keep the bronchioles open by pursing their lips. Lip pursing adds PEEP (positive end expiratory pressure). Without passive exhalation, patients have to use their chest muscles to drive every breath -- this burns a ton of energy. Patients lose weight (cachexia) and muscle tone everywhere but their chest (barrel chest).

ALPHA-1 ANTITRYPSIN DEFICIENCY

Lungs + Liver

Most emphysema is due to smoking. But there is another cause -- a genetic disorder called Alpha-1 Antitrypsin Deficiency.

Here’s how it works. The liver makes proteins called antiproteases that are responsible for breaking down proteases (it degrades the degraders). Antiproteases promote connective tissue growth by destroying proteases. The A1A protein is mutated in this disease. The mutated end-product is misshapen, misfolded and dysfunctional. The hepatocytes that create it are unable to secrete it, so it accumulates in the liver, which can lead to liver damage over time.

Let’s shift our attention to the lungs. The lack of A1A results in connective tissue destruction. The lung’s elastin is gobbled up. The alveolar septae are all degraded in an even homogenous pattern, and this pattern of damage is called panacinar. The acinus refers to the alveoli plus the small bits of bronchioles that feed into the alveoli. In contrast, smoking-related emphysema involves centriacinar destruction. I can’t overstate how important this concept is!

A1AD is actually a wide spectrum, and there are many different patterns of presentation (the details of which are unimportant). Just know that A1AD is autosomal co-dominant. There is a mutation, turning the normal PiM gene into the bad PiZ gene. Patients can be PiMM (healthy), PiZZ (diseased) or PiMZ (heterozygous, they get especially awful COPD if they smoke). A1AD classically presents in adulthood, usually around 30 or 40. They are often described as “too old for asthma, and too young for COPD.”

COPD TREATMENT

Quit smoking for starters

The treatment of COPD is simple in concept, but the actual details are confusing to students. The main two goals are to (a) cool down inflammation with steroids and (b) open up the airways with beta-agonists and muscarinic-antagonists.

The acute treatment of COPD consists of a dose of oral steroids, a nebulized SAMA breathing treatment (Ipratropium) plus-or-minus an antibiotic (Azithromycin) if they have a worsening or colorful cough. If their oxygen saturation is below 90%, they will probably benefit from some supplemental oxygen.

The chronic treatment is a little more tricky. It’s like a ladder, where you start at the bottom rung and escalate up, gauging their progress using Spirometry measurements as you go. Start with a LAMA (Tiotropium). Then add an inhaled steroid. If insurance will cover this, you can try adding Roflumilast, a PDE-4 blocker (different from the PDE-5 blocker Viagra, but both work by relaxing smooth muscle cells). The final step is to use oral steroids, but as the side effects are profound, you want to avoid this if you can. In more severe cases, patients require supplemental oxygen around the clock.

Note that COPD responds better to Muscarinic blockers (SAMA, LAMA), while asthma responds better to Beta agonists (SABA, LABA). However, in real life it’s common to find exceptions to this.

This is a typical COPD chest x-ray. The lungs are especially large and dark, a reflection of the obstructive injury.

ASTHMA

Recurrent allergic lung condition

Asthma is very easy to spot. I should know, because I have it. Look for a child who is asymptomatic at their baseline but periodically wheezes. These flare ups are colloquially called asthma attacks. The wheezing is due to turbulent airflow, which results from bronchoconstriction. Pathophysiology-wise, asthma is due to fuckery in the terminal bronchioles -- it has nothing to do with the alveoli.

MOA: Asthma is a type 1 hypersensitivity. An allergen (dust mites in my case) will enter the body. It can bind to IgE receptors, triggering mast cell degranulation. Histamine is released in bulk. Histamine and other inflammatory mediators induce constriction in the SMCs surrounding the bronchioles. Each time this inflammatory cascade occurs, the patient becomes dyspneic and wheezy. Remember - this is an obstructive lung disease, so they have difficulty expiring. Their expiratory phase will be much longer (4 to 5 times longer) than the inspiratory phase. Distancing the patient from the allergen will (usually) resolve their symptoms in about an hour or so. Administration of Albuterol will fix their symptoms more rapidly. In very severe cases (status asthmaticus), their symptoms are refractory to treatment and may be fatal. Note, hypoxia is a very late finding in asthma. If you have an asthmatic patient with hypoxia, they are about to die. This is in comparison to COPD, where hypoxia is seen all the time.

In between asthma attacks, patients are asymptomatic. But repeated asthma attacks will eventually cause some permanent long-term damage in the airways. This is called airway remodeling. The mechanism for this revolves around Eosinophils and Leukotrienes. Inflammation has an immediate phase (wheezing and dyspnea) and a delayed phase (eosinophil mobilization, leukotriene accumulation). The delayed phase is clinically silent, but causes long term damage. It involves cytokines such as IL4, IL5 and IL13. Chronic inflammation results in the deposition of a small amount of connective tissue (scarring). Over time, this connective tissue becomes significant, and like atherosclerosis of the airways, will result in narrowing of the tube.

IL4 promotes class switching, so B-cells make more IgE (B cells need the correct tools FOuR the job)
IL5 summons eosinophils (there are 5 letters in eosin)
IL13 creates mucus

Diagnosis: In real life, the diagnosis of asthma is a simple one. A kid who periodically wheezes has asthma, end of story. But there are some fancy tests that will clinch the diagnosis.

A sputum biopsy is abnormal in asthma, although it’s rarely used. You will be looking for two abnormal findings in their sputum, both of which are caused by the Major Basic Protein. MBP is secreted by Eosinophils, and it promotes epithelial detachment in the lungs. The shed epithelium is coughed up, and is full of little histological clues.Curschmann spirals are mucus plugs that are shaped like springs. Charcot-Leyden crystals are precipitations of eosinophilic secretions (such as Major Basic Protein).

You can induce asthma with a drug called Methacholine. Methacholine is a muscarinic agonist. When it activates M3 receptors, the bronchi constrict. Healthy patients can compensate for this bronchoconstriction, and they won’t experience any wheezing. But in asthmatics, Methacholine will trigger a mild asthma attack that can be detected with spirometry.

Spirometry isn’t very helpful in asthma. That’s because you don’t waste your time with it during an asthma attack (spirometry is never performed on an acutely sick patient). And spirometry will be pretty much normal in between flares. That said, if you were to perform breathing tests during an attack, the results would be similar to COPD. One notable exception is that the DLCO is normal in asthma but low in COPD.

Aspirin-Induced Asthma - a small number of unlucky people get asthma attacks whenever they take aspirin. Asthma blocks COX enzymes, but this means that more arachidonic acid is available to enter the LOX pathway (which produces leukotrienes). Leukotrienes play a big role in asthma. One telltale sign for this disorder is nasal polyps (which are otherwise only seen in cystic fibrosis). Montelukast is especially helpful here.

Curshman spirals Charcot Leyden Crystal

ASTHMA TREATMENT

Similar to COPD, the basic principles of treating asthma are to (a) cool down inflammation with a steroid and (b) open up their airways with beta agonists and muscarinic antagonists. Modulating the autonomic tone plays a big role in pharmacological treatment of asthma.

The acute treatment of asthma consists of a SABA inhaler (Albuterol) plus a dose of oral steroids (Dexamethasone). If they fail to improve, just continue to give more Albuterol. Very severe cases are called status asthmaticus, and they can require intubation and the ICU.

The chronic treatment of asthma is quite complicated, but I’ll keep it simple. You don’t have to memorize the chart below, but the ladder concept is important.

Here are drugs that aren’t used much anymore:

Cromolyn (Mast Cell Stabilizers). Turns out they don’t work. It was thought that they might be helpful as prophylaxis if you took it prior to the allergen exposure. Studies have shown that they are ineffective, and so they’ve become unpopular. Important for historical reasons I guess?

Theophylline (a Methylxanthine) An adenosine blocker, similar to caffeine, and it inhibits phosphodiesterase (bronchodilation) but it’s super dirty. Don’t worry much about it. The combination of meh-level effectiveness and serious side effects (cardiotoxic, neurotoxic) have led to this drug’s fall from grace. It’s so toxic that it can only be administered in the hospital. Note - if you're treating SVT in a patient taking Theophylline, you would have to double the dose of adenosine.

Zileuton (LOX Inhibitor). I think it’s kind of fallen by the wayside? It seems like a more side-effect-heavy version of Montelukast -- it is hepatotoxic.

Bolded drugs treat asthma.

The goal is to activate beta-2

note- Epinephrine is only used for severe cases

BRONCHIECTASIS

Big floppy airways

Bronchiectasis is the permanent dilation of the large airways. It’s caused by A LOT of recurrent pneumonia. It's fairly rare.

Why does it occur?

Keep in mind that bacteria love stagnant mucus. Bacterial infection (and the neutrophilic inflammation) will eventually cause damage to the connective tissues in the large airways. That dilates the airways a bit. But this is a vicious cycle -- dilation means that the airway’s volume increases, which allows for even more fluid and mucus to accumulate, so there will be more food for bacteria! So what conditions are associated with a broken ciliary elevator?

Cystic fibrosis obviously causes this (thick mucus breaks the cilia elevator). Pseudomonas is a common bug.

Tumors can cause this, because tumors can interrupt the ciliary elevator, blocking the clearance of mucus, and phlegm builds up underneath.

Kartagener's Syndrome is a rare (but boards favorite) cause. The cilia stop beating. This is due to an autosomal recessive mutation affecting dynein, one of the crucial proteins inside each and every cilia (and flagella too). Aside from recurrent lung infections, the loss of cilia also causes infertility (sperm have a flagella), sinus infections and situs inversus (organs on the opposite side, MOA unknown). Aside from situs inversus, it looks nearly identical to CF.

Allergic Bronchopulmonary Aspergillosis is a weird lung “infection” seen in kids with structurally inadequate lungs (CF, asthma). Aspergillosis is ubiquitous, but healthy lungs easily clear it away with the ciliary elevator. If that elevator is broken, aspergillosis can colonize the lung. Aspergillosis induces an allergic response! They have a chronic, unrelenting hyper-IgE induced lung injury. Suspect it when a CF patient has pneumonia that doesn’t clear up with antibiotics. Give steroids and Voriconazole.

Smoking is also associated with Bronchiectasis, but the actual importance of this association isn’t clear.

What’s so bad with permanent bronchodilation? Isn’t that what we use to treat asthma?

The airways become so large that air no longer flows in an orderly direction. Instead of a river, it becomes a lake. If you introduce a breath of air into a maximally dilated tube, it just kind of swirls around, and all the energy is dissipated.

They’re probably short of breath, but are there any unique symptoms?

There’s one helpful sign. They have a productive cough, and their sputum smells terrible. That’s because their mucus has been sitting inside their giant dilated airways for days and weeks. Standing liquids (in general) become infected. Infected things smell bad. The other causes of purulent sputum include a lung abscess or pneumonia from anaerobic bacteria. They can also get some less unique symptoms like hemoptysis and clubbing. And it will inevitably progress to pulmonary HTN and cor pulmonale if left untreated. You diagnose it with a chest CT. The dilated airways will be dramatically obvious.

Do you treat Bronchiectasis with a bronchoconstrictor, like Propranolol?

No. It doesn’t work that way I guess (weirdly, some patients have symptomatic improvement from bronchodilators). There aren’t any great treatments for this condition though. Steroids and antibiotics sorta slow it down, but the only curative treatment is a lung transplant :(