Restrictive lung diseases: Pathology review

While on your rounds, you see two individuals. First is Alicia, a 28-year-old African American individual who comes in with progressive shortness of breath and cough. She also mentions that she lost weight in the past six months and that she had tuberculosis a few years ago. Examination reveals painful red skin lesions on each side of her nose and the anterior surface of both legs, along the tibia. The rest of the examination was normal. Next, you see a 65-year-old male named Richard, who presents with gradually progressive dyspnea on exertion and dry cough. He has no history of underlying lung disease or other relevant symptoms. On examination, there is nail clubbing but no other signs that could suggest a particular etiology, like pneumonia or COPD. Pulmonary function tests were performed in both cases, showing signs of a restricted pattern, including a significant reduction in forced vital capacity.

Both seem to have some type of restrictive lung disease. But first, a bit of physiology. The lung is compliant, meaning that it can expand and contract because its connective tissue is made up of proteins like elastin and collagen. Compliance is defined as the volume change produced by a change in the distending pressure, and is expressed as the ratio of ΔV, the change in volume, to ΔP, which is the change in pressure. In other words, the higher the compliance, the easier it is for the lungs to expand. In contrast, the lung’s tendency to collapse and push the air back out is called elastic recoil, which is balanced by the outward pull of the chest wall.

Now, remember that breathing also involves the structures around the lungs, like the ribs, intercostal muscles, diaphragm, or pleura. During inhalation, the diaphragm and intercostal muscles contract to pull the ribs up and out and expand the chest cavity. This creates a vacuum that pulls the lungs open to allow air in, which eventually reaches the alveoli and specifically, a thin membrane called the respiratory membrane, where gas exchange occurs. Air is then expelled by exhalation, when the diaphragm and intercostal muscles relax to allow the chest wall to fall and return the chest cavity to normal.

Ok, so restrictive lung diseases are a group of conditions in which inhalation fills the lungs far less than normal. There are two types of restrictive lung diseases; diffuse parenchymal lung diseases and extrapulmonary lung diseases. In diffuse parenchymal lung diseases or DPLDs, previously called interstitial lung diseases, the lung tissue itself is damaged. The result is a fibrotic, rigid lung with reduced compliance and increased recoil that won’t easily allow air to enter during inhalation, thereby reducing lung volumes.

On your test, if you see graphs or questions mentioning dramatically decreased compliance, you should think of DPLDs since a reduced ΔV/ΔP ratio is the hallmark of pulmonary fibrosis. In the extrapulmonary type, something else besides the lungs interferes with the breathing mechanics and prevents chest expansion and lung filling. For example, in scoliosis, because the spine is bent sideways, it can push on the lung on the affected side, impairing lung expansion and filling.

Generally, these abnormalities result in a few characteristic changes in 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.

Ok, so in restrictive lung diseases, first, there’s a decrease in forced vital capacity or FVC, which is the air exhaled forcefully after taking a deep breath. Second, residual volume or RV decreases as well, and it is the air left in the lungs after exhaling as hard as possible. RV and any lung capacity that includes RV cannot be measured by spirometry, because it can’t be breathed out even if the person tries to. And this is why plethysmography is necessary. Third, there is also a reduction in total lung capacity or TLC, calculated by adding FVC to RV.

Now, fourth, there’s also a decrease in functional residual capacity or FRC, which is the volume of air that remains in the lungs after normal expiration. FRC can also be calculated by adding RV to expiratory reserve, or the air that can still be breathed out after normal expiration. Fifth, there’s a decrease in forced expiratory volume in 1 second or FEV1, which is the air exhaled with maximum effort in the first second.

And finally, the FEV1/FVC ratio, which is normally between 0.7 and 0.8, usually stays about the same because both volumes decrease proportionally. One particularity you might come across is that the ratio can increase if FVC is reduced more than the FEV1. This can happen in some DPLDs, where there’s increased elastic recoil, allowing air to be pushed out faster during the first second of expiration.

Now, besides the typical PFTs changes, most DPLDs are also marked by a decrease in the lung’s diffusing capacity for carbon monoxide or DLCO , which is a measure of how well gases are transferred between the lungs and the blood. The decrease occurs because, in DPLDs, there is a thickened, fibrotic respiratory membrane, so gases have a hard time passing through it. Another high-yield fact to know is that because less oxygen makes it into the bloodstream, the result is an elevated Arterial-alveolar or A-a gradient, which is the difference between the partial pressure of oxygen in the alveoli, written as PAO2 and the arterial partial pressure of oxygen, written as PaO2.

In time, because the lung is damaged and filling impaired, some areas of the lung will receive less oxygen than the others but, at the same time, blood flow will stay the same throughout the lungs. This is called a ventilation-perfusion mismatch, and it can lead to hypoxemia, mostly because there’s less oxygen available for blood to pick up. Hypoxemia is also made worse by an intrapulmonary shunt, which is when the pulmonary arterioles start to constrict to adapt to hypoxemia, effectively shuttling or diverting blood away from the areas that don’t receive any oxygen to the ones that do. But if the damage is widespread, then it can lead to vasoconstriction of pulmonary arterioles, which causes pulmonary hypertension. That makes it hard for the right ventricle to pump out blood, causing the right ventricle to hypertrophy, a process called cor pulmonale.

Another high yield concept is how restrictive 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. In other words, the volume you’re gonna exhale is the forced vital capacity and what will be left after maximal expiration inside the lung will be the residual volume. And these two combined give us the total lung capacity. Now since in most cases of restrictive lung disease, the residual volume and total lung capacity are decreased, the loop will typically show a shift to the right

Now, another thing to keep in mind is that in healthy people, airflow is slower at low lung volumes because elastic recoil decreases proportionately with lung volumes. Low volumes are also associated with high airway resistance because the deflated lungs exert little radial traction on the conducting airways. Radial traction is the force exerted by the lung parenchyma to keep the airways open. By contrast, it’s important to understand that those with restrictive pulmonary diseases have low lung volumes but airflow is actually higher than normal, mostly because both elastic recoil and radial traction are increased, usually due to the fibrotic pulmonary interstitium full of collagen.

Let’s now talk about the main causes of restrictive lung diseases. Diffuse parenchymal lung diseases or DPLDs, are conditions that affect the interstitium, the alveoli, the respiratory membrane, as well as the blood vessels and pleura. DPLDs can be broadly classified into two categories. First, there are those with a known cause, which can be subclassified into granulomatous diseases, like sarcoidosis and hypersensitivity pneumonitis; occupational exposures, also called pneumoconiosis, like asbestosis, silicosis, berylliosis, and coal workers' pneumoconiosis; and miscellaneous diseases, like rheumatoid arthritis, granulomatosis with polyangiitis, Goodpasture syndrome, pulmonary Langerhans cell histiocytosis, and drug toxicity. And second, there are those with an unknown cause, mostly represented by idiopathic pulmonary fibrosis.

To start with, granulomatous lung diseases, besides sarcoidosis and hypersensitivity pneumonitis, also include contact dermatitis and the reactions resulting from the tuberculin and Candida extract skin tests. Now, these are usually a result of a type IV hypersensitivity reaction, which is also called a delayed-type hypersensitivity because it takes 2-3 days to develop. This is a cell-mediated immune response triggered by antigens.The antigen causes a chain reaction that is frequently tested.

So first, the antigen gets picked up by an antigen-presenting cell or APC, like a dendritic cell or an alveolar macrophage. The APC then presents the antigen to a CD4+ T-helper cells or “Th cell,” and, at the same time, starts to secrete interleukine 12 or, IL-12, which binds to the IL-12 receptor of a CD4+ Th cell, causing it to differentiate into a Th1 cell. This stimulates Th1 cells to start secreting IL-2, , which helps both it and other T cells in the area proliferate, as well as secrete interferon gamma, which activates phagocytes like macrophages.

The activated macrophages, now called epithelioid macrophages because they have lots of pink cytoplasm similar to squamous epithelial cells, are attracted to the site of antigen exposure. Here, they surround the antigen, forming the center of a ball-like nodule called a granuloma, which is meant to "wall off" the antigen and prevent it from spreading. On the periphery of the granuloma, there are CD4+ Th cells, and multinucleated giant cells, which are formed when several activated macrophages fuse together. The giant cells are also called Langhans giant cells, and have multiple nuclei, which are arranged peripherally in the shape of a horseshoe.

Another particularity of the Langhans giant cells is that they contain cytoplasmic inclusions called Schaumann bodies which are made of calcium and protein deposits. There are also asteroid bodies that look like tiny stars, which are likely pieces of cytoskeleton or lipids. Keep in mind that these Langhans cells are especially common in sarcoidosis.

Now, there are two types of granulomas: caseating, which are associated with central necrosis and seen in infectious etiologies like tuberculosis, and noncaseating, which have no central necrosis and are seen with autoimmune diseases like sarcoidosis, hypersensitivity pneumonitis, or Crohn’s disease. Ok, so finally, if the antigen is removed, then the lungs heal up quickly. However, if exposure or the antigen persists, fibroblasts are attracted to the site of injury where they start the process of scarring by depositing fibrin, resulting in a fibrotic lung that is stiff and less compliant, which, as a consequence, limits lung expansion and volumes.

Now that we’ve looked at the general pathology, let’s look at the first disease: Sarcoidosis. The precise trigger of this condition isn’t known, but there are some associated risk factors that are frequently tested. Genetic risk factors include being of African descent and having a family member with sarcoidosis, and younger females are more commonly affected. Environmental risk factors include a prior infection with Mycobacterium tuberculosis and Borrelia burgdorferi. However, in sarcoidosis, these pathogens are long gone when the autoimmune damage sets in.

Basically, dendritic cells, a type of APC, go haywire without the presence of a specific pathogen that the body is trying to destroy, attracting T cells and macrophages to a particular spot of healthy tissue, where they form granulomas. And because it is a systemic disease, sarcoidosis can involve nearly every organ, even if it usually involves hilar lymph nodes, which are located near the point where the bronchi meets the lungs.

Sarcoidosis is usually asymptomatic or it can cause unspecific signs and symptoms like fever, weight loss, fatigue, and enlarged lymph nodes. Because it’s a systemic disease, there can also be more specific symptoms depending on which part of the body is affected. If the lungs are affected, it can cause shortness of breath, coughing, and hypoxemia. If the skin is involved, it can lead to nodules called erythema nodosum. This is very high yield so remember that they typically develop on the lower legs, along the tibia. These nodules are caused by inflammation of fat within the skin layer, and they’re red, hard, and painful.

Another possible skin lesion is lupus pernio, which refers to red to purple skin lesions on the face resembling those found in lupus. When the eye is involved, sarcoidosis can also cause uveitis, which is inflammation in the pigmented layer of the eye beneath the cornea and sclera. The heart can also be affected, leading to restrictive or dilated cardiomyopathy. When the joints are involved, sarcoidosis can cause rheumatoid arthritis-like arthropathy as suggested by tender, warm, swollen joints with limited mobility.

Another high-yield fact to remember is that in many granulomatous diseases, especially in sarcoidosis, individuals can also develop hypercalcemia due to the enzyme 1alpha-hydroxylase being released by alveolar macrophages. The enzyme converts the vitamin D precursor to its active form called calcitriol, which in return increases intestinal absorption of calcium and bone resorption, causing hypercalcemia. Some signs of hypercalcemia include diminished deep tendon reflexes, skeletal muscle weakness, and in some cases, depression and stupor.

The liver is also involved in up to 75% of individuals with sarcoidosis and this may present with hepatomegaly, abdominal pain, cirrhosis or cholestatic liver disease with jaundice. And finally, the condition can affect the brain, causing neurosarcoidosis. The most important sign of neurosarcoidosis is Bell's palsy, a type of facial paralysis that makes it impossible to control the facial muscles on the affected side. This can manifest as muscle twitching, weakness, or total loss of the ability to move one side of the face.

Besides a restrictive pattern on PFTs, sarcoidosis diagnosis also includes a chest X-ray or CT scan. The most common findings, both on tests and in real life, are bilateral hilar or mediastinal lymphadenopathy and coarse reticular opacities due to interstitial infiltration by inflammatory cells, and as the condition evolves, a honeycombing pattern, usually in the upper lobes.

Blood tests might reveal high levels of calcium and an increased level of angiotensin converting enzyme or ACE, which is produced by T cells. Another helpful clue is finding an elevated CD4+/CD8+ cell ratio in the fluid obtained by bronchoalveolar lavage. In that procedure, a bronchoscope is passed through the mouth or nose and into the lungs where fluid is squirted out, recollected, and examined. The ratio increases because the immune reaction causes CD4+ T cells to accumulate in the interstitium and alveoli, whereas the CD8+ T cell count stays the same.

One final thing to know about sarcoidosis, is that a transesophageal lung biopsy showing scattered non-caseating granulomas might be needed to confirm the diagnosis. Needle biopsy of the liver can be also used to check for the presence of scattered noncaseating granulomas.

Most people with sarcoidosis don’t usually need treatment because symptoms resolve spontaneously within a few weeks, with complete remission occurring within a few years. But if there are severe symptoms, steroids can help control the inflammatory response.

Okay, next up we have hypersensitivity pneumonitis which is when an inhaled antigen causes an excessive immune reaction in the lung. It can be caused by many organic antigens, from coffee bean dust, to moldy sugarcane, to bacterial spores in the mist from hot tubs, and the resulting disease is often named for the profession at risk.

For instance, the Farmer’s lung is caused by the spores of actinomycetes that live in moist, newly harvested hay. Malt worker’s lung is from Aspergillus spores from moldy barley. Pigeon breeder's lung is caused by breathing in proteins from bird poop or feathers, but other animal proteins can also cause the disease.

Now, unlike most granulomatous diseases, hypersensitivity pneumonitis can trigger both a type III hypersensitivity reaction, in which case it’s acute, and a type IV hypersensitivity reaction, in which case it’s chronic. Basically, once antigen reaches the alveoli, it is picked up by dendritic cells or alveolar macrophages which take it to the nearest lymph node, where they present it to Th1 cells.

Th1 cells then activate B cells to produce IgG antibodies that go into the bloodstream, where they meet the antigens that cross over from the alveoli, and form immune complexes. This leads to acute hypersensitivity pneumonitis, which is a type III hypersensitivity reaction and is immune complex-mediated. Specifically, these complexes then get deposited in the basement membrane of the pulmonary capillaries, activating the complement system and attracting neutrophils to the site. Neutrophils degranulate, meaning they dump lysosomal enzymes and reactive oxygen species into the area, leading to inflammation and necrosis of the capillaries as well as nearby alveoli. If exposure to the trigger continues or if the acute response is unsuccessful, it leads to chronic hypersensitivity pneumonitis, which is a type IV hypersensitivity reaction with granuloma formation.

The signs and symptoms of acute hypersensitivity pneumonitis include fever, shortness of breath, cough, chest tightness, and headache, which typically develop within hours after exposure and resolve gradually within 12 hours to several days following exposure removal.

Chronic hypersensitivity pneumonitis has an insidious onset, meaning symptoms develop slowly and worsen over months to years. Eventually, this leads to sustained shortness of breath, and in severe cases, respiratory failure.

Besides a restrictive pattern on PFTs, diagnosis is based on a chest x-ray or CT showing numerous poorly defined small opacities throughout both lungs, sometimes with sparing of the apices and base. Occasionally, ground-glass opacification, which is an area of increased opacity with preserved bronchial and vascular markings, can be the predominant or only finding.