Charles A. Powell, MD, MBA: The lung is a window to the world. The lung is exposed to the air that we breathe, and the lung is also fed by our vasculature, it’s exposed both ways. In normal individuals in normal health, the lung handles everything fine. In some cases, the exposure of the lung, whether it be to something that’s inhaled, or ingested, or infused, can cause a reaction within the lung parenchyma. That’s the lung tissue. Specifically, when we’re talking about interstitial lung disease, we’re now talking about the interstitium, which is that tissue that separates out the different sacs we have that exchange air, the alveoli. There’s a very thin tissue layer that separates all the different air sacs. Within that layer of tissue lies vasculature, and lymphatics, and room for immune cells to travel, and normally it’s a very thin membrane. But in the setting of exposure that is injurious to the lung, there will be travelling of the immune cells to the interstitium, the interstitium will become inflamed, it will become enlarged, it will expand the area between the air spaces. It will make it more difficult for the lungs to exchange gases. It will make the lungs stiffer. It will make it then more difficult to breathe and cause shortness of breath. The overall inflammation irritation will cause a cough.

That is what happens in interstitial lung disease, and it will be associated with different patterns that we can see on a chest CT scan, some with the patterns you mentioned: a ground glass pattern, an organizing pneumonia pattern, a hypersensitivity pneumonitis pattern where there are small nodules especially in the upper lobes. In severe cases there will be a pattern where there will be diffuse opacities in bilateral lungs that looks like an ARDS [acute respiratory distress syndrome] pattern. All those potential patterns can occur in interstitial lung disease, but it’s really important to know that those same patterns can be caused by other reasons than exposure of drugs. They can be caused by infections. They can be caused by other lung diseases such as collagen vascular diseases, and so interstitial lung disease and interstitial lung disease attributed to drug exposure is a diagnosis of exclusion. As we approach a patient who has symptoms and abnormal findings, we have to always keep in mind that there’s a differential diagnosis. When we exclude other causes then we land on a drug-related pneumonitis as a cause in a particular patient.

Joyce A. O’Shaughnessy, MD: That was awesome, thank you. That was really clear. Thank you so much. What do you carry around, Mark, when you’re reading these CT scans? What gives you the old red flag that “Oh my gosh, there may be something going on here drug related in my patient’s lungs?”

Mark D. Pegram, MD: You start with taking a careful history, and this is really getting back to fundamentals of physical diagnosis. Signs and symptoms we mentioned, dry cough, shortness of breath, chest pain, low-grade fever, hemoptysis, dyspnea on exertion. Careful physical examination is important when you’re working up this condition. It’s an opportunity to hone your skills with a stethoscope. You may hear rales or rhonchi on physical examination, E to A changes, bronchophony; whispered pectoriloquy can reflect underlying consolidation, for example. Charles mentioned common radiographic findings typically demonstrating ground glass opacities, but many other appearances can present as drug-induced interstitial lung disease: air space consolidation, reticular opacities, centrilobular lung nodules, etc. Serial chest imaging is very important. When you find an alteration, early referral to pulmonary medicine is really critical. It’s very important to collaborate. Multidisciplinary care is the expectation for management of drug-induced ILD. It’s not just an option because pulmonary may want further studies to rule out infection, for example, including bronchoscopy with bronchoalveolar lavage. The lavage specimen can be used to rule out lymphocytic carcinomatosis by sending it off for cytology. Also be sure to do cell counts to look for eosinophilia.There are many considerations for this diagnosis.

In my reading, I found a very nice paper that was just published in the journal called CHEST this year, and they had a very nice classification for drug-induced interstitial lung disease. It basically boils down to 5 points—first, temporal exposure to the causative agent. Now, “temporal” can be in quotes because the onset of interstitial lung changes from trastuzumab deruxtecan had a median of about 4 months and maxes out at around 1 year. Most of them occur within the first year and then it plateaus. For a drug like carmustine, you might see fibrosis 10 years after the exposure. For immune checkpoint inhibition, you might see it after they’ve already discontinued the immune checkpoint inhibitor. So “temporal” is in quotes. You always have to be mindful of that. Then there is development of pulmonary infiltrates commonly in a bilateral nonsegmental distribution, meticulous exclusion of all the possible causes. Dechallenge producing measurable improvement in symptoms is another nuance that drug cessation can not only be therapeutic, but it can also aid in the diagnosis. Since it is a diagnosis of exclusion, if you discontinue the offending agent and they get better, that implies the offending agent. Finally, to be rigorous, rechallenge could be used to aid in the diagnosis because if you see it come back, then you know for certain that’s what it was. That can be dangerous, so we don’t often do that in the case of drug-induced ILD in oncology. There are some circumstances with particular tumor types or particular stages of diseases where it may be worth the risks from rechallenge. That is still on the table in some rare cancers.

Joyce A. O’Shaughnessy, MD: Fabulous. Thank you. Thank you very much, Mark. That was a great approach to this, it’s systematic, and it’s great to hear that publication, too.

Transcript edited for clarity.