Quincke's legacy

I remember hearing about the new drug class of angiotensin-converting enzyme (ACE) inhibitors when I started medical school in 1981. Yeah, I am that old. Captopril was the first out of the gate, approved by the FDA in 1981, followed by enalapril in 1985, right around the time of my graduation. So when I started residency both of these drugs were still quite new.

The first two things we were taught to watch out for with these medications were the side effects of renal failure in patients with renal artery stenosis and hypotension, as well as the more mysterious and visually impressive angioedema.

I saw two cases during internship, then no more for several years. But one day, I was rounding as an attending when an intern called me into a room to see a patient with swollen lips and tongue who was having mild respiratory distress. I smiled smugly and opined that it must be from an ACE inhibitor. Hubris always gets you. In fact, the patient had no history of medication use, chemical exposures, or insect bites. And these symptoms had appeared three times since he was 17 years old. This old case of what is sometimes known as Quincke's disease crossed my mind when I read a recent New England Journal of Medicine article, “Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.”

It all ties back to some history even more ancient than I am. Heinrich Irenaeus Quincke was a German physician known as the Clinician of Kiel. He is famous for multiple medical advances, including the identification of isolated uvular angioedema in 1882.

Another important one was the institution and popularization of the lumbar puncture, using the Quincke needle. He was the first to study cerebral spinal fluid, describing low glucose levels in the setting of infection, and to use lumbar puncture to treat hydrocephalus.

Not limiting himself to the central nervous system, he described what is termed the Quincke sign. This sign is the visualization of capillary pulsation in the fingernail bed in severe aortic regurgitation. (As an aside, Quincke joins several other signs of this condition, such as the Corrigan pulse, the Duroziez murmur, and the Becker, de Musset, and Müller signs. What a cornucopia of eponyms!)

But returning to hereditary angioedema, it is a rare genetic disorder that in most cases is caused by genetic mutations leading to a C1 esterase deficiency. Angioedema can also be acquired from a hematologic malignancy. Patients may present with localized angioedema involving the skin, upper airway, genitalia, or GI tract. On labs, the C4 level will be low and generally the C1 esterase will be, too, unless it's a variant where levels are normal but the function is abnormal.

Corticosteroids, antihistamines, and epinephrine, the bastion of response to anaphylaxis, are of no benefit. C1 esterase inhibitor can be infused as an IV, and there are other subcutaneous options, including kallikrein inhibitors. The newest therapy, sebetralstat, which made me think about Quincke, is an oral kallikrein inhibitor and joins the similar drug berotralstat, which is only approved for prophylaxis, among the treatment options for angioedema.

I am an aficionado and proponent of the oral exam in hospitalized patients, and in my primer, Q is always for Quincke. For those patients who do have his eponymous disease, new oral immunologic therapy options are a bridge from the past to the future. And, finally, remember that if you have a patient with this condition, do not prescribe ACE inhibitors!