A Riddle Wrapped In a Mystery, Inside an Enigma

                 Why, after more than forty years with no history of allergies, would a man suddenly wake in the middle of the night, covered in red, fiercely itching hives, his throat and mouth so swollen he can’t speak, and his blood pressure so low he can’t stand without fainting?

                  The obvious answer would be a new allergy to medication, or perhaps food or an insect sting.  But after an ambulance ride to the ER and a hefty dose of epinephrine, antihistamine, steroids, pepcid and IV fluids to boost his blood pressure, the patient tells the attending physician reviewing his history that there were no new medications, no new foods, no stings—nothing at all out of the ordinary about that day. In fact, he’d been asleep longer than most allergic reactions take to develop before the onset of symptoms.

                  The ER attending calls the patient’s primary doctor, and they decide to pass the mystery on to an allergy specialist to solve. But after a thorough round of testing, followed by more tests, and then more—the tests show nothing. Nada.  Zip—oh, maybe a touch of sensitivity to ragweed, but nothing that would trigger anaphylaxis.

                  So what does the primary physician do now? This patient lives near enough to a hospital for an EpiPen to get him there, and has insurance coverage if he needs more follow-up. But what if he didn’t? What does a physician in an outlying area do when trying to help a patient with a potentially life-threatening condition with no identifiable cause?

                  Eight months after the original episode, the patient makes another late night trip to the ER. Then a few weeks later, it happens again—then, yet again. The reactions are becoming more frequent. That’s when the patient is referred to Carol Smith, MD of Birmingham Allergy and Asthma Specialists.

                  “There are so many potential causes and so many labs that could be done. It’s important to start out with a thorough history to narrow down which labs should be done,” Smith said. “The first thing to determine is whether it really is anaphylaxis.

                  “Could there be a nonimmunological explanation--perhaps a flushing syndrome or a vasovagal reaction? A true anaphylactic reaction is IgE mediated with mast cells releasing histamines that cause vasodilatation and can include hives, flushing and swelling. In addition to the cutaneous symptoms, there can be airway and GI involvement. The difference is that while other reactions may be uncomfortable, an anaphylactic reaction can be life threatening. Vasodilatation causes a drop in blood pressure with the potential for hypovolemic shock. Documented hypotension is a strong indicator of a true case of anaphylaxis.”

                  Ask the right questions, and you may be able to get a sense of where the problem lies before ordering labs, Smith said.

                  “A good place to start is with medications the patient is taking, including supplements and over the counter drugs. Even aspirin can cause problems. A new food allergy is less common in adults than in children, but you need to know everything patients have been eating. Have they had recent infections, bug bites or stings, dental procedures, or have they been in contact with latex?

“Where has the patient been that day, and what has he been doing? There are times of the year when a lot of guys say they’ve been hunting,” Smith said. “In addition to a different environment, exposure to cold, heat, and exercise can be involved. Sometimes there can be a combined reaction to food and exercise when the patient doesn’t react to the same food alone.”

Even sexual activity can be a factor, and not only because of possible contact with latex.

“Seminal fluid itself can be an allergen, or can be a problem after a man eats a food that causes an allergic reaction in his partner. It’s rare, but I’ve seen it,” Smith said.

                  Another possibility that recently came to light is the Alpha-Gal reaction to meats from antibodies that develop after bites from Lone Star ticks that are common in the South. The antibody binds to a carbohydrate present on beef, pork, lamb and other mammalian meats and can cause a delayed reaction up to six hours after a meal.

                  “This seemed to be a likely cause of the problem in the patient who was referred to me,” Smith said. “He had classic symptoms, with beef for dinner, and the onset of symptoms almost six hours later.  However, the labs were negative. We were left with what continues to appear to be idiopathic anaphylaxis.”

                  To paraphrase Churchill, idiopathic anaphylaxis is something of a riddle wrapped in a mystery, inside an enigma. Some studies suggest that abnormalities in receptors on the surface of mast cells may be a predisposing factor. Other studies have followed hundreds of patients for many years without identifying a cause.

Whether in one specific case symptoms are occurring without an external trigger or the trigger is something that current allergy tests simply aren’t designed to identify is a difficult question. Conditions such as mastocytosis and clonal mast cell disorders are another rare possibility that can result in similar symptoms, but physicians typically evaluate the frequency of episodes and other indications before putting patients through testing that can be uncomfortable and expensive.

                  “To know whether you’re dealing with immunological anaphylaxis or a nonimmunologic cause, blood draws taken during the early stages of a reaction can be helpful. Histamine and tryptase levels can tell you whether you’re dealing with anaphylaxis and its severity,” Smith said. “You may want to advise patients to request the tests if there are future episodes, or have a request on file at the ER most likely to see the patient.”

                  Until a more specific diagnosis is possible, the key to managing idiopathic anaphylaxis is focusing on what can be done to reduce the severity and frequency of reactions and to prepare patients to deal with emergencies until they can reach medical help. Patients should have one or more EpiPens and they and their families should be trained to use them. A daily dose of medications like Zyrtec or Cingular may be helpful, and patients with frequent severe reactions may need prednisone with the dosage tapered slowly.

                  Smith and her mystery patient are still working to identify a specific trigger causing his problem.  However, he seems to be responding well to a daily dose of Zyrtec. There have been several occasions when he began to experience the itching and redness of an impending reaction, but they resolved within a few minutes.

                  Now, at last, he can go to bed with a reasonable expectation of being able to sleep through the night.