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Is your patient really allergic to penicillin?

Skin tests and drug challenges help reveal who has a true allergy

September 2017

HERE’S AN all-too-common scenario: A patient reports being allergic to penicillin. But how many patients are truly allergic to penicillin, and what are your options if they are?

Speaking at this year’s Society of Hospital Medicine annual meeting in Las Vegas, Paige Wickner, MD, MPH, program director of the allergy and immunology fellowship at Boston’s Brigham and Women’s Hospital, noted that penicillin is the most common drug allergy, one claimed by 10% of the general population. In addition, said Dr. Wickner, one-quarter of hospitalized patients have one or more recorded antimicrobial reactions.

Here’s the problem: “Having a listed penicillin allergy has measurable effects on length of stay, mortality and morbidity, and readmission rates,” she pointed out. “It’s also linked to greater use of expensive broad-spectrum antibiotics, as well as to increased risk of health care-associated infections including C. diff, VRE and MRSA.”

“Penicillin allergy disappears over time at the rate of 10% a year.” 

Wickner~ Paige Wickner, MD, MPH
Brigham and Women’s Hospital

Further, Dr. Wickner explained, “Penicillin allergy disappears over time at the rate of 10% a year. So when we have tested and challenged patients who carry this listed allergy in multiple studies, 90% or more are no longer truly allergic.”

That’s good news, given how often doctors override allergy alerts. Dr. Wickner was co-author of a study appearing in the May 2016 Journal of the American Informatics Association, which found that inpatient physicians overrode more than 80% of allergy-related alerts. Those overrides included more than 75% of alerts for patients who apparently had listed life-threatening reactions—such as anaphylaxis and angioedema—to their allergic agent.

“That’s very concerning,” she noted. “Much of the time, the override goes OK, until it doesn’t.”

A breakdown of allergic hypersensitivity
When consulting on an allergy, said Dr. Wickner, “it’s all about the history.” She’s interested in what specific medication patients had a reaction to, what indication they were taking it for, how soon after taking the drug a reaction began and how severe it was, and what alternative drugs patients may have successfully tried since their reaction.

Physicians may remember from medical school the Gell-Coombs classification of allergic hypersensitivity into four types: I, II, III and IV. Type I allergies, said Dr. Wickner, are those where patients have IgE-mediated, immediate reactions that can range from mild flushing or wheezing to anaphylaxis.

Types II and III, which include vasculitis and serum sickness, can be benign—with maculopapular rashes—or scary, such as Stevens-Johnson syndrome, drug rash eosinophilia systemic symptoms or acute generalized exanthematous pustulosis.

“With severe type II-IV allergic reactions, we have very few tools to diagnose or even intervene on patients,” Dr. Wickner pointed out. But “both allergists and non-allergists have a lot of opportunities to intervene on type I reactions.”

How to skin test
Skin testing is the way to find out whether patients are actually allergic to a drug. “There are very few drugs that we can’t prepare a test for, even if it’s not in the published literature,” Dr. Wickner said. “Don’t be afraid to ask an allergy consultant to help you out and see if testing is possible to a particular agent.”

Skin testing consists of administering a very small amount of a suspect drug to patients’ skin via a tiny needle that barely punctures the skin. “On adults, we use the volar surface of the forearm and in kids, we do it on their back,” she pointed out. “It really doesn’t hurt, and when I have pediatric patients, I’ll show them by doing it on myself.”

You then wait 15 minutes. “What you’re looking for is a mosquito-bite-type response, which indicates a positive reaction”, she said. For patients who have a negative reaction, she then proceeds to intradermal testing, using a needle to introduce “a little bit of the drug antigen under the skin.” When an intradermal test is negative, clinicians then proceed to a drug challenge to make sure patients aren’t allergic, giving patients a small dose of a drug (often a one-tenth dose), then checking their vitals and giving them the rest of the dose if they’re OK.

One commercial skin-test product available for penicillin allergy is called Pre-Pen, which has a negative predictive value of better than 90%, Dr. Wickner said.

And while physicians can do blood tests, “we always prefer skin testing to blood testing, if possible,” she pointed out. For one, there aren’t a lot of blood tests for drug allergies. Also, “we worry about false positives, and blood testing is usually more expensive.”

For either a food or a drug allergy for which there isn’t a commercial test, Dr. Wickner recommended what’s known as the “prick-prick” method: “You literally prick the food and then the patient, and you’ve done a test. It is cheap, but patients have to be off antihistamine, which is often an impediment with inpatients.”

Drug alternatives
While skin tests are effective, it’s tough to test in the hospital, given patients’ short length of stay. And even though Dr. Wickner’s allergy group has 23 physicians, “we really struggle with the volume of listed patients with penicillin allergies”: 220,000 or 10% of the patients in their system.

To help practitioners manage patients with penicillin allergies, a colleague at Massachusetts General Hospital—Kimberly Blumenthal, MD—developed a hypersensitivity pathway that “at least helps patients get more narrow-spectrum antibiotics without skin testing or an allergy consult.”

Described in the October 2015 issue of Annals of Allergy, Asthma & Immunology, the pathway incorporates guidance on alternative drugs, given individual patients’ history and hypersensitivity. It also relies on the use of test dose procedures, challenging patients with progressively increased doses of an alternative antibiotic to make sure patients won’t have an adverse reaction.

That pathway was also adopted at Brigham and Women’s. It has now been put into an app called the Partners Penicillin/Cephalosporin Hypersensivity Pathway that has been spread throughout the hospitals in the Partners HealthCare system in Massachusetts.

Dr. Wickner was a co-author of a study posted this February by The Journal of Allergy and Clinical Immunology, which compared the standard of care for patients reporting a penicillin allergy to those who were skin-tested as well as to those managed according to this pathway app. Compared to standard of care, skin-tested patients showed an almost six-fold greater use of penicillin and cephalosporins in the hospital, while those managed according to the computerized guidance had a nearly two-fold increased use.

Cephalosporin allergies
What do you do if a patient has a legitimate penicillin or cephalosporin allergy but needs a cephalosporin? Dr. Wickner urged hospitalists to ask an allergist for help or to at least study a cross-reactivity table. The cross-reactivity rate between penicillins and cephalosporins, said Dr. Wickner, is about 3%.

Most patients with cephalosporin allergies in the U.S., she explained, are not allergic to the common beta-lactam form. Instead, “they’re allergic to the side chains, and different cephalosporins have different side chains.”

Further, “allergies don’t go by generation, so you can’t say, ‘Patients are allergic to first-generation cephalosporins, so I’ll give then second- or third-generation, and they’ll be OK.’ ” Cefazolin, however, has a different side chain than all other cephalosporins, “so that’s a really good one to think about.”

There’s also very low cross-reactivity between carbapenems and penicillin. Several studies, including one in the June 29, 2006, issue of the New England Journal of Medicine, have used different carbapenems to challenge patients with penicillin allergies, finding no reaction in most. “You can graded-dose challenge patients without any testing, or you can test them,” said Dr. Wickner. “But I wouldn’t give them carbapenems without some sort of observation.”

She also noted that aztreonam “is a very safe alternative for penicillin-allergic patients, so you don’t need any special testing or challenge.” Her one caution with aztreonam is its cross-reactivity with ceftazidime. “The side chain of both drugs is the same,” she noted. “The only time I’d worry about giving aztreonam to a patient with penicillin allergy is if that patient has a listed ceftazidime allergy as well.”

One possible route for patients with a proven drug allergy is desensitization, the temporary induction of clinical tolerance to a drug.

In desensitization, patients are given different solutions of the drug to which they’re allergic—starting with a 1/1000 dose—with increasing doses given at 15-minute intervals. A four-bag, 16-step protocol, for instance, will take nearly seven hours to complete.

“We can desensitize people to most medications in patients who absolutely need a particular drug for front-line therapy,” Dr. Wickner said, including cancer patients who’ve responded to a certain chemotherapeutic agent but then become allergic to it. How long that temporary fix lasts, she added, is related to the drug’s half-life. “So if we miss two doses after a patient undergoes desensitization, we have to re-desensitize.”

But desensitization isn’t for everyone. “We can desensitize maculopapular rashes and IgE-mediated reactions including anaphylaxis, and those go really well,” she said. “The patients we don’t try to desensitize are those with severe cutaneous reactions, like Stevens-Johnson syndrome. With those, our hands are tied.”

Desensitization has to be done in an ICU with an allergist or a pharmacist, and it is agent-specific. “If you desensitize patients to ceftazimine, you’re not going to be able to give them penicillin,” she pointed out. Patients also have to be compliant with their course of therapy.

“There’s nothing worse than having patients in the ICU with one-on-one nursing, putting them through desensitization, and then have that medication drop off their list when they’re transferred back to the floor,” she said. “You have to desensitize them all over again.”

Phyllis Maguire is Executive Editor of Today’s Hospitalist.

Treating anaphylaxis
ANAPHYLAXIS IS an acute, life-theatening systemic allergic reaction, said Paige Wickner, MD, MPH, program director of allergy and immunology at Boston’s Brigham and Women’s Hospital, speaking at this year’s Society of Hospital Medicine conference. With anaphylaxis, 90% of patients have a cutaneous reaction, with flushing being very common, while between 40% and 60% have respiratory involvement as well.

“I tell patients, ‘If you’re debating whether it’s anaphylaxis, give yourself the EpiPen and we’ll talk later, when you’re safe, about whether that was the right thing to do,’ ” Dr. Wickner said.

As for which dose of epinephrine to use in the hospital, “we’re talking about the one-to-1000 concentration of epinephrine, 0.3 to 0.5 mg, given in the anterior-lateral part of the thigh,” she said. And be careful with code cart differences, she warned: Epi drips for blood pressure support, for instance, are a one-to-10,000 dose.

“Many hospitals do not stock EpiPens on code carts because of their cost and the need to replace them regularly,” said Dr. Wickner. “They must be drawn up and drawn up correctly.” Following anaphylaxis, about one-third of patients need a second dose of epinephrine, while as many as 20% have a biphasic reaction, sometimes 72 hours after their initial one.

“It’s not a reaction to another medication, but to the initial trigger,” she noted. “So watch out for that.”

She also passed along her recommendations for using an EpiPen: Make sure patients are sitting or lying down. And “don’t be dramatic,” like you’re restarting patients’ heart with adrenaline, said Dr. Wickner: People have made that mistake and have lodged the EpiPen needle in bone. Instead, “it’s simple pressure, click, hold it there for five seconds.”

One big mistake people make is thinking an EpiPen is like a ballpoint pen. “They inject their finger instead of their thigh,” she said. “You can necrose your digit and lose your finger.”

Or they successfully deliver the epinephrine into the air. Further advice she gives patients when they’re being discharged: If you need to self-administer an EpiPen, do so and then call 911. “Don’t have your buddy or neighbor drive you to the hospital, and don’t drive yourself,” she said.

In addition to epinephrine, other treatments for anaphylaxis include oxygen for hypoxemia, inhaled beta-2 agonists for refractory bronchospasm and IV fluids for refractory hypotension.

And “corticosteroids may help prevent a biphasic or late-phase reaction,” said Dr. Wickner. “But don’t give a steroid instead of epinephrine to a patient having a severe allergic reaction. That won’t help.” Patients taking beta-blockers may not respond to epinephrine, “so you may need to reverse the beta-blocker.”

If you’re not sure you’re dealing with anaphylaxis, “check a serum tryptase,” she noted. “That’s our only lab, and it has specific draw requirements.” The sample needs to be drawn within 15 minutes to three hours after an initial reaction, then sent to a lab on ice.

No link between shellfish and contrast allergies
WHEN IT COMES TO food allergies, new allergies develop in between 2% and 4% of adults, with shellfish being the most common. That’s according to Paige Wickner, MD, MPH, program director of allergy and immunology at Boston’s Brigham and Women’s Hospital, who spoke at this spring’s Society of Hospital Medicine conference. Reactions to food allergies take place within seconds or minutes up to two hours, and “there is no utility to broadly testing food that’s not involved in a reaction.”

Neither an allergy to shellfish nor iodide (which isn’t an allergen) correlates to a contrast allergy, “which happens quite frequently.” As many as 15% of patients have an adverse reaction to high-osmolar contrast media, while only 3% or fewer react to low-osmolar contrast or the iso-osmolar iodixanol.

Like many hospitals, Dr. Wickner said hers maintains
 a premedication regimen
 for patients with contrast hypersensitivity. That regimen includes an emergent as well as a non-emergent protocol, and a modified one for patients with diabetes or steroid intolerance. The rate of breakthrough reactions among patients who have been premedicated and
 are given low-osmolar contrast
is only 0.7%, according to one study, and 0.13% according to another, although the reaction severity is typically the same.

Published in the September 2017 issue of Today’s Hospitalist
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