From the start, U.S. health officials have advised that recipients of COVID-19 vaccines be monitored for 15 minutes afterward in case of a severe allergic reaction — 30 minutes for those with a history of serious allergies.

The precaution was prompted in part by an ingredient in the Pfizer-BioNTech and Moderna vaccines called polyethylene glycol (PEG), a substance known to provoke allergic reactions in a small number of people.

Fast-forward eight months, and there is good news — accompanied by a bit of a mystery. Severe allergic reactions to the vaccines have been rare, yet in most of those cases, PEG does not seem to be the culprit. A nationwide study is underway to determine what other factors might be to blame.

In the meantime, now that universities and employers have begun to implement vaccine mandates, most are playing it safe — generally stating they will grant requests for exemption to those with a documented allergy to PEG, even though most such people have gotten vaccinated with no problem.

Beyond that, the allowable medical exemptions vary widely by institution. Some spell out a short list of conditions, most of them rare. Others leave it open-ended, requiring that the person’s health-care provider document any reasons for an exemption request.

Below is a crash course on what to keep in mind. And a reminder: Eligibility for an exemption does not mean the person must seek it. Physicians say that in nearly every case, people prone to severe allergies can safely get a vaccine — and should do so — with proper medical supervision.

That happened to Dina Roman, 40, of Northeast Philadelphia. She experienced anaphylaxis once as a teenager after taking another type of medication, ending up in the emergency room.

So when she went to a Penn Medicine clinic in the spring for a first dose of the Moderna vaccine and providers pulled up her medical history, they kept an extra-close eye on her afterward. She had no issues.

“I was good to go,” she said. “That’s why we’re underneath doctors’ care. They’ve got the training to watch over you.”

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What is an allergy?

That question is not as straightforward as it sounds. Lots of people say they are allergic to something when what they really mean is that they are intolerant, perhaps in the sense that they have trouble digesting it, as with milk.

As a result, people with true allergies (to milk or any other substance) may have a hard time getting others to realize the severity of their condition, said Robert Zemble, division chief of allergy at Lehigh Valley Health Network.

“They may be shrugged off,” he said.

An allergy is defined as a chronic condition in which the person’s immune system responds abnormally to a foreign substance. Symptoms can include itching, sneezing, and a life-threatening condition called anaphylaxis, which is marked by difficulty in breathing, a feeling that the throat is closing off, and sudden swelling.

Further complicating matters: Certain allergy-like symptoms can occur without involvement of the immune system, said Elizabeth J. Phillips, an allergist and professor at Vanderbilt University Medical Center. A person undergoing an anxiety attack, for example, may experience difficulty breathing and skin rashes.

An allergist can identify a true allergy with diagnostic tools such as skin tests.

Who is allergic to PEG?

PEG is a common ingredient in all sorts of pharmaceutical products, including laxatives, certain “contrast agents” administered before ultrasound scans, and that unpleasant bowel prep that must be drunk before a colonoscopy.

But the substance comes in multiple forms, and a person who is allergic to one is not necessarily allergic to others. Overall, such allergies are rare.

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“Most allergists that are really alert to this are only seeing a handful of these types of cases over their lifetimes,” Phillips said.

No cases of anaphylaxis were identified in clinical trials of the vaccines. Still, because a type of PEG is used as a stabilizing agent in the Pfizer-BioNTech and Moderna vaccines, U.S. health officials recommended the post-injection waiting period, in case any recipients need treatment with one of those injector “pens” that contain epinephrine.

Same for the vaccine made by Johnson & Johnson, which contains a different substance to which a small number of people are allergic, called polysorbate.

How common are allergic reactions to the COVID-19 vaccines?

Allergy-like symptoms have been reported in as many as 2% of vaccine recipients, in most cases mild. Episodes of anaphylaxis are far rarer — occurring in just one out of 4,000 recipients of the vaccines made by Pfizer-BioNTech and Moderna. Few, if any, such cases have been identified after the single-dose J&J vaccine.

And most cases of anaphylaxis do not seem to be the result of a PEG allergy, perhaps because the type of PEG in the vaccines consists of smaller molecules than the kinds that normally cause allergies, Phillips said.

She and her Vanderbilt colleagues are participating in a national study to identify the true culprit. Penn State Health Milton S. Hershey Medical Center also is involved.

In the meantime, the good news is that with proper supervision, people experiencing an allergic reaction after the first dose of a vaccine generally seem able to handle the second dose, which confers much stronger protection against COVID-19.

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In a study in JAMA Internal Medicine, published online in July, Phillips and colleagues from other institutions described the experiences of 189 patients who had allergic reactions after a first dose of the Pfizer or Moderna vaccine. Of that group, 159 agreed to get a second dose, and all tolerated it, though 32 experienced a mild reaction. Some were given antihistamines in advance as a precaution, while others were given the allergy-calming drugs afterward, as needed.

But Phillips cautioned that some patients with a first-dose reaction might not know, or be able, to seek expertise from an allergist.

“People’s access to care is not equal,” she said. “A lot of patients have felt orphaned after they’ve had a reaction to the vaccine.”

COVID-19 vaccine and pregnancy

In addition to PEG allergies, some institutions spell out other conditions that may warrant a vaccine exemption. At Penn Medicine, among them is pregnancy.

That’s because the health system was among the first employers to announce a vaccine mandate for its employees, stating in May that staff would have until Sept. 1 to get vaccinated. At the time, while the vaccines were considered safe during pregnancy, the evidence was still emerging. So Penn decided to allow pregnancy as an exemption, chief medical officer Patrick J. Brennan said.

“We were recommending [the vaccine] to pregnant women,” he said. “We just thought at that point we would make that allowance. It was a timing issue.”

Since then, the evidence has gotten even stronger, with no sign that the vaccines increase the risk of miscarriage or other complications. Although pregnancy remains on Penn’s form as an allowable exemption, that doesn’t mean the person has to request it, Brennan said.

» READ MORE: Pennsylvania’s state colleges say they can’t require vaccines. Some faculty think politics are at play.

Are other medical exemptions allowed?

It depends on the institution. Penn Medicine also allows exemptions to adults with multisystem inflammatory syndrome, a rare complication of COVID-19 that is found more often in children. The form states that other “severe” conditions may qualify, as well, provided that a health-care provider supplies adequate documentation.

At Rowan University, the form for students seeking an exemption is vague, asking only that students submit “a signed statement of medical exemption” from a primary care provider. (Likewise, on a vaccine exemption form for Inquirer employees, no specific conditions are listed, but a health-care provider must describe the reason for the request and affirm that there is a basis for the exemption to a “responsible degree of medical certainty.”)

Zemble, the president-elect of the Pennsylvania Allergy & Asthma Association, cautioned that unlike hospital systems, some employers and universities may be ill-equipped to evaluate exemption requests from external sources.

“It’s more kind of fraught with possibly less experienced clinicians giving exemptions when they may not actually be warranted,” he said.

Religious exemptions and the COVID-19 vaccine

Pennsylvania and New Jersey both require schools and employers to grant exemptions to vaccine requirements if they run counter to the person’s religious beliefs. That was the case before the pandemic for other vaccines, and the same holds true for COVID-19.

But as with the medical exemptions, institutions vary in how they handle such requests. Some require the person to provide the name of the religion as well as a brief description of the relevant religious doctrine or practice.

Penn Medicine’s form goes well beyond that, consisting of seven pages with 12 questions, some of them with detailed subsections. Among them: whether the person has sought exemptions to the health system’s flu vaccine requirement in previous years, and if not, to explain why the religious belief would preclude vaccination for COVID but not for the flu.

Very few, if any, organized religions object to vaccination, other than a handful of faith-healing denominations, according to a list compiled by Vanderbilt University Medical Center.

During the pandemic, plenty of religious leaders have done the opposite, advocating that parishioners sign up for a vaccine and even opening their doors for use as vaccine clinics.

Some Catholics have raised concerns that the three authorized vaccines were tested on human cells derived from abortions performed decades ago. But the Vatican has deemed all three to be “morally acceptable.” And last week, the Archdiocese of Philadelphia advised its priests not to assist parishioners in obtaining religious exemptions.