Q:

1/14/2014
Healthy 30 year old female received the High dose Fluzone and 48 hours later developed generalized pruritus, then generalized maculopapular rash. No fever, joint aches, blisters, or hives. She is not allergic to egg or gelatin, which is not contained in this vaccine. She had a 4 inch area of erythema at injection site. She was treated with prednisone and benadryl. Should she avoid all flu shots in the future? Should she be skin tested to the High Dose Fluzone even though it was not an immediate reaction? Is there danger of inducing a type 4 steven johnson reaction if she was skin tested?

A:

Thank you for your inquiry.

The questions that you asked are certainly germane, but in actuality cannot be answered with complete confidence. Because of this, I would philosophically favor a different approach. I would approach your patient in a matter similar to that which we employ in patients with reports of reactions to local anesthetics. The most important issue in such a patient is to be able to administer a local anesthetic in the future. In these instances, we usually select a local anesthetic to which the patient has not been exposed, and then do a graded drug challenge preceded by skin testing.

In your patient's case, the most important issue is whether or not she will be able to take future influenza vaccines. In a fashion analogous to our approach to local anesthetic reactions, I would choose an unrelated vaccine and pursue its administration by graded challenge. To do this, of course, requires the knowledge of the contents of the vaccines and how they are made.

Here is a very helpful website which allows you to easily access all vaccines, and ascertain their manufacturing process and their contents. This is the Johns Hopkins Bloomberg School of Public Health Institute for Vaccine Safety.

You will find on this website that there are no less than 11 different influenza vaccines available, and when one peruses their contents and the manufacturing process for each, one sees a great deal of variability. I have copied for you below, just as an example, this information for Fluzone High-Dose and for Flublok. Each of these is made by a different manufacturer, and as you can see, except for the viruses themselves, there is very little if any resemblance between the manufacturing processes and the contents of each vaccine.

You can choose other influenza vaccines as well from the website mentioned above and ascertain their contents.

With this information available, you would then decide whether or not the risk/benefit ratio favors a graded challenge to a different vaccine, or whether you should simply counsel the patient not to take influenza vaccine again. If you decide, in consultation with your patient, that the risk/benefit ratio favors the administration of influenza vaccine, I would perform a graded challenge to the new vaccine as follows:

I would give 0.1 cc doses every three to four days until a total of 0.5 cc has been administered.

It would be assumed that, since her reaction occurred 48 hours after the administration of the vaccine, you would be able to detect any symptoms before the administration of the next dose, and these symptoms hopefully would be milder since the dose would be much smaller.

As you can see, this approach would obviate any concern regarding the readministration of Fluzone or skin testing to Fluzone. In addition, should her reaction have been to any content of Fluzone, it would eliminate the risk of re-exposure.

Also this approach would the answer your question regarding "avoiding all flu shots in the future."

Finally, there is no predictability about the occurrence of Stevens-Johnson syndrome. There is no way to answer this question, but the risk would probably be small since the clinical picture you described is not suggestive of Stevens-Johnson syndrome. But the administration of a different vaccine would at least, from a common sense standpoint, reduce this possibility.

Normally, using this procedure, we delay the challenge until the next influenza season since theoretically your patient should be protected after immunization this season.

Of course, the advantage of using this technique is that should she react again, you will be certain that the reaction was to the viral content itself and not to excipients or to the manufacturing technique.

Finally, you might also consider reporting this adverse response. For your convenience, I have copied below the contact information of Sanofi Pasteur, Inc., and a link to a pertinent government website:

To report SUSPECTED ADVERSE REACTIONS, contact Sanofi Pasteur Inc., Discovery Drive, Swiftwater, PA 18370 at 1-800-822-2463 (1-800-VACCINE) or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

Thank you again for your inquiry and we hope this response is helpful to you.

Flublok:
Flublok [Influenza Vaccine] is a sterile, clear, colorless solution of recombinant hemagglutinin (HA) proteins from three influenza viruses for intramuscular injection. It contains purified HA proteins produced in a continuous insect cell line (expresSF+®) that is derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda, and grown in serum-free medium composed of chemically-defined lipids, vitamins, amino acids, and mineral salts. Each of the three HAs is expressed in this cell line using a baculovirus vector (Autographa californica nuclear polyhedrosis virus), extracted from the cells with Triton X-100 and further purified by column chromatography. The purified HAs are then blended and filled into single-dose vials.

Flublok is standardized according to United States Public Health Service (USPHS) requirements. For the 2013 - 2014 influenza season it is formulated to contain 135 mcg HA per 0.5 mL dose, with 45 mcg HA of each of the following 3 influenza virus strains: A/California/7/2009 (H1N1), A/Texas/50/2012 (H3N2; antigenically like the cell-propagated prototype virus A/Victoria/361/2011), and B/Massachusetts/2/2012.

A single 0.5 mL dose of Flublok contains sodium chloride (4.4 mg), monobasic sodium phosphate (0.195 mcg), dibasic sodium phosphate (1.3 mg), and polysorbate 20 (Tween®20) (27.5 mcg). Each 0.5 mL dose of Flublok may also contain residual amounts of baculovirus and host cell proteins (≤ 28.5 mcg), baculovirus and cellular DNA (≤ 10 ng), and Triton X-100 (≤ 100 mcg).

Fluzone High-Dose:
Fluzone High-Dose (Influenza Virus Vaccine) for intramuscular injection is an inactivated 9 influenza virus vaccine, prepared from influenza viruses propagated in embryonated chicken eggs. 10 The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. Influenza 11 virus is concentrated and purified in a linear sucrose density gradient solution using a continuous 12 flow centrifuge. The virus is then chemically disrupted using a non-ionic surfactant, Octylphenol 13 Ethoxylate (Triton® X-100), producing a "split virus". The split virus is further purified and then 14 suspended in sodium phosphate-buffered isotonic sodium chloride solution. The Fluzone High-15 Dose process uses an additional concentration factor after the ultrafiltration step in order to obtain 16 a higher hemagglutinin (HA) antigen concentration.

Active Substance: Split influenza virus, inactivated strainsa: 180 mcg HA total
A (H1N1) 60 mcg HA
A (H3N2) 60 mcg HA
B 60 mcg HA
Other: Sodium phosphate-buffered isotonic sodium chloride solution QSb to appropriate volume
Formaldehyde ≤100 mcg
Octylphenol Ethoxylate ≤250 mcg

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology