Volume 120, Issue 2 , Pages 478-481, August 2007
Irritant skin test reactions to common vaccines
Article Outline
To the Editor:
Concerns about possible allergic reactions to immunizations are frequently raised by both patients/parents and primary caretakers. Estimates of true allergic reactions to routine vaccines range from 1 per 50,000 doses for diphtheria-tetanus-pertussis vaccine to about 1 per 500,000 to 1,000,000 doses for most other vaccines.1 Although these per-dose estimates suggest that reactions are extraordinarily rare, the large number of doses administered makes this a relatively common clinical problem.
Skin testing for immediate-type hypersensitivity is indicated for some patients with suspected allergic reactions to immunizations.2, 3 Standard skin testing to vaccines involves the use of both prick (puncture) and intradermal (intracutaneous) skin tests at varying concentrations. However, the interpretation of these skin test results is complicated in many instances by irritant reactions. Although it is clear from clinical experience that irritant reactions do occur to some vaccines, the frequency with which they occur has never been formally evaluated.
Twenty healthy adult volunteers with no history of food or drug allergy or adverse vaccine reactions were tested to 10 common vaccines (Table I). Each vaccine was tested at a full-strength skin prick dose with a bifurcated needle and at 1:100, 1:10, and full-strength intradermal doses. All test results were read at 15 minutes and compared with results with positive (histamine) and negative (diluent) controls. All antihistamines were withheld for 7 days before skin testing. For intradermal tests, 0.02 mL was injected by using a 0.5-mL syringe with a 27-gauge needle. Dilutions were prepared at the time of testing with normal saline with 0.03% human serum albumin.
Table I. Specific vaccines tested
| Vaccine | Trade name | Manufacturer |
|---|---|---|
| DtaP | Infanrix | GlaxoSmithKline, Glenval, Belgium |
| DT | Diphtheria and Tetanus Toxoids Adsorbed USP (For Pediatric Use) | Sanofi Pasteur, Swiftwater, Pa |
| MMR | M-M-R II | Merck & Co, Inc, Whitehouse Station, NJ |
| Hib | ActHIB | Sanofi Pasteur, Lyon, France |
| Hepatitis B | Engerix-B | GlaxoSmithKline, Glenval, Belgium |
| IPV | IPOL | Sanofi Pasteur, Lyon, France |
| Varicella | Varivax | Merck & Co, Inc, Whitehouse Station, NJ |
| Hepatitis A | Havrix | GlaxoSmithKline, Glenval, Belgium |
| Pneumococcal | Prevnar | Wyeth, Collegeville, Pa |
| Influenza virus | Fluzone | Sanofi Pasteur, Swiftwater, Pa |
After skin testing, subjects were observed for 1 hour. They were instructed to call with any possible late reactions so that a clinic visit could be arranged. Follow-up telephone calls were conducted at 48 to 72 hours and 7 days after skin testing to assess for any delayed reactions. Where possible, those with delayed reactions were seen by the investigator. The protocol was approved by the Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health, and all subjects signed informed consent forms.
Any skin test result with a wheal that exceeded that produced by the negative control by more than 3 mm was considered positive. The frequency of such reactions to each vaccine at each concentration was recorded. A nonirritating concentration for each vaccine was established by identifying the highest concentration at which all participants had a wheal response of less than 3 mm greater than that elicited by the negative control.
Twenty-three subjects participated in the study, 15 female and 8 male patients between the ages of 20 and 59 years. Sixteen underwent testing to all 10 vaccines, and 7 underwent testing to a subset of vaccines, primarily because no influenza vaccine was available at study initiation. Each vaccine was tested at all concentrations, even if a positive result occurred at a lesser concentration.
No positive (irritant) result occurred with skin prick testing to any vaccine. At the 1:100 concentration, all intradermal test results were negative except for 1 subject with weakly positive test results to both diphtheria–tetanus–acellular pertussis (DTaP) and diphtheria-tetanus (DT) vaccines and 3 with positive test results to influenza vaccine (Table II). At the 1:10 concentration, positive test results occurred in 1 (5%) subject to DT vaccine, in 1 (5%) subject to Prevnar (Wyeth, Collegeville, Pa), in 2 (10%) subjects to DTaP vaccine, and in 11 (55%) subjects to influenza vaccine. At full strength, positive intradermal test results occurred with all vaccines except hepatitis A and inactivated poliomyelitis vaccine and were most common with measles, mumps, and rubella (MMR; 20/20 [100%]); varicella (20/20 [100%]); influenza (13/20 [65%]); and Haemophilus influenzae b (Hib; 5/20 [25%]) vaccines. All subjects with a positive result at one concentration also had positive results at all higher concentrations. No subject had persistence of their immediate-type reactions, with all positive test results resolving over 1 to 24 hours. On follow-up assessment, 1 subject was unable to be contacted. All other subjects were contacted by telephone, and 12 subjects were seen by the investigator to assess delayed-type reactions. At the 1:100 concentration, there were 2 delayed reactions to influenza vaccine and 1 to DTaP vaccine at 48 to 72 hours. Delayed reactions were common for most vaccines at the 1:10 and full-strength concentrations at the 48- to 72-hour follow-up, many of which were still present at the 7-day follow-up (Table II). For those that were directly observed, reactions ranged from mild erythema to 18 mm of induration. The largest and most frequent delayed reactions occurred to DTaP, DT, and influenza vaccine, followed by Prevnar, varicella, and Hib vaccines.
Table II. Immediate- and delayed-type responses to intradermal testing
| Immediate reactions (n = 20) | Delayed reactions (n = 19) | ||||
|---|---|---|---|---|---|
| No. positive (n = 20) | Wheal (range; mm) | Erythema (range; mm) | 48-72 h (no. positive) | 7 d (no. positive) | |
| DT | |||||
 1:100 | 1 | 3 | 3 | 0 | 0 |
| 1:10 | 1 | 5 | 15 | 7 | 2 |
| Full strength | 2 | 4-9 | 15-28 | 11 | 7 |
| DTaP | |||||
| 1:100 | 1 | 5-16 | 3 | 1 | 0 |
| 1:10 | 2 | 3-4 | 6-18 | 8 | 5 |
| Full strength | 4 | 5-16 | 15-20 | 12 | 9 |
| Hepatitis A | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 1 | 0 |
| Full strength | 0 | — | — | 2 | 1 |
| Hepatitis B | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 1 | 0 |
| Full strength | 1 | 3 | 6 | 2 | 1 |
| Hib | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 5 | 3 |
| Full strength | 5 | 3-5 | 3-15 | 8 | 6 |
| Influenza | |||||
| 1:100 | 3 | 3-5 | 4-8 | 2 | 0 |
| 1:10 | 11 | 4-6 | 15-20 | 10 | 2 |
| Full strength | 13 | 4-8 | 14-38 | 10 | 3 |
| IPV | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 1 | 0 |
| Full strength | 0 | — | — | 1 | 0 |
| MMR | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 1 | 1 |
| Full strength | 20 | 4-9 | 7-30 | 5 | 2 |
| Prevnar | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 1 | 4 | 8 | 6 | 2 |
| Full strength | 3 | 3-4 | 5-20 | 8 | 4 |
| Varicella | |||||
| 1:100 | 0 | — | — | 0 | 0 |
| 1:10 | 0 | — | — | 6 | 2 |
| Full strength | 20 | 4-8 | 7-30 | 8 | 3 |
All vaccines have the potential to cause allergic reactions, and several vaccine components could be allergenic, including the vaccine itself, preservatives, and stabilizers.4 Specific vaccine components that have been implicated in vaccine reactions include egg protein, gelatin, neomycin, thimerosal, and other additives.2, 3, 4, 5, 6, 7, 8 Specific testing, especially to egg and gelatin, might be very helpful in the evaluation of some vaccine reactions,6, 7 whereas in other cases specific testing of vaccine components might be unavailable or unrevealing. In those instances skin testing with the intact vaccine could be the only diagnostic option.2, 3, 8
Although guidelines for the evaluation of patients with suspected allergic reactions to vaccines have been proposed,2, 3 there are no standardized approaches. These guidelines typically recommend skin prick testing with the full-strength vaccine and intradermal testing with a 1:100 dilution. However, in clinical practice it is not uncommon for allergists to use intradermal skin tests at higher concentrations, up to and including full-strength undiluted vaccine.
We reported in 1992 that 3 of 6 adult control subjects had irritant effects to a 1:100 concentration of MMR, at which point we took all intradermal testing out of our MMR testing protocol.9 Aside from that limited sample, knowledge regarding the irritant effects of different vaccines is based solely on clinical experience. We therefore undertook this study in an effort to determine the frequency with which irritant reactions occur to 10 common vaccines.
Some very clear patterns emerge from the results of this study. First, skin prick testing, even with full-strength vaccine, is unlikely to be complicated by irritant effects. Likewise, irritant effects are very uncommon with intradermal testing at 1:100 dilutions. Even though this did occur with 1 subject to DT and DTaP vaccines, these were small positive test results. It is also clear that irritant reactions are rare at all concentrations for some vaccines, including hepatitis A, hepatitis B, and inactivated poliomyelitis vaccines. With influenza, 3 of 20 subjects had positive results at the 1:100 concentration, with the largest being a 5-mm wheal with an 8-mm flare. Although not common, the clinician should be aware that these reactions might occur, even at this concentration, especially given the fact that this is a concentration that has been formally recommended for testing patients with egg allergy before administration of an influenza vaccine.10
At the 1:10 and full-strength concentrations, irritant reactions were very common for some vaccines. Most problematic were full-strength MMR and varicella vaccines, both full-strength and 1:10 influenza vaccines, and, to a lesser extent, full-strength DTaP, DT, Hib, and Prevnar vaccines. Whether these higher concentrations would ever be needed from a clinical standpoint is essentially unknown, aside from the data published on MMR and influenza,9, 11 which showed that these vaccines could be safely administered after a negative full-strength skin prick test result for MMR vaccine and a negative 1:100 intradermal test result for influenza vaccine.
The delayed-type reactions that were seen will not affect the interpretation of skin test results but should be recognized as potential complications of vaccine skin testing. These were uncommon with testing at the 1:100 dilutions but were very common for some vaccines at the 1:10 and full-strength concentrations.
It is important to recognize several limitations to this study. First, the numbers of subjects tested per vaccine are relatively small. Although the results provide a representation of the relative likelihood of a vaccine having irritant effects, they cannot be taken as conclusive.
Second, these vaccines are mostly used in children, but these data were collected only in adults because of safety concerns and ethical issues. It is possible that children, especially those with atopy, would be more reactive than the adults included in this protocol and that the frequency of irritant effects might be higher than those reported here.
Third, it is possible that some of these irritant reactions did truly represent positive immediate-type allergic responses, although this is unlikely given the population studied and the rarity of allergic reactions to vaccines.
Finally, for many of these vaccines, multiple brands are available from different manufacturers. Although irritant effects are likely to be similar for the different formulations of the same vaccine, this might not always be the case.
Even with these limitations, these results provide clinicians with useful guidelines as to choosing appropriate concentrations for vaccine skin testing. Clearly, intradermal skin testing with full-strength MMR vaccine or Varivax (Merck & Co, Inc, Whitehouse Station, NJ) will routinely be complicated by irritant responses, and intradermal testing with full-strength or 1:10 influenza would be of limited value. Aside from the need to cautiously interpret testing with influenza at the 1:100 concentration, for all other vaccines, this concentration would be expected to produce few, if any, irritant responses.
References
- Red book 2000. 25th ed.. Elk Grove Village (IL): American Academy of Pediatrics; 2000;
- . Allergenic components of vaccines and avoidance of vaccination-related adverse events. Curr Allergy Rep. 2001;1:11–17
- . Adverse reactions to vaccines. In: Adkinson NF, Yunginger JW, Busse WW, Bochner BS, Holgate ST, Simons FER editor. Allergy: principles and practice. 6th ed. St Louis: Mosby; 2003;p. 1669–1675
- Allergens table. Components of vaccines. Institute of Vaccine Safety. Available at: http://www.vaccinesafety.edu/components.htm. Accessed May 22, 2007.
- . Sensitization to thimerosal in atopic children. Contact Dermatitis. 1999;40:94–97
- . Anaphylaxis from yellow fever vaccine. J Allergy Clin Immunol. 1999;103:698–701
- Gelatin-specific humoral and cellular immune responses in children with immediate- and nonimmediate-type reactions to live measles, mumps, rubella, and varicella vaccines. J Allergy Clin Immunol. 1997;100:130–134
- Anaphylaxis to the 23-valent pneumococcal vaccine in child: a case-control study based on immediate responses in skin tests and specific IgE determination. Vaccine. 2001;19:4588–4591
- . Egg hypersensitivity and adverse reactions to measles, mumps, and rubella vaccine. J Pediatr. 1992;120:878–881
- Red book 2006. 25th ed.. Elk Grove Village (IL): American Academy of Pediatrics; 2006;p. 46-8
- Safe administration of influenza vaccine to patients with egg allergy. J Pediatr. 1998;133:624–628
Disclosure of potential conflict of interest: R. A. Wood has consulting arrangements with Dey Pharmaceuticals, has received grant support from Genentech and Merck, and is on the speakers' bureau for GlaxoSmithKline, Merck, and Dey. N. Halsey has received grant support from Wyeth Laboratories and has served as an expert witness in vaccine injury compensation litigation. R. Setse has declared that she has no conflict of interest.
PII: S0091-6749(07)00867-6
doi:10.1016/j.jaci.2007.04.035
© 2007 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 120, Issue 2 , Pages 478-481, August 2007
