To the Editor:
Immediate-type hypersensitivity to cow’s milk affects approximately 1% to 2% of young children, can persist, and can be fatal.
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Vaccines against tetanus, diphtheria, and pertussis are routinely given to children in multiple doses throughout childhood. Anaphylactic reactions to these vaccines are rare and are generally attributed to the vaccine toxoids.3
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The US national Vaccine Adverse Events Reporting System lists 39 anaphylactic reactions to DTaP, DTP, or Tdap vaccines for patients aged 0 to 17 years from 2007-2010.5
In this period we observed 8 children in our single center with a history of anaphylactic reactions to booster doses of these vaccines. We noted that these vaccines are labeled as being processed in medium containing casamino acids (derived from cow’s milk), raising the concern that residual casein in the vaccines might have triggered these reactions. We are not aware of prior reports linking milk contamination to anaphylaxis from these vaccines. To investigate this possibility, we reviewed the medical history of the affected children and tested 8 lots of the vaccines for residual casein.CDC Wide-ranging Online Data for Epidemiologic Research online search tool. Rockville (MD): Vaccine Adverse Event Reporting System. Available at: http://vaers.hhs.gov/data/data/. Accessed April 16, 2011.
The clinical characteristics of the 8 children were obtained by means of chart review (approved by the institutional review board) and are shown in Table I. These patients were selected based on reports of anaphylactic reactions to the vaccines and not because of a history of milk allergy. Each patient had symptoms consistent with anaphylaxis
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within 1 hour of administration of the vaccine. Six of the patients had prior acute allergic reactions to cow’s milk, including severe reactions in 5 patients and reactions to trace exposures in 4 patients. One patient was given a diagnosis of milk allergy based on serologic testing performed to evaluate atopic dermatitis, and another was given a diagnosis based on serologic testing to evaluate proctocolitis. Each of the patients had an increased milk-specific IgE level documented within 2 years of the reaction to the vaccine. Although milk-specific IgE levels do not necessarily correlate with severity, the recorded levels are far above those that typically correlate with reactivity.- Sampson H.A.
- Muñoz-Furlong A.
- Campbell R.L.
- Adkinson Jr., N.F.
- Bock S.A.
- Branum A.
- et al.
Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
J Allergy Clin Immunol. 2006; 117: 391-397
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Table IClinical characteristics of the children who reacted to the tetanus vaccines
| Age at time of reaction (y) | Sex | Milk allergy history | Asthma history | Milk-specific IgE level (kIUA/L) | Symptoms of reaction after vaccination | Treatments given | Vaccine administered | Time to reaction after vaccine administration |
|---|---|---|---|---|---|---|---|---|
| 4 | Male | Proctocolitis from cow’s milk–based formula at 3 mo of age | Yes | 82.9 | Diffuse hives, respiratory distress | Diphenhydramine, oral steroid | DTaP | 10 min |
| 5 | Male | Hives, lip angioedema, wheezing at 3 y of age after eating turkey with milk contamination | Yes | >100 | Repetitive cough, sneezing, rhinorrhea | Albuterol, diphenhydramine | DTaP | 10 min |
| 5 | Male | Urticaria, edema of the face, and wheezing after contact with milk-based formula at 2 y of age | Yes | >100 | Generalized urticaria, facial swelling, wheezing, retractions, difficulty breathing | Diphenhydramine, epinephrine | DTaP | Immediately |
| 6 | Male | Milk was eliminated based on allergy testing as an infant after presenting with atopic dermatitis | Yes | >100 | Cough, hives, facial swelling | Levalbuterol, diphenhydramine | DTaP | Within 15 min |
| 11 | Male | Urticaria and vomiting at 11 mo of age after eating yogurt; facial swelling and diffuse rash at 8 y of age after eating turkey with milk contamination | Yes | 58.9 | Generalized urticaria, sneezing, congestion, wheezing | Levalbuterol, diphenhydramine, oral steroid | Tdap | Within 10 min |
| 11 | Female | Vomiting after milk-based formula as an infant; angioedema of hands after contact with spilled milk at 1 y of age | Yes | 96.1 | Throat tightness, wheezing, respiratory distress | Epinephrine | Tdap | Driving home from pediatrician |
| 16 | Female | Cough, wheezing, and vomiting after milk at 1 y of age; respiratory distress, vomiting, hypotension, and cardiac arrest after eating pasta sprinkled with cheese at 8 y of age | No | >100 | Nasal congestion, watery eyes, hives, wheezing, chest tightness | Diphenhydramine, oral steroid | Tdap | Within 1 h |
| 17 | Male | Hives, lip, and tongue swelling; diarrhea; and abdominal pain at 4 y of age | Yes | >100 | Wheezing, respiratory distress, flushing of face and neck | Epinephrine | Tdap | Within 20 min |
The vaccine package inserts for the DTaP and Tdap vaccines, including those for Adacel, Boostrix, Daptacel, Infanrix, Kinrix, Pediarix, and Pentacel, all state that either the tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein or that the C tetani is grown in modified Mueller-Miller casamino acid medium.
Additionally, for the acellular pertussis vaccine components, all of the vaccines use a modified Stainer-Scholte medium, but only the Adacel, Pentacel, and Daptacel vaccines specifically mention this being modified with casamino acids. To determine whether there was casein in the vaccines, we performed assays on 5 different lots of the Tdap vaccine and 3 different lots of the DTaP vaccine. We also performed assays on 3 different lots of the influenza vaccine and 1 lot of the hepatitis B vaccine, which do not report processing in medium containing casamino acids, to act as negative controls.
For the assays, 96-well Immulon 4HBX plates (Fisher Scientific, Pittsburgh, Pa) were coated overnight with 50 μL/well of 1 μg/mL casein (Sigma-Aldrich, St Louis, Mo) diluted in 0.05 mol/L carbonate-bicarbonate buffer (pH 9.6). After washing (3 times) with phosphate-buffered saline containing 0.05% Tween-20 (PBS-T), the plates were blocked with 0.1 mL of PBS-T–ovalbumin 0.07% (OVA grade V, Sigma-Aldrich) per well for 1 hour. Samples (1:1 and 1:2 dilutions) and standards (0.19-190 ng/mL) were prepared and mixed (1:1) with rabbit anti-casein polyclonal antibody (a gift from Ross Laboratories, Columbus, Ohio) diluted at 1:50,000 in blocking buffer. This inhibition mix was incubated for 2 hours at 37°C. A mixture (1:1) of the same antibody with blocking buffer without competing casein was also prepared for cutoff determination. Fifty microliters per well of the test mixture was then pipetted in quadruplicates into the coated microtiter plates and incubated for 1 hour at 31°C. After washing (3 times) with PBS-T, 50 μL/well of horseradish peroxidase–labeled goat anti-rabbit IgG (Sigma-Aldrich) diluted to 0.4 μg/mL in blocking buffer was added and incubated for 1 hour at 31°C. Plates were washed (6 times) with PBS-T, and 50 μL/well of TMB (KPL, Inc, Gaithersburg, Md) was added and allowed to develop at room temperature for 60 minutes. Absorbance values were read at 650 nm with SoftMax Pro software, and the concentration of casein in analytes was obtained from the linear part of the standard curve by using a 5-parameter model. The presence of casein was confirmed in all samples of the Tdap and DTaP vaccines, whereas no casein was found in the negative controls (Table II).
Table IIMean casein concentrations in vaccine samples examined
| Vaccine | Brand name | Lot numbers | Casein (ng/mL) |
|---|---|---|---|
| Tdap | Adacel | C3727BA | 12.7 |
| Tdap | Adacel | C3518AA | 13.6 |
| Tdap | Adacel | C3819AA | 8.1 |
| Tdap | Adacel | C3246BA | 17.3 |
| Tdap | Adacel | C3448AA | 11.8 |
| DTaP | Daptacel | C3192BA | 10 |
| DTaP | Infanrix | AC14B099BA | 18.3 |
| DTaP | Infanrix | AC14B121BB | 12.2 |
| Influenza | Fluarix | AFLUA531BA | 0 |
| Influenza | Fluzone | UT3667AA | 0 |
| Influenza | Fluvirin | 111814P1 | 0 |
| Hepatitis B (recombinant) | Recombivax | 1023Y | 0 |
In summary, we identified 8 patients with severe milk allergy who reacted with anaphylaxis to Tdap or DTaP vaccines, which are processed in a broth derived from casein. We identified casein in 8 lots of the vaccines, raising the concern that residual casein in the vaccines might result in reactions for highly sensitive patients with milk allergy.
Allergic reactions have been noted to trace amounts of ingested milk protein.
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We suspect that smaller injected doses, similar to insect sting–induced anaphylaxis, trigger reactions in sensitive patients because digestion is bypassed. Most children with cow’s milk allergy receive these vaccines without incident, but the patients we identified have very severe milk allergy, very high milk-specific IgE levels, and, for 4 of them, past reactions to trace milk contamination. These children tolerated their initial vaccinations but reacted to booster doses. This observation is most likely explained by increasing milk sensitivity of the children as they aged, as reflected in the personal histories of several of the children. The number of patients at our single center and their clinical features of severe milk allergy and immediate severe reactions to the vaccine argue against alternative explanations for the reactions. Unfortunately, we were not able to test the lots of the vaccines associated with the reactions, and there might be variability in milk protein content influencing the risks.In conclusion, our novel observation raises a concern regarding booster vaccination of children with high levels of milk allergy with Tdap and DTaP. Although the children we identified appear by history and testing to be exquisitely allergic to milk, we cannot accurately define a high-risk group based on this case series. Clearly, many highly sensitive children with milk allergy tolerate the vaccines because these reactions are apparently rare. Further studies will be necessary to make more definitive recommendations regarding which children might be at risk. Manufacturer investigation and possible labeling or elimination of casein from the vaccines might avoid this risk. In the interim, we recommend continuing the standard practice for DPT vaccination in all children, but advise caution when administering booster doses in highly sensitive milk-allergic children.
References
- Food allergy.J Allergy Clin Immunol. 2010; 125: S116-S125
- Further fatalities caused by anaphylactic reactions to food, 2001-2006.J Allergy Clin Immunol. 2007; 119: 1016-1018
- Anaphylactic reaction to diphtheria-tetanus vaccine in a child: specific IgE/IgG determinations and cross-reactivity studies.Vaccine. 2002; 20: 3409-3412
- Immediate allergy to tetanus toxoid vaccine: determination of immunoglobulin E and immunoglobulin G antibodies to allergenic proteins.Ann Allergy Asthma Immunol. 2003; 90: 238-243
CDC Wide-ranging Online Data for Epidemiologic Research online search tool. Rockville (MD): Vaccine Adverse Event Reporting System. Available at: http://vaers.hhs.gov/data/data/. Accessed April 16, 2011.
- Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397
- Utility of food-specific IgE concentrations in predicting symptomatic food allergy.J Allergy Clin Immunol. 2001; 107: 891-896
- Allergic reactions to milk-contaminated “non-dairy” products.N Engl J Med. 1991; 324: 976-979
- A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much?.Clin Exp Allergy. 2004; 34: 689-695
Article info
Publication history
Published online: May 30, 2011
Footnotes
Disclosure of potential conflict of interest: H. A. Sampson is a consultant for Allertein Therapeutics, LLC; has received research support from the Food Allergy Initiative and the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH); is a consultant and scientific advisor for the Food Allergy Initiative; is a medical advisor for the Food Allergy & Anaphylaxis Network; is a scientific advisor for the University of Nebraska–FARRP; and is 45% owner of Herbal Springs, LLC. S. H. Sicherer is a consultant for the Food Allergy Initiative and has received research support from the NIAID/NIH. The rest of the authors have declared that they have no conflict of interest.
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© 2011 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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- Comments on cow’s milk allergy and diphtheria, tetanus, and pertussis vaccinesJournal of Allergy and Clinical ImmunologyVol. 128Issue 2
