Immune reactions specific for bovine collagen are rare but occur (1). Gelatin and alpha-galactose sensitivity may be responsible for acute reactions to bovine collage (Ask the Expert question below). However, the time course you describe suggests a cell mediated immune response. It is possible that humoral immune response to “central determinants” of the helix may be evident late due to the time required to ‘unwind’ the collagen triple helix and expose the antigenic determinants (2,3). There is some evidence that dietary exposure to collagen may induce an immune response (4). Estimates are that 2-4% of the population have some form of pre-existing sensitivity to bovine collagen, and approximately 1% may react to collagen. Granulomatous, foreign-body reactions to collagen have been reported (5). There are collagen immune responses causing arthritis, and there has been discussions of possible human autoimmune connective tissue disease being mediated by autoimmune responses to collagen. There is debate as to the significance of collagen immune responses and these diseases.
Testing for immune responses to collagen are not standardized or proven to be of clinical value. Furthermore, in this case, prick testing for specific-IgE to collagen or gelatin or alpha-gal would not seem relevant due to the time course of events. Testing to collagen is reported in the literature with marshmallow extract (10 weight/volume), boiled gelatin extracts, catgut suture placement, patch testing to collagen filler used for injection, oral gelatin challenge (see Ask The Expert question below) and others.
In light of the delayed reaction, I would suggest patch testing with the collagen material used for the surgical procedure. This could be macerated and mixed with petrolatum or applied directly to the skin for 48-72 hours. I would not pursue testing for IgE to collagen or related antigens, such as alpha-gal, because of the time course of the reaction. I could not find similar cases in the literature to provide guidance for management. Topical tacrolimus and oral cyclosporin 5mg/kg/day are reported to improved delayed reactions to injected or implanted bovine cartilage (6,7). This may be a consideration if you are convinced that a delayed type hypersensitivity reaction is responsible for the manifestations.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI
1. Lynn, A. K., I. V. Yannas, and W. Bonfield. "Antigenicity and immunogenicity of collagen." Journal of Biomedical Materials Research Part B: Applied Biomaterials: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials 71.2 (2004): 343-354.
2. Furthmayr F, Stoltz M, Becker U, Beil W, Timpl R. Chicken antibodies to soluble rat collagen. II. Specificity of the reactions with individual polypeptide chains and cyanogen bromide peptides of collagen. Immunochemistry 1972; 9: 789–798.
3. Dodge GR, Poole AR. Immunohistochemical detection and immunochemical analysis of type-II collagen degradation in human normal, rheumatoid, and osteoarthritic articular cartilages and in explants of bovine articular-cartilage cultured with interleukin-1. J Clin Invest 1989; 83: 647–661.
4. Charriere G, Bejot M, Schnitzler L, Ville G, Hartmann DJ. Reactions to a bovine collagen implant—Clinical and immunological study in 705 patients. J Am Acad Dermatol 1989; 21: 1203–1208.
5. McGregor DH, MacArthur RI, Carter T. Avitene granulomas of colonic serosa. Ann Clin Lab Sci 1986; 16: 296–302.
6. Moody, Brent R., and Roberta D. Sengelmann. "Topical tacrolimus in the treatment of bovine collagen hypersensitivity." Dermatologic surgery 27.9 (2001): 789-791.
7. Baumann, Leslie S., and Francisco Kerdel. "The treatment of bovine collagen allergy with cyclosporin." Dermatologic surgery 25.3 (1999): 247-249.
12/23/2014: Gelatin allergy
A patient at age four had a history of very large local to the site of her MMR vaccination accompanied by wheezing, runny nose and sneezing. Doctor felt the reaction was related to the gelatin in the vaccine. Incidentally this patient also has a history of anaphylaxis to peanut and tree nut ingestion.
Last year she had RAST testing for her foods but also Gelatin. Bovine gelatin result was 0.81 and Porcine was 0.30- she has been avoiding gelatin through the years. She is now 11 years of age and her RAST was repeated and Porcine was 1.08 and basic Gelatin RAST was .48. Doctor would like to perform an open food challenge for gelatin. We would like to have any information you can provide on how to perform this and with what product to use.
There is an extensive literature discussing the relationship between gelatin allergy, collagen allergy and 1,3 alpha-gal sensitivity, most of this with bovine products. One consideration would be to test for alph-gal sensitivity since your patient had a systemic response to the vaccination. You could also test for mammalian meat allergy with prick testing and Dr. Commins group at the University of Virginia uses an intradermal test to identify sensitive individuals with a delayed reaction to mammalian meat due to alpha-gal sensitivity. I am not aware of delayed reactions occurring from gelatin but the overlap between alpha-gal, collagen and gelatin allergy at least raises the question. The paper from Bogdanovic et al also associated milk allergy in children with gelatin allergy so you might consider testing for milk sensitivity. The same paper noted that 16% of the beef meat allergic children and 38% of the pork meat sensitive subjects were sensitive by testing to gelatin, and only 4 had a positive in vitro test to gelatin without meat sensitivity. They also showed that bovine and pork gelatin show extensive in vitro cross-reactivity.
The Mullins reference refers to gelatin challenge intravenously, which I would not suggest. However, extrapolating from the study we could conclude that the dose for an oral challenge could certainly start at the same dose used for the IV challenge in the study, 20 mg, and increase to 400 mg at intervals of every 15 minutes.
In summary, if your patient has no history of anaphylaxis to beef, cow’s milk or pork meat, there is a reduced likelihood of anaphylaxis to gelatin. I would be comfortable with initiating an outpatient challenge with oral gelatin beginning with a dose of 3-5 mg (first minute of IV dosing) and increasing 10 fold every 15-30 minute to a dose of 300-500 mg and then doubling every 30 minutes until a cumulative dose of more than 20-30 grams. I would then observe for several hours before discharge (total time 5-7 hours). If there is a history of allergy to beef, cow’s milk or pork or inability to eat food items with gelatin, then I would suggest a similar desensitization/graded challenge protocol in hospital. I would wait 24 hours to be sure there is no delayed reaction and then administer the MMR.
Mullins, Raymond James, et al. "Relationship between red meat allergy and sensitization to gelatin and galactose-a-1, 3-galactose." Journal of Allergy and Clinical Immunology 129.5 (2012): 1334-1342.
Background: We have observed patients clinically allergic to red meat and meat-derived gelatin.
Objective: We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test result, and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and galactose-a-1,3-galactose (a-Gal).
Methods: Adult patients evaluated in the 1997-2011 period for suspected allergy/anaphylaxis to medication, insect venom, or food were skin tested with gelatin colloid. In vitro (ImmunoCAP) testing was undertaken where possible.
Results: Positive gelatin test results were observed in 40 of 1335 subjects: 30 of 40 patients with red meat allergy (12 also clinically allergic to gelatin), 2 of 2 patients with gelatin colloid–induced anaphylaxis, 4 of 172 patients with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02-0.4 g), and 4 of 368 patients with drug allergy. Test results were negative in all patients with venom allergy (n = 241), nonmeat food allergy (n = 222), and miscellaneous disorders (n = 290). ImmunoCAP results were positive to a-Gal in 20 of 24 patients with meat allergy and in 20 of 22 patients with positive gelatin skin test results. The results of gelatin skin testing and anti–a-Gal IgE measurements were strongly correlated (r = 0.46, P < .01). a-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 µg/g gelatin by means of inhibition RIA.
Conclusion: Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The detection of a-Gal in gelatin and correlation between the results of a-Gal and gelatin testing raise the possibility that a-Gal IgE might be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, a-Gal, and gelatin (with or without clinical reactivity) remains uncertain.
J Allergy Clin Immunol. May 2012; 129(5): 1334-1342.e1.
Published online Apr 3, 2012. doi: 10.1016/j.jaci.2012.02.038
The relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose
Raymond James Mullins, MB BS, PhD, Consultant Physician, Clinical Immunology and Allergy, Hayley James, BS, Thomas A.E. Platts-Mills, MD, PhD, FRS, and Scott Commins, MD, PhD
Background: We have observed patients clinically allergic to red meat and meat-derived gelatin.
Objective: We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and alpha-Gal.
Methods: Adult patients evaluated 1997-2011 for suspected allergy/anaphylaxis to medication, insect venom or food were skin tested with gelatin colloid. In vitro (ImmunoCap) testing was undertaken where possible.
Results: Positive gelatin tests were observed in 40/1335 individuals; 30/40 patients with red meat allergy (12 also clinically allergic to gelatin); 2/2 with gelatin colloid anaphylaxis; 4/172 with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02 to 0.4g); 4/368 with drug allergy. Testing was negative in all patients with venom allergy (n=241), non-meat food allergy (n=222), and miscellaneous disorders (n=290). ImmunoCap was positive to alpha-Gal in 20/24 meat allergics and in 20/22 with positive gelatin skin tests. The results of gelatin skin testing and anti-alpha-Gal IgE were strongly correlated (r=0.46; P<0.01). Alpha-Gal was detected in bovine gelatin colloids at concentrations of ~ 0.44 to 0.52ug/gm gelatin by inhibition radioimmunoassay.
Conclusion: Most patients allergic to red meat were sensitized to gelatin and a subset was clinically allergic to both. The detection of alpha-Gal in gelatin and correlation between the results of alpha-Gal and gelatin testing raises the possibility that alpha-Gal IgE may be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, alpha-Gal and gelatin (with or without clinical reactivity) remains uncertain.
Mullins RJ et al: Allergic reactions to oral, surgical and topical bovine collagen: Anaphylactic risk for surgeons
Australian and New Zealand Journal of Ophthalmology
Volume 24, Issue 3, pages 257-260, August 1996
Background: Two cases of allergic (IgE-mediated) reaction to bovine collagen are described. Both patients developed conjunctival oedema in response to the topical application of highly purified bovine collagen to the eye during opthalmic surgery (corneal shields and catgut suture material). One patient developed periocular angioedema and angioedema of the throat after the ingestion of bovine collagen in the form of gelatin-containing foods.
Methods: The presence of allergen-specific IgE was evaluated by skin prick testing with collagen-derived products, and by topical challenge with a highly purified bovine collagen-derived corneal shield.
Results: In both patients, application of collagen to the eye reproduced the original subconjunctival oedema. In one patient, skin testing with purified and crude extracts of bovine collagen in the form of a corneal shield, catgut suture material and edible gelatin demonstrated evidence of collagen-specific IgE.
Conclusions: Clinical reactions to collagen are rare. Neverthless, patients with a history of allergic reactions to bovine collagen-derived products should be investigated because of the widespread use of collagen-derived therapeutic devices, the potential for immunological cross-reactivity with dietary collagen (gelatin) and the potential for anaphylaxis.
Takahishi et al:Laminin ?-1 and collagen a-1 (VI) chain are galactose-a-1,3-galactose-bound allergens in beef.
Volume 69, Issue 2, pages 199-207, February 2014
Background: Sensitization to the carbohydrate galactose-a-1,3-galactose (a-Gal) has been reported in patients with beef allergy. However, the proteins responsible for this allergy have not yet been identified. This study aimed to identify beef proteins that predominantly react with serum IgE in Japanese patients with beef allergy.
Methods: Sera were collected from 29 patients with beef allergy who had allergic reaction(s) such as urticaria, abdominal pain, vomiting, and anaphylactic shock after ingestion of beef and pork; the sera tested positive for IgE against beef and pork. IgE-binding proteins were detected by immunoblotting sera from the patients and identified using a combination of two-dimensional gel electrophoresis and peptide mass fingerprinting techniques. The involvement of carbohydrate in the binding of IgE to allergens was examined by periodate treatment and an inhibition assay with cetuximab by immunoblotting. Specific IgE binding to cetuximab was measured using the CAP-fluorescent enzyme immunoassay.
Results: Two IgE-binding proteins (240 kDa and 140 kDa) were detected in beef extract and identified as laminin ?-1 and the collagen a-1 (VI) chain fromBos taurus, respectively. Periodate treatment or the inhibition assay resulted in the loss of IgE binding to these proteins. Immunoblotting with anti-a-Gal antibody revealed the presence of a-Gal on the 240- and 140-kDa beef proteins. The amount of IgE bound to cetuximab was significantly correlated with that to beef in the patients with beef allergy.
Conclusion: The carbohydrate moiety (a-Gal) on laminin ?-1 and collagen a-1 (VI) chain are possibly common IgE-reactive proteins in the Japanese patients with beef allergy.
J Allergy Clin Immunol. Author manuscript; available in PMC Nov 1, 2010.
Published in final edited form as:
J Allergy Clin Immunol. Nov 2009; 124(5): 1108-1110.
Published online Aug 8, 2009. doi: 10.1016/j.jaci.2009.06.021
Bovine and Porcine Gelatin Sensitivity in Milk and Meat-Sensitized Children
Jelena Bogdanovic, Ph.D.,a Neal A. Halsey, M.D.,b Robert A. Wood, M.D.,a and Robert G. Hamilton, Ph.D.
I hope this information is of help to you and your patient.
All my best.
Dennis K. Ledford, MD, FAAAAI