Patients with positive patch test to formaldehyde can be safely vaccinated with formaldehyde‐containing vaccines

Prophylactic vaccination against influenza and other epidemic viruses is recommended for citizens above 65 years. Several vaccines may contain traces of formaldehyde and are contra‐indicated in patients hypersensitive (in the broadest possible meaning) to formaldehyde. Thorough knowledge on the various subtypes of hypersensitivity is sparse among non‐dermatologists and non‐allergists, and therefore many patients are prevented from vaccination based on a positive patch test to formaldehyde. The purpose of this retrospective study was to investigate whether patients with positive patch test to formaldehyde subsequently receiving a formaldehyde‐containing vaccine and developed a severe adverse reaction.


| INTRODUCTION
Sensitization to formaldehyde most frequently manifests as contact dermatitis although rare cases of systemic symptoms upon exposure to formaldehyde in vaccines have been described. [1][2][3][4] Vaccination against viral diseases such as influenza often elicit local or systemic adverse reactions both of hypersensitivity and non-hypersensitivity nature, but are rarely severe and should only in severe cases, for example, severe cutaneous adverse reactions or anaphylaxis prevent the patient from revaccination. [3][4][5][6] The risk of elicitation an adverse reaction to a vaccine must certainly in every patient be balanced against the risk for life threatening viral disease in the unvaccinated patient.
Licensed drugs must label all constituents in the formulation of the final product; thus, potential presence of residues arising from the manufacturing process must be mentioned, even if the amount is very minute (https://fmk-online.dk/Secured, accessed January 2022 [in Danish language]). Therefore, formaldehyde is labelled as an ingredient in the majority of commercially available virus vaccines in Denmark. Labelling includes the sentence 'Hypersensitivity to the ingredients, egg and chicken proteins, ovalbumin, gentamicin, formaldehyde, cetyltrimethylammonium-bromide or polysorbat 80' (author's translation).
Thorough knowledge on differences between immediate type (type 1) reactions, delayed type (type IV) reactions, other t-lymphocyte mediated reactions and other types of adverse reactions is sparse among colleagues without dermatological or allergological training. Although the word 'hypersensitivity' probably refers to severe reactions only, physicians and patients in many cases misinterpret the labelling, preventing life protecting vaccinations. Legislation requires, that the licensed health person ask the patient for possible 'allergy to vaccines or constitutions herein' prior to administration of the vaccination and therefore patients with contact allergy to formaldehyde answer affirmatively and either abstain from receiving vaccinations (FMK-online), or the patients are excluded from vaccination by the health personnel.
Formaldehyde is a toxic and carcinogenic auxiliary substance, widely used in many vaccines and in a number of manufacturing processes, including textiles, paints, plastics, gloves, and the leather industry as well as cosmetics, hair, and nail products. 7 The purpose of adding formaldehyde to vaccines in the manufacturing process is to inactivate bacteria and viruses in the vaccines. Subsequently, formaldehyde is removed from the vaccines during various purification processes, but small trace amounts <0.1 mg 6,8 may remain in the final product. Formaldehyde in vaccines is considered to be safe for two reasons: First, formaldehyde is an essential intermediate in human metabolism and is required for the synthesis of pyrimidines, purines, and amino acids so all human beings have detectable quantities of formaldehyde in the circulation. Second, quantities of formaldehyde at least 600-fold higher than that contained in vaccines have been administered safely to animals. 8 Assessment of safety of a given medical procedure should ideally include investigations on the most sensitive group of patients at risk.
Since we failed to identify a more suitable patient group than patients with a prior positive patch test reaction to formaldehyde, since these patients are often misunderstood by health personel in context to vaccination and since these data were readily available in our internal database, this patient group was chosen for this retrospective study.

| METHODS
Patch testing with formaldehyde was performed using TRUE-test R including formaldehyde (180 μg/cm 2 ) and formaldehyde 2% in aqueous solution (Chemotechnique Diagnostics, Vellinge, Sweden), in Finn Chambers 1. 9 We use TRUE-test R

| ETHICS
The study was approved by the Danish Data Protection Agency (no. 20/53636).

| Patch testing
In total, 169 patients were positive for formaldehyde by patch testing    [4][5][6][7] In most cases, patients developed a maculo-papular reactions on the chest, shoulders, antecubital fossa or arms. 7 Furthermore, immunizations are highly effective in preventing infectious diseases and therefore an indispensable public health measure. 5

| LIMITATIONS
The study is retrospective and only include severe adverse reactions to vaccination requiring hospitalization. Whether this patient group experience an increased frequency and/or severity of less severe side effects remains unknown. Further, some patients died for other reasons or were resident in regions, where legislation prevented us from obtaining vaccination data, reducing the cohort by a significant number.

| CONCLUSION
In conclusion, citizens >50 years of age, who have tested positive for formaldehyde by patch test, can be safely vaccinated with formaldehydecontaining vaccines without experiencing severe reactions requiring hospitalization. This recommendation of course does not extend to patients reporting anaphylaxis to a formaldehyde-containing vaccine.