







































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: celso@alergoimuno.med.br; 
 
Cite as: Olivier, Celso Eduardo, Daiana Guedes Pinto, Ana Paula Monezzi Teixeira, Cibele Silva Miguel, Jhéssica Letícia 
Santos Santana, Regiane Patussi Santos Lima, Nicole Sartoreto Rocha, and Raquel Acácia Pereira Gonçalves Santos. 2025. 
“Endotyping Cellular and Humoral Immunoreactivity Against Formaldehyde in Patients With Atopic and/Or Contact Dermatitis”. 
Asian Journal of Immunology 8 (1):70-81. https://doi.org/10.9734/aji/2025/v8i1161. 

 
 

Asian Journal of Immunology 
 
Volume 8, Issue 1, Page 70-81, 2025; Article no.AJI.134825 
 

 
 

 

 

Endotyping Cellular and Humoral 
Immunoreactivity against 

Formaldehyde in Patients with Atopic 
and/or Contact Dermatitis 

 
Celso Eduardo Olivier a*, Daiana Guedes Pinto a,  

Ana Paula Monezzi Teixeira a, Cibele Silva Miguel a,  

Jhéssica Letícia Santos Santana b,  

Regiane Patussi Santos Lima c, Nicole Sartoreto Rocha d  

and Raquel Acácia Pereira Gonçalves Santos a  
 

a Instituto Alergoimuno de Americana, Brazil. 
b Instituto de Ensino e Pesquisa do Hospital de Amor de Barretos, Brazil. 

c Lavoisier Laboratórios, São Paulo, Brazil. 
d Faculdade de Americana, São Paulo, Brazil. 

 
Authors’ contributions  

 
This work was carried out in collaboration among all authors. Author CEO conceptualized the study, 

did data curation, formal analysis, literature review, and wrote the original draft. Authors DGP, APMT, 
CSM, NSR, JLSS and RPSL performed the laboratory procedures. Author RAPGS performed the 

cutaneous tests. All authors read and approved the final manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2025/v8i1161  
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  

peer review comments, different versions of the manuscript, comments of the editors, etc are available here: 
https://pr.sdiarticle5.com/review-history/134825  

 
 

Received: 19/02/2025 
Published: 25/04/2025 

 

Original Research Article 

https://doi.org/10.9734/aji/2025/v8i1161
https://pr.sdiarticle5.com/review-history/134825


 
 
 
 

Olivier et al.; Asian J. Immunol., vol. 8, no. 1, pp. 70-81, 2025; Article no.AJI.134825 
 
 

 
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ABSTRACT 
 

Background: Several publications report that formaldehyde is responsible for hypersensitivity 
reactions in patients with contact dermatitis, as diagnosed by "in vivo" provocation tests. There is 
no standardized lab exam that can endotype the mechanisms responsible for these phenotypes, 
Aim: To evaluate the potential of the Tube Titration of Precipitins (TTP) and the Leukocyte 
Adherence Inhibition Test (LAIT) to discriminate and endotype cellular and humoral 
immunoreactivity against formaldehyde in patients with contact dermatitis. 
Methods: We retrospectively examined the medical charts of two cohorts (n = 100, each) of 
patients diagnosed with atopic dermatitis and/or contact dermatitis with clinical suspicion of 
formaldehyde hypersensitivity, who were investigated with the help of TTP or ex vivo challenge 
tests monitored by LAIT against formaldehyde. The registered results were distributed in ranges 
through cascade distribution charts. The statistical characteristics of these cohorts were calculated.  
Results: TTP showed a distribution concentrated over the more diluted titrations with no negative 
result. The mean was estimated at 1:385; the median at 1:512; and the standard deviation at 1:166. 
The LAIT results demonstrated a wide range. The LAI ranged from 0% to 100%. The mean was 
57.5%; the median was 65.5%; the standard deviation was 37.4%. 
Conclusion: Our preliminary results support that the TTP and LAIT performed with formaldehyde 
solution may discriminate diverse degrees of humoral and cellular immunoreactivity in patients 
suffering from atopic and/or contact dermatitis. By evaluating the utility of TTP and LAIT as 
diagnostic tools, the study provides preliminary evidence for endotyping immunoreactivity, which 
could advance precision medicine in allergy management. The findings may guide clinicians in 
identifying hidden formaldehyde exposure in products and inform safer therapeutic strategies for 
sensitized patients. It is worthwhile conducting more in-depth studies to evaluate the usefulness of 
TTP and LAIT in endotyping non–IgE-mediated hypersensitivity to formaldehyde. 

 

 
Keywords: Atopic dermatitis; contact dermatitis; endotype; hypersensitivity; formaldehyde; leukocyte 

adherence inhibition test; precipitins; precision medicine. 
 

ABBREVIATIONS 
 
LAI: Leukocyte Adherence Inhibition 
LAIT: Leukocyte Adherence Inhibition Test 
TTP: Tube Titration of Precipitins 
 

1. INTRODUCTION  
 
The American Contact Dermatitis Society elected 
Formaldehyde as the "Allergen of the Year 2015" 
(Pontén & Bruze 2015). Formaldehyde (known 
as methanal, methylene oxide, oxymethyline, 
methylaldehyde, and oxomethane) is the 
simplest aldehyde, with the chemical structure 
H2C=O (Gerberich & Seaman 2013). Usually 
stored as an aqueous solution containing 
variable amounts of methanol (formalin), it turns 
on a colorless, pungent, suffocating, flammable 
gas when liberated into the atmosphere 
(Commission, 2024). Formaldehyde in aqueous 
solutions spontaneously hydrates to H(H2C=O) 
OH and aggregates to form mixtures of hydrated 
oligomers: H(H2C=O)n OH depending on 
formaldehyde concentration. Methanol stabilizes 
aqueous formaldehyde solutions by decreasing 

the average value of n (Dankelman & Daemen 
1976).  
 
The "plastic age" was inaugurated in 1910 by 
polymerizing formaldehyde and phenol, 
producing bakelite (Braun et al., 2013). 
Nowadays, several industrial uses have been 
discovered for formaldehyde, turning it into an 
intermediate chemical tool for the production of 
adhesives, fabrics, polymers, resins, plastics, 
paints, lacquers, dyes, explosives, and so forth, 
stimulating the industrial research of diverse 
patented productions methods worldwide 
(Walker, 1964 DIsponible at "Internet Archive": 
https://archive.org/details/formaldehyde0000walk
). Formaldehyde may also be formed and 
liberated in the atmosphere by the incomplete 
combustion of tobacco, wood, coal, gasoline, 
diesel, and ethanol in internal combustion 
engines (Dias et al., 2012). Gaseous 
formaldehyde at higher concentrations can 
irritate the eyes and mucous membranes of the 
respiratory tract, even producing asthma 
(Bardana & Montanaro 1991; Pougnet et al., 
2025; Zhang et al.; 2025). 
 



 
 
 
 

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Initially used as a disinfectant, embalming 
(anatomy dissection classrooms), and viral 
inactivator for the production of vaccines, 
nowadays, formaldehyde is listed as a human 
carcinogen with restricted uses (Commission, 
2021). Formaldehyde is prohibited from use in 
cosmetic products in most countries. However, 
the so-called formaldehyde releasers are usually 
allowed (Commission, 2019). To avoid the 
inconveniences of formalin, chemists developed 
the formaldehyde releasers (or formaldehyde 
donors), reversible linear or cyclic polymers of 
formaldehyde that slowly release free 
formaldehyde at levels suppressing microbial 
growth but (theoretically) sufficiently low not to 
harm humans (De Groot et al., 2009). These 
formaldehyde releasers (such as quaternium-15, 
Diazolidinyl urea, DMDM hydantoin, 
imidazolidinyl urea, 2-bromo-2-nitropropane-1,3-
diol (bronopol), germall-115, preventol, and so 
forth) are found in cosmetics (creams, lotions, 
make-up removers, soaps, shampoos, 
deodorants, toiletries, nail products), cleaning 
household products (detergents) and industrial 
chemical products (Flyvholm & Andersen, 1993). 
Soon, it was realized that formaldehyde 
releasers were also causes of contact dermatitis 
in patients sensitized to formaldehyde (Dahlquist 
& Fregert 1978). 
 
Recently, it was reported that about three-
quarters of tested US tattoo inks analyzed by the 
chromotropic acid method resulted in a positive 
for formaldehyde releasers (Liou et al., 2021).  
 
Until recently, textile finishes released an 
elevated level of free formaldehyde (textile-
formaldehyde resins), causing frequent textile 
dermatitis in individuals sensitive to 
formaldehyde. However, nowadays, clothing 
finishes release much less free formaldehyde, 
and allergic contact dermatitis from clothing due 
to formaldehyde releasers is much less frequent 
than in the past decades. (Lazarov et al., 2003).  
 
Nowadays, the main question about 
formaldehyde hypersensitivity is not about the 
known products with the declared presence of 
formaldehyde or formaldehyde releasers in their 
composition but the undeclared presence of 
formaldehyde in industrial products. In a recent 
sampling, it was demonstrated by high-
performance liquid chromatography (HPLC) that 
23 of 130 cosmetic products (18%) (without 
formaldehyde or formaldehyde releasers on the 
package ingredient list) were presenting variable 

amounts (0.5–507 ppm) of formaldehyde 
(Søgaard et al., 2024). 
 
The undeclared presence of formaldehyde in 
industrial products results from the air oxidation 
of ethoxylated alcohols, such as polyethylene 
glycols (Bergh et al., 1998). Polyethylene glycols 
are polymers of ether monomers such as 
ethylene glycol, ethylene oxide, or oxyethylene, 
usually available as mixtures of different chain 
lengths polymers, used as emulsifiers in 
industrialized food and food supplements (E 
1521), medicines (macrogol), cosmetics and 
housecleaning products (Olivier et al. 2024e). 
Even corticoid creams may present 
formaldehyde, mainly when presenting macrogol 
in their composition (Dahlquist et al., 1980). 
 
The methyl ester of the aspartic 
acid/phenylalanine dipeptide (aspartame) may 
also be degraded to formaldehyde and produce 
systemic allergic dermatitis (Veien & Lomholt 
2012, Hill & Belsito 2003, Castanedo-Tardan et 
al., 2009). 
 
Besides producing their characteristic 
hypersensitivity conditions (generalized and 
localized allergic contact dermatitis, airborne 
symptoms such as rhino-conjunctivitis and 
asthma, immediate-type allergies such as 
urticaria and anaphylaxis), hypersensitivity to 
formaldehyde may also aggravate preexisting 
dermatoses, producing flares of atopic dermatitis, 
stasis dermatitis, and rosacea (Goossens & 
Aerts 2022). 
 
Formaldehyde is unanimous among the diverse 
batteries recommended for composing diagnostic 
cutaneous contact test kits (patch tests) 
(Bruynzeel et al., 1995).  
 
When cutaneous tests are inconclusive, the best 
way to diagnose formaldehyde hypersensitivity is 
the exclusion/provocation test, when the patient 
interrupts the use of the suspected allergen until 
the symptoms disappear. Then, the allergen is 
re-introduced to observe reactions. However, this 
is particularly difficult when polysensitization 
dominates the clinical picture. In order to shorten 
the list of suspected allergens, we performed 
triage tests to elect the allergens that will be 
emphasized in the exhaustive in vivo 
exclusion/provocation tests. 
 
Cellular immunoreactivity against haptens and 
hapten-carrier conjugates had been classically 



 
 
 
 

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evaluated by the Leukocyte Adherence Inhibition 
Test (LAIT) (Kuratsuji, 1981). 
 
Humoral immunoreactivity against haptens has 
been classically evaluated by precipitin research 
(Rittenberg & Amkraut 1966). 
 
To evaluate cellular immunoreactivity, we employ 
in our facilities the LAIT (Olivier et al. 2022b, 
Olivier et al. 2022a, Olivier et al. 2022c, Olivier et 
al. 2023b, Olivier et al. 2023a). 
 
To evaluate the humoral immunoreactivity, we 
employ at our facilities the Tube Titration of 
Precipitins (TTP) (Olivier et al. 2021c, Olivier et 
al. 2021e, Olivier et al. 2023c, Olivier et al. 2024f, 
Olivier et al. 2025b). 
 
The present study hypothesizes that the LAIT 
and the TTP may help differentiate diverse 
endotypes and degrees of immunoreactivity 
against formaldehyde among patients suffering 
from non–IgE-mediated atopic and/or contact 
dermatitis. To evaluate the potential of the LAIT 
and the TTP to endotyping non-IgE-mediated 
immunoreactivity against formaldehyde, we 
retrospectively compiled the electronic medical 
charts of patients with these conditions who were 
investigated with these procedures in our 
outpatient clinic.  
 

2. MATERIALS AND METHODS  
 

2.1 Subjects 
 
After receiving Institutional Review Board 
approval from the Instituto Alergoimuno de 
Americana (Brazil; 03/2025), we proceeded with 
the electronic chart review of 10,270 outpatients 
who attended our facility from January 2018 to 
April 2025.  
 
A cohort of 100 outside patients had been 
submitted to TTP with formaldehyde solution for 
presenting Atopic and/or Contact Dermatitis. This 
cohort counted 29 males; mean age 38.8 years; 
SD 19.6 years; range 3 to 90 years; median 38 
years; modes: 7; 9; and 70 years (each appeared 
4 times); geometric mean = 32 years.  
 
A cohort of 100 outside patients had been 
submitted to an ex vivo allergen challenge test 
with formaldehyde solution monitored with LAIT 
for presenting non–IgE-mediated atopic and/or 
contact dermatitis. This cohort counted 29 males; 
mean age 44.7 years; SD 19.1 years; range 9 to 
91 years; median 45 years; modes = 35; 48 and 

58 years (each appeared three times); geometric 
mean = 39.5 years.  
 
This study did not include patients under 
biological and/or systemic anti-inflammatory 
therapy. These procedures were offered to 
patients with clinical suspicion of formaldehyde 
hypersensitivity who demonstrated a non-
reactive or inconclusive skin test performed with 
formaldehyde solution (Olivier et al. 2013). 
 

2.2 Formaldehyde Solution  
 
The formaldehyde solution was prepared with 1.5 
mL of a solution of formaldehyde 10% (Perfyl 
Tech®) diluted to 15 mL with distilled water to 
finalize a 1 mg/mL solution to perform the allergic 
skin tests, TTP and LAIT.  
 

2.3 Ex vivo Investigation: Leukocyte 
Adherence Inhibition Test 

 
2.3.1 Procedure for allergen ex vivo 

challenging  
 
We performed the LAIT as previously described 
(Olivier et al. 2012, Olivier et al. 2014, Olivier et 
al. 2021a, Olivier et al. 2021b, Olivier et al. 
2021d). Shortly, each donor's fresh plasma was 
divided into two parts and used in paralleled ex 
vivo challenging tests with Formaldehyde 
solution and the unchallenged plasma assay. We 
collected plasma with high leukocyte content 
(buffy coat) from the heparinized tube after one 
hour of sedimentation at 37 °C. Then, we 
distributed aliquots of 100 μL into Eppendorf 
tubes kept under agitation for 30 minutes (200 
rpm at 37 °C) with Formaldehyde solution (10μL) 
or without Formaldehyde solution (when used as 
control). 
 
2.3.2 Procedure for adherence assay  
 

After incubation, the plasma was allocated into a 
standard Neubauer hemocytometer counting 
chamber with a plain, non-metallic glass surface 
and left to stand for 2 hours at 37 °C in the 
humidified atmosphere of the covered water bath 
to allow leukocytes to adhere to the glass. Next, 
we counted the leukocytes, removed the 
coverslip, and washed the chamber by 
immersion in a beaker with PBS (phosphate-
buffered saline) at 37 °C. Then, we added a drop 
of PBS to the hemocytometer's chamber and 
allocated a clean coverslip over it. The remaining 
cells were counted in the same squares as 
previously examined.  



 
 
 
 

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2.3.3 Procedure for calculation  
 

The percentage of Leukocyte Adherence (LA) of 
each assay was estimated as: (the number of 
leukocytes observed on the hemocytometry 
chamber after washing divided by the number of 
leukocytes observed on the hemocytometry 
chamber before washing) and multiplied by 100 
(%). The Leukocyte Adherence Ratio (LAR) was 
estimated based on the ratio between the LA 
from the antigen-specific challenged plasma and 
the LA from the unchallenged control plasma: 
LAR = LA of the challenged sample divided by 
LA of unchallenged control plasma multiplied by 
100 (%). To further calculate the Leukocyte 
Adherence Inhibition (LAI), we subtracted the 
LAR from 100 (%). We employed the LAI results 
for the cascade distribution chart and the 
statistics calculations, both performed with the 
help of the Microsoft Excel® statistical package. 
 

2.4 In vitro Investigation: Tube Titration of 
Precipitins (TTP) 

 

As previously reported, a transparent vitreous 
tube array performed the semi-quantitative TTP 
against the Formaldehyde solution (Olivier et al. 
2024b, Olivier et al. 2024c, Olivier et al. 2024a, 
Olivier et al. 2024d, Olivier et al. 2025a). Shortly, 
the patient's blood was collected in a clot-
activator collecting tube. After separation, the 
serum was centrifugated at 2,000 rpm for 10 
minutes. The allergen extracts were allocated in 
sets of eleven glass tubes at progressive 
duplicated serum dilutions. The progressive 
dilutions were combined with the 15 μL of the 

antigen solution with 250 μL of the patient's 
serum, progressively diluted into physiological 
saline solution (NaCl 0,9%) in the dilution ratios 
of 1:1; 1:2; 1:4; 1:8; 1:16; 1:32; 1:64; 1:128; 
1:256; and 1:512. One tube was a blank control 
done with the water and serum to observe 
occasional spontaneous precipitation (Sia Test). 
After 24 hours, the tubes were examined, and 
the titers (the highest dilution factor that yields a 
positive reading) were recorded (Williams & 
Chase. 1971). 
 

3. RESULTS 
 
As a retrospective survey, there was no research 
protocol; therefore, we report the incidental 
immune investigation as registered in the digital 
medical charts. 
 
The TTP showed a distribution concentrated over 
the more diluted titrations (Fig 1). There was no 
negative result. The mean was estimated at 
1:385; the median was 1:512; the standard 
deviation was estimated at 1:166; the mode was 
1:512 (appeared 61 times). All Sia tests were 
negative. 
 
The cascade distribution of LAI results 
demonstrated a wide range (Fig.2). The LAI 
ranged from 0% to 100%. The mean was 57.5%; 
the median was 65.5%; the standard deviation 
was 37.4%; the mode was 0% (appeared eleven 
times). About half the patients presented high 
immunoreactivity during the ex vivo challenge 
test (LAI > 60%). 

 

 
 

Fig. 1. Cascade distribution chart of the tube titration of precipitins (x-axis %) resulting from 
the Formaldehyde solution against the serum of a cohort of 100 tests/subjects (y-axis) 



 
 
 
 

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Fig. 2. Cascade distribution chart of the range groups of Leukocyte Adherence Inhibition (LAI) 
results (x-axis %) of ex vivo formaldehyde solution monitored by the Leukocyte Adherence 

Inhibition Test (LAIT), according to the respective number of outcomes over a cohort with 100 
tests/subjects (y-axis) 

 
All patients evaluated with TTP demonstrated 
some degree of humoral immunoreactivity, and 
most presented positivity by the more diluted 
titrations. Eleven patients did not present cellular 
immunoreactivity against Formaldehyde (LAI = 
zero%), while others presented an extensive 
range of inhibition of the leukocyte adherence 
after the ex vivo provocation test. 

 
4. DISCUSSION 
 
Despite being universally recognized by its 
sensitizing properties, little is known about the 
intrinsic physiopathology of the immunoreactivity 
(or immunoreactivities) against formaldehyde.  

 
Formaldehyde can establish cross-linking 
reactions among several amino acids, producing 
deformation in the proteins' tertiary structure and 
altering their immunoreactivity (Sompuram et al. 
2004, Fraenkel-Conrat et al., 1947; Fraenkel-
Conrat & Olcott, 1948b; Fraenkel-Conrat & Olcott 
1948a). When absorbed into human blood 
current, formaldehyde may conjugate with serum 
proteins, such as the Human Serum Albumin 
(HAS), forming hapten-carrier complexes able to 
develop the production of antibodies (IgE, IgM, 
IgG, and IgA) against their non-self-conjugates 
(Patterson et al. 1986, Patterson et al. 1989). 
IgE-mediated sensitization against formaldehyde 
is not an easy diagnosis but has already been 
described in children exposed to gaseous 
formaldehyde (Kramps et al. 1989, Wantke et al. 

1996a, Wantke et al. 1996b, Mizuki & Tsuda 
2001).  
 

Additionally, to the capacity to produce 
antibodies against the formaldehyde-HAS 
conjugated, analysis of individuals occupationally 
exposed to formaldehyde demonstrated elevated 
T antigen memory cells and lymphocyte 
subpopulations of T-helper/suppressor (H/S) 
ratios ranging from 0.8 to 3.3, suggesting chronic 
antigenic stimulation by formaldehyde (Thrasher 
et al., 1988). 
 

There is no standardized lab examination to 
(unequivocally) diagnose non–IgE-mediated 
formaldehyde hypersensitivity or to suggest 
formaldehyde immunoreactivity. However, 
endotyping the mechanisms responsible for 
allergic phenotypes is crucial for diagnosing and 
supervising treatments under personalized 
medicine and recognizing differential diagnoses 
among phenotypes (Olivier. 2024). Several 
phenotypes have been described; however, the 
endotypes have been poorly explored since the 
main clinical tools to verify hypersensitivity 
against formaldehyde are still the cutaneous 
tests.  
 

As a proof-of-concept, we submitted 
formaldehyde to an ex vivo challenge monitored 
by the LAIT to demonstrate cellular 
immunoreactivity. In the same proof-of-concept 
mentality, we titrated precipitins against 
formaldehyde to demonstrate humoral 



 
 
 
 

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immunoreactivity. Despite non-reactive or 
inconclusive skin tests, we propose these 
procedures to patients with atopic dermatitis 
and/or contact dermatitis with a strong clinical 
suspicion of hypersensitivity to formaldehyde. 
The clinical reasoning to indicate these tests is in 
the assumption that these immunoassays may 
function as triage tests to reinforce the need for a 
more exhaustive diagnostic exclusion-
provocation test (when the patient excludes the 
suspected allergen until the symptoms disappear 
and then re-introduces the allergen to observe 
the reactions). 
 
As a retrospective cohort analysis, there was no 
prospective plan. We spreadsheeted a 
compilation of registered results produced by 
TTP and LAIT, exploring humoral and cellular 
immunoreactivity against formaldehyde. These 
assays provide clues about humoral and cellular 
immunoreactivity, and the results are distributed 
in an extensive spectral range, presumably 
between immune tolerance and symptomatic 
hypersensitivity. Results provided by LAIT and 
TTP were interpreted as markers of the immune 
response after contact with the specific antigen, 
configuring themselves as techniques to identify 
exposition to the antigen, immune stimulation, 
and immunoreactivity, as proposed by the 
exposome-wide association study (Chung et al. 
2024). 
 
At the clinical set, the diagnosis of formaldehyde 
allergy is accomplished by anamnesis, skin tests, 
and in vivo provocation tests; however, when 
employing a multi-omics approach, several 
clinical phenotypes and endotypes may be 
differentiated (Yoon & Bunyavanich 2025). 
 
This retrospective survey demonstrated that the 
TTP and the ex vivo challenge test monitored by 
LAIT against formaldehyde can demonstrate 
significant cellular and humoral immunoreactivity 
in patients diagnosed with atopic and/or contact 
dermatitis. However, these immunoassays did 
not prove per se that hypersensitivity to 
formaldehyde is responsible for these patients' 
symptoms. This association may only be 
confirmed by further in vivo provocation studies. 
 
None of our patients presented an exclusive 
reaction to Formaldehyde. We assessed every 
patient simultaneously with several chemical and 
biological allergens, demonstrating positive 
results for some of them, according to clinical 
suspicions. The most vital suggestion driven by 
the results is that allergic patients may impair 

their symptoms by using creams or cosmetics 
contaminated with formaldehyde. 
 

In our practice, when preceding in vivo 
cutaneous tests with formaldehyde, we observe 
immediate cutaneous reactions (obtained by the 
skin scrape test) and delayed reactions obtained 
by a forty-eight-hour contact test or a 
photosensitized ninety-six-hour contact test 
(patch test). Based on this clinical experience, 
we can hypothesize that at least three endotypes 
are associated with formaldehyde 
hypersensitivity, which may be produced by at 
least three mechanisms: a predominantly 
humoral, a predominantly cellular, and a 
compound of both. 
 

Integrating TTP and LAIT into clinical workflows 
may guide clinicians in identifying hidden 
hypersensitivity due to formaldehyde exposure in 
products and inform safer therapeutic strategies 
for sensitized patients. 
 

5. CONCLUSION 
 

Our preliminary results show that the LAIT and 
TTP may differentiate diverse cellular and 
humoral immunoreactivity degrees against 
formaldehyde in patients clinically diagnosed with 
non–IgE-mediated allergies. LAIT and TTP are 
inexpensive, can be performed with minimum 
laboratory equipment, and can be incorporated 
into strategies to address health disparities in 
respiratory and food allergies (Anagnostou et al., 
2025). As a preliminary report, the propaedeutic 
meaning of the presented results and the 
possibility of interferents must be yet established 
(Anouar et al., 2024). More studies focused on 
the quality-by-design approach with prospective 
larger double-blind cohorts need to evaluate the 
potential contribution of LAIT and TTP for 
endotyping immunoreactivity of patients 
suspected of symptomatic hypersensitivity 
against formaldehyde and other similar 
preservatives (Chiarentin et al., 2023). 
 

6. LIMITATIONS 
 

This study is a retrospective analysis of data 
collected over six years. There was no protocol 
research, no control group, and the subject's 
data were limited to the essentials available on 
our electronic sheets. Therefore, we could not 
establish a cross-comparison between positive 
and negative controls to validate the results. The 
number of subjects is appropriate for a 
preliminary study; however, future studies must 
be more comprehensive. The lack of a research 



 
 
 
 

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77 

 

protocol implies the possibility of a bias produced 
by the physician's point of view, who suggested 
the exam barely on clinical suspicion led purely 
by the anamnesis and physical examination. The 
study lost many of these patients to follow-up, so 
assuring the relationship between the 
immunoassays' results and the patient's clinical 
outcome is impossible. 
 

7. FUTURE DIRECTIONS AND 
RECOMMENDATIONS FOR CLINICAL 
PRACTICE 

 

The primary intended use of in vitro or ex vivo 
allergen challenge tests is to spare the patients 
from being submitted to unnecessary, 
exhaustive, and dangerous in vivo challenge 
tests. Exploring the humoral and the cellular 
arms of immune systems, the TTP and LAIT 
alone or combined may represent, in the near 
future, a tool for allergists to construct an 
etiologic diagnosis from their patients, as well as 
determine the endotypes (mechanisms) of 
hypersensitivity, in order to choose more 
convenient and personalized therapies for them. 
Adding data provided by TTP and LAIT may also 
contribute to streamlining biomedical research 
and improving tools such as Large Language 
Models, usually used by clinicians as a decision 
support system to enhance diagnostic accuracy 
(Abers & Mathias 2025). 
 

CONSENT 
 

As a retrospective survey of results recorded in 
cognito, consent was given collectively by the 
institution's ethics committee following the 
principles of the Declaration of Helsinki (WMA, 
2013). 
 

ETHICAL APPROVALS 
 

The authors have collected and preserved 
written ethical approval per international 
standards. 
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
 

Author(s) hereby declare that NO generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc.) and text-to-image 
generators have been used during the writing or 
editing of this manuscript.  
 

ACKNOWLEDGEMENTS 
 

The Instituto Alergoimuno de Americana funded 
this work. We want to thank the laboratory 
technicians Alessandra Vieira de Oliveira and 

Luciana Sacilotto Carvalho for their help with the 
exams. 

 
COMPETING INTERESTS  
 
Authors have declared that they have no known 
competing financial interests or non-financial 
interests or personal relationships that could 
have appeared to influence the work reported in 
this paper. 

 
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