Date Published: March 28, 2017
Publisher: Public Library of Science
Author(s): Neuza M. Alcantara-Neves, Rafael V. Veiga, João C. M. Ponte, Sérgio S. da Cunha, Silvia M. Simões, Álvaro A. Cruz, Maria Yazdanbakhsh, Sheila M. Matos, Thiago Magalhães Silva, Camila A. Figueiredo, Lain C. Pontes-de-Carvalho, Laura C. Rodrigues, Rosemeire L. Fiaccone, Philip J. Cooper, Maurício L. Barreto, Hsin-Chih Lai.
The dissociation between specific IgE and skin prick test reactivity to aeroallergens, a common finding in populations living in low and middle-income countries, has important implications for the diagnosis and treatment of allergic diseases. Few studies have investigated the determinants of this dissociation. In the present study, we explored potential factors explaining this dissociation in children living in an urban area of Northeast Brazil, focusing in particular on factors associated with poor hygiene.
Of 1445 children from low income communities, investigated for risk factors of allergies, we studied 481 with specific IgE antibodies to any of Blomia tropicalis, Dermatophagoides pteronyssinus, Periplaneta americana and Blatella germanica allergens. Data on demographic, environmental and social exposures were collected by questionnaire; serum IgG and stool examinations were done to detect current or past infections with viral, bacterial, protozoan and intestinal helminth pathogens. We measured atopy by skin prick testing (SPT) and specific IgE (sIgE) to aerollergens in serum (by ImmunoCAP). SIgE reactivity to B. tropicalis extract depleted of carbohydrates was measured by an in-house ELISA. Total IgE was measured by in house capture ELISA. SNPs were typed using Illumina Omni 2.5.
Negative skin prick tests in the presence of specific IgE antibodies were frequent. Factors independently associated with a reduced frequency of positive skin prick tests were large number of siblings, the presence of IgG to herpes simplex virus, Ascaris lumbricoides and Trichuris trichiura infections, living in neighborhoods with infrequent garbage collection, presence of rodents and cats in the household and sIgE reactivity to glycosylated B. tropicalis allergens. Also, SNP on IGHE (rs61737468) was negatively associated with SPT reactivity.
A variety of factors were found to be associated with decreased frequency of SPT such as unhygienic living conditions, infections, total IgE, IgE response to glycosylated allergens and genetic polymorphisms, indicating that multiple mechanisms may be involved. Our data, showing that exposures to an unhygienic environment and childhood infections modulate immediate allergen skin test reactivity, provide support for the “hygiene hypothesis”.
Atopy can be defined by either a positive skin prick test (SPT) or the presence of allergen-specific IgE in serum (sIgE) and, generally in high-income countries, both measurements tend to be consistent in the same individual . It is expected, therefore, that an individual with a detectable sIgE would also have a positive SPT to the same allergen, and vice-versa, but for practical reasons SPT has been more frequently used in clinical practice and research. However, there is growing evidence for a dissociation between SPT positivity and sIgE, particularly in marginalized populations living in low and middle-income countries. The dissociation has been observed either as a negative SPT in subjects with detectable sIgE or, less frequently, as an absence of sIgE in a SPT-positive individual. The ISAAC phase II study involving large samples from affluent and non-affluent populations observed a dissociation between detectable sIgE and negative SPT in four non-affluent study centers ranging 31.1–78.9% . Other studies, conducted in rural children of Europe  or Africa [3,4], have shown also large proportions of children with positive sIgE to be SPT negative for the same allergens. A possible explanation for this dissociation is the down-regulation of allergic effector responses in skin, such that individuals with measurable levels of sIgE fail to develop immediate hypersensitivity responses. Some environmental exposures, in particular helminths [3–5] and other childhood infections [2–6], have been associated with a suppression of in vivo skin immediate (Type I) hypersensitivity responses.
1,355 of 1,445 children enrolled had both SPT and sIgE measured. Detection of serum sIgE equal or above 0.70 kU/L for at least one of four measured allergens (D. pteronyssinus, B. tropicalis, B. germanica and P. americana) or a positive SPT for at least one of the same four allergens was observed in 510 (37.6%) and 401 (29.4%) of the children, respectively. Among all tested children, 2.7%, 2.4%, 4.3% and 8.1%, had positive SPT but were negative for sIgE anti-B. tropicalis D. pteronyssinus B. germanica and P. americana respectively (data not shown).
In the present study, we explored potential factors that might explain the dissociation between SPT and sIgE to the same allergen that has been observed in marginalized populations living in low and middle-income countries (LMICs) such as Brazil. We analyzed data from children living in poor neighborhoods in the city of Salvador in a tropical coastal region of Brazil. Because previous studies have showed a low prevalence of SPT reactivity among children with childhood infections [4,14] we focused in particular on childhood infections, and factors associated with poorly hygienic living conditions. We observed statistically significant inverse associations between SPT reactivity and living in an unhygienic environment (i.e. greater number of siblings, intestinal helminth infections, having household cat and rodent infestations, and infrequent garbage collection) among children with aeroallergen-specific IgE (sIgE) indicating that such an environment may be an important determinant of this dissociation. The observation that distinct factors affected the SPT-sIgE association for D. pteronyssinus and B. tropicalis supports the idea that the mechanisms linking IgE with SPT for these two mites species may be distinct [18,19], although power for the analysis of individual aeroallergens was limited.
In conclusion, we have explored the role of poor hygiene exposures and genetic factors as an explanation for reduced SPT positivity observed in some LMIC settings in children with specific IgE for the same aeroallergens. Our observations do provide support for a role of poor hygiene exposures including childhood infections in mediating this effect, but other factors may have a role including host genetic factors, indicating that diverse mechanisms could be important. Potential mediating mechanisms identified here were increased glycosylation of aeroallergen-specific IgE and high levels of total IgE. A better understanding of how allergic effector responses are modulated could lead to the development of novel strategies for the prevention and control of allergic diseases.