Since the World War II, prevalence of asthma and allergic diseases has been dramatically increasing. This phenomenon is thought to be mainly due to environmental changes. Since Strachan reported the association between allergy and environment, especially hygiene status, the mechanisms how environmental factors affect allergy are still not fully understood. For several decades, association of environment with allergy has been investigated using single exposure studies, which are not enough to clarify the etiology of a complex multifactorial disease, such as asthma. Recently, the concept of exposome can offer an alternative approach to improve our understanding of the mechanistic connection between exposure to various environmental factors and asthma. These developments will lead to better strategies for preventing the development and deterioration of asthma.

This review focuses on the role of food as a risk/aggravation factor for atopic dermatitis (AD). With respect to the causal association between AD and food allergy (FA), AD has recently been recognized as a cause, rather than a result, of FA. The potential risk of specific food elimination as a treatment for AD has thus been a concern. With respect to the relationships among diet, obesity and AD, the dietary patterns of children and/or mothers during pregnancy and lactation have been shown to affect the clinical course of AD. Further, obesity has been noted as a causal and/or aggravating factor for AD. Possible mechanisms include changes in the intestinal environment, increases in inflammatory adipocytokines and Th17 deviation. However, to date, the level of evidence remains relatively low regarding the relationship between food and not only AD, but also human health as a whole. Further progress in this field is expected.

In infants, reported risk factors of food sensitization and allergies include a family history of allergy, decreased function of the skin barrier, exposure to environmental food allergens, and lack of sunlight exposure. Dermatitis treatment is recommended to prevent entry of food allergens into the skin, and timely transition to baby food may help to build oral tolerance of allergens. After infancy, high titers of allergen-specific IgE antibodies become an important factors of persistent food allergies. Management of food allergies include food elimination and, to build tolerance, regular ingestion of tolerated amounts of food to which a patient is allergic. Risk factors for food-induced anaphylaxis include those related to the allergen (such as doses of allergen ingested and allergen-specific characteristics), patient behaviors (such as exercise, drug use, and ability to use an epinephrine auto-injection kit), other intrinsic factors (such as allergen-specific IgE levels, gender, comorbid asthma, and infection status), and patient compensation mechanisms (such as responses by the immune, endocrine, and circulatory systems). Patients should practice particular caution regarding triggers and co-factors such as allergen exposure, drug use, and exercise. In case of anaphylaxis, patients should be instructed to take appropriate actions such as adrenaline self-injection and prompt visit to emergency care.

The so-called hygiene hypothesis that increased exposure to certain microorganisms during early childhood protects against the development of allergy, began with an epidemiological study reported in 1989. The study demonstrated that the prevalence of allergic rhinitis decreased with an increase in the number of siblings, especially older ones, and that the effect extended into adulthood.

Thirty years after the publication of the study, Japan has become more hygienic, and the birthrate continues to decline, and then the association between the number of sibling and the prevalence of allergic rhinitis in adulthood is not clear. However, the more hygienic counter measures against covid-19, such as social distancing and mask wearing, did not always have negative effects on allergic rhinitis. Because the impact of the measures on the development of pediatric allergic diseases is still unclear, the present article aims to assess their effects on the onset or exacerbation of allergic rhinitis based on currently available data.

Recent research has shown that feeding allergenic foods in infancy has a greater inhibitory effect on the development of food allergies (FA) than eliminating the allergenic foods in infancy. In future, FA research is expected to shift toward prevention rather than treatment. However, dietary guidance for infants at high risk of FA must be conducted in a safety manner, and methodologies for such strategies must be established as early as possible. We conducted a multicenter randomized trial in infants with atopic dermatitis to compare the subsequent development of FA to mixed powder (MP) consisting of a mixture of dried egg white, powdered milk, wheat, soy, peanuts, buckwheat and gut flora preparations, versus placebo. The results showed that the MP group had significantly fewer FA episodes than the placebo group. Adverse reactions experienced were minor, such as facial redness after administration, but none were serious. Treating eczema from infancy and carefully early feeding of allergenic foods may prevent many FA.

Passive smoking is associated with the risk of decreased respiratory function as well as the onset and severity of asthma in children. It is also associated with elevated total IgE levels and sensitization to food and inhalant allergens. Maternal smoking during pregnancy negatively affects fetal lung development and leads to decreased respiratory function after birth. In addition, it elevates the risks of decreased respiratory function and severe asthma in school-aged children. Passive smoking in pregnant women reduces the number of regulatory T cells in umbilical cord blood by epigenetic mechanisms, thus increasing the risk of atopic dermatitis, allergen sensitization, and wheezing during infancy. Evidence indicates that passive smoking increases disease risk due to exposure to tobacco smoke, and any interventions that legislate prevention of passive smoking decrease disease risk. Notably, the current global standard is that people are protected by legislations with penalties that were established based on the WHO Framework Convention on Tobacco Control (FCTC), which bans smoking in all public places. The risk of allergic diseases caused by passive smoking can be prevented or reduced by achieving the goals of the FCTC and maintaining an appropriate smoke-free environment consistently from the fetal period to adulthood.

Allergy is an immunologic reaction to an innocuous antigen. Therefore, its main sites are the skin and mucosa, which are the interface between the inside and outside of the body. The intestinal microbiota has a symbiotic relationship with the human host, influencing the immunologic reaction by acting on the immune cells of the intestinal tract, and also affecting the barrier function by acting on the intestinal epithelium. Abundant factors associated with the development of allergic diseases indicate the involvement of the intestinal microbiota, and the intestinal microbiota are implicated in the development of allergy. However, the clinical question of whether intervention to the intestinal microbiota can prevent allergy is not easy to answer. Some systematic reviews suggest that probiotics may have a preventive effect on atopic dermatitis. However, current guidelines to allergic diseases do not recommend probiotics or prebiotics for prevention, because of insufficient evidence. Although the conditions for intervention with intestinal microflora are not inconclusive at present, results of future studies are highly anticipated.

I describe alpha-Gal syndrome, pork-cat syndrome, and bird-egg syndrome as examples of food allergies that begin with animal sensitization (Table 1). Alpha-Gal syndrome is more common in adults to the elderly with blood group A or O, pork-cat syndrome is more common in children to adults with a history of cat breeding, and bird-egg syndrome is more common in adult women raising birds. All of these diseases can be cured by appropriate diagnosis and appropriate management. This article introduces the diagnosis and treatment of food allergies that begin with animal sensitization, especially alpha-Gal syndrome, pork-cat syndrome and bird-egg syndrome.

People with pollen allergy may cause allergic reactions immediately following ingestion of certain uncooked plant foods containing cross-reacting proteins to pollen allergen, which pathology is called pollen-food allergic syndrome. It is caused by the cross-antigenicity of the protein family of Bet v 1 homologues found in pollen and fruits. Symptoms are less likely to occur if the product is heat-treated. This is due to the heat-labile and denaturable three-dimensional structure of this protein. On the other hand, people with cypress pollen allergy who experienced allergy to fruits, have been reported in southern France, and the involvement of allergen 'Gibberellin-regulated protein (GRP) ' is a causative antigen in PFAS. GRP is a protein reported as the cause of severe peach allergies. Although it is a small molecule, it has 6 pairs of S-S bounds, it has a stable three-dimensional structure against heat, and has a strong resistance to digestive enzymes, so it can be sensitized to the intestinal tract. Therefore, the problem is that the allergic symptoms spread to the whole body and allergic symptoms become severe. Since it has also been reported in Japanese cedar pollen, GRP is expected to become an important issue in PFAS in Japan.

Gibberellin-regulated proteins (GRPs) are known as a causative allergen for severe fruit allergies. To date, five GRPs, including Peach Prup 7, Ume Pru m 7 and Orange Cit s 7, have been registered internationally. GRPs are resistant to heat and digestive enzymes. GRPs cause the clinical form of food-dependent exercise-induced anaphylaxis due to the involvement of cofactors such as exercise. Clinically, eyelid edema and laryngeal tightness are frequently observed. We should pay attention to false-negative results for allergen sources in specific IgE antibody measurements. In recent years, GRPs derived from Japanese cedar pollen Cry j 7 and cypress pollen Cup s 7 have been identified. The recent reports suggested that cross-reactivity between fruit GRPs and Cry j 7 could result in pollen-food allergy syndrome.

Natto allergy is representative of late-onset anaphylaxis, which usually develops about half a day after ingestion. Patients frequently develop generalized urticaria, dyspnea, even hypotension and loss of consciousness. The major allergen is poly-γ-glutamic acid (PGA), which consists of mucilage of natto. The route of sensitization to PGA is presumed to be skin due to jellyfish sting. Interestingly, approximately 90% of natto-allergic patients have a history of marine sports.

Crustaceans belong to the subphylum Crustacea of the phylum Arthropoda, and include shrimp, crabs, and mantis shrimp. The 2022 National Monitoring Survey of Immediate Type Food Allergy ranked crustaceans as the eighth most likely food to cause food allergies in people of all ages, and the first and second most likely food to cause first-case allergies in 7-17 year olds and those older than 18 years, respectively. Most allergy cases occur after school age. Immediate-type symptoms are common. Crustaceans frequently cause food-dependent exercise-induced anaphylaxis. Prognosis is largely unreported, but tolerance acquisition is thought to be low. The major allergen in the crustacean subphylum is considered to be tropomyosin, but other allergens such as arginine kinase, myosin light chain, and myofibrillar calcium-binding protein have been reported. These components have high amino acid sequence homology in the arthropod phylum, and cross-antigenicity has been confirmed not only within the crustacean subphylum, but also between the chelicerata and hexapod subphyla of the arthropod phylum and the crustacean subphylum. Specific IgE antibody tests for crude antigens are insufficient both sensitivity and specificity, and the utility of component-specific IgE antibody tests is being investigated, but there are many other issues, including regional differences.

Allergy to tree nuts is on the rise in Japan: tree nuts were the third most common causative allergen in a national survey of immediate-type reactions in 2020 and the most reported causative allergen in a comprehensive survey of pediatric anaphylaxis conducted in Aichi Prefecture. Walnuts, cashews, almonds, and macadamia nuts, in that order, are the most frequently ingested tree nuts. The usefulness of component-specific IgE antibody titers in diagnosing tree nut allergy has been widely reported. Measurement of specific IgE titers of Jug r 1 and Ana o 3 allergens, which are 2S albumins in walnuts and cashew nuts, respectively, are covered by universal health insurance in Japan. Due to reported cutoff points of 0.98 U_A/mL for Jug r 1 and 2.20 U_A/mL for Ana o 3 for 95% positive predictive value, patients with values higher than these should be regarded as allergic to the specific nuts. Specific IgE antibody titers against 11S globulin in almonds and 7S globulin in macadamia nuts have also been reported to have diagnostic utility. Oral immunotherapy has been reported to be effective for tree nut allergies.

Parvalbumin is a sarcoplasmic protein and a major fish allergen. It is present in nearly all fish species, and patients with fish allergies often exhibit symptoms after consuming multiple fish species due to cross-reactivity between fish species. Over 10 types of other allergens, including collagen, aldolase, and enolase, have been reported. Scombroid poisoning and Anisakis allergy are important differential diseases. Fish allergy diagnosis cannot be made based on the specific immunoglobulin E antibody alone in many cases. Ultimately, a confirmatory oral food challenge test is required. Fish is a major source of vitamin D. Moreover, increasing the number of fish species that can be ingested is important from a nutritional perspective. Fish stock and canned tuna can be consumed without symptoms in many cases. Redfish, such as tuna, marlin, and skipjack are low in parvalbumin and are good candidates to try first. Thus, immunotherapy using hypoallergenic fish is being attempted as a new treatment.

Fish roe is an important allergen in Japan, with immediate-type symptoms often occurring in children aged 1-6 years. Salmon roe allergy accounts for about 95% of all cases, with only a few reports of pollock roe allergy and capelin roe allergy. The β'-component of vitellogenin, a precursor of egg yolk protein, is considered the major allergen in fish roes. It has been reported that specific IgE antibody levels can predict salmon roe allergy, and thus predict a positive result in an oral food challenge test. On the other hand, it has been reported that the ratio of pollock roe-specific IgE antibody titer to salmon roe-specific IgE antibody titer is useful in predicting positivity for pollock roe allergy. Research on fish roe allergies other than salmon and pollock is extremely limited, and there have been few studies on capelin roes, which are often served in school lunches in Japan. Recently, there have been some reports of caviar allergies reported overseas, suggesting that there may be regional differences in intake status. Studies on fish roe allergy are generally lacking, and further research is required on the topic in the future.

Objective: Few studies have been conducted on low dose oral food challenge (OFC) for severe peanut allergy in Japan. We aimed to determine an appropriate dose for the OFC for severe peanut allergy.

Methods: This retrospective study included patients who had allergic reactions to peanuts or had serum Ara h2-specific IgE levels of 4.0 UA/mL or higher and received a small dose (0.1 g or 0.3 g) of peanuts for OFCs at Showa University Hospital between January 2015 and December 2021. The OFCs were performed using an escalating 2-dose method involving an interval of 40 min.

Results: In total 51 cases were included, of which 33 were from the 0.1 g group and 18 were from the 0.3 g group. No significant differences were noted in background factors and allergen-specific IgE levels in both groups. The OFC-positive rate was significantly higher in the 0.3 g group (72.2%) than in the 0.1 g group (33.3%). A comparison of symptom grades by positive threshold dose showed that patients with a positive threshold of 0.03 g (1/3 amount of 0.1 g) had lower symptom grades than those with a threshold of 0.1 g (3/3 amount of 0.1 g and 1/3 amount of 0.3 g) or a threshold of 0.3 g (3/3 amount of 0.3 g).

Conclusion: The challenging dose for OFC for severe peanut allergies should be set to 0.1g or less.

We experienced two cases with anaphylactic symptoms after ingestion of macadamia nuts. In case 1, a moisturizer containing macadamia nut oil was used for a year before the onset of symptoms. Thus, skin sensitization was suspected. In both cases, prick-to-prick test with roasted macadamia nuts were positive. Antigenic protein of macadamia nuts was extracted and reacted with the patient's serum by immunoblotting, detecting positive bands around 20kDa, 50 kDa, 60kDa, and 65 kDa in case 1, as well as around 18kDa, 20 kDa, 50 kDa, 60kDa in case 2. As what we know of, no IgE binding has been reported for the 60kDa, 65 kDa protein in previous studies. The involvement of skin sensitization should be investigated by further identification of macadamia nut antigenic proteins and components, as well as analysis of oil components.

Purpose: To examine the changes in food allergy (FA) management in nurseries.

Methods: A questionnaire survey was conducted in August 2021 in all licensed nurseries in Shiga Prefecture, Japan, and the results were compared to those of a survey conducted with the same methods and in the same area in 2013. The chi-square test was used to analyze the differences, and P-values <0.05 were considered to indicate statistical significance.

Results: In 2021, 261 nurseries (74.6% of the total; included 30,047 children) were included in the analysis. Compared to the results of 2013, the percentage of nurseries using the FA management instruction sheet prepared by the Ministry of Health, Labour and Welfare, and the percentage of nurseries with children who carry an epinephrine auto-injector (EpiPen^®) significantly increased. The percentage of nurseries that were ready to use an EpiPen^® in case of emergency also increased. There was a significant decrease in the percentage of nurseries that had experienced an allergic reaction event on-site within the past year, but there was no significant difference in the percentage of nurseries that had experienced a grade 2 or higher allergic reaction event.

Conclusions: The number of children who carry an EpiPen^® has increased, and the management of children with FA has improved. However, more efforts are needed for the management of severe cases.

Lichenification is a chronic lesion of atopic dermatitis (AD) and results mainly from thickening of the skin due to repeated scratching. Lichenified lesions are usually intractable, and treatment using steroid ointments is invariably challenging. We investigated the efficacy of dupilumab in management of overall skin lesions of the head and neck, upper and lower extremities, and the trunk in patients with childhood-onset AD; we particularly focused on its effects on lichenification.

The study included four patients with AD onset in infancy, in whom dupilumab treatment was initiated at ≥15 years of age. We recorded the Eczema Area and Severity Index (EASI) score for each of the 4 symptoms (Erythema Edema/Papulation Excoriation Lichenification) at the following time points: before, 1 month after, 2 months after, 6 months after, and 12 months after treatment initiation.

Four patients were diagnosed with AD in infancy and continued to receive treatment. The EASI score for lichenification alone at the time of dupilumab initiation ranged from 3.2 to 13.2; however, the EASI score improved within 4 to 12 weeks of drug therapy. EASI scores for manifestations other than lichenification also improved.

Dupilumab effectively treated generalized lichenified skin lesions in patients with childhood-onset AD.

Parvalbumin, a major allergen of fish, is present in almost all fish species. Individuals with an allergy to fish often present with allergic symptoms to multiple fish species and tend to test positive for specific IgE antibodies to multiple fish species. We report a case in which all measurable fish-specific IgE antibody titers were negative and the patient, a 10-year-old Japanese boy, had allergic symptoms only to yellowtail and greater amberjack. He had no history of food allergy. After eating yellowtail and greater amberjack at a school lunch, he developed generalized urticaria and abdominal pain while running in the school yard. The results of a skin prick test were positive for yellowtail and suspiciously positive for greater amberjack. An oral food challenge test (OFC) was performed to confirm the diagnosis. The results showed that yellowtail induced generalized urticaria and abdominal pain, and greater amberjack induced anaphylaxis. The patient was able to consume fish other than these two species, and all measurable fish-specific IgE antibody titers were negative, suggesting that allergens specific to the two fish species, as opposed to parvalbumin, were the cause. This patient's case emphasizes that individuals presenting with allergic symptoms to only a limited number of fish species require close attention.