The prevalence of ocular allergies has been increasing worldwide for the past several decades. The geographical distribution and hot spots of rhinoconjunctivitis have been documented in a global survey by the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC indicated that Africa, Latin America, and Japan were notable for their high prevalence of rhinoconjunctivitis. The outcomes of follow-up studies of regional differences and the characteristics of allergic conjunctivitis are summarized in this review.

Currently, comorbid diseases and socioeconomic and environmental factors, including climate and air pollution, are proposed to contribute to the regional differences in the prevalence of allergic conjunctivitis. Of them, rhinitis has been shown repeatedly to be significantly associated with allergic conjunctivitis. Their mechanistic aspects on association with the prevalence of systemic allergic diseases have been reviewed by examining the birth cohort or in vitro analyses.

A vision threatening form of ocular allergy, vernal keratoconjunctivitis, is prevalent in the African countries and Japan. Of the proposed associated factors, air pollution was shown to contribute not only to aggravating the symptoms but also to the increase in the incidence of its severe forms. Its mechanistic aspects are discussed in this review in the context of comorbid diseases.

Allergic conjunctival diseases (ACDs) are inflammatory diseases of the conjunctiva and cornea caused predominantly by the IgE-mediated immediate hypersensitivity response. Allergic conjunctival diseases include allergic conjunctivitis, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis. In clinical practice of ACDs, an ocular allergy test using biomarker measurement is a crucial examination technique for diagnosing, evaluating severity, and determining the efficacy of medical treatment. The ocular allergy test includes the tear test for evaluating the concentration of biomarkers in tears and an ocular surface test for assessing the expression levels of messenger ribonucleic acid (mRNA) biomarkers on the ocular surface. The clinical usefulness of several biomarkers has been demonstrated in patients with ACDs; specifically, eosinophil cationic protein and eotaxin-2 as eosinophilic inflammation biomarkers; interleukin-4 and thymus and activation regulated chemokine (CCL17/TARC) as Th2 inflammation biomarkers; eotaxin, tumor necrosis factor-alpha and soluble IL-6 receptor as giant papillae biomarkers; and osteopontin and periostin as allergic inflammation and remodeling biomarkers. Furthermore, the ocular allergy test, quantitative evaluation methods using biomarkers have allowed for better understanding of the immunological and pathophysiological mechanisms of ACDs. Therefore, the search for a biomarker is important to make an ocular allergy test useful. In previous ocular allergy tests, the biomarkers for allergic inflammation in patients with chronic ACDs including VKC and AKC were substantial. However, the selection of biomarkers associated with the early phase reaction of immediate hypersensitivity and innate immunity responses needs to be addressed in future investigations.

We have summarized the past efforts and results of objective measurement methods for conjunctival hyperemia classification. Severity classification using conjunctival blood vessel occupancy rate, ocular surface temperature analysis, and artificial intelligence have been reported to be clinically useful, as they have been found to correlate with the severity of conjunctival hyperemia by doctors. The AI method using slit lamp microscope images, whose main purpose is to be widely used in daily clinical practice, can be spread all over the world. As a result, it may lay the foundation for clinical research using large amounts of clinical data collected on the same basis without human bias.

Allergic conjunctivitis affects approximately 15-20% of the global population and can permanently deteriorate one's quality of life (QoL) and work productivity, leading to societal work force costs. Although not fully understood, allergic conjunctivitis is a multifactorial disease with a complex network of environmental, lifestyle, and host contributory risk factors. To effectively enhance the quality of treatment for patients with allergic conjunctivitis, as well as other allergic diseases, the field must first comprehend the pathology underlying various individualized subjective symptoms and stratify the disease according to risk factors and presentations. Such competent stratification and societal reconstruction that targets the alleviation of the damage due to allergic diseases would greatly help ramify personalized treatments and prevent the projected increase in societal costs imposed by allergic diseases.

Owing to the rapid advancements in the information and technology sector, medical big data are greatly accessible and useful to decipher the pathophysiology of many diseases. Such data collected through multi-omics and mobile health have been effective for research on chronic diseases including allergic and immune-mediated diseases. Novel big data containing vast and continuous information on individuals with allergic conjunctivitis and other allergic symptoms are being used to search for causative genes of diseases, gain insights into new biomarkers, prevent disease progression, and, ultimately, improve QoL. The individualized and holistic data accrued from new angles using technological innovations are helping the field realize the principles of P4 medicine: predictive, preventive, personalized, and participatory medicine.

Bronchial asthma is characterized by chronic airway inflammation, which manifests clinically as variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma may induce airway remodeling and become intractable. The prevalence of asthma has increased; however, the number of patients who die from it has decreased (1.3 per 100,000 patients in 2018). The goal of asthma treatment is to control symptoms and prevent future risks. A good partnership between physicians and patients is indispensable for effective treatment. Long-term management with therapeutic agents and the elimination of the triggers and risk factors of asthma are fundamental to its treatment. Asthma is managed by four steps of pharmacotherapy, ranging from mild to intensive treatments, depending on the severity of disease; each step includes an appropriate daily dose of an inhaled corticosteroid, which may vary from low to high. Long-acting β₂-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs, while anti-immunoglobulin E antibodies and other biologics, and oral steroids are reserved for very severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β₂-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by selecting treatment steps for asthma based on the severity of the exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-exacerbated respiratory disease, and pregnancy are also important conditions to be considered in asthma therapy.

Allergen-specific immunotherapy (AIT) is the mainstay treatment for the cure of allergic disorders, with depicted efficacy and safety by several trials and meta-analysis. AIT impressively contributes to the management of allergic rhinitis, asthma and venom allergies. Food allergy is a new arena for AIT with promising results, especially via novel administration routes. Cell subsets with regulatory capacities are induced during AIT. IL-10 and transforming growth factor (TGF)-β are the main suppressor cytokines, in addition to surface molecules such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) within the micro milieu. Modified T- and B-cell responses and antibody isotypes, increased activity thresholds for eosinophils, basophils and mast cells and consequent limitation of inflammatory cascades altogether induce and maintain a state of sustained allergen-specific unresponsiveness. Established tolerance is reflected into the clinical perspectives as improvement of allergy symptoms together with reduced medication requirements and evolved disease severity. Long treatment durations, costs, reduced patient compliance and risk of severe, even life-threatening adverse reactions during treatment stand as major limiting factors for AIT. By development of purified non-allergenic, highly-immunogenic modified allergen extracts, and combinational usage of them with novel adjuvant molecules via new routes may shorten treatment durations and possibly reduce these drawbacks. AIT is the best model for custom-tailored therapy of allergic disorders. Better characterization of disease endotypes, definition of specific biomarkers for diagnosis and therapy follow-up, as well as precision medicine approaches may further contribute to success of AIT in management of allergic disorders.

Strategic Outlook toward 2030: Japan's Research for Allergy and Immunology (Strategy 2030) is the national research strategy based on Japan's Basic Law on Measures Against Allergic Diseases, a first of its kind worldwide. This strategy was established by a multi-disciplinary committee consisting of administrators of the Ministry of Health, Labour and Welfare of Japan, young and senior experts from various research societies and associations, and representatives of patient and public groups. Whereas the issues of transition, integration, and international collaboration have yet to be solved in this research realm in Japan, identification of unmet needs, digitization of information and transparent procedures, and strategic planning for complex problems (a process dubbed MIERUKA by the Toyota Way) are crucial to share and tackle the same vision and goals. The committee developed three specific actions focusing on preemptive treatment, interdisciplinarity and internationality, and life stage. The real success of Strategy 2030 is made by the spontaneous contributions of doctors, dentists, veterinarians, and other medical professionals; basic and clinical research scientists, research supporters, and pharmaceutical/medical device companies; manufacturers of food, healthcare, and home appliances; and patients, their families, and the public. The hope is to establish a stable society in which people can live long, healthy lives, as free as possible from allergic and immunological diseases, at each individual life stage. This article is based on a Japanese review first reported in Arerugi, introduces the developmental process and details of Strategy 2030.

Background: Hospitalization is a major cause of medical expenditure for asthma. Budesonide inhalation suspension (BIS) may assist in reducing asthma-related symptoms in severe asthma exacerbation. However, its effectiveness for hospitalized patients remains poorly known. The objective of this study is to determine associations of BIS with asthma hospitalization.

Methods: We retrospectively analyzed 98 patients who were admitted to our hospital due to severe asthma exacerbation (24 treated with BIS in combination with procaterol) from April 2014 to January 2019. Length of stay, recovery time from symptoms (wheezes), and hospitalization costs were compared between the 2 groups according to clinical factors including the use of BIS and sings of respiratory infections (i.e. C-reactive protein, the presence of phlegm, and the use of antibiotics). Multivariate logistic regression analysis was performed to determine factors contributing to hospitalization outcomes.

Results: The use of BIS was associated with shorter length of stay, faster recovery time from symptoms, and more reduced hospitalization costs (6.0 vs 8.5 days, 2.5 vs 5.0 days, and 258,260 vs 343,350 JPY). Signs of respiratory infection were also associated with hospitalization outcomes. On a multivariate regression analysis, the use of BIS was a determinant of shortened length of stay and reduced symptoms and medical costs for asthma hospitalization along with signs of respiratory infection.

Conclusions: BIS may contribute to shorten length of hospital stay and to reduce symptoms and medical expenditure irrespective of the presence or absence of respiratory infection.

Background: In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV₁), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%).

Methods: Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV₁, asthma control, asthma-related quality of life, and markers of type 2 inflammation.

Results: In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV₁ at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV₁ improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils.

Conclusions: In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity.

Background: There is very limited evidence regarding long-term prognosis of chronic cough. We examined longitudinal outcomes among patients with chronic cough, and explored predictors of cough persistence.

Methods: A retrospective cohort was constructed of adults who had newly visited a specialist cough clinic in 2012-2013. All had undergone systematic investigation for chronic cough. The Hull Airway Reflux Questionnaire (HARQ) was administered to assess reflux cough symptoms. A follow-up survey was conducted in 2016-2017 to assess cough persistence.

Results: From 418 candidates, 323 participated in the follow-up study; main analyses focused on patients with chronic persistent cough (n = 64; 19.8%) and remitted cough (n = 193; 59.8%). Compared with remitted cough group, chronic persistent cough group had more family history of chronic cough (17.2% vs. 4.7%, p = 0.001) and cold air-sensitive cough (62.5% vs. 44.6%, p = 0.013). The total HARQ score did not differ; however, two items (cough with eating and cough with certain foods) scored significantly higher in chronic persistent cough. In multivariate analyses, a family history of chronic cough (adjusted odds ratio 4.27 [95% confidence interval 1.35-9.89]), cold air-sensitive cough (2.01 [1.09-3.73]), and cough with eating (1.22 [1.02-1.45]) were associated with chronic persistent cough at 4 years.

Conclusions: Cough persists in about 20% of patients after 4 years following systematic assessment and treatments. Several cough characteristics, such as family history, cold air-sensitivity, or reflux cough, may be associated with cough persistence. Larger cohort studies are warranted to further understand long-term prognosis and confirm predictors of persistence in patients with chronic cough.

Background: Condition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear.

Methods: We analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B₂ (TXB₂), prostaglandin D₂-methoxime (PGD₂-MOX), and leukotriene B₄ (LTB₄) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays.

Results: The log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB₂ levels seemed to increase. However, the log LTB₄ and log PGD₂-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV₁) in the BA-SAR-JCP group (r = -0.52, p < 0.01).

Conclusions: In the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.

Background: We examined the feasibility, efficacy and safety of slow low-dose oral immunotherapy (SLOIT) for egg, milk, wheat allergies, with accepted severity-stratified initial and maintenance doses.

Methods: Children with food allergies defined by low-dose oral food challenges (LD-OFCs) to hen's egg (cumulative protein dose up to 983 mg, n = 133), cow's milk (287 mg, n = 50), and wheat (226 mg, n = 45) were recruited. Participants were divided into two groups [SLOIT and control (complete avoidance]) based on their preferences. Participants who selected SLOIT were instructed to take the safe dose daily, with monthly increases, aiming to increase the dose by 10 times in one year. The primary outcome was the proportion of participants who passed the LD-OFCs following 1 year of therapy.

Results: The participants in SLOIT group ingested their antigen 92.9% of the therapy's day on average. The proportion of participants who passed LD-OFCs was 35.9% (61/170) in the SLOIT group and 8.7% (4/46) in the control group (P < .001); no large differences were observed among allergens. Among the subjects who failed LD-OFCs, the median change in the total dose in the LD-OFC was 235% (interquartile range: 100%-512%) in the SLOIT group and 100% (42%-235%) in the control group (P < .001). Provoked allergic symptoms were observed in only 0.58% (280/48,486) per programmed intake and approximately 50% of the SLOIT group did not experience any obvious allergic symptoms throughout therapy.

Conclusions: SLOIT showed significant feasibility, efficacy and safety, providing a promising option to manage patients with severe food allergies.

Background: Pollen food Syndrome (PFS) to Rosaceae fruits and soybean, related to Bet v 1 homologue sensitization has been reported increasingly throughout Japan, possibly due to the wide distribution of alder.

Methods: In 2015, we conducted a school-based questionnaire survey among two age groups; students in primary school (Years 1-2) and secondary school (Years 8-9) from each of the 47 prefectures of Japan. We analyzed the prevalence, demographic and clinical characteristics of children with oral symptoms to Rosaceae fruits/soybean; defined as oral symptoms occurring shortly after ingesting apple, peach, cherry or soybean. Additionally, we assessed the correlation between the prevalence and external data on alder sensitization rates by prefecture.

Results: Responses from 41,264 primary and 35,302 secondary school students were analyzed. The prevalence of oral symptoms to Rosaceae fruits/soybean was 0.99%, 95%CI: 0.89-1.09% and 2.75%, 95%CI: 2.59-2.93% among each age group, respectively. Children with oral symptoms were more likely to have parental and personal history of allergic disease compared to those without symptoms. Oral symptoms were experienced more often in children with severe spring allergic rhinitis or have both allergic rhinitis and wheeze. There was a strong correlation between the prevalence of oral symptoms and alder sensitization rates by prefecture among both age groups (r = 0.63, p < 0.001 and r = 0.76, p < 0.001, respectively).

Conclusions: Oral symptoms to Rosaceae fruits/soybean, which is suggestive of PFS was reported by 1-3% Japanese school children. It was associated with the geographic alder sensitization rate, supporting the underlying sensitization to Bet v 1.