The Japanese Guideline for Childhood Asthma (JGCA) 2020 is a translation of the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL) 2017 into English, which was published by the Japanese Society of Pediatric Allergy and Clinical Immunology. It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. These guidelines will be of interest to non-specialist physicians involved in the care of children with asthma. In JPGL, JPGL2017 is the first evidence-based guidelines updated according to the GRADE system and Minds approach, and it addresses eight clinical questions about the treatment of childhood asthma. In children aged ≤5 years, infant and preschool asthma is diagnosed according to the response to short acting beta2 agonists or the effect of a therapeutic trial during 1 month with controller treatment and worsening after treatment cessation. Long-term management both promotes pharmacological therapy and measures against risk factors that induce exacerbation, better patient education and a partnership with trinity. In addition, long-term management should not be carried out without review but rather be based on a cycle of evaluation, adjustment and treatment. In JPGL2017, the transdermal patch and oral beta2 agonists are positioned as drugs within the concept of “short-term additional treatment” to be used until the symptoms are stabilized when the control state transiently deteriorates.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today.

To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

The definition, classification, pathogenesis, test methods, clinical findings, criteria for diagnosis, and therapies of allergic conjunctival disease are summarized based on the Guidelines for Clinical Management of Allergic Conjunctival Disease 2019. Allergic conjunctival disease is defined as “a conjunctival inflammatory disease associated with a Type I allergy accompanied by some subjective or objective symptoms.” Allergic conjunctival disease is classified into allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. Representative subjective symptoms include ocular itching, hyperemia, and lacrimation, whereas objective symptoms include conjunctival hyperemia, swelling, folliculosis, and papillae. Patients with vernal keratoconjunctivitis, which is characterized by conjunctival proliferative changes called giant papilla accompanied by varying extents of corneal lesion, such as corneal erosion and shield ulcer, complain of foreign body sensation, ocular pain, and photophobia. In the diagnosis of allergic conjunctival diseases, it is required that type I allergic diathesis is present, along with subjective and objective symptoms accompanying allergic inflammation. The diagnosis is ensured by proving a type I allergic reaction in the conjunctiva. Given that the first-line drug for the treatment of allergic conjunctival disease is an antiallergic eye drop, a steroid eye drop will be selected in accordance with the severity. In the treatment of vernal keratoconjunctivitis, an immunosuppressive eye drop will be concomitantly used with the abovementioned drugs.

Atopic dermatitis (AD) is a disease characterized by relapsing eczema with pruritus as a primary lesion, which is frequently encountered in clinical practice. Skin barrier dysfunction leads to enhanced skin irritability to non-specific stimuli and epicutaneous sensitization. In the lesion site, a further inflammation-related reduction in skin barrier function, enhanced irritability and scratching-related stimuli deteriorate eczema, leading to vicious cycle of inflammation. The current strategies to treat AD in Japan from the perspective of evidence-based medicine consist of three primary measures: (i) the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation; (ii) topical application of emollients to treat the cutaneous barrier dysfunction; and (iii) avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. The guidelines present recommendations to review clinical research articles, evaluate the balance between the advantages and disadvantages of medical activities, and optimize medical activity-related patient outcomes with respect to several important points requiring decision-making in clinical practice.

Five years have passed since the Japanese Pediatric Guideline for Food Allergy (JPGFA) was first revised in 2011 from its original version. As many scientific papers related to food allergy have been published during the last 5 years, the second major revision of the JPGFA was carried out in 2016. In this guideline, food allergies are generally classified into four clinical types: (1) neonatal and infantile gastrointestinal allergy, (2) infantile atopic dermatitis associated with food allergy, (3) immediate-type of food allergy (urticaria, anaphylaxis, etc.), and (4) special forms of immediate-type of food allergy such as food-dependent exercise-induced anaphylaxis and oral allergy syndrome (OAS). Much of this guideline covers the immediate-type of food allergy that is seen during childhood to adolescence. Infantile atopic dermatitis associated with food allergy type is especially important as the onset of most food allergies occurs during infancy. We have discussed the neonatal and infantile gastrointestinal allergy and special forms of immediate type food allergy types separately. Diagnostic procedures are highlighted, such as probability curves and component-resolved diagnosis, including the recent advancement utilizing antigen-specific IgE. The oral food challenge using a stepwise approach is recommended to avoid complete elimination of causative foods. Although oral immunotherapy (OIT) has not been approved as a routine treatment by nationwide insurance, we included a chapter for OIT, focusing on efficacy and problems. Prevention of food allergy is currently the focus of interest, and many changes were made based on recent evidence. Finally, the contraindication between adrenaline and antipsychotic drugs in Japan was discussed among related medical societies, and we reached an agreement that the use of adrenaline can be allowed based on the physician's discretion. In conclusion, this guideline encourages physicians to follow the principle to let patients consume causative foods in any way and as early as possible.

Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative allergens. These are socioeconomically important diseases that can lead to work interruptions for patients and potentially job loss. We published the first guideline for managing occupational allergic diseases in Japan. The original document was published in Japanese in 2013, and the following year (2014) it was published in English. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis, occupational anaphylaxis shock, and the legal aspects of these diseases. Providing general doctors with the knowledge to make evidence-based diagnoses and to understand the occupational allergic disease treatment policies, was a breakthrough in allergic disease treatment.

Due to the discovery of new occupational allergens and the accumulation of additional evidence, we published a revised version of our original article in 2016, and it was published in English in 2017. In addition to including new knowledge of allergens and evidence, the 2016 revision contains a “Flowchart to Diagnosis” for the convenience of general doctors.

We report the essence of the revised guidelines in this paper.

Interleukin (IL)-24 is a member of the IL-20 family of cytokines and is produced by various types of cells, such as CD4⁺ T cells, NK cells, mast cells, keratinocytes, bronchial epithelial cells, and myofibroblasts. Previous studies suggest that IL-24 plays an essential role in the pathogenesis of pro-inflammatory autoimmune disorders such as psoriasis, arthritis, and inflammatory bowel diseases. However, the role of IL-24 in the pathogenesis of allergic diseases has been elusive. It has already been reported that IL-24 is involved in the pathogenesis of allergic lung and skin diseases. Moreover, we have recently revealed for the first time the pivotal functions of IL-24 in IL-13-mediated skin barrier dysfunction in atopic dermatitis (AD), which is known to be a characteristic of AD caused by Th2 cytokines such as IL-4 or IL-13. In this review, we show recent advances in the basic characteristics of IL-24 and its novel functions in the pathogenesis of allergic skin inflammation, focusing on AD. A better understanding of the role of IL-24 in allergic diseases can lead to the development of new therapeutic options.

Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.

Background: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS.

Methods: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence.

Results: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin.

Conclusions: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

Background: Current guidelines recommend that any patient who has experienced anaphylaxis should be prescribed one or more epinephrine autoinjectors (EAI) for immediate self-treatment. However, the etiology of anaphylaxis and prescription patterns of EAI have not been widely examined in Japan.

Methods: This was a retrospective cohort study using a large Japanese claims database (JMDC, Tokyo, Japan). We included patients with severe anaphylaxis who received epinephrine in a hospital or outpatient clinic from 2011 to 2016. We extracted patients who were prescribed EAIs and examined the annual trend of EAI prescription rates and refill patterns.

Results: We identified 1255 eligible patients. Among them, 361 patients (28.8%) were prescribed EAIs within 30 days after their initial severe anaphylactic episode. In patients who were prescribed EAIs, 65.9% were prescribed EAIs from the same facility in which initial treatment was given for severe anaphylaxis. The prescription rates of EAI significantly increased from 11.1% in 2011 to 30.9% in 2016. Among patients with initial EAI prescriptions, 97.3% refilled their EAI prescriptions at least once and 40.5% refilled their prescriptions annually during the 3 year follow up period.

Conclusions: EAI prescription rates were relatively low in patients who experienced severe anaphylaxis in Japan. Physicians should prescribe EAIs to all patients who were treated for anaphylaxis under their care and avoid delegating the responsibility of prescribing EAIs to other facilities. Initial prescription of EAIs can result in improved regular refill and dissemination practices.

Background: We aimed to evaluate the influence of cold airflow from the air conditioner on skin barrier function and filaggrin degradation products (FDPs) in children with atopic deramtitis (AD).

Methods: In a case-control study, 28 children with AD and 12 normal children without AD were exposed to one of two air conditioner modes (conventional or wind-free) for 2 h. Skin temperature, transepidermal water loss (TEWL), and skin pH were measured on right cheek and forearm at pre- and post-exposure time points. We also measured filaggrin and FDPs from the volar surface of the forearm.

Results: In AD patients, skin temperature on the forearm decreased after exposure to the conventional and wind-free modes (P < 0.001 and P = 0.026), and TEWL on the cheek and the forearm decreased in the wind-free mode (P = 0.037 and 0.002). Skin pH on the cheek increased only after exposure to the conventional mode in AD group (P = 0.002). However, no changes in TEWL and skin pH were found after exposure to either the conventional or the wind-free mode in the control group. In AD children, the levels of pyrrolidone carboxylic acid (PCA) and cis-urocanic acid (UCA) were reduced only after exposure to the conventional mode (all P = 0.033). The percent changes of PCA and cis-UCA were higher in the AD group than those in the control group after exposure to conventional mode (P = 0.029 and 0.046).

Conclusions: Skin barrier function in children with AD may be altered by the exposure to cold airflow from a conventional air conditioner.

Background: An imbalance in gut microbiota is implicated in several pathological conditions, including allergic diseases. This study investigates the association between gut microbiota composition and sensitization to two inhaled antigens.

Methods: The study comprised 1109 local residents who had participated in the Iwaki Health Promotion Project in 2016. Blood samples were analyzed for levels of antigen-specific IgE against Japanese cedar pollen (JCP) and house dust (HD1). Fecal samples were analyzed for bacterial 16S rRNA (ribosomal ribonucleic acid) using next generation sequencing. The percent composition of gut microbes was compared between patients sensitized and unsensitized group for JCP and HD1 to determine whether the rate of sensitization to inhaled antigens associates with specific bacterial orders composing the gut microbiota.

Results: In participants aged 20-49 years, the percent composition of Bacteroidales was significantly higher among participants sensitized to JCP than in those unsensitized. The percent composition of Lactobacillales was significantly higher in participants unsensitized to HD group than in those sensitized to that antigen. In addition, participants with low Bacteroidales and high Bifidobacteriales or Lactobacillales has low sensitization rates to HD compared with high Bacteroidales and low Bifidobacteriales or Lactobacillales.

Conclusions: The presence of bacteria of order Lactobacillales, Bifidobacteriales, and Bacteroidales in the gut microbiota may affect sensitization to inhaled allergens.

Background: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected.

Methods: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants.

Results: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic.

Conclusions: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.