Diving deep into fish allergen immunotherapy: Current knowledge and future directions.

Fish allergy is one of the "big nine" categories of food allergens worldwide, and its prevalence is increasing with the higher demand for this nutritious food source. Fish allergies are a significant health concern as it is a leading cause of food anaphylaxis, accounting for 9% of all deaths from anaphylaxis. The gaps in treating fish allergies at present are the incomplete identification of fish allergens, lack of component-resolved diagnosis of fish allergens in the clinical setting, and the variability in sensitization profiles based on different fish consumption practices. Allergen immunotherapy (AIT) improves tolerance towards accidental consumption of fish and is longer lasting than pharmacotherapy. Current practice or research of fish AIT ranges from the use of whole fish via oral desensitization, to the use of purified recombinant parvalbumin and its hypoallergenic variant, passive IgG immunization, and modifying the allergenicity of parvalbumin by changing the diet of farmed fish. However, the focus of fish allergen-based studies in the context of AIT has been restricted to parvalbumins. More research is required to understand the involvement of other fish allergens, and several other strategies of AIT including peptide vaccines, DNA vaccines, hybrid allergens, and the use of nanobodies that have the capacity to treat multiple allergens have been proposed. For AIT, other important aspects to consider are the route of desensitization, and the biomarkers to assess the success of immunotherapy. Finally, we also address several clinical considerations for fish AIT.

Asia Pacific perspectives on the second year of the COVID-19 pandemic: A follow-up survey.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic is currently in its third year. This follow-up survey was commissioned by the Asia Pacific Association of Allergy Asthma and Clinical Immunology (APAAACI) Task Force on COVID-19 to compare and contrast changes in the epidemiology, clinical profile, therapeutics and public health measures of the pandemic in the Asia Pacific region. METHODS: A questionnaire-based survey comprising 32 questions was electronically sent out to all 15 member countries of APAAACI using Survey Monkey® from 1 December 2021 to 28 February 2022. RESULTS: Seventeen responses were received from 14/15 (93.4%) member countries and 3 individual members. Mild-to-moderate COVID-19 predominated over severe infection, largely contributed by COVID-19 vaccination programmes in the region. The incidence of vaccine adverse reactions in particular anaphylaxis from messenger ribonucleic acid (mRNA) vaccines was no longer as high as initially anticipated, although perimyocarditis remains a concern in younger males. Novel therapeutics for mild-to-moderate disease including neutralizing antibodies casirivimab/imdevimab (REGEN-COV®) and sotrovimab (Xevudy®), anti-virals Paxlovid® (nirmatrelvir and ritonavir) and Molnupiravir pre-exposure prophylaxis for high-risk persons with Tixagevimab and Cilgavimab (Evusheld) are now also available to complement established therapeutics (e.g., remdesivir, dexamethasone and baricitinib) for severe disease. In the transition to endemicity, public health measures are also evolving away from containment/elimination strategies. CONCLUSIONS: With access to internationally recommended standards of care including public health preventive measures, therapeutics and vaccines among most APAAACI member countries, much progress has been made over the 2-year period in minimizing the morbidity and mortality from COVID-19 disease.

An online survey of clinical practice for allergic rhinitis among the Asia-Pacific representatives.

BACKGROUND: Physicians' knowledge and practice which are consistent with evidence-based guidelines can improve allergic rhinitis (AR) patients' care. Compared with western countries, the available literature about Asian doctors' perceptions and clinical practices regarding Allergic Rhinitis and its Impacts on Asthma (ARIA) guidelines is limited. OBJECTIVE: To collect detailed information about the practical management patterns specific for AR patients and investigate compliance with ARIA in the clinical practice of Asian physicians and elucidate the possible inadequacy in the existing ARIA guidelines. METHODS: An e-mail with a structured questionnaire was sent to members of the Asia-Pacific Association of Allergy, Asthma and Clinical Immunology. The questionnaire consisted of doctors' characteristics, environment of medical practice, routine clinical practice following ARIA guidelines and patients' adherence to the prescription. RESULTS: Physicians from 14 countries and regions sent valid questionnaires back, 94.12% of whom were senior doctors with more than 10 years of experience. 88.24% of doctors diagnosed AR depending on the history combined with allergy tests. 82.35% of participants employed the classification criteria by ARIA. 94.12%, 88.24% and 41.8% of respondents recommended intranasal corticosteroids, oral antihistamines and leukotriene receptor antagonists as first-line medications. 5.88% treated perennial AR by intranasal corticosteroids alone. 11.76% of clinicians recommended no allergen immunotherapy (AIT) or biologics and 58.82% of interviewees reported AR patients occasionally or sometimes agreed with the recommendation of AIT. CONCLUSIONS: There was high compliance with ARIA guidelines in Asian senior physicians' actual notion and practice in the management of AR. New-generation ARIA guidelines are imperative for unmet needs.

Socialization During the COVID-19 Pandemic: The Role of Social and Scientific Networks During Social Distancing.

In the COVID-19 era, while we are encouraged to be physically far away from each other, social and scientific networking is needed more than ever. The dire consequences of social distancing can be diminished by social networking. Social media, a quintessential component of social networking, facilitates the dissemination of reliable information and fighting against misinformation by health authorities. Distance learning, telemedicine, and telehealth are among the most prominent applications of networking during this pandemic. Additionally, the COVID-19 pandemic highlights the importance of collaborative scientific efforts. In this chapter, we summarize the advantages of harnessing both social and scientific networking in minimizing the harms of this pandemic. We also discuss the extra collaborative measures we can take in our fight against COVID-19, particularly in the scientific field.

Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia.

Background: Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA. Results: Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients. Conclusion: This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

Defining p47-phox deficient Chronic Granulomatous Disease in a Malay family.

BACKGROUND: The most common autosomal form of Chronic Granulomatous Disease, p47-phox deficient CGD, generally features a GT (deltaGT) deletion in the GTGT sequence at the start of exon 2 on the NCF-1 gene. This consistency is due to the coexistence of and the recombination between 2 homologous pseudogenes (psi s) and NCF-1. The GTGT: deltaGT ratio mirrors the NCF-I: NCF-1 psi ratio and is 2:4 in normal individuals. OBJECTIVE: To determine the molecular basis of the Autosomal-CGD in a family with 2 children, a male and female, affected by the disease. The female patient suffered recurrent infection, retinitis pigmentosa and discoid lupus. METHODS: Chemiluminescence (CL) was used to study the respiratory burst, while genetic analysis was done by RT-PCR, PCR, deltaGT and the 20bp gene scans. RESULTS: The CL response of the patient was profoundly low. The patient's p47-phox band was absent in the RT-PCR for NADPH-oxidase component mRNAs. The deltaGT scan showed that the patient's GTGT: deltaGT ratio was 0:6, the parents' and the younger brother's was 1:5 and the younger sister's was 2:4. Examination of other NCF-1/ NCF-1 psi s differences showed that the father had a compound deltaGT allele ie. deltaGT-20bp, inherited by the patient, and that both parents had compound GTGT alleles with a single 30bp segment in intron 1. CONCLUSIONS: The patient was a classic, homozygous deltaGT p47-phox deficient CGD with one allele harbouring a compound deltaGT-20bp gene. The deltaGT and 20bp gene scans offer a relatively simple and efficient means of defining a p47-phox deficient CGD patient.

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.

Strategies and Future Opportunities for the Prevention, Diagnosis, and Management of Cow Milk Allergy.

The prevalence of food allergy has increased over the last 20-30 years, including cow milk allergy (CMA) which is one of the most common causes of infant food allergy. International allergy experts met in 2019 to discuss broad topics in allergy prevention and management of CMA including current challenges and future opportunities. The highlights of the meeting combined with recently published developments are presented here. Primary prevention of CMA should start from pre-pregnancy with a focus on a healthy lifestyle and food diversity to ensure adequate transfer of inhibitory IgG- allergen immune complexes across the placenta especially in mothers with a history of allergic diseases and planned c-section delivery. For non-breastfed infants, there is controversy about the preventive role of partially hydrolyzed formulae (pHF) despite some evidence of health economic benefits among those with a family history of allergy. Clinical management of CMA consists of secondary prevention with a focus on the development of early oral tolerance. The use of extensive Hydrolysate Formulae (eHF) is the nutrition of choice for the majority of non-breastfed infants with CMA; potentially with pre-, probiotics and LCPUFA to support early oral tolerance induction. Future opportunities are, among others, pre- and probiotics supplementation for mothers and high-risk infants for the primary prevention of CMA. A controlled prospective study implementing a step-down milk formulae ladder with various degrees of hydrolysate is proposed for food challenges and early development of oral tolerance. This provides a more precise gradation of milk protein exposure than those currently recommended.

Clinical and demographic pattern of chronic granulomatous disease (CGD) from a multicenter perspective: Malaysia's experience over 26 years.

BACKGROUND: A retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia. METHODS: Data from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed. RESULTS: Twenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia. CONCLUSION: This study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

Diagnostic procedures & practices in drug allergy/hypersensitivity: a survey of 13 Asian countries.

BACKGROUND: The issues and challenges in the diagnosis of drug allergy/hypersensitivity among children and adults in Asia are likely to be different from non-Asian countries. OBJECTIVE: To study the diagnostic modalities used in the evaluation and management of drug allergy/drug hypersensitivity reactions (DHRs) among member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI). METHODS: A questionnaire comprising 41 questions was circulated electronically to member societies and individual members of APAAACI between January 23, 2020 and March 6, 2020. RESULTS: Twenty-six respondents from 15 member societies and 1 individual member responded. European DHR guidelines were most commonly used. Skin prick and intradermal testing was used by 100%, with only 60% having access to commercial penicillin skin test reagents. In vitro-specific IgE tests were used by 75%, and basophil activation test by 56.3% for immediate DHR. Patch tests were used by 75% in contrast to lymphocyte transformation tests by 25% for nonimmediate DHR. Drug provocation tests were used by 68.8%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (93.3%). Human leukocyte antigen (HLA) genotype testing was mandatory among 25% respondents before new carbamazepine prescriptions, and 8.3% for allopurinol prescriptions. CONCLUSIONS: There was increased use of skin testing for iodinated contrast media hypersensitivity and patch testing for nonimmediate DHR. HLA genotype testing prior to new carbamazepine, allopurinol and abacavir prescriptions remain variable despite strong associations for severe cutaneous adverse reactions with Asian ethnicity. Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across APAAACI member societies.

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

Background: The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. Objective: To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. Methods: The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. Results: A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI (r = -0.696, p = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI (r = -0.788, p < 0.001; r = -0.739, p = 0.002). HDI positively correlated with average testing level (r = 0.742, p = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. Conclusion: There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.

Drug hypersensitivity reactions in Asia: regional issues and challenges.

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.

Asia Pacific Association of Allergy Asthma and Clinical Immunology White Paper 2020 on climate change, air pollution, and biodiversity in Asia-Pacific and impact on allergic diseases.

Air pollution, climate change, and reduced biodiversity are major threats to human health with detrimental effects on a variety of chronic noncommunicable diseases in particular respiratory and cardiovascular diseases. The extent of air pollution both outdoor and indoor air pollution and climate change including global warming is increasing-to alarming proportions particularly in the developing world especially rapidly industrializing countries worldwide. In recent years, Asia has experienced rapid economic growth and a deteriorating environment and increase in allergic diseases to epidemic proportions. Air pollutant levels in many Asian countries especially in China and India are substantially higher than are those in developed countries. Moreover, industrial, traffic-related, and household biomass combustion, indoor pollutants from chemicals and tobacco are major sources of air pollutants, with increasing burden on respiratory allergies. Here we highlight the major components of outdoor and indoor air pollutants and their impacts on respiratory allergies associated with asthma and allergic rhinitis in the Asia-Pacific region. With Asia-Pacific comprising more than half of the world's population there is an urgent need to increase public awareness, highlight targets for interventions, public advocacy and a call to action to policy makers to implement policy changes towards reducing air pollution with interventions at a population-based level.

Partially hydrolyzed formula in non-exclusively breastfed infants: A systematic review and expert consensus.

OBJECTIVES: Guidance and evidence supporting routine use of partially hydrolyzed formula (pHF) versus intact cows' milk protein (CMP) formula are limited in non-exclusively breastfed infants. The aim of this review was to better clarify issues of routine use of pHF in non-exclusively breastfed infants who are not at risk for allergic disease by using a systematic review and Delphi Panel consensus. METHODS: A systematic review and Delphi consensus panel (consisting of eight8 international pediatric allergists and gastroenterologists) was conducted to evaluate evidence supporting growth, tolerability, and effectiveness of pHF in non-exclusively breastfed infants. RESULTS: None of the studies reviewed identified potential harm of pHF use compared with CMP in non-exclusively breastfed infants. There was an expert consensus that pHF use is likely as safe as intact CMP formula, given studies suggesting these have comparable nutritional parameters. No high-quality studies were identified evaluating the use of pHF to prevent allergic disease in non-exclusively breastfed infants who are not at risk for allergic disease (e.g., lacking a parental history of allergy). Limited data suggest that pHF use in non-exclusively breastfed infants may be associated with improved gastric emptying, decreased colic incidence, and other common functional gastrointestinal symptoms compared with CMP. However, because the data are of insufficient quality, the findings from these studies have to be taken with caution. No studies were identified that directly compared the different types of pHF, but there was an expert consensus that growth, allergenicity, tolerability, effectiveness, and clinical role among such pHF products may differ. CONCLUSIONS: Limited data exist evaluating routine use of pHFs in non-exclusively breastfed infants, with no contraindications identified in the systematic review. An expert consensus considers pHFs for which data were available to be as safe as CMP formula as growth is normal. The preventive effect on allergy of pHF in infants who are not at risk for allergic disease has been poorly studied. Cost of pHF versus starter formula with intact protein differs from country to country. However, further studies in larger populations are needed to clinically confirm the benefits of routine use of pHF in non-exclusively breastfed infants. These studies should also address potential consumer preference bias.

Ethnicity influences disease characteristics and symptom severity in allergic rhinitis patients in Malaysia.

BACKGROUND: The number of available reports regarding the influence of ethnicity on clinical features of allergic rhinitis (AR), especially disease severity in tropical climates, is limited. We aimed to compare clinical parameters and disease severity in AR patients of different ethnicities. METHODS: Malay, Chinese, and Indian AR patients (n = 138) with confirmed sensitivity to Dermatophagoides pteronyssinus, Dematophagoides farinae, and Blomia tropicalis were tested for mite-specific immunoglobulin E (sIgE) levels. A detailed questionnaire was used to collect data on nasal symptom score (NSS), ocular symptom score (OSS), sum of symptoms score (SSS), quality of life score (QLS), symptomatic control score (SCS), and total sum of scores (TSS) and correlate the derived data with patients' demography, mite-polysensitivity, and sIgE levels. RESULTS: AR-related symptoms were most severe in Malays and least in Chinese (p < 0.01). Age (r = 0.516 to 0.673, p < 0.05) and duration of AR (r = 0.635 to 0.726, p < 0.01) correlated positively with severity domains (NSS, SSS, QLS, and TSS) in Chinese. Duration of concurrent allergies was highest in Malays (p < 0.05). Polysensitivity predicted increased sIgE levels in Malays (r = 0.464 to 0.551, p < 0.01) and Indians (r = 0.541 to 0.645, p < 0.05) but affected NSS, SSS, and TSS only in Indians (r = 0.216 to 0.376, p < 0.05). sIgE levels were lowest among Chinese but correlated strongly with NSS, OSS, SSS, and TSS (r = 0408 to 0.898, p < 0.05). CONCLUSION: Clinical parameters in AR may be influenced by race. Symptoms were most severe among Malays but did not correlate with other variables examined. Although Indian ethnicity did not impact disease severity, duration of concurrent allergies and mite-polysensitivity was associated with more severe disease. Age, duration of disease, and sIgE levels may be useful indicators of disease severity in Chinese.