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Immunology and Allergy Clinics of North... Nov 2021Eosinophilic esophagitis is a recently defined condition that has dramatically increased in prevalence in the last several decades. It may occur at any age, but the... (Review)
Review
Eosinophilic esophagitis is a recently defined condition that has dramatically increased in prevalence in the last several decades. It may occur at any age, but the clinical presentation in young children is often more vague than the classic solid food dysphagia and food impacting that are the major presenting symptoms of eosinophilic esophagitis in adults and adolescents. Successful therapies exist, including medications and dietary modifications, but disease typically recurs when the intervention is discontinued.
Topics: Adolescent; Adult; Child; Child, Preschool; Deglutition Disorders; Eosinophilic Esophagitis; Humans
PubMed: 34602230
DOI: 10.1016/j.iac.2021.07.011 -
Current Allergy and Asthma Reports Apr 2023This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic... (Review)
Review
PURPOSE OF REVIEW
This review focuses on immunologic findings, relationships among immunologic findings and associated conditions of autoimmunity and atopy, and management of immunologic disease in chromosome 22q11.2 deletion syndrome (22q11.2DS, historically known as DiGeorge syndrome).
RECENT FINDINGS
The implementation of assessment of T cell receptor excision circles (TRECs) in newborn screening has led to increased detection of 22q11.2 deletion syndrome. While not yet applied in clinical practice, cell-free DNA screening for 22q11.2DS also has the potential to improve early detection, which may benefit prompt evaluation and management. Multiple studies have further elucidated phenotypic features and potential biomarkers associated with immunologic outcomes, including the development of autoimmune disease and atopy. The clinical presentation of 22q11.2DS is highly variable particularly with respect to immunologic manifestations. Time to recovery of immune system abnormalities is not well-defined in current literature. An understanding of the underlying causes of immunologic changes found in 22q11.2DS, and the progression and evolution of immunologic changes over the lifespan have expanded over time and with improved survival. An included case highlights the variability of presentation and potential severity of T cell lymphopenia in partial DiGeorge syndrome and demonstrates successful spontaneous immune reconstitution in partial DiGeorge syndrome despite initial severe T cell lymphopenia.
Topics: Infant, Newborn; Humans; DiGeorge Syndrome; Chromosome Deletion; Neonatal Screening; Lymphopenia; Chromosomes
PubMed: 36897497
DOI: 10.1007/s11882-023-01071-4 -
Clinical Reviews in Allergy & Immunology Dec 2019House dust mites are an unsurpassed cause of atopic sensitization and allergic illness throughout the world. The major allergenic dust mites Dermatophagoides... (Review)
Review
House dust mites are an unsurpassed cause of atopic sensitization and allergic illness throughout the world. The major allergenic dust mites Dermatophagoides pteronyssinus, Dermatophagoides farinae, Euroglyphus maynei, and Blomia tropicalis are eight-legged members of the Arachnid class. Their approximately 3-month lifespan comprises egg, larval, protonymph, tritonymph, and adult stages, with adults, about one fourth to one third of a millimeter in size, being at the threshold of visibility. The geographic and seasonal distributions of dust mites are determined by their need for adequate humidity, while their distribution within substrates is further determined by their avoidance of light. By contacting the epithelium of the eyes, nose, lower airways, skin, and gut, the allergen-containing particles of dust mites can induce sensitization and atopic symptoms in those organs. Various mite allergens, contained primarily in mite fecal particles but also in shed mite exoskeletons and decaying mite body fragments, have properties that include proteolytic activity, homology with the lipopolysaccharide-binding component of Toll-like receptor 4, homology with other invertebrate tropomyosins, and chitin-cleaving and chitin-binding activity. Mite proteases have direct epithelial effects including the breaching of tight junctions and the stimulation of protease-activated receptors, the latter inducing pruritus, epithelial dysfunction, and cytokine release. Other components, including chitin, unmethylated mite and bacterial DNA, and endotoxin, activate pattern recognition receptors of the innate immune system and act as adjuvants promoting sensitization to mite and other allergens. Clinical conditions resulting from mite sensitization and exposure include rhinitis, sinusitis, conjunctivitis, asthma, and atopic dermatitis. Systemic allergy symptoms can also occur from the ingestion of cross-reacting invertebrates, such as shrimp or snail, or from the accidental ingestion of mite-contaminated foods. Beyond their direct importance as a major allergen source, an understanding of dust mites leads to insights into the nature of atopy and of allergic sensitization in general.
Topics: Allergens; Animals; Antigens, Dermatophagoides; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunization; Population Dynamics; Pyroglyphidae
PubMed: 29936683
DOI: 10.1007/s12016-018-8693-0 -
Pediatric Research Jul 2021Asthma is the most common chronic pediatric lung disease that has traditionally been defined as a syndrome of airway inflammation characterized by clinical symptoms of... (Review)
Review
Asthma is the most common chronic pediatric lung disease that has traditionally been defined as a syndrome of airway inflammation characterized by clinical symptoms of cough and wheeze. Highlighting the complex and heterogeneous nature of asthma, this review summarizes recent advances in asthma classification that are based on pathobiology, and thereby directly addresses limitations of existent definitions of asthma. By reviewing and contrasting clinical and mechanistic features of adult and childhood asthma, the review summarizes key biomarkers that distinguish childhood asthma subtypes. While atopy and its severity are important features of childhood asthma, there is evidence to support the existence of a childhood asthma endotype distinct from the atopic endotype. Although biomarkers of non-atopic asthma are an area of future research, we summarize a clinical approach that includes existing measures of airway-specific and systemic measures of atopy, co-existing morbidities, and disease severity and control, in the definition of childhood asthma, to empower health care providers to better characterize asthma disease burden in children. Identification of biomarkers of non-atopic asthma and the contribution of genetics and epigenetics to pediatric asthma burden remains a research need, which can potentially allow delivery of precision medicine to pediatric asthma. IMPACT: This review highlights asthma as a complex and heterogeneous disease and discusses recent advances in the understanding of the pathobiology of asthma to demonstrate the need for a more nuanced definitions of asthma. We review current knowledge of asthma phenotypes and endotypes and put forth an approach to endotyping asthma that may be useful for defining asthma for clinical care as well as for future research studies in the realm of personalized medicine for asthma.
Topics: Asthma; Biomarkers; Child; Humans; Inflammation; Phenotype; Respiratory Sounds
PubMed: 33173175
DOI: 10.1038/s41390-020-01231-6 -
Clinical Reviews in Allergy & Immunology Dec 2019Atopy and fungi have a long associative history. Fungal spores were among the first substances to which humans were noted to be sensitized. Humans contact fungal spores... (Review)
Review
Atopy and fungi have a long associative history. Fungal spores were among the first substances to which humans were noted to be sensitized. Humans contact fungal spores in the outdoor, indoor, and occupational environments. As organisms, fungi have their own kingdom and are found in all environmental niches on earth. Currently, fungal exposure in the indoor environment especially related to wet housing conditions is of particular concern. Sensitization rates to fungi typically exceed 5% of the general public with higher rates among the atopic population. Alternaria is the best studied of the allergic fungi; however, cross sensitization to multiple fungi is well documented. Recent advances in understanding mechanisms of the innate immune system are beginning to explain why the fungal atopy relationship is unique and why fungal sensitivity seems to extend to many non-atopic individuals. Evidence has been accumulated that indicates fungal allergen exposure can be via intact spores as well as spore and mycelial fragments. Germinating spores produce a different and often increased allergen picture. Much evidence has been developed through animal studies that extends the mechanisms surrounding long-term low-level fungal exposure. However, it should be emphasized that the presence of fungi in the air does not necessarily equate with illness. Indeed, in the absence of an atopic individual and/or a significant immune response against fungi, there is little evidence suggesting pathology. Allergists frequently deal with patients who have concerns about indoor fungal exposure and respiratory disease in those patients with an allergic response.
Topics: Allergens; Animals; Antigens, Fungal; Disease Susceptibility; Environmental Exposure; Fungi; Host-Pathogen Interactions; Humans; Hypersensitivity, Immediate
PubMed: 31321665
DOI: 10.1007/s12016-019-08750-z -
Nutrients Jun 2022The increasing prevalence of food allergies is a growing public health problem. For children considered high risk of developing food allergy (particularly due to the... (Review)
Review
The increasing prevalence of food allergies is a growing public health problem. For children considered high risk of developing food allergy (particularly due to the presence of other food allergies or severe eczema), the evidence for the early introduction of allergenic foods, and in particular peanut and egg, is robust. In such cases, the consensus is clear that not only should such foods not be delayed, but that they should be introduced at approximately 4 to 6 months of age in order to minimize the risk of food allergy development. The early introduction of allergenic foods appears to be an effective strategy for minimizing the public health burden of food allergy, though further studies on the generalizability of this approach in low-risk populations is needed.
Topics: Allergens; Arachis; Child; Food Hypersensitivity; Humans; Infant; Prevalence
PubMed: 35807745
DOI: 10.3390/nu14132565 -
EClinicalMedicine Mar 2023Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta...
Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study.
BACKGROUND
Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis.
METHODS
This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18-75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5-2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch-Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch-Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891.
FINDINGS
Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, -50.6% versus -29.4% (LS-mean difference [95% CI], -21.2% [-40.82, -1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, -54.4% versus -32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), -56.3% versus -30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]).
INTERPRETATION
Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis.
FUNDING
Kiniksa Pharmaceuticals, Ltd.
PubMed: 36816342
DOI: 10.1016/j.eclinm.2023.101826