Medical Journal Reviews


2024

January

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: a systematic review and meta-analysis
Yang J, Lei S
Frontiers in Immunology 2023;14:1274241 (15 December)
https://doi.org/10.3389/fimmu.2023.1274241

In this article, the authors systematically compare the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in children with allergic rhinitis (AR), exploring multiple outcomes including: symptom scores (SSs), medication scores (MSs), symptom and medication scores (SMSs), new sensitizations, development of asthma, and improvement, as well as  treatment-related adverse events (TRAEs). The quality of the included studies was assessed by the modified Jadad scale and Newcastle-Ottawa scale (NOS) and meta-regression was carried out to explore the source of heterogeneity. Subgroup analysis was further conducted in terms of study design (randomized controlled trials [RCTs], cohort studies), allergen (house dust mites [HDMs], grass pollen), treatment duration (≥ 24, 12-23 or < 12 months), allergen immunotherapy (AIT) modality (drops or tablets), and AIT protocol (continuous, pre-seasonal, co-seasonal, or after the grass pollen season [GPS]). Sensitivity analysis was conducted for all outcomes. A Bayesian framework and a Monte Carlo Markov Chain (MCMC) model were developed for indirect comparison. Through their analysis, they found 50 studies with 10813 AR children included, of which 4122 were treated with SLIT, 1852 treated with SCIT, and 4839 treated with non-SLIT or non-SCIT therapy. For direct comparison, the SLIT group had a similar SS to the SCIT group (pooled standardized mean difference [SMD]: 0.41, 95% confidence interval [CI]: -0.46, 1.28, P = 0.353). Comparable MSs were observed in the SLIT and SCIT groups (pooled SMD: 0.82, 95%CI: -0.88, 2.53, P = 0.344). For indirect comparison, no significant differences were found in SSs (pooled SMD: 1.20, 95% credibility interval, CrI: -1.70, 4.10), MSs (pooled SMD: 0.57, 95%CrI: -1.20, 2.30), SMSs (pooled SMD: 1.80, 95%CrI: -0.005, 3.60), new sensitizations (pooled relative risk [RR)]: 0.34, 95%CrI: 0.03, 3.58), and development of asthma (pooled RR: 0.68, 95%CrI: 0.01, 26.33) between the SLIT and SCIT groups; the SLIT group illustrated a significantly lower incidence of TRAEs than the SCIT group (pooled RR: 0.17, 95%CrI: 0.11, 0.26).

Regulation of macrophage polarization in allergy by noncoding RNAs
Ishibashi O, Muljo SA, Islam Z
Noncoding RNA 2023;9(6):75 (11 December)
https://doi.org/10.3390/ncrna9060075

This review summarizes the current knowledge regarding regulation of macrophage polarization in allergy by noncoding RNAs. Allergy is a type 2 immune reaction triggered by a variety of allergens, including food and environmental substances such as peanuts, plant pollen, fungal spores, and the feces and debris of mites and insects. Macrophages are myeloid immune cells with phagocytic abilities that process exogenous and endogenous antigens. Upon activation, they can produce effector molecules such as cytokines as well as anti-inflammatory molecules. The dysregulation of macrophage function can lead to excessive type 1 inflammation as well as type 2 inflammation, which includes allergic reactions. Thus, it is important to better understand how macrophages are regulated in the pathogenesis of allergies. Emerging evidence highlights the role of noncoding RNAs (ncRNAs) in macrophage polarization, which in turn can modify the pathogenesis of various immune-mediated diseases, including allergies. The authors stress that understanding the roles of these ncRNAs in macrophage polarization will provide new insights into the pathogenesis of allergies and identify potential novel therapeutic targets

Telehealth interventions for transition to self-management in adolescents with allergic conditions: A systematic review
Sullivan MO, Curtin M, Flynn R et al
Allergy 2023; Published online ahead of print (1 December)
https://doi.org/10.1111/all.15963

Telehealth is an emerging approach that uses technology to provide healthcare remotely. Recent publications have outlined the importance of supporting the transition to self-management of adolescents with allergic conditions. However, no synthesis of the evidence base on the use and impact of telehealth interventions for this purpose has been conducted to date. This review explores these interventions, and their implementation. Four databases were searched systematically. References were independently screened by two reviewers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was undertaken. Eighteen articles were found, reporting on 15 telehealth interventions. A total of 86% targeted adolescents with asthma. Mobile applications were the most common telehealth modality used, followed by video-conferencing, web-based, virtual reality and artificial intelligence. Five intervention content categories were identified; educational, monitoring, behavioral, psychosocial, and healthcare navigational. Peer and/or healthcare professional interaction, gamification and tailoring may increase engagement. Overall, these studies showed positive effects of the interventions or no difference from active controls, in self-management outcomes such as knowledge, health outcomes such as quality-of-life, and economic outcomes such as healthcare utilization. The most common implementation outcomes reported were acceptability, appropriateness, feasibility and fidelity. Certainly, Telehealth will be more often used in the care of our patients over time. Thus, better understanding of the literature is essential to aid us in optimization.

Home monitoring of asthma exacerbations in children and adults with use of an AI-aided stethoscope
Emeryk A, Derom E, Janeczek K et al
Annals of Family Medicine 2023;21(6):517-525
https://doi.org/10.1370/afm.3039

With the advent of new medical devices, patients with asthma are now able to self-monitor at home, providing potentially a more complete picture of their disease than occasional in-person clinic visits. This raises a pertinent question: which devices and parameters perform best in exacerbation detection? One hundred forty-nine patients with asthma (90 children, 59 adults) participated in a 6-month observational study. Participants (or parents) regularly (daily for the first 2 weeks and weekly for the next 5.5 months, with increased frequency during exacerbations) performed self-examinations using 3 devices: an artificial intelligence (AI)-aided home stethoscope (providing wheezes, rhonchi, and coarse and fine crackles intensity; respiratory and heart rate; and inspiration-to-expiration ratio), a peripheral capillary oxygen saturation (SpO2) meter, and a peak expiratory flow (PEF) meter and also filled out a health state survey. The resulting 6029 examinations were evaluated by physicians for the presence of exacerbations. For each registered parameter, a machine learning model was trained, and the area under the receiver operating characteristic curve (AUC) was calculated to assess its utility in exacerbation detection. They found that the best single-parameter discriminators of exacerbations were wheeze intensity for young children (AUC 84% [95% CI, 82%-85%]), rhonchi intensity for older children (AUC 81% [95% CI, 79%-84%]), and survey answers for adults (AUC 92% [95% CI, 89%-95%]). The greatest efficacy (in terms of AUC) was observed for a combination of several parameters. The authors suggested that introduction of this tool to the health care system might enhance asthma exacerbation detection substantially and make remote monitoring of patients easier.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms
Yepes-Nuñez JJ, Guyatt GH, Gómez-Escobar LG et al
Journal of Allergy and Clinical Immunology 2024;151(1):147-158
https://doi.org/10.1016/j.jaci.2022.09.020

Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. To better understand this potential relationship, the authors systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD as part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline Update on Atopic Dermatitis. Raters independently screened, extracted data, and assessed risk of bias in duplicate, then synthesized intervention effects using frequentist and Bayesian random effects models. The GRADE approach determined the quality of evidence. They found  23 randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite and showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT’s effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings.

2023

January

WAO Reviews – Editors' Choice

The WAO Reviews editors, Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD - FACAAI - FAAAAI, select articles on a monthly basis for their importance to clinicians who care for patients with asthma and allergic/immunologic diseases.

Immediate hypersensitivity reactions to iodinated contrast media: The diagnosis of allergy by skin testing
Caron J, Graf S, Delebarre-Sauvage C
Clinical and Translational Allergy 2022;12(12):e12214 (4 December)
https://doi.org/10.1002/clt2.12214

In the retrospective analysis by Caron et al, they found that among 74 patients with an immediate hypersensitivity reaction (IHR) to iodinated contrast media (ICM), the rate of allergic patients confirmed by positive prick test or diluted intradermal test was 8.1%. They also found that 12.5% of re‐exposed patients had a recurrent IHR despite negative skin tests.  The authors conclude that evaluation with IDT to ICM and development of DPT may provide an additional “safety net” to uncover recurrent ICM reactors.

Role of chemokines and inflammatory cells in respiratory allergy
Bao Y, Zhu X
Journal of Asthma and Allergy 2022;15:1805-1822 (21 December)
https://doi.org/10.2147/JAA.S395490

In the review Bao and colleagues explore the role of the chemokine system in the respiratory immune response and discuss how respiratory disease modulates overall chemokines to shape the type and outcome of the immune response to the treatment of respiratory allergic disease so that we can further deepen our knowledge of chemokines and their role in respiratory allergy. The concept of “one airway, one disease” has been espoused for some time, whereby in the upper and lower airways, allergic mechanisms interact with each other. In the initial stage of respiratory allergic inflammation, allergens contact the respiratory epithelium, which produces chemokines and inflammatory factors, which cause allergic reactions by binding to the corresponding receptors and chemotactic various inflammatory cells to reach the epithelium and tissues. It also drives inflammatory cells to activate and produce more inflammatory factors, thus producing an amplification effect. Inflammatory cell aggregation and activation are very complex and interact with each other in a lattice structure. By blocking the action of various chemokines, inflammatory cell aggregation is reduced, and ultimately the symptoms of respiratory allergy are alleviated. Chemokines can serve as cues for coordinated recruitment of immune cells into and out of tissues, as well as directing the spatial organization of immune cells within tissues and cellular interactions. Chemokines are critical in directing immune cell migration and thus have an important role in the direction of respiratory allergy: however, chemokines are also involved in the production and recruitment of immune cells that contribute to respiratory allergy. The authors conclude by suggesting that future drug research and development should consider this network structure in their new research directions.

A sputum bioassay for airway eosinophilia using an eosinophil peroxidase aptamer
Ali MM, Wolfe MG, Mukherjee M et al
Science Reports 2022;12:22476 (28 December)
https://doi.org/10.1038/s41598-022-26949-7

Eosinophils are well known to play a significant role in the pathogenesis of asthma and other airway diseases. Directing patient treatment based on the level of eosinophilia has been shown to be extremely effective in reducing exacerbations and therefore has tremendous potential as a routine clinical test. In this manuscript Ali et al. describe the in vitro selection and optimization of DNA aptamers that bind to eosinophil peroxidase (EPX). Fifteen rounds of magnetic bead aptamer selection were performed prior to high throughput DNA sequencing. The top 10 aptamer candidates were assessed for EPX binding using a mobility shift assay. This process identified a lead aptamer candidate termed EAP1-05 with low nanomolar affinity and high specificity for EPX over other common sputum proteins. This aptamer sequence was further optimized through truncation and used to develop an easy-to-use colourimetric pull-down assay that can detect EPX over a concentration range from 1 – 100 nM in processed sputum. Following this, 46 clinical samples were processed using a new sputum dispersal method, appropriate for a rapid assessment assay, which avoids centrifugation and lengthy processing times. The assay demonstrated 89% sensitivity and 96% specificity in detecting eosinophilia (compared to gold standard sputum cytometry), with results being available in under an hour. The authors suggest that this assay could allow for an easy assessment of eosinophil activity in the airway to guide anti-inflammatory therapy for several airway diseases.

Resistant Chronic Spontaneous Urticaria - A Case Series Narrative Review of Treatment Options
Khan S, Chopra C, Mitchell A et al
Allergy & Rhinology 2022;13 (21 December)
https://doi.org/10.1177/21526575221144951

Chronic spontaneous urticaria (CSU) can be extremely debilitating to sufferers and challenging for the treating clinician. The National Institute of Health and Clinical Excellence (NICE) in the United Kingdom (UK) recommendation of omalizumab for patients who fail to respond to high-dose anti-histamines has improved treatment options and quality of life; however, there is still a lack of clear guidelines for treatment of patients resistant to standard and anti-IgE therapies. In this paper, Khan et al. explore the therapeutic strategies available by examining nine extremely resistant CSU cases, highlighting the heterogeneity between guidelines from different societies. Patients with anti-histamine-resistant urticaria either remained on omalizumab or were started on immunosuppressive drugs (dapsone or ciclosporin) when they stopped responding to omalizumab. Clinical assessment, skin biopsies (when available) and previously published reports were considered before using dapsone (for predominantly neutrophilic infiltration), or ciclosporin at doses between 2 and 4 mg/kg/day. One patient with ciclosporin-resistant urticaria responded to mycophenolate mofetil. Two patients remained on long-term omalizumab due to its relative safety and efficacy. Its safety was especially important in one patient with underlying antibody deficiency where omalizumab was preferred over risks of using immunosuppressive medications. The authors stress that these case studies highlight the real-world difficulties in managing patients with resistant CSU and the need for generating evidence-based recommendations regarding alternative therapeutic options, including consideration of the use of biologics in tandem with immunosuppressive drugs.

Peanut-Induced Anaphylaxis in Children: A Literature Review
Alshajarah HA, Alghamdi HA, Alberi ZA et al
Cureus 2022;14(12): e32946 (26 December)
https://doi.org/10.7759/cureus.32946

Peanut allergy has become more common among children and is considered one of the most common triggers for fatal anaphylaxis. Treatment of symptoms during a reaction is only one aspect of managing anaphylaxis; other elements include rigorous dietary avoidance and education about settings that could put the patient at a high risk of unintentional exposure. In this review, the authors examine the prevalence, mechanism, diagnosis, treatment, and emergency action of peanut-induced anaphylaxis among children. Peanuts are the most common food to cause fatal anaphylaxis and a common cause of food allergies. The research cited in this review, demonstrates that the peanut allergy prevalence differs across cultures, and that while early oral peanut exposure may reduce the occurrence of peanut allergy, early non-oral exposure may have the opposite effect. They close by stressing that research involving oral immunotherapy, anti-IgE antibody, and herbal formulations have all demonstrated promise, but more research is needed. To conclude, peanut allergies have increased frequently during the past 10 years, especially in Westernized nations. Given that peanut allergy poses a danger for fatal anaphylaxis, response management is crucial. The current standard of care for those with nut allergies comprises complete food avoidance and the administration of injectable epinephrine to treat systemic symptoms.

2022

January

WAO Reviews – Editors' Choice

Articles are selected for their importance to clinicians who care for patients with asthma and allergic and immunologic diseases by WAO Reviews Editors Juan Carlos Ivancevich, MD, and John J. Oppenheimer, MD, FACAAI, FAAAAI.

Regulated on Activation, NormalT cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma
Li N, Mirzakhani H, Kiefer A et al
iScience 2021;24(10):103163 (24 September)
DOI: https://doi.org/10.1016/j.isci.2021.103163

Regulated on Activation, NormalT cell Expressed and Secreted (RANTES) has been implicated in allergic asthma and in T cell-dependent clearance of infection. The RANTES receptor family includes CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses result in the induction of RANTES production by epithelial cells. In this study, the authors explored the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma, extending this study by examining the airways of adults with and without asthma and finally translating these results to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Through these studies, they found an unpredicted therapeutic role of RANTES in the actual resolution of allergen-induced asthma, presumed through orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.

The majority of children sensitized before school age develop allergic disease before adulthood: A longitudinal population=based study
Bunne J, Hedman L, Perzanowski M et al
Journal of Allergy and Clinical Immunology: In Practice 2021; Published online ahead of print (22 October)
DOI: https://doi.org/10.1016/j.jaip.2021.10.023

While it is known that allergic sensitization increases the risk of and asthma and allergic rhinitis, the impact of age at onset of sensitization has been less studied. To understand this relationship better, the authors examined the cumulative incidence of asthma and rhinitis up to age 19 years in relation to age at onset of sensitization to airborne allergens. To do so, they invited all children in grades one and two (median age 8 years) in two municipalities in Northern Sweden to undergo skin prick tests and perform a questionnaire regarding allergic diseases (88% participated). At ages 12 and 19 years the protocol was repeated, with n=1510 individuals participating in all three examinations. Specific IgE was collected in a random sample at age 19, n=770. The authors stratified age of onset of sensitization to: ≤8 years, 8-12 years, 12-19 years, and never sensitized, finding that at age 19, those sensitized ≤8 year had the highest risk of asthma (RR 4.68 (95%CI 3.14- 66 6.97) and rhinitis (RR 22.3 (95%CI 13.3-37.6), with 84% had developing either asthma or rhinitis. They furthermore found that the combination of sensitization ≤8 year and family history of allergic diseases rendered high risks for asthma (RR 10.6 [6.71-16.7]) and rhinitis (RR 36.3 [18.9-69.7]). Individuals sensitized ≤8 year showed the significantly highest level of sensitization, as judged by number of positive skin tests and titers of specific IgE.

Psychological impacts of COVID-19 on people with asthma, allergic rhinitis and food allergy
Burrows AG, Ellis AK
Annals of Allergy Asthma and Immunology 2021; Published online ahead of print (28 December)
DOI: https://doi.org/10.1016/j.anai.2021.12.013

In this paper, Drs. Burrows and Ellis examine the psychological Impact of COVID-19 on people with allergic illness, finding that asthma patients perceived their risk of severe disease from COVID-19 as greater, which negatively impacted their psychological wellbeing. Presently, there are only limited data regarding the impact of COVID-19 in allergic rhinitis (AR) and food allergy (FA) patients; however, it has been found that some AR patients experienced high anxiety and depression compared to healthy controls. Parents and caregivers of children with asthma and FA were also affected with a higher psychological burden during COVID-19. The authors note that it is important that physicians be aware of the potential coincidence of mental illness and chronic allergic diseases, and refer these patients, and their caregivers, to appropriate resources, while also continuing to manage their allergic disease(s).

Long-term real-world effectiveness of allergy immunotherapy in patients with allergic rhinitis and asthma: Results from the REACT study, a retrospective cohort study
Fritzsching B, Contoli M, Porsbjerg C et al
Lancet Regional Health – Europe 2021;13:100275 (30 November)
DOI: https://doi.org/10.1016/j.lanepe.2021.100275

While a multitude of studies has demonstrated the efficacy of allergen immunotherapy (AIT), the long-term, real-life effectiveness of AIT has not been as well studied. To resolve this issue, the REACT (Real world effectiveness in allergy immunotherapy) was performed.  REACT was a retrospective cohort study using claims data between 2007 and 2017 in patients with a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analyzed both as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up. There were 46,024 AIT-treated subjects matched with control subjects, and 14,614 were included in the pre-existing asthma cohort. They found that compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in both AR as well as asthma prescriptions (both asthma controller and reliever prescriptions). Additionally, the AIT group had a significantly greater likelihood of stepping down asthma treatment (P <0.0001) as well as a demonstrated reduction in severe asthma exacerbations (P<0.05).  They also found reductions in pneumonia with antibiotic prescriptions, hospitalizations, and duration of inpatient stays in the group on AIT. Overall, this study extends the existing RCT evidence for AIT, demonstrating long-term and sustained effectiveness of AIT in the real world, with an associated reduced likelihood of asthma exacerbation or pneumonia in patients with concurrent asthma.

Clinicopathological characteristics of IgG4-related lung disease
Liu J, Liu Y, Shen X et al
BMC Pulmonary Medicine 2021; 21(1):413 (15 December)DOI: https://doi.org/10.1186/s12890-021-01781-3

Immunoglobulin G4-related lung disease (IgG4-RLD) is a rare entity. To improve upon our ability to diagnose this illness, the authors retrospectively analyzed the clinical and histopathological characteristics of patients with pathologically confirmed IgG4-RLD. From a group of 4838 patients seen in their facility with pulmonary biopsy results, they found 65 patients with suspected IgG4-RLD, of whom analysis of these 10 patients revealed an average age of 59.7 years at diagnosis, and a male-to-female ratio was 9:1. The initial clinical manifestations were nonspecific, with cough being the most common symptom (4/10). More than one organ was involved in most patients (8/10), and mediastinal/hilar lymph node involvement was often observed (7/10). Serum IgG4 was analyzed in 6 patients and found to be elevated. Computed tomography (CT) of the chest and/or 18F-fuorodeoxyglucose positron emission tomography-computed tomography imaging revealed that 5 patients had a mixed type, 3 patients had the solid nodular type, and 2 patients had the bronchovascular type. All pulmonary masses and large nodules with solid patterns had spiculated margins and inhomogeneous enhancement with or without pleural indentation and a lobulated appearance. Abundant lymphoplasmacytic cell infiltration and fibrosis were observed in all patients. The expression of IgG4 and IgG was upregulated in the pulmonary sections. Seven patients were treated with glucocorticoids with or without additional immunosuppressants and responded well.