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Medical Journal Review

November 2021

WAO Reviews – Editors’ Choice

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

Neutralization of SARS-CoV-2 requires antibodies against conformational receptor-binding domain epitopes
Gattinger P, Niespodziana K, Stiasny K et al
Allergy 2021; Published online ahead of print (28 August)

The determinants of successful humoral immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of critical importance for the design of effective vaccines and the evaluation of the degree of protective immunity conferred by exposure to the virus. Furthermore, as novel variants emerge, understanding their likelihood of suppression by population antibody repertoires has become increasingly important. In this study Gattinger et al analyzed the SARS-CoV-2 polyclonal antibody response in a large population of clinically well-characterized patients after mild and severe COVID-19 using a panel of microarrayed structurally folded and unfolded SARS-CoV-2 proteins, as well as sequential peptides, spanning the surface spike protein (S) and the receptor-binding domain (RBD) of the virus. They found that the S- and RBD-specific antibody responses were dominated by immunoglobulin G (IgG), mainly IgG1, which were directed against structurally folded S and RBD and three distinct peptide epitopes in S2. The virus-neutralization activity of patients´ sera was highly correlated with IgG antibodies specific for conformational but not sequential RBD epitopes and their ability to prevent RBD binding to its human receptor angiotensin-converting enzyme 2 (ACE2). Twenty percent of patients selectively lacked RBD-specific IgG. They also found that immunization with folded, but not with unfolded RBD, induced antibodies against conformational epitopes with high virus-neutralizing activity. Conformational RBD epitopes required for protection do not seem to be altered in the currently emerging virus variants.

Thoracic involvement and imaging patterns in IgG4-related disease
Muller R, Habert P, Ebbo M et al
European Respiratory Review 2021;20(162):210078

Immunoglobulin G4-related disease (IgG4-RD) is a rare orphan disease. Lung, pleura, pericardium, mediastinum, aorta, and lymph node involvement has been reported with variable frequency and mostly in Asian studies. The objective of this study was to explore thoracic involvement (assessed by high-resolution thoracic computed tomography, CT) in Caucasian patients with IgG4-RD. Thoracic CT scans were retrospectively collected through the French case registry of IgG4-RD and a single tertiary referral center and reviewed by two experts in thoracic imagery blinded from clinical data. A total of 48 IgG4-RD patients with thoracic involvement were analyzed. All had American College of Rheumatology/European League Against Rheumatism classification scores ⩾20 and comprehensive diagnostic criteria for IgG4-RD. CT scan findings showed heterogeneous lesions, with severe pattern observed: peribronchovascular involvement (56%), lymph node enlargement (31%), nodular disease (25%), interstitial disease (25%), ground-glass opacities (10%), pleural disease (8%), and retromediastinal fibrosis (4%). In 37% of cases, two or more patterns were associated. Asthma was significantly associated with peribronchovascular involvement (p=0.04). Among eight patients evaluated by CT scan before and after treatments, only two patients with interstitial disease displayed no improvement. Overall, this indicated that thoracic involvement of IgG4-RD is heterogeneous and likely underestimated with the main thoracic CT scan patterns are peribronchovascular thickening and thoracic lymph nodes.

Health effects of exposure to chlorination by-products in swimming pools
Couto M, Bernard A, Delgado L et al
Allergy 2021;76(11):3257-3275

Concerns have been raised regarding the potential negative effects on human health of water disinfectants used in swimming pools, specifically chlorine. Chlorine readily reacts with natural organic matter that are introduced in the water mainly through the bathers, leading to the formation of potentially harmful chlorination byproducts (CBPs). The formation of CBPs is of particular concern, since some have been epidemiologically associated with the development of a variety of illnesses. The higher the concentration of volatile CBPs in the water, the higher their concentration in the air above the pool, and different routes of exposure to chemicals in swimming pools (water ingestion, skin absorption, and inhalation) contribute to the individual exposome. Some CBPs may affect the respiratory and skin health of those who stay indoors for long periods, such as swimming instructors and pool staff, as well as competitive swimmers. Whether less frequent or intense exposure, particularly in children, may also be affected has been a matter of debate. In this article, the authors explore the current evidence regarding the health effects of both acute and chronic exposures in different populations (work-related exposures, intensive sports, and recreational attendance), noting that early and chronic exposure to swimming pool CBP may have a promoting effect not only on airway inflammation and hyperreactivity, but also on the process of allergic sensitization itself. They also note that early age exposure (baby and pre-school swimming) may be a relevant personal risk factor for respiratory health effects of CBP exposure in swimming pools, given the progressive increase in maturation of respiratory tract.

What we know and still ignore on COVID-19 immune pathogenesis and a proposal based on the experience of allergic disorders
Maggi E, Assarone BG, Canonica GW, Moretta L
Allergy 2021; Published online ahead of print (28 September)

The coronavirus disease 2019 (COVID-19) pandemic started in March 2020 and has resulted in over 5 million confirmed deaths worldwide as far as August 2021. We have recently been overwhelmed by a wide and varying literature regarding how the immune system recognizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and contributes to COVID-19 pathogenesis. Although originally considered a respiratory viral disease, COVID-19 is now recognized as a far more complex, multi-organ-, immuno-mediated-, and heterogeneous disorder. Though efficient innate and adaptive immunity may control infection, when the patient fails to mount an adequate immune response at the start, or in advanced disease, a high innate-induced inflammation can lead to different clinical outcomes through heterogeneous compensatory mechanisms. The variability of viral load and persistence, the genetic alterations of virus-driven receptors/signaling pathways and the plasticity of innate and adaptive responses may all account for the extreme heterogeneity of pathogenesis and clinical patterns. Patients should be stratified for evolving symptoms and carefully monitored for surrogate biomarkers of innate and adaptive immunity. This tact would aid in identifying each endo-type (and its related phenotype) and to treat patients precisely with agents targeting pathogenic mechanisms.

Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory testing in a US Regional Health System
Warren CM, Snow TT, Lee AS et al
JAMA Network Open 2021;4(9):e2125524 (17 September)

Anaphylactic reactions associated with the Food and Drug Administration (FDA)–authorized mRNA COVID-19 vaccines have been reported. The goal of this study was to characterize the immunologic mechanisms underlying allergic reactions to these vaccines via analysis of a case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants all received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of IgG and IgE antibodies to PEG were obtained to determine possible mechanisms. Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria for anaphylaxis, and all reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. The authors conclude that based on this case series, women and those with a history of allergic reactions appear to have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non–IgE-mediated immune responses to PEG may be responsible in most individuals and further study is needed.


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