Fast gadolinium-based contrast agent challenge test searching for an alternative contrast mediaTo the Editor,Gadolinium-based contrast agents (GBCA) are used in contrast-enhanced magnetic resonance imaging. Hypersensitivity reactions (HSR) to GBCA are scarce, with an incidence of 0.07% and a recurrence rate of 30%, being urticaria the most common presentation (91%), with 0.52/10000 of severe reactions reported1. Recommendation of an alternative GBCA without checking tolerance is dangerous, due to high cross-reactivity between them2. Moreover, premedication is not enough1, showing an overall rate of breakthrough reactions of 39%3.Allergy studies to achieve a safe recommendation in HSR to GBCA have been performed. Negative predictive value of skin-tests to GBCA has been estimated in 84%1. Therefore, more than 10% of patients could react using an alternative negative skin-tested GBCA, and thus, good tolerance to GBCA should be confirmed through a drug challenge-test (DCT)4. These tests are usually performed at graded administrations, and with observation periods between doses1,5. However, since GBCA is usually given as a bolus during radiologic exams, DCT at slow rates cannot be extrapolated to further administrations. Trying to avoid this limitation, we study the tolerance of an alternative GBCA, by means of a fast DCT, approaching the infusion rates used in clinical practice.In accordance with the safety warnings to avoid linear GBCA, we have only used the macrocyclic drugs gadobutrol (Gb) and gadoteric acid (Ga). After obtaining signed informed consent from the patients, skin pricktests (SPT) with undiluted macrocyclic GBCA commercial solutions were done. When SPT at 20 min yielded negative results, intradermal tests (IDT) with 1:10 dilutions were performed, with subsequent readings at both 20 min and 24 hours.A fast DCT with negative skin-tested GBCA was then performed, following our methodology to study HSR to iodinated contrast media, previously described elsewhere6. Doses were 0.2 mg/kg for Ga and 0.1 mg/kg for Gb. First, one third of the total dose of Ga was administered at a rate of 120 cc/hour and, immediately after, the remaining 2/3 at 80 cc/hour. In case of Gb, infusion rates were half those of Ga, i.e., 1/3 at 60 cc/hour and 2/3 at 40 cc/hour. Total infusion time was 8 minutes for both of them. Well-tolerated GBCA was finally recommended for subsequent examinations, and its tolerance was recorded if it was used later.Study results of sixteen patients that were enrolled are summarized in Table 1. They were 12 women and 4 men, with median age of 45.5 years (range 28-73). Adverse reactions to GBCA were immediate in 13 patients (12 urticaria or exanthema, and 1 anaphylaxis), and delayed exanthema in the remaining 3. Gb was involved in 11 reactions, and unknown GBCA in the other 5. Most of the patients (14/16) had been previously exposed to GBCA.Median delay to perform the allergy study was 10 months (range 2-72 months). All skin-tests were negative, except in one patient who showed an immediate positive SPT to Gb, which had been the GBCA involved in the adverse reaction. In our study, we have estimated a negative predictive value of skintests to GBCA of 89%. DCT were negative in 14 patients (12 with Ga, and 2 with Gb). Finally, 15 out of 16 patients had an alternative GBCA, avoiding the use of premedication. In fact, tolerance has been confirmed in 7 of them in subsequent examinations.Safety of our protocol has been confirmed because our 2 positive DCT showed only mild reactions (delayed exanthema and immediate urticarial, both with Ga), and also by including a patient with previous anaphylaxis to GBCA.Here we present a prospective protocol to identify a safe alternative GBCA, including DCT at high infusion rates. Further studies will be necessary on this item/to check this.
Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a “fixed” bronchial obstruction due to structural changes unresponsive to current therapies, from a “reversible” one as demonstrated by lung function normalization during biological therapies not previously obtained even with high dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent tissue-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert “fixed” remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.
Background Protecting the skin barrier in early infancy may prevent atopic dermatitis (AD). We investigated if daily emollient use from birth to 2 months reduced AD incidence in high risk infants at 12 months. Methods This was a single-center, two-armed, investigator-blinded, randomized controlled clinical trial (NCT03871998). Term infants identified as high risk for AD (parental history of AD, asthma or allergic rhinitis) were recruited within 4 days of birth and randomised 1:1 to either twice-daily emollient application for the first 8 weeks of life (intervention group), using an emollient specifically formulated for very dry, AD-prone skin, or to standard routine skin care (control group). The primary outcome was cumulative AD incidence at 12 months. AD <6 months was diagnosed based on clinical presence of AD. The UK Working Party Diagnostic Criteria were applied when diagnosing AD between 6 and 12 months. Results 321 infants were randomised (161 intervention and 160 control), with 61 withdrawals (41 intervention, 20 control). The cumulative incidence of AD at 12 months was 32.8% in the intervention group vs. 46.4% in the control group, p = 0.036 [Relative risk (95%CI): 0.707 (0.516, 0.965)]. One infant in the intervention group was withdrawn from the study following development of a rash that had a potential relationship with the emollient. There was no significant difference in the incidence of skin infections between the intervention and control groups during the intervention period (5.0% vs. 5.7%, P>0.05). Conclusions This study has demonstrated that early initiation of daily specialized emollient use until 2 months reduces the incidence of AD in the first year of life in high-risk infants.
LetterDelta or Omicron BA.1/2-neutralizing antibody levels and T-cell reactivity after triple-vaccination or infectionTo the editor,In Germany, SARS-CoV-2 infections in fall 2021 were caused by the Delta variant of concern (VOC B.1.617.2), which was completely replaced by the Omicron VOC (BA.1, B.1.529.1/BA.2, B.1.529.2) in winter. Meanwhile, the BA.2 sublineage dominates, apparently having a selection advantage1.We studied the kinetics of anti-spike (S) protein IgG and Delta neutralizing antibodies (NA) as well as the release of interferon-gamma (IFN-γ) from SARS-CoV-2-specific T-cells in 152 individuals (117 women, 35 men, median age 41 years) who received two doses of vector vaccine (AstraZeneca, AZD, N=34), mRNA vaccine (BioNTech or Moderna, mRNA, N=62), or a combination of both (N=56) followed by an mRNA vaccine boost (N=81). In a subset of 15 age- and gender-matched vaccinees and in ten triple-vaccinated and two unvaccinated patients with previous BA.1 infection, the Delta- and Omicron BA.1/BA.2 NAs and T-cell reactivity were examined. For comparison, variant-specific antibody responses of unvaccinated patients after infection with Alpha- (N=10) or Beta VOCs (N=1) were included.Within 279 days after the second vaccination, a decrease in anti-S IgG concentrations (Figures S 1A-C) and Delta NA titers (Figure 1A) was measured regardless of the immunization regimen. The booster vaccination led to a significant increase of anti-S IgG concentrations (Figures S1 D-F) and of Delta NA titers (Figure 1B). The IgG levels and Delta NAs reached four weeks after the mRNA vaccine booster were 1.3 - 1.7-fold higher than after the second mRNA dose, but this difference was significant only for IgG (Figures 1A, C; Figures S 1A-C, G-I). The release of IFN-γ as a measure of SARS-CoV-2 T-cell reactivity was demonstrated for months after second vaccination. In contrast to the Delta NA levels, IFN-γ concentrations were independent of the underlying vaccination schedule and increased slightly after the third immunization (Figures 1D, E). The parameters of humoral and cellular immunity decreased again after the booster vaccination (Figures 1C, F; Figures S 1G-I).As reported by others 1-4, NAs to Omicron BA.1 were induced by the mRNA vaccine booster, but also against the predominant BA.2 sublineage, which was previously unclear. The BA.2 NA geometric mean titer (GMT) was higher than the BA.1 NA GMT (Figure 2A). With respect to the results presented in Figures 1C and 2B, we suspect that NAs against the Omicron VOC will decline rapidly after booster vaccination alone. High NA titers against Omicron BA.1/BA.2 and against Delta VOC were exclusively observed in triple-vaccinated individuals two to three weeks after Omicron breakthrough infection (Figure 2A). This indicates broadened immunity covering additional viral variants and may also explain why few BA.2 infections have occurred in this group of individuals to date 5. Because Omicron is a distinct serotype 6, only NAs against this VOC were detectable in two unvaccinated BA.1-infected individuals (Figure 2A), while unvaccinated Alpha- and Beta VOC patients developed isolated NAs against the antigenically more related Delta VOC (Figure S 2A). Accordingly, both BA.1 patients had very low IgG levels against the receptor-binding domain (RBD) of a Wuhan-like virus (Figure S 2B), whereas IgGs against the higher preserved nucleocapsidprotein were barely affected (Figures S 2C, D). The results of a surrogate neutralization assay confirmed very limited humoral immunity after Omicron infection alone (Figure S 2E).The increase of IFN-γ release by mRNA booster vaccination was moderate (Figures 1D, E), while the breakthrough infection insignificantly increased IFN-γ release by a factor of 1.9 - 2.6 (Figure 2C).In conclusion, the importance of pre-existing vaccine-induced immunity is clearly demonstrated. The booster vaccination with the conventional mRNA vaccine resulted in measurable BA.1/BA.2 NAs. However, a multivalent vaccine could induce higher titers, which could provide better protection.
Background: Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. Methods: We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. Results: A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared to pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared to pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. Conclusion: We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings have implications for future vaccination strategies and possibly cross-reactive T cell immunity.
Humans inhale, ingest and touch thousands of fungi each day. The ubiquity and diversity of the fungal kingdom are in sharp contrast with their complex and relatively blurred taxonomy and scarce knowledge about their distribution, pathogenic effects, and effective interventions at the environmental and individual levels. Here, we present an overview of salient features of fungi as permanent players of the human exposome and key determinants of human health. Improved understanding of the fungal exposome sheds new light on the epidemiology of fungal-related diseases, their immunological substratum, the currently available methods, and biomarkers for environmental and medical fungi. Unmet needs are described and potential approaches are highlighted as perspectives.
Similar IgE Binding Patterns in Gulf of Mexico and Southeast Asian Shrimp Species in US Shrimp Allergic PatientsSara Anvari1,2*, Shea Brunner1,2*, Karen Tuano1,2, Brenda Bin Su1,2, Shaymaviswanathan Karnaneed3, Andreas L. Lopata3, Carla M. Davis1,21Baylor College of Medicine, Texas Children’s Hospital, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, Texas2Baylor College of Medicine, William T. Shearer Center for Human Immunobiology, Houston, Texas3James Cook University, Australian Institute of Tropical Health and Medicine, Centre for Molecular Therapeutics, Douglas, QLD, Australia*co-first authors
Background Cow’s milk protein allergy (CMPA) is one of the most common food allergies in infancy. Most infants with CMPA tolerate baked milk from diagnosis and gradually acquire increased tolerance. Nevertheless, parents often display significant anxiety about this condition and a corresponding reluctance to progress with home introduction of dairy due to concerns about possible allergic reactions. Objective: To evaluate the impact on gradual home introduction of foods containing cows milk after a supervised, single low dose exposure to whole milk at time of diagnosis. Methods Infants less than 12 months old, referred with suspected IgE-mediated cow’s milk allergy were recruited to an open-label randomised, controlled trial of intervention - a single dose of fresh cow’s milk, using the validated dose of milk that would elicit reactions in 5% of CMPA subjects - the ED 05 – vs routine care. Both groups implemented graded exposure to CM (using the 12 step MAP Milk Tolerance Induction Ladder), at Home. Parents completed food allergy quality of life and State and Trait Anxiety Inventories (STAI). Main outcome measures were milk ladder position at 6 months and 12 months post randomisation. Results: Sixty patients were recruited, 57 (95%) were followed to 6 months. By 6 months 27/37 (73%) intervention subjects had reached step 6 or above on the milk ladder compared to 10/20 (50%) control subjects (p=0.048). By 6 months 11/37 (30%) intervention subjects had reached step 12 (ie drinking unheated cow’s milk) compared to 2/20 (10%) of the controls (p=0.049). Twelve months post randomisation 31/36(86%) of the intervention group and 15/19(79%) of the control group were on step 6 or above. However, 24/37 (65%) of the intervention group were at step 12 compared to 7/20 (35%) of the control group (p=0.03). Maternal STAIs were significantly associated with their infants’ progress on the milk ladder and with changes in skin prick test and spIgE levels at 6 and 12 months. Conclusion This study demonstrates the safety and effectiveness of introduction of baked milk implemented immediately after diagnosis of cows milk allergy in a very young cohort. A supervised single dose of milk at the ED 05 significantly accelerates this further, probably by giving parents the confidence to proceed. Maternal anxiety generally reflects infants’ progress towards completion of the milk ladder, but pre-existing high levels of maternal anxiety are associated with poorer progress.
Objective: There is a need for the immunogenicity of different boosters after widely used inactivated vaccine regimens. We aimed to determine the effects of BNT162b2 and CoronaVac boosters on the humoral and cellular immunity of individuals who had two doses of CoronaVac vaccination. Methods: The study was conducted in three centers (Koc University Hospital, Istanbul University Cerrahpasa Hospital, and Istanbul University, Istanbul Medical School Hospital) in Istanbul. Individuals who had two doses of CoronaVac and no history of COVID-19 were included. The baseline blood samples were collected three to five months after two doses of CoronaVac. Follow-up samples were taken one and three months after third doses of CoronaVac or one dose of mRNA BNT162b2 boosters. Neutralizing antibody titers were detected by plaque reduction assay. T cell responses were evaluated by Elispot assay and flow cytometry. Results: We found a 3.38-fold increase in neutralizing antibody titers (Geometric Mean Titer [GMT], 78.69) one month after BNT162b2 booster and maintained at the three months (GMT, 80). However, in the CoronaVac group, significantly lower GMTs than BNT162b2 after 1 month and 3 months (21.44 and 28.44, respectively) indicated the weak immunogenicity of the CoronaVac booster (p<0.001). In the ELISpot assay, IL-2 levels after BNT162b2 were higher than baseline and CoronaVac booster (p<0.001) and IFN-γ levels were significantly higher than baseline (P<0.001). The CD8+CD38+CD69+ and CD4+CD38+CD69+ T cells were stimulated significantly at the 3 rd month of the BNT162b2 boosters. Conclusion: The neutralizing antibody levels after three months of the BNT162b2 booster were higher than the antibody levels after CoronaVac. On the other hand, specific T cells might contribute to immune protection. By considering the waning immunity, we suggest a new booster dose with BNT162b2 for the countries that already have two doses of primary CoronaVac regimens.
Background. The use of eliciting doses (EDs) for food allergens is necessary to inform individual dietary advice and food allergen risk-management. The Eliciting Dose 01 (ED01) for milk and egg, calculated from populations of allergic subjects undergoing diagnostic Oral Food Challenges (OFCs), are 0.2 mg total protein. The respective Eliciting Dose 05 (ED05) are 2.4 mg for milk and 2.3 mg for egg. As about 70% children allergic to such foods may tolerate them when baked, we sought to verify the EDs of that subpopulation of milk and egg-allergic children. Methods. We retrospectively assessed consecutive diagnostic OFC for fresh milk and egg between January 2018 and December 2020 in a population of baked food-tolerant children. Results. Among 288 children (median age 56 - IQR 36-92.5 months, 67.1% male) included, 87 (30.2%) returned positive OFC results, 38 with milk and 49 with egg. The most conservative ED01 were 0.3 mg total protein (IQR 0.03-2.9) for milk and 14.4 mg total protein (IQR 3.6-56.9) for egg. The respective ED05 were 4.2 (IQR 0.9-19.6) mg for milk and 87.7 (IQR 43-179) mg for egg. Such thresholds are respectively 1.5 (milk ED01), 1.75 (milk ED05), 72 (egg ED01), and 38.35 (egg ED05) times higher than the currently used thresholds. Conclusions The subpopulation of children allergic to milk and egg, but tolerant to baked proteins, displays higher reactivity thresholds than the general population of children allergic to milk and egg. Their risk stratification, in both individual and population terms, should consider this difference. In baked milk-tolerant children, milk causes reactions at lower doses than egg in our group of egg-tolerant children. This could be associated with the relative harmlessness of egg compared to milk in the determinism of fatal anaphylactic reactions in children