Late Hypersensitivity Reactions to the BNT162b2 SARS-CoV-2 Vaccine Are Linked to Delayed Skin Sensitization and Prior Exposure to Hyaluronic Acid.

Background: Late hypersensitivity reactions (HSRs) to the BNT162b2-vaccine have raised concerns regarding its safety, particularly as further immunizations are required. The yield of skin testing with the BNT162b2v is unclear, as well as the risk factors and outcomes of re-immunization after late HSRs. Objective: We studied a series of patients with late HSRs to BNT162b2v. Methods: Patients referred to the Sheba medical center from December 2020 to May 2021 with late HSRs to the first dose of BNT162b2 were included. HSRs were defined as late if they appeared or lasted >24 h after inoculation. We compared late HSRs to immediate HSRs that appeared within minutes−2 h after vaccination. Intradermal testing with PEG-containing medication and BNT162b2v was performed. Results: A total of 17 patients that presented with late HSRs (study group) were compared to 34 patients with immediate HSRs (control group). Delayed sensitivity to intradermal testing of the BNT162b2v was observed in 9/17 (53%) of the study group compared to 4/34 (12%) in the control group (p = 0.01). Former exposure to a dermal filler with hyaluronic acid was documented among 7/17 (41%) vs. 2/34 (6%) in the study and control groups, respectively, (p = 0.0038). All patients who presented with late HSRs were advised to receive subsequent doses of the BNT162b2v vaccine with or without concomitant medication, and all were re-immunized successfully. Conclusions: Late HSRs to BNT162b2v were linked with positive responses to intradermal testing with the vaccine and prior exposure to derma fillers with hyaluronic acid. This may elude to an immune mechanism triggered by former exposures. Although further studies are needed, late HSRs to the BNT162b2-vaccine did not prevent patients from receiving subsequent doses of the vaccines.

Impact of an extended challenge on the effectiveness of ß-lactam hypersensitivity investigation.

BACKGROUND: Drug provocation tests (DPTs) are the gold standard in the diagnosis of ß-lactam hypersensitivity. However, no consensus exists on the need for extended provocation tests, even though the effectiveness of the short DPT is relatively low and there has been an increase in the relative incidence of nonimmediate hypersensitivity reactions. OBJECTIVE: To evaluate the effectiveness of a 7-day (extended) DPT compared with a 1-day-only (short) DPT in the management of hypersensitivity reactions to ß-lactam antibiotics. METHODS: Patients referred to the allergy clinic of the Sheba Medical Center for suspected ß-lactam hypersensitivity from January 2008 to December 2012 underwent in vivo skin tests and an immediate short DPT with the culprit drug. Unless an immediate reaction was clearly documented, patients were offered a 7-day, extended DPT. Long-term effectiveness, calculated as the subsequent use of the tested antibiotic, and satisfaction levels were assessed with a telephone questionnaire. RESULTS: Of 49 negative DPT results, 26 (53%) were long and 23 (47%) were short. A total of 78% of the patients who underwent the long DPT reported that they used the drug compared with 61% of those who underwent only the short DPT (P = .049). Most patients were very satisfied with the drug allergy evaluation process. CONCLUSIONS: An extended DPT protocol increased the effectiveness of the allergy workup in our center without compromising patient satisfaction and safety, and it should be recommended to patients with a history of nonimmediate reaction to ß-lactam.

The second generation and asthma: Prevalence of asthma among Israeli born children of Ethiopian origin.

BACKGROUND: Immigrant populations moving from undeveloped countries with low asthma prevalence have shown increased asthma prevalence in their new Westernized environment. We compared the prevalence of asthma among Israeli born children of Ethiopian origin to that in non-Ethiopian children. METHODS: Cross sectional study. Data was retrieved for children aged 6-18 years in four clinics with a large proportion of patients of Ethiopian origin. For each Israeli born child from Ethiopian origin we matched an Israeli born child of any other origin of the same age and gender, receiving primary care from the same physician at the same clinic. Asthma was defined as any visit to a primary care physician, emergency room or hospitalization related to asthma symptoms or subsequent purchasing of any asthma medication during 2008. RESULTS: 1217 children of Ethiopian origin and 1217 matched controls were studied. More Ethiopian children came from families with a low socioeconomic status (23.9% vs. 17%, p < 0.001), and with significantly lower parental smoking (5.1% vs. 40.1%, p < 0.001). The prevalence of asthma was 92/1217 (7.5%) among children of Ethiopian origin, compared to 122/1217 (10.0%) among the control group (OR = 0.74, 95% CI: 0.56-0.98, p = 0.032). When adjusted for tobacco exposure, the OR for risk of asthma in the Ethiopian children was 0.80 (95% CI: 0.59-1.09, p = 0.16). CONCLUSION: Asthma prevalence in the second generation of Israeli born children of Ethiopian origin does not seem to differ from other children in their community. This observation supports the theory that environmental exposures, rather than genetic factors, dictated the increase in asthma in this immigrant population.

Serological and clinical characteristics of children with peanut sensitization in an Asian community.

In the past two decades, peanut allergy prevalence has increased in the West but has been perceived as having remained low in Asia. To review the clinical presentation of Asian children with peanut hypersensitivity and measure their IgE responses to major peanut allergens. We enrolled 31 children presenting with various allergies and a positive skin prick test to peanut from the Children's hospital outpatient allergy clinic in Singapore. A detailed questionnaire was completed by parents. The children's serum IgE specific to native Ara h 1, native Ara h 2, and recombinant Ara h 3 were detected using ELISA. Of the 31 patients, 19 had previously documented reactions to peanuts, while 12 had no previous clinical reaction. Most, 89.5% (17/19) of first reactions featured skin changes (urticaria, erythema, angioedema), but only 36.8% (7/19) involved skin symptoms alone. Respiratory symptoms and GI symptoms occurred in 42.1% and 26.3% of patients respectively and did not occur as the sole manifestation of reaction. The most common GI manifestation was emesis, present in 26.3% (5/19) of subjects. Two children experienced impaired consciousness with systemic, anaphylactic events. Although most sought treatment for their first peanut reaction only one patient received epinephrine. Half of our patients reported a subsequent accidental ingestion after the diagnosis of peanut allergy, with a median time from diagnosis to first accidental ingestion of 4 months and a reported increased severity of reaction in approximately half of the repeat exposures. Eighty-seven percent of children had specific IgE directed against at least one of the major peanut allergens. Among all patients, 87.1% had IgE specific to both Ara h 1 and Ara h 2 and 54.8% to rAra h 3. Asian children with peanut sensitization have clinically similar presentations and respond to the same major allergenic proteins as their Western counterparts. The perceived differences between the populations in this context do not stem from divergent clinical or immunological responses.

Severe anaphylactic reaction to ibuprofen in a child with recurrent urticaria.

An acute anaphylactic reaction after a conventional antipyretic dose of ibuprofen was diagnosed in a child with allergic rhinitis, recurrent idiopathic urticaria, and nonimmunologic cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs and acetaminophen. The patient reported several previous, mild (isolated cutaneous) hypersensitivity reactions after exposure to acetaminophen or ibuprofen. There was no evidence of an underlying inflammatory disease except as described above. Patients with chronic or recurrent idiopathic urticaria and those with atopic disease represent groups at increased risk of nonsteroidal antiinflammatory drug hypersensitivity. Mild hypersensitivity reactions to acetaminophen and/or ibuprofen may precede subsequent, more-severe adverse reactions. Risks and benefits of continued use of nonsteroidal antiinflammatory drugs in these children should be carefully considered.

Hypersensitivity to paracetamol in Asian children with early onset of nonsteroidal anti-inflammatory drug allergy.

BACKGROUND: The published incidence of paracetamol cross-reactivity in adults and adolescents with nonsteroidal anti-inflammatory drug (NSAID) reactions is low and all data on such reactions in young children is sparse. The study aim was to characterize the clinical presentation and cross-reactivity with paracetamol in patients with a reported onset of NSAID hypersensitivity before 6 years of age. METHODS: A retrospective case review was done of patients with cross-reactive hypersensitivity reactions to antipyretic/analgesic medications from the pediatric allergy clinic of the Kendang Kerbau Hospital, Singapore. Included patients reported the onset of such reactions before 6 years of age. Hypersensitivity was established through a detailed history of recurrent reactions to NSAIDs or an oral provocation test. RESULTS: Eighteen patients fulfilled the diagnostic criteria within the study period. Eighty-three percent had cross-reactive reactions with paracetamol. When compared to the group of children with later onset of NSAID hypersensitivity, children with onset before 6 years of age had a significantly increased likelihood of reacting to paracetamol (odds ratio 9.6, 95% confidence interval 1.6-58.0, p < 0.05). CONCLUSION: Paracetamol seems to be a major eliciting drug in this group of children.

Nonsteroidal anti-inflammatory drug hypersensitivity in preschool children.

: Although extensively studied in adults, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity in children, especially in young children, remains poorly defined. Pediatricians, prescribing antipyretics for children, rarely encounter significant problems, but the few epidemiologic studies performed show conflicting results. Although it is clear that some patients with acetylsalicylic acid (ASA)-sensitive asthma have their clinical onset of disease in childhood and bronchoconstriction after ASA challenge is seen in 0 to 22% of asthmatic children so challenged, ibuprofen at antipyretic doses may cause acute respiratory problems only in a very small number of mild to moderate asthmatics. The recently elucidated mechanism of action of acetaminophen may explain some occurrences of adverse reactions in patients with cross-reactive NSAID hypersensitivity on the basis of its inhibitory activity on the newly described enzyme, cyclooxygenase (COX)-3. This nonspecific sensitivity to inhibition of COX is most likely genetically determined and shows a remarkable association with atopic disease even in the very young age group and possibly an increased predilection in specific ethnic groups. This review summarizes state-of-the-art published data on NSAID hypersensitivity in preschool children.

[Sublingual immunotherapy--coming of age?].

BACKGROUND: Immunotherapy is the only therapeutic modality in allergic patients with long lasting effects on the reactivity of the immune system to specific allergen exposure. Classical, subcutaneous, immunotherapy is associated with ubiquitous local and rare but potentially life-threatening systemic side effects. Sublingual immunotherapy is a relatively new modality of treatment, utilizing daily gradually increasing concentrations of allergen that are placed sublingually for a few minutes and swallowed afterwards. AIMS: To summarize "state of the art" concepts on sublingual immunotherapy, its mechanisms of action as well as safety and efficacy in the treatment of allergic disease. METHODS: A Medline search was performed through the PubMed service of the National Library of Medicine, for the period 1985 to December 2004, using "sublingual" and "imm unotherapy" in the title or abstract. The latest Cochrane Library meta-analysis on the subject was extracted as well as the original publications on which the analysis is based. RESULTS: Sublingual immunotherapy is a safe treatment in patients of all ages with asthma and other allergic diseases. The modality is more effective than placebo in the treatment of allergic rhinitis in adults. Our local experience supports a remarkable safety profile and efficacy. CONCLUSIONS: Sublingual immunotherapy is a promising treatment for allergic patients. Further study is needed but it seems reasonable to assume that an increasing number of patients will benefit from this modality in the near future.

Early presentation with angioedema and urticaria in cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs among young, Asian, atopic children.

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAIDs), mainly ibuprofen, are used extensively among children as analgesic and antipyretic agents. Our initial survey in the Kendang Kerbau Children's Hospital in Singapore showed NSAIDs to be the second most common adverse drug reaction-causing medications among children of Asian descent. We attempted to characterize the clinical and epidemiologic profile of NSAID reactions in this group of patients. METHODS: A retrospective case series from a hospital-based pediatric drug allergy clinic was studied. A diagnosis of NSAID hypersensitivity was made with a modified oral provocation test. Atopy was evaluated clinically and tested with a standard panel of skin-prick tests. We excluded from analysis patients with any unprovoked episodes of urticaria and/or angioedema, patients < 1 year of age, and patients who refused a diagnostic challenge test. RESULTS: Between March 1, 2003, and February 28, 2004, 24 patients, including 14 male patients (58%) and 18 Chinese patients (75%), with a mean age of 7.4 years (range: 1.4-14.4 years), were diagnosed as having cross-reactive NSAID hypersensitivity. A family history consistent with NSAID hypersensitivity was elicited for 17% of patients. None of the patients reported any episodes of angioedema/urticaria unrelated to NSAIDs. The median cumulative reaction-eliciting dose was 7.1 mg/kg. Facial angioedema developed for all patients (100%) and generalized urticaria for 38% of challenged patients, irrespective of age. There was no circulatory compromise, but respiratory symptoms of tachypnea, wheezing, and/or cough were documented for 42% of patients. A cross-reactive hypersensitivity response to acetaminophen was documented for 46% of our patients through their history and for 25% through diagnostic challenge. Compared with patients with suspected adverse drug reactions to antibiotics, patients in the NSAID group were older (7.4 vs 4.8 years) and more likely to have a diagnosis of asthma (odds ratio: 7.5; 95% confidence interval: 3.1-19). CONCLUSIONS: Early presentations of facial angioedema and urticaria are key features of dose- and potency-dependent, cross-reactive reactions to NSAIDs in a subpopulation of young, Asian, atopic children. Significant overlap with acetaminophen hypersensitivity, especially among very young patients, for whom the use of a cyclooxygenase-2-specific medication may not be feasible, severely limits options for medical antipyretic treatment.

Bimodal skin reactivity to histamine in atopic children in Singapore: influence of specific sensitizations.

Histamine skin prick test (SPT) is used as the 'golden standard' for positive control in in vivo immediate type hypersensitivity testing. The skin reactivity to histamine can, however, be modulated by a bevy of extraneous factors. We aimed to define whether histamine skin reactivity in atopic children in Singapore is influenced by age, ethnic origin, gender, environmental exposure or specific sensitization patterns. A retrospective analysis of children, with specific aeroallergen sensitization (as measured by at least one allergen-specific SPT with a wheal size > 3 mm compared with the negative control) from the outpatient speciality clinic of the KK Children's Hospital, during 06/2002-06/2003. A total of 315 patients were included, 235 (75%) were males, 252 (80%) were Chinese, age mean was 7.7 yr (range: 2-15). Patients were referred to the SPT with a diagnosis of one or more of: allergic rhinitis 287 (91%), asthma 112 (36%) or atopic dermatitis 60 (19%). The mean histamine response showed a bimodal distribution, independent of age, ethnic origin, gender or phenotypical expression of allergic disease. Histamine skin reactivity was higher in atopic patients with polysensitization (mean 5.0 mm vs. 2.9 mm in monosensitized patients, p < 0.001), and in patients with mould sensitization (mean 5.1 mm vs. 3.3 mm in patient not sensitized to moulds, p < 0.001). The presence of passive smoking increased the likelihood of a diminished histamine skin response. Histamine skin response data strongly suggested the presence of two heterogeneous subpopulations. Children with polysensitization and mould sensitization were more likely to show a large significant histamine response, whereas children with passive smoke exposure, showed a diminished skin reactivity to histamine.

Symptomatic hypogammaglobulinemia in infancy and childhood - clinical outcome and in vitro immune responses.

BACKGROUND: Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. METHODS: Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. RESULTS: 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. CLINICAL PRESENTATION: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. CONCLUSIONS: The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign.

Aeroallergen sensitization in pediatric allergic rhinitis in Singapore: is air-conditioning a factor in the tropics?

Singapore is a unique blend of a tropical environment with a high standard of hygiene and public health care. The objective was to define the prevalence, clinical characteristics, and environmental risk factors of specific aeroallergen sensitization in pediatric allergic rhinitis patients in this unique environment. The method adopted was a retrospective analysis of allergic rhinitis patients, undergoing aeroallergen skin prick testing (SPT), in the outpatient specialty clinic of the KK Children's hospital, from July 2001 to June 2002. A total of 202 patients were included, 161 (80%) males, 167 (83%) Chinese, age mean 7.6 yr (range 2-14 yr). The most prevalent clinical symptoms were: watery rhinorrhea 61%, blocked nose 61%, sneezing 52%, snoring 17%, and epistaxis 12%. SPT results were positive for house dust mites in 97% of children, pets (20%), molds (19%), pollens (15%), and kapok (10%). Mold sensitization was significantly more prevalent in households without air-conditioning (aircon), 49% vs. 10% with aircon (odds ratio 9.4, 95% CI 3.8-22.9). Polysensitization (sensitization to three or more allergens) was similarly more prevalent in households without aircon, 51% vs. 14% with aircon (odds ratio 6.4, 95% CI 2.8-14.7). It was concluded that indoor aeroallergen sensitization is the major associated factor with clinical allergic rhinitis in children in Singapore. Patients living in households without air-conditioning are at increased risk of mold sensitization and polysensitization.