Direct oral challenge for immediate and non-immediate beta-lactam allergy in children: A real-world multicenter study.

BACKGROUND: Allergy to beta-lactam antibiotics (BLA) is frequently suspected in children, but a drug provocation test (DPT) rules it out in over 90% of cases. Direct oral DPT (DODPT), without skin or other previous tests, is increasingly been used to delabel non-immediate BLA reactions. This real-world study aimed to assess the safety and effectiveness of DODPT in children with immediate and non-immediate reactions to BLAs. METHODS: Ambispective registry study in children (<15 years), attended between 2016 and 2023 for suspected BLA allergy in 15 hospitals in Spain that routinely perform DODPT. RESULTS: The study included 2133 patients with generally mild reactions (anaphylaxis 0.7%). Drug provocation test with the implicated BLA was performed in 2014 patients (94.4%): 1854 underwent DODPT (86.9%, including 172 patients with immediate reactions). One hundred forty-five (7.2%) had symptoms associated with DPT, although only four reactions were severe: two episodes of anaphylaxis and two of drug-induced enterocolitis syndrome, which resolved rapidly with treatment. Of the 141 patients with mild reactions in the first DPT, a second DPT was considered in 87 and performed in 57, with 52 tolerating it without symptoms. Finally, BLA allergy was ruled out in 90.9% of the sample, confirmed in 3.4%, and remained unverified, usually due to loss to follow-up, in 5.8%. CONCLUSIONS: Direct oral DPT is a safe, effective procedure even in immediate mild reactions to BLA. Many reactions observed in DPT are doubtful and require confirmation. Severe reactions are exceptional and amenable to treatment. Direct oral DPT can be considered for BLA allergy delabeling in pediatric primary care.

Epidemiology of pediatric parapneumonic pleural effusion during 13-valent pneumococcal conjugate vaccine implementation.

INTRODUCTION: The reported incidence of parapneumonic pleural effusion, including empyema, has shown fluctuations in the last decades. It has been related to the implementation of different types of conjugate pneumococcal vaccines. METHODS: We have retrospectively reviewed data from all 10 public hospitals in Alicante Province (Spain) covering a population of 279,000 children under 15 years of age, between 2010 and 2018. Effusions less than 10 mm (PE-) and those of 10 mm or more (PE+) were separated. RESULTS: A total of 366 episodes of parapneumonic pleural effusion have been analyzed, 178 PE- (48.6%) and 188 PE+ (51.4%), with a median age of 4 years (interquartile range: 2-7 years) and marked seasonality with the maximum in winter and the minimum in summer. A culture proven bacterial agent was identified in 34 patients (9.3%), mainly Streptococcus pneumoniae (24 patients) followed by Streptococcus pyogenes (7 patients). The most frequent S. pneumoniae serotype was 19A (6 patients) and 3 vaccine failures were observed. The mean annual incidence rate was 14.3 cases per 100,000 children under 15 years of age (7.0 for PE- and 7.3 for PE+). No significant changes were observed in incidence over time, but noticeable differences in incidence were observed in different health departments. CONCLUSIONS: We have not found temporal variations in incidence of parapneumonic effusion despite the implementation of the 13-valent pneumococcal conjugate vaccine. The unexplained disparity in incidence between close departments is noteworthy.

Positive drug provocation with beta-lactam antibiotics in children: A single test may not be enough.

BACKGROUND: Drug provocation tests (DPTs) are considered the gold standard for diagnosing beta-lactam allergy. However, positive results tend to be mild and difficult to interpret. This study aimed to describe pediatric patients with a presumedly positive or inconclusive DPT, assess the decision to repeat the DPT, and describe its outcome. METHODS: Retrospective review of all presumedly positive or inconclusive DPTs performed in six pediatric allergy clinics from 2017 to 2019. We describe the interpretation of results, focusing on the decision to repeat the DPT and its outcome. RESULTS: Of 439 children challenged with a beta-lactam, 26 (5.9%) with a presumedly positive or inconclusive result were included in this study. Most were girls (n = 16, 61.5%), and the median age was 5 years (range 1-13). The initial DPT used amoxicillin (n = 13, 50.0%), amoxicillin-clavulanic acid (n = 12, 46.2%), or cefadroxil (n = 1, 3.8%). Reactions were early (n = 11, 42.3 %), delayed (n = 14, 53.8 %), or not registered (n = 1, 3.8 %), but mild in all cases. A second confirmatory DPT was proposed in 19 patients (73.1%) and performed in 17 patients (65.4%). Nine DPTs were performed from 1 day to 4 months after the first DPT, and the remaining eight took place 6 months to 2 years later. Fifteen children tolerated the drug in the second DPT: 88.2% of those reevaluated and 57.5% of the whole study group. CONCLUSION: The positive predictive value of DPT may be lower than expected. Given the mildness of observed reactions, a second confirmatory DPT is warranted within a few weeks or months.

First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

Drug reexposure in children with severe mucocutaneous reactions.

In pediatric patients, severe cutaneous adverse reactions (SCARs) frequently occur in the course of acute illnesses, mostly infections, which are usually treated with antibiotics or analgesics. The drug provocation test (DPT) is contraindicated in such situations, due to the risk of triggering a new severe reaction. As a consequence, lifelong avoidance is recommended. However, causation is uncertain in most cases. The dilemma arises when avoiding the drug is not harmless for the patient. We have attended three patients who were referred to our pediatric allergy unit with a history of SCAR related in time to simultaneous use of paracetamol and ibuprofen. Medical records and images of the patients were reviewed with the assistance of a dermatologist, and alternative diagnoses were considered in both cases. The ALDEN score for implicated drugs was calculated. After considering a high probability of ibuprofen tolerance and obtaining informed consent from the patients, we performed a sequential allergy workup including in vitro tests, skin tests, and finally DPT in two of the patients, confirming ibuprofen tolerance. In conclusion, although generally contraindicated, DPT may be considered for some useful drugs after careful evaluation of the risk-benefit balance, preceded by a sequential study including in vitro and skin tests.

Population-Based Cohort of Children With Parapneumonic Effusion and Empyema Managed With Low Rates of Pleural Drainage.

Introduction: The most appropriate treatment for parapneumonic effusion (PPE), including empyema, is controversial. We analyzed the experience of our center and the hospitals in its reference area after adopting a more conservative approach that reduced the use of chest tube pleural drainage (CTPD). Methods: Review of the clinical documentation of all PPE patients in nine hospitals from 2010 to 2018. Results: A total of 318 episodes of PPE were reviewed; 157 had a thickness of <10 mm. The remaining 161 were 10 mm or thicker and were subdivided into three increasing sizes: PE+1, PE+2, and PE+3. There was a strong relationship between the size of the effusion and complicated effusion/empyema, defined by its appearance on imaging studies or by the physical or bacteriological characteristics of the pleural fluid. The size of effusion was also strongly related to the duration of fever and intravenous treatment and was the best independent predictor of the length of hospital stay (LHS) (p < 0.001). CTPD was placed in 2.9% of PE+1 patients, 19.3% of PE+2, and 63.9% of PE+3 (p < 0.001). The referral of patients with PE+1 decreased over time (p = 0.033), as did the use of CTPD in the combined PE+1/PE+2 group (p = 0.018), without affecting LHS (p = 0.814). There were no changes in the use of CTPD in the PE+3 group (p = 0.721). Conclusions: The size of the PPE is strongly correlated with its severity and with LHS. Most patients can be treated with antibiotics alone.

Burden of severe 2009 pandemic influenza A (H1N1) infection in children in Southeast Spain.

INTRODUCTION: Most of the published studies on patients admitted with 2009 pandemic influenza are not population based. We have compiled the clinical information regarding all children admitted with 2009 pandemic influenza A (H1N1) infection during the season 2009-2010 in our defined population, in order to have an unbiased view of the most severe side of the clinical spectrum of the infection and to quantify its burden. METHODS: Children <15 years-old admitted to any of 3 hospitals in South-East Spain with 2009 pandemic influenza A (H1N1) detected by means of reverse transcriptase polymerase chain reaction. High quality data were extracted from clinical records specially designed for the pandemic. RESULTS: Eighty two children fulfilled the inclusion criteria. The hospitalization rate was 68 per 100,000 children <15 years-old; in those <5 years-old the rate was of 131 and in <1 year-old, 234 per 100,000. An estimated 0.7% of the children who suffered from pandemic influenza were admitted (1.7% in <5 years-old). Intensive care was required for 5% of the hospitalized patients living in the study area. Mortality was roughly estimated about 1 per 100,000 children <15 years-old and was associated with the presence of very severe comorbidities or co-infections. Only 20% of the admitted children were ≥ 5 years-old and without risk factors. The disease followed a generally benign course despite the modest use of oseltamivir (49% of the patients). CONCLUSIONS: Clinical and epidemiological data are very similar to those observed in other places and in interpandemic seasons with a high influenza activity.