Maintenance Therapy for Children and Adolescents with Asthma: Guidelines and Recommendations from the Emilia-Romagna Asthma (ERA) Study Group.

Asthma is the most frequent chronic disease of childhood, affecting up to 20% of children worldwide. The main guidelines on asthma maintenance therapy in pediatrics suggest different approaches and describe different stages of asthma to determine the most appropriate treatment. This project aims to summarize the most recent evidence regarding maintenance therapy for asthma in children and adolescents. A multidisciplinary panel of experts was asked clinical questions regarding the treatment of children and adolescents with asthma. Overall, 10 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results showed that the choice of medication depends on the severity of the child's asthma, phenotype, age, preference, and individual factors. In addition to medications, the identification of comorbidities and modifiable factors is crucial to obtaining good control. Asthma in children is heterogeneous, and its evolution varies over time. Since most recommendations for asthma management in childhood are extrapolated from clinical studies performed in adults, more clinical trials specifically designed for young children should be conducted.

COVID-19 restrictions and hygiene measures reduce the rates of respiratory infections and wheezing among preterm infants.

BACKGROUND AND AIM: During the 2020 and 2021 Italian COVID-19 pandemic social restrictions and strict hygiene measures were recommended to limit the spread of SARS-CoV-2. We aimed to assess whether rates of respiratory infections and wheezing in preterm infants have changed during the pandemic. METHODS: Single center, retrospective study. Preterm infants in the first 6 months of life discharged home prior to (Period 1, January 2017 - December 2019) or during the pandemic (Period 2, January 2020 - March 2021) were compared. Rates of respiratory infection and wheezing in preterm infants with or without bronchopulmonary dysplasia (BDP) were assessed. RESULTS: During period 2 premature infants had lower rates of respiratory infections (36 out of 55 in Period 1 vs 11 out of 28 in Period 2, P=0.023) and wheezing (20 out of 55 in Period 1 vs 1 out of 28 in Period 2, P=0.001). This difference remained significant when infants with BPD (all grades) were analyzed separately (respiratory infections 26 out of 40 in Period 1 vs 7 out of 24 in Period 2, P=0.005; wheezing 16 out of 40 in Period 1 vs 1 out of 24 in Period 2, P=0.001). In contrast, respiratory infections and wheezing in preterm infants without BPD did not change after pandemic. CONCLUSIONS: Episodes of respiratory infections and wheezing among preterm infants were reduced during pandemic. We highlight the importance of proper family education for preventing respiratory tract infections in preterm infants with BPD, beyond the extraordinary conditions of the COVID-19 pandemic.

Risk Factors Affecting Development and Persistence of Preschool Wheezing: Consensus Document of the Emilia-Romagna Asthma (ERA) Study Group.

Wheezing at preschool age (i.e., before the age of six) is common, occurring in about 30% of children before the age of three. In terms of health care burden, preschool children with wheeze show double the rate of access to the emergency department and five times the rate of hospital admissions compared with school-age asthmatics. The consensus document aims to analyse the underlying mechanisms involved in the pathogenesis of preschool wheezing and define the risk factors (i.e., allergy, atopy, infection, bronchiolitis, genetics, indoor and outdoor pollution, tobacco smoke exposure, obesity, prematurity) and the protective factors (i.e., probiotics, breastfeeding, vitamin D, influenza vaccination, non-specific immunomodulators) associated with the development of the disease in the young child. A multidisciplinary panel of experts from the Emilia-Romagna Region, Italy, addressed twelve key questions regarding managing preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes). Systematic reviews have been conducted on PubMed to answer these specific questions and formulate recommendations. The GRADE approach has been used for each selected paper to assess the quality of the evidence and the degree of recommendations. Based on a panel of experts and extensive updated literature, this consensus document provides insight into the pathogenesis, risk and protective factors associated with the development and persistence of preschool wheezing. Undoubtedly, more research is needed to improve our understanding of the disease and confirm the associations between certain factors and the risk of wheezing in early life. In addition, preventive strategies must be promoted to avoid children's exposure to risk factors that may permanently affect respiratory health.

Management of Preschool Wheezing: Guideline from the Emilia-Romagna Asthma (ERA) Study Group.

Preschool wheezing should be considered an umbrella term for distinctive diseases with different observable and measurable phenotypes. Despite many efforts, there is a large gap in knowledge regarding management of preschool wheezing. In order to fill this lack of knowledge, the aim of these guidelines was to define management of wheezing disorders in preschool children (aged up to 5 years). A multidisciplinary panel of experts of the Emilia-Romagna Region, Italy, addressed twelve different key questions regarding the management of preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes) and systematic reviews have been conducted on PubMed to answer these specific questions, with the aim of formulating recommendations. The GRADE approach has been used for each selected paper, to assess the quality of the evidence and the degree of recommendations. These guidelines represent, in our opinion, the most complete and up-to-date collection of recommendations on preschool wheezing to guide pediatricians in the management of their patients, standardizing approaches. Undoubtedly, more research is needed to find objective biomarkers and understand underlying mechanisms to assess phenotype and endotype and to personalize targeted treatment.

Management of Children with Acute Asthma Attack: A RAND/UCLA Appropriateness Approach.

Bronchial asthma is the most frequent chronic disease in children and affects up to 20% of the pediatric population, depending on the geographical area. Asthma symptoms vary over time and in intensity, and acute asthma attack can resolve spontaneously or in response to therapy. The aim of this project was to define the care pathway for pediatric patients who come to the primary care pediatrician or Emergency Room with acute asthmatic access. The project was developed in the awareness that for the management of these patients, broad coordination of interventions in the pre-hospital phase and the promotion of timely and appropriate assistance modalities with the involvement of all health professionals involved are important. Through the application of the RAND method, which obliges to discuss the statements derived from the guidelines, there was a clear increase in the concordance in the behavior on the management of acute asthma between primary care pediatricians and hospital pediatricians. The RAND method was found to be useful for the selection of good practices forming the basis of an evidence-based approach, and the results obtained form the basis for further interventions that allow optimizing the care of the child with acute asthma attack at the family and pediatric level. An important point of union between the primary care pediatrician and the specialist hospital pediatrician was the need to share spirometric data, also including the use of new technologies such as teleconsultation. Monitoring the progress of asthma through spirometry could allow the pediatrician in the area to intervene early by modifying the maintenance therapy and help the patient to achieve good control of the disease.

Psychosocial assessment of families caring for a child with acute lymphoblastic leukemia, epilepsy or asthma: Psychosocial risk as network of interacting symptoms.

The purpose of this study is to assess psychosocial risk across several pediatric medical conditions and test the hypothesis that different severe or chronic pediatric illnesses are characterized by disease specific enhanced psychosocial risk and that risk is driven by disease specific connectivity and interdependencies among various domains of psychosocial function using the Psychosocial Assessment Tool (PAT). In a multicenter prospective cohort study of 195 patients, aged 5-12, 90 diagnosed with acute lymphoblastic leukemia (ALL), 42 with epilepsy and 63 with asthma, parents completed the PAT2.0 or the PAT2.0 generic version. Multivariate analysis was performed with disease as factor and age as covariate. Graph theory and network analysis was employed to study the connectivity and interdependencies among subscales of the PAT while data-driven cluster analysis was used to test whether common patterns of risk exist among the various diseases. Using a network modelling approach analysis, we observed unique patterns of interconnected domains of psychosocial factors. Each pathology was characterized by different interdependencies among the most central and most connected domains. Furthermore, data-driven cluster analysis resulted in two clusters: patients with ALL (89%) mostly belonged to cluster 1, while patients with epilepsy and asthma belonged primarily to cluster 2 (83% and 82% respectively). In sum, implementing a network approach improves our comprehension concerning the character of the problems central to the development of psychosocial difficulties. Therapy directed at problems related to the most central domain(s) constitutes the more rational one because such an approach will inevitably carry over to other domains that depend on the more central function.

QuantiFERON-TB Performs Better in Children, Including Infants, than in Adults with Active Tuberculosis: a Multicenter Study.

Immunological tests, including the QuantiFERON-TB Gold In-Tube (QFT-IT) assay, represent an important aid for diagnosing active tuberculosis (TB) and latent TB infections in children, but concerns about their use in children <5 years of age persist. This is a multicenter retrospective study comparing a population of 226 children to 521 adults with pulmonary or extrapulmonary TB. The aim was to evaluate the QFT-IT performance, analyzing both qualitative and quantitative results, according to age, birthplace, and disease localization. Compared to culture, QFT-IT sensitivity was 93.9%, 100%, and 94.4% in children ≤2, 2 to 5, and 5 to 16 years of age, respectively, and was significantly higher than that in adults (81.0%) (P < 0.0001). The rate of indeterminate test results for children (2.2%) was significantly lower than that for adults (5.2%) (P < 0.0001). In children, QFT-IT sensitivity was not affected by disease localization or birthplace (Italy born versus foreign born). Interferon gamma (IFN-γ) values in response to TB antigen and mitogen were significantly higher in children than in adults (TB antigen, median of 10 versus 1.66 IU IFN-γ/ml; mitogen, median of 10 versus 6.70 IU IFN-γ/ml; P < 0.0001). In summary, this study supports the use of QFT-IT as a complementary test for the diagnosis of pediatric TB even under 2 years of age. Our observations could be applicable to the new version of the test, QuantiFERON-TB Gold Plus, which has recently been shown to have similar sensitivity in active TB, although data in children are still lacking.

Pediatric Tuberculosis in Italian Children: Epidemiological and Clinical Data from the Italian Register of Pediatric Tuberculosis.

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries.

Performance of interferon-γ release assay for the diagnosis of active or latent tuberculosis in children in the first 2 years of age: a multicenter study of the Italian Society of Pediatric Infectious Diseases.

BACKGROUND: The diagnosis of latent or active tuberculosis in children is often challenging. Recently, interferon-γ release assays have been licensed, but their diagnostic accuracy in young children remains questionable as frequent false-negative or indeterminate results have been reported. METHODS: We performed a multicenter, retrospective study in children 0-24 months of age who were tested at least once with QuantiFERON-TB Gold-in-tube (QTF-IT) ± tuberculin skin test (TST), to analyze its use and performance in clinical practice. RESULTS: Eight-hundred and twenty-three children (449 males, median age 13.5 months) were enrolled. QTF-IT sensitivity and specificity for active tuberculosis were 92.4% and 98.6%, respectively. Indeterminate tests (4.2 %) were not related to age (P = 0.838) or gender (P = 0.223); 32 children (91.4 %) with an indeterminate QTF-IT ultimately resulted uninfected. In the 616 subjects with valid paired results of QTF-IT and TST, sensitivity and specificity were comparable (91.1% vs. 85.1% and 98.1% vs. 97.9%, respectively). Diagnostic concordance between tests was higher in Bacillus Calmétte-Guerin nonvaccinated children (κ = 0.802). A high rate of discordant tests was observed in latent infections. CONCLUSIONS: QTF-IT showed good sensitivity and specificity, and a low rate of indeterminate results in the first 2 years of life, supporting its use at this age. However, considering costs and the similar performance between QTF-IT and TST, it is reasonable to suggest the latter as first-line testing in young children. The complementary use of TST and interferon-γ release assays may be considered in selected cases to improve the accuracy of testing.

Performance of commercial blood tests for the diagnosis of latent tuberculosis infection in children and adolescents.

BACKGROUND: The accurate diagnosis of latent tuberculosis infection reduces the risk of progression to severe disseminated disease. However, in young children, a major limitation of the standard tuberculin skin test is that false-negative results cannot be detected. The new interferon-gamma release assays QuantiFERON-TB Gold (Cellestis Carnegie Victoria, Australia), QuantiFERON-TB In-Tube (Cellestis), and T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) show promise of greater accuracy, but they may also be affected by impaired cellular immunity, resulting in indeterminate results (ie, insufficient response in positive-control wells). OBJECTIVE: To evaluate the impact of age on the performance of interferon-gamma release assays when used in a routine hospital setting among children tested for suspected active or latent TB infection. METHODS: We retrospectively studied 496 children 0 to 19 years of age who had been tested with the tuberculin skin test and at least 1 interferon-gamma release assay: 181 with QuantiFERON-TB Gold and 315 with QuantiFERON-TB In-Tube. In 154 of the children, paired interferon-gamma release assay testing was available: 87 with QuantiFERON-TB Gold/T-SPOT.TB and 67 with QuantiFERON-TB In-Tube/T-SPOT.TB. RESULTS: Compared with T-SPOT.TB, the rates of indeterminate results were significantly higher for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. QuantiFERON-TB Gold and QuantiFERON-TB In-Tube also gave indeterminate results more frequently in children <4 years of age than in those >/=4 years of age. Indeterminate results were associated with younger age for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube but not for T-SPOT.TB. Considering age as a binary variable (<4 and >/=4 years of age), a significantly higher concentration of phytohaemagglutinin-produced interferon-gamma was observed in older children with both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. CONCLUSIONS: Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children <4 years of age.

Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study.

BACKGROUND: Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. METHODS: We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. FINDINGS: Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p<0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p<0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p<0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). INTERPRETATION: T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.

Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection.

RATIONALE: Interferon (IFN)-gamma blood tests may improve the current level of diagnostic accuracy for tuberculosis infection. The QuantiFERON-TB Gold (QFT-Gold) has been used in selected populations and shows higher specificity than the tuberculin skin test (TST). OBJECTIVE: To evaluate the QFT-Gold test in unselected patients and assess the level of agreement with the TST. METHODS: The test has been routinely performed on whole blood samples in our microbiology laboratory for 8 months. Demographic, clinical, and microbiological data have been collected and correlated to the QFT-Gold results. MEASUREMENTS AND MAIN RESULTS: Of 318 patients tested, 68 (21.4%) gave an indeterminate (low positive mitogen control) QFT-Gold result. Indeterminate results were significantly overrepresented in patients with a negative TST (28.9% vs. 6.6% in TST-positive patients; p < 0.0001, chi2 test) and were more frequent in patients receiving immunosuppressive therapies than in those who were not receiving such treatments (odds ratio, 3.35; 95% confidence interval, 1.84-6.08; p < 0.0001). After excluding indeterminate results, the concordance between QFT-Gold and TST was significantly lower in Bacille Calmette-Guérin-vaccinated individuals (41.5%) than in nonvaccinated individuals (80.3%) (p < 0.0001). In 11 patients with active tuberculosis (5 culture-confirmed), QFT-Gold provided more positive results than the TST (66.7% vs. 33.3%; p = 0.165). CONCLUSIONS: The QFT-Gold test is feasible in routine hospital use for the diagnosis of tuberculosis infection. As with the TST, immunosuppression may negatively affect the test's performance, with a significant rate of indeterminate results in the most vulnerable population.