Recurrent Wheezing Research Articles

Recurrent Wheezing in a Child: Unraveling Atypical Presentations of Cystic Fibrosis and Polymorphisms: A Case Report

Background: Cystic Fibrosis (CF), is the most common, life-limiting, single-gene disease affecting the Caucasian population, with a reported incidence of1/3500 births. It is inherited in an autosomal recessive fashion and its diagnosis is notably challenging, since in several cases CF may not be detected by the newborn screening test and the sweat test, which are frequently reported negative of with doubtful results, especially in cases with atypical symptoms at onset or with uncommon mutations or polymorphisms. Case Presentation: In this case, we present a case of CF presented with recurrent wheezing, reporting multiple negative or borderline sweat tests. The genetic evaluation revealed delta F508 (CF- causing) and heterozygous poly T5 polymorphism TG11 (TG)11T5. Conclusion: The importance of this case lies in the recognition of wheezing as a symptom and not as a disease, thus many conditions such as CF have to be considered in its diagnostic process. Finally, it is of utmost importance to bear in mind that many mutations or polymorphisms might evade newborn screening and sweat tests.

New advances in RSV: Is prevention attainable?

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI), hospitalization, and mortality in infants and young children globally. The greatest burden of severe disease and mortality occurs in low-middle income countries (LMICs), with large and vulnerable childhood populations. The highest rates of RSV-hospitalization occur in healthy-term infants under 3 months of age. Preterm infants, children with chronic lung disease of prematurity, Down's syndrome, congenital heart disease, or immunodeficiency also have a higher risk of severe RSV-LRTI. Early-life RSV-LRTI has also been associated with chronic sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment. A RSV pre-fusion (F) maternal vaccine and long-acting monoclonal antibody (nirsevimab) have been licensed for the prevention of RSV-LRTI in infants and young children. Studies show high efficacy and effectiveness particularly for preventing severe RSV-LRTI. Maternal RSV vaccine given at 24-36 weeks of pregnancy was effective in preventing RSV medically attended LRTI and severe RSV-LRTI through 6 months after birth in a phase 3 study conducted in 18 countries over two RSV seasons. Vaccination was safe with no significant difference in adverse events between infants born to mothers who received RSV preF vaccine compared to placebo. A numerical imbalance in preterm births that occurred predominantly in South Africa, unrelated to vaccine timing or gestational age at vaccination and unassociated with mortality, coincided with COVID-19 delta and omicron waves. Nirsevimab, given as a single dose prior or during the RSV season, had high efficacy in preventing RSV-LRTI hospitalization in infants in preterm and in full-term infants, as well as in young children with underlying conditions through 150 days post administration in phase 2 and 3 trials. High effectiveness against hospitalization or severe disease in infants and in at-risk children up to 2 years of age has also been reported in several countries where implementation has occurred. RSV-LRTI is now a preventable disease in infants and young children. Rapid implementation of these highly effective interventions has occurred in many high-income countries, but access remains very limited in LMICs. Access to such RSV preventive interventions is urgently needed for all children to strengthen child health and promote global equity.

A smartphone app for preschool wheezing and reliability of medical history collection

BackgroundThe use of mobile applications helps improving self-management in adolescents with asthma. However, no evidence is available for children with preschool wheezing. In addition, we have no data on the reliability of medical history collected at visits. The first aim was to assess the feasibility of a smartphone app in the management of preschool wheezing; secondly we aimed to evaluate the reliability of anamnestic data collected during face-to-face medical interviews.MethodsChildren with recurrent wheezing, age between 25 and 72 months, were randomly assigned to the intervention group, provided with a smartphone app for symptoms monitoring and asthma attack treatment, or to the control group, with a written action plan. At follow-up medical history was collected and the asthma control test and a clinical questionnaire were completed. App acceptability was also explored. Respiratory symptoms, medication and utilization of healthcare resources were collected. Plus, medical information obtained from the paper questionnaires was compared with data daily recorded by the app.ResultsWe enrolled 85 preschool children with recurrent wheezing: 43 assigned to the intervention and 42 to the control group. The average (SD) adherence to e-Diary compilation was 60 (15)%. The acceptance and usability of the intervention was favorable as 70% and 93% of participants in the intervention arm described the app as ‘’simple and intuitive’’ at Visit1 (after 3 months from enrollement) and Visit2 (3 months later than Visit1), respectively and 95% and 98% found it useful in symptoms management. There were no significant differences between the two groups in clinical outcomes. At Visit1, the cACT median score (IQR) was 23,5 (21–25) for the control group (42 patients) and 23 (21–24) for the intervention group (43 patients). At Visit2 (41 controls and 42 in the intervention group) it was 25 (24–25) and 24 (24–25), respectively. Secondary analysis of data from the intervention group showed higher incidence of daily symptoms recorded by the app in comparison with the paper questionnaire, suggesting that collection of retrospective medical history may not be completely reliable.ConclusionsThe smartphone app is usable and acceptable by families of preschool wheezers. Future controlled trial are needed to prove an impact on clinical outcomes or its efficacy in a telemedicine program. Finally a daily questionnaire could provide physicians with a more reliable clinical picture as reflected better daily asthma symptoms than the written retrospective questionnaire filled at clinical visit.

Association between socioeconomic deprivation, ethnicity and health outcomes in preschool children with recurrent wheeze in England: a retrospective cohort study

BackgroundPreschool-aged children have among the highest burden of acute wheeze. We investigated differences in healthcare use, treatment and outcomes for recurrent wheeze/asthma in preschoolers from different ethno-socioeconomic backgrounds.MethodsRetrospective cohort study...

Recurrent wheezing and asthma-Epidemiology and environmental determinants.

Wheeze is the musical continuous sound produced by oscillations in any critically narrowed airways, and heard mostly on expiration. It is common in preschool age, about half of all children will experience an episode of wheezing by their sixth birthday. Asthma is usually characterized by cough, wheeze, chest tightness and fast breathing. It is a significant global health issue and affects both children and adults. The prevalence is on the increase, especially in LMIC. Studies from different populations have revealed the key role influencing the progression from preschool wheezing to childhood asthma. Recurrent wheezing is four or more episodes in the preceding year and has a spectrum of phenotypes and with heterogeneous features. Phenotypes of wheezing were proposed to facilitate the identification of young children who are at risk of subsequent development of asthma. The epidemiology and environmental determinants of recurrent wheezing and asthma are discussed.

Environmental exposures associated with early childhood recurrent wheezing in the mother and child in the environment birth cohort: a time-to-event study

BackgroundAntenatal factors and environmental exposures contribute to recurrent wheezing in early childhood.AimTo identify antenatal and environmental factors associated with recurrent wheezing in children from birth to 48 months in the...

Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children

Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e–118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6′-sialyllactose (P = 2.2e–9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P < 0.01). Thus, we report novel genetic factors associated with HMOs, some of which may protect the respiratory health of children.

Effects of pregnancy and lactation prebiotics supplementation on infant allergic disease: A randomized controlled trial

BackgroundIngestion of prebiotics during pregnancy and lactation may have immunomodulatory benefits for the developing fetal and infant immune system and provide a potential dietary strategy to reduce the risk of allergic diseases. ObjectiveThe aim of this trial was to determine whether maternal supplementation with dietary prebiotics reduces the risk of allergic outcomes in infants with hereditary risk. MethodsWe undertook a double-blind, randomized controlled trial in which pregnant women were allocated to consume prebiotics (14.2g daily of galacto-oligosaccharides and fructo-oligosaccharides in ratio 9:1) or placebo (8.7g daily maltodextrin) powder from <21 weeks gestation until 6-months postnatal during lactation. Eligible women had infants with a first-degree relative with a history of medically diagnosed allergic disease. The primary outcome was infant medically diagnosed eczema by 1-year of age, and secondary outcomes included allergen sensitization, food allergy, and recurrent wheeze by 1-year of age. Results652 women were randomized between June 2016 and November 2021 (n=329 prebiotics, n=323 placebo). There was no significant difference between groups in the percentage of infants with medically diagnosed eczema by 1-year of age (prebiotics 31.5% (103/327 infants) compared to placebo 32.6% (105/322 infants); adjusted relative risk 0.98 (95% CI 0.77, 1.23; p=0.84). Secondary outcomes and safety measures also did not significantly differ between groups. ConclusionWe found little evidence that maternal prebiotics supplementation during pregnancy and lactation reduces the risk of infant medically diagnosed eczema by 1-year of age in infants who are at hereditary risk of allergic disease.

Deep multiomic profiling reveals molecular signatures that underpin preschool wheeze and asthma

Wheezing in childhood is prevalent, with over one-half of all children experiencing at least 1 episode by age 6. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear. This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multiomic profiling. Unsupervised, group-agnostic integrative multiomic factor analysis was performed using host/bacterial (meta)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old. Two multiomic factors were identified: one characterizing preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression toward asthma from ages 1 to 18 was dominated by changes related to airway epithelial cell gene expression, type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae. These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.

Rhinovirus characteristics associated with viremia in childhood asthma.

Although rhinoviruses play a major role in exacerbations of childhood asthma, the presence of rhinovirus (RV) RNA in plasma, referred to as viremia, has been investigated in a few studies. The aim of the study was to investigate the presence of rhinovirus viremia at the time of asthma exacerbation and to describe the molecular characteristics of rhinoviruses associated with viremia. We conducted an observational, prospective, multicenter study in eight pediatric hospitals (VIRASTHMA2). Preschool-aged recurrent wheezers (1-5 years) hospitalized for a severe exacerbation were included. Reverse-transcription polymerase chain reaction (RT-PCR) and molecular typing for RV/enteroviruses (EV) were performed on nasal swabs and plasma. Plasma specimens were available for 105 children with positive RT-PCR for RV/EV in respiratory specimens. Thirty-six (34.3%) had positive viremia. In plasma, 28 (82.4%) of the typable specimens were RV-C, five (14.7%) were EV-D68, and one was RV-A (2.9%). In all cases, the RV/EV type was identical in the plasma and respiratory specimens. In conclusion, RV/EV viremia is frequent in severe exacerbations of preschool recurrent wheezers, particularly in RV-C infections.

Pediatric asthma knowledge: Insights from a Portuguese central hospital study.

Asthma is a common chronic condition in children, with parental and child health literacy affecting health outcomes and asthma control. This study examined pediatric asthma knowledge at a Portuguese central hospital and its determinants. We conducted a comparative cross-sectional study, applying the Asthma Knowledge Questionnaire (QCSA), answered by adolescents and/or caregivers. The sample was categorized into two groups based on the presence or absence of respiratory conditions, such as asthma or recurrent wheezing, in children. Those with such conditions (Group A) were further divided into two subgroups: those receiving general pediatric care (Group A2) and those receiving specialized care, followed in pulmonology or allergology consultations (Group A1). The study involved 154 participants, predominantly female (74%) with an average age of 31.2 years ( ± 13.4). The average QCSA score was 14.8 ( ± 3.2), and Group A exhibited a statistically higher score, 15.5 points ±3.2 versus Group B, 14.2 points ± 3.2, p = .034. Group A1 achieved significantly better scores (16 points: range 4-21) than Group A2 (14 points: range 9-21) (p = .029). Scores were correlated positively with the duration of specialized follow-up (ρ = .326; p = .027). Asthma knowledge was correlated with the level of education (r = .468; p < .001). The number of wheezing episodes (r = -.466; p < .001) within the past year were associated to QCSA scores. In summary, the presence of respiratory condition, the follow-up in specialized appointments and higher levels of education were associated with greater asthma knowledge.

Traffic Proximity and Recurrent Wheeze Development by Severe Bronchiolitis Status.

Traffic Proximity and Recurrent Wheeze Development by Severe Bronchiolitis Status.

Effect of respiratory microflorae colonization on short and long‐time outcomes of respiratory syncytial virus infection in children: A scoping review

AbstractRespiratory syncytial virus (RSV) is an essential cause of lower respiratory tract infection in children under 2 years of age, especially under 6 months. In decades, studies have shown that the respiratory tract microflorae with RSV infection were related to disease severity and played a role in the development of recurrent wheezing, but the effect of respiratory microflorae on RSV infection are still underestimated. This study aims to conclude the effect of respiratory microflorae colonization on RSV infectious disease severity and recurrent wheezing and provide suggestions for future research directions from the perspective of respiratory tract florae. We conducted a scoping review. Studies were eligible if they reported on the effect of microflorae on RSV infectious diseases among children. We exacted the following information: title, publication time, first author's country, and article type. We finally included 33 articles in this scoping review. The number of studies rapidly increased since 2013 and the highest number of hospitalizations were reported in children &lt;2 years. More than half (69.70%) were conducted in America and most studies are original studies (57.58%). The Review highlighted that the respiratory microflorae played an important role in RSV infectious disease severity and recurrent wheezing. We found that Streptococcus pneumoniae (S.pn), Haemophilus influenza (HI), Moraxella catarrhalis (M.ca), and Staphylococcus aureus (SA) were the dominant profiles in children with RSV infection. Understanding the respective role of respiratory microflorae on RSV infection and its mechanisms would improve prevention and treatment strategies from the perspective of microflorae.

Population Attributable Risk of Wheeze in 2-

There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2-<6-year-old children previously surveilled in a primary study for RSV-LRTI from birth to their second birthday (RSV-LRTI<2Y). From 2013 to 2021, 2-year-old children from 8 countries were enrolled in this extension study (NCT01995175) and were followed through quarterly surveillance contacts until their sixth birthday for the occurrence of parent-reported wheeze, medically-attended wheeze or recurrent wheeze episodes (≥4 episodes/year). PAR% was calculated as PAR divided by the cumulative incidence of wheeze in all participants. Of 1395 children included in the analyses, 126 had documented RSV-LRTI<2Y. Cumulative incidences were higher for reported (38.1% vs. 13.6%), medically-attended (30.2% vs. 11.8%) and recurrent wheeze outcomes (4.0% vs. 0.6%) in participants with RSV-LRTI<2Y than those without RSV-LRTI<2Y. The PARs for all episodes of reported, medically-attended and recurrent wheeze were 22.2, 16.6 and 3.1 per 1000 children, corresponding to PAR% of 14.1%, 12.3% and 35.9%. In univariate analyses, all 3 wheeze outcomes were strongly associated with RSV-LRTI<2Y (all global P < 0.01). Multivariable modeling for medically-attended wheeze showed a strong association with RSV-LRTI after adjustment for covariates (global P < 0.0001). A substantial amount of wheeze from the second to sixth birthday is potentially attributable to RSV-LRTI<2Y. Prevention of RSV-LRTI<2Y could potentially reduce wheezing episodes in 2-<6-year-old children.

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases.

The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and 'omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

Frequency and Severity of Cow’s Milk Allergy Reactions in Children: A Prospective Audit

Milk ranks as the second most common allergen, following peanuts. Recent studies from Spain and theUSA reports an annual frequency of accidental allergic reactions (AAR) ranging from 34% to 40%. AAR severity is influenced by food allergens and the presence of atopic diseases such as asthma, eczema, hay-fever, and recurrent wheezing. This study aimed to determine the frequency of accidental allergic reactions in children with cow’s milk protein allergy between September 2011 to September 2012. The study design employed is missing. A structured questionnaire was used and the guardians of the patients were guided in answering by the research assistants (Students). The questionnaire was conducted on 62 patients (35 males, 27 females) with a median age of 67 months. The inquiries were about the number and locations of accidental reactions, their severity, other food allergies, and risk factors such as asthma, hay-fever, recurrent wheezing, and eczema. Symptoms were classified as mild, moderate, or severe, and previous and current skin prick test results were recorded. Between 2011 and 2012, the frequency of AAR was found to be 57% (inclusive of adults). Among the children, 37 (60%) experienced 51 accidental reactions in the past year, with 43% classified as mild, 19% as moderate, and 38% as severe. The majority of reactions (60%) occurred at home, and treatment primarily involved the use of Chlorphenamine [Piriton©] (79%). Three anaphylactic reactions occurred and were identified leading to hospitalization and administration of epinephrine. Oral exposure was the primary route (89%), with milk-containing products being the most common allergen sources (51%). The main cause of AAR was attributed to mislabeling and misreading of labels, especially in newly implemented recipes and non-packaged cereal products like homemade croissants sold in cafes and restaurants. Other causes included high levels of peanut traces and hazelnuts in cookies and chocolates. In conclusion, accidental allergic reactions are prevalent in children and are often caused by contamination, mislabeling, recipe changes by companies, misinterpretation by caregivers, and direct milk intake. Risk factors for AAR severity include hay fever, peanut allergy, multiple atopic diseases, and wheal size.

Child Opportunity Index Mobility, Recurrent Wheezing, and Asthma in Early Childhood: A Population-Based Prospective Cohort Study

We prospectively examined associations between mobility in neighborhood opportunity and early childhood recurrent wheezing/asthma. Downward mobility was associated with developing asthma, but not recurrent wheezing, though associations were attenuated after adjusting for family-level socioeconomic status. Elucidating how neighborhoods impact asthma may inform asthma equity initiatives in early childhood.

A novel syndrome of silent rhinovirus-associated bronchoalveolitis in children with recurrent wheeze

BackgroundRhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important. ObjectiveTo examine the associations of RV on lung lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n=616). MethodsChildren underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers. ResultsDespite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n=341), those with RV alone (n=127) had greater (p < 0.05) isolated neutrophilia (43% versus 16%), mixed eosinophils and neutrophils (26% versus 11%), and less pauci-granulocytic (27% versus 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum c-reactive protein (CRP), but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 [0.76-0.88, p < 0.001], but higher, 1.58 [1.01-2.51, p = 0.04], with high-dose daily corticosteroid treatment. ConclusionsChildren with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age, and not informed by markers of type-2 inflammation. We speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism.

Clinical efficacy of bronchoalveolar lavage in the treatment of small airway diseases in children.

This study aimed to evaluate the efficacy of bronchoalveolar lavage (BAL) in the treatment of children with small airway diseases. Children [n = 112; boys: 76, girls: 36 (ratio 2.1:1); age range: 1 month-10 years; median age: 12 months] with small airway diseases diagnosed by high-resolution computed tomography (HRCT) were enrolled in this study. The patients were assigned to either the BAL group (BAL and conventional therapy) or the control group (conventional therapy only). The duration of cough, fever, wheezing, hospitalization duration, disease course before admission, treatment cost, HRCT recovery time, and re-hospitalization rate were compared between the two groups. The median disease course before admission of the BAL group patients was longer than that of the controls (p = 0.006). The duration of cough and wheezing in the BAL group was significantly longer than that in the control group (p = 0.012 and p = 0.001, respectively). The recovery time of cough, the re-hospitalization rate, and the total expenditure incurred for the BAL group were lower than those for the control group (p = 0.027, p = 0.026, and p = 0.000, respectively). At 2 months after discharge, the small airway lesions were found to be absorbed in 86.2% of BAL group patients vs. 64.1% of control group patients. At 6 months after discharge, the lesions were not fully absorbed in 3.4% of the BAL group patients compared to 20.5% in the control group patients. BAL is suitable for patients with a long disease course before admission, a long duration of coughing, and recurrent wheezing. BAL treatment of small airway diseases in children can promote the disappearance of clinical symptoms, accelerate the improvement of imaging, reduce the rate of re-hospitalization, and reduce the cost of treatment.

Long-acting Muscarinic Antagonists and Their Role in Children with Recurrent Wheezing or Asthma: An Updated Review

Long-acting Muscarinic Antagonists and Their Role in Children with Recurrent Wheezing or Asthma: An Updated Review