Elevated IgE Levels-An Allergy or an Underlying Inborn Error of Immunity in Children with Recurrent Infections?

Elevated immunoglobulin E (IgE) is a hallmark of allergic diseases. However, high IgE levels also occur in a number of other infectious and noninfectious diseases. In most cases, elevated IgE levels indicate allergy, eczema, or chronic skin infection. Very high IgE levels are not uncommon in patients with active eczema but more often indicate monogenic atopic disorder or inborn errors of immunity with an atopic phenotype. We conducted a retrospective study of 385 children with suspected immune deficiency referred to the clinic over a 9-year period. Measurement of IgE, IgG, IgA, IgM, and IgG subclasses in blood samples revealed that nearly one-third of the patients had elevated serum IgE levels. Most of the cases with elevated IgE were children with underlying atopy-mainly atopic dermatitis and, to a lesser extent, bronchial asthma-whereas 40.12% (37 children) had no atopy at all. In the most severe cases (with extremely elevated IgE or severe dermatitis), we confirmed genetic mutations for underlying immunodeficiency. Our results indicate that allergic phenotype should not be underestimated and that children with more severe allergic disease should be evaluated for an underlying inborn error of immunity. If inborn error of immunity (IEI) is suspected, a comprehensive immunologic evaluation is required. Genetic testing helps identify the specific genetic abnormality, which provides important insight into the immunopathogenesis of the disease and accurate determination of optimal therapy.

Periostin and IFN-γ levels in serum and nasopharyngeal aspirate in infants with viral-induced wheezing - 2 year follow-up.

BACKGROUND: The present study assesses the immune response in children with viral-induced wheezing by examining the two factors-interferon-gamma (IFN-γ) and periostin in serum and nasopharyngeal aspirate (NPA). The aim was to find a pattern with the severity and frequency of wheezing episodes. METHODS: Sixty-nine infants (40 boys and 29 girls), with a mean age of 11.4±6 (2 - 23) months, hospitalized with a first or recurrent episode of bronchial obstruction were enrolled in this study. The serum and NPA concentrations of IFN-γ and periostin were assessed by ELISA methodology. Fifty of the children (72%) were followed for 2 years. RESULTS: We detected lower NPA IFN-γ production in boys, infants with atopic status, family history of asthma, and respiratory syncytial virus infection. Recurrent wheezing in children was associated with a twice lower concentration of IFN-γ in NPA compared to those with the first episode (7.1 vs. 14.8 pg/ml, p=0.05). Higher serum periostin level was established in children over 12 mo in the group of recurrent wheezers with persistent manifestations compared to those without symptoms during the follow-up (410.5 vs. 269.7 ng/ml, p = 0.03). Multivariate logistical regression model assessed high level of serum periostin, male gender, atopy, family history of asthma, and severity of the attack as significant risk factors for persistent compared to intermittent wheezing (r < sup > 2 < /sup > = 0.87, p = 0.04). CONCLUSIONS: Our results demonstrated that recurrent viral-induced wheezing is associated with decreased IFN-γ production and increased periostin response and their correlation with severity and persistence of symptoms were the main outcome measures.

Prevalence and Genetic Characteristics of Human Bocaviruses Detected in Patients with Acute Respiratory Infections in Bulgaria.

Нuman bocaviruses (hBoVs) are often associated with acute respiratory infections (ARIs). Information on the distribution and molecular epidemiology of hBoVs in Bulgaria is currently limited. The objectives of this study were to investigate the prevalence and genetic characteristics of hBoVs detected in patients with ARIs in Bulgaria. From October 2016 to September 2019, nasopharyngeal/oropharyngeal swabs were prospectively collected from 1842 patients of all ages and tested for 12 common respiratory viruses using a real-time RT-PCR. Phylogenetic and amino acid analyses of the hBoV VP1/VP2 gene/protein were performed. HBoV was identified in 98 (5.3%) patients and was the 6th most prevalent virus after respiratory-syncytial virus (20.4%), influenza A(H1N1)pdm09 (11.1%), A(H3N2) (10.5%), rhinoviruses (9.9%), and adenoviruses (6.8%). Coinfections with other respiratory viruses were detected in 51% of the hBoV-positive patients. Significant differences in the prevalence of hBoVs were found during the different study periods and in patients of different age groups. The detection rate of hBoV was the highest in patients aged 0-4 years (6.9%). In this age group, hBoV was the only identified virus in 9.7%, 5.8%, and 1.1% of the children diagnosed with laryngotracheitis, bronchiolitis, and pneumonia, respectively. Among patients aged ≥5 years, hBoV was detected as a single agent in 2.2% of cases of pneumonia. Phylogenetic analysis showed that all Bulgarian hBoV strains belonged to the hBoV1 genotype. A few amino acid substitutions were identified compared to the St1 prototype strain. This first study amongst an all-age population in Bulgaria showed a significant rate of hBoV detection in some serious respiratory illnesses in early childhood, year-to-year changes in the hBoV prevalence, and low genetic variability in the circulating strains.

The Prevalence and Genetic Characterization of Human Metapneumovirus in Bulgaria, 2016-2019.

INTRODUCTION: We investigated the prevalence of human metapneumovirus (hMPV) among patients with acute respiratory infections in Bulgaria, and performed genetic characterization of the F gene of these strains. METHODS: Nasopharyngeal swabs collected from patients of a range of ages were tested by using real-time PCR for 12 respiratory viruses. The F gene was sequenced, and phylogenetic and amino acid analyses of the F gene/protein were performed. RESULTS: A total of 1,842 patients were examined during a 3-year period; 1,229 patients (66.7%) were positive for at least one respiratory virus. hMPV was identified in 83 (4.5%) patient samples. Eleven (13%) of hMPV-positive patients were coinfected with another respiratory virus. The hMPV incidence rate in the 2016/2017, 2017/2018, and 2018/2019 winter seasons was 5.4, 5.4, and 3.1%, respectively. hMPV was mainly detected in specimens collected between January and May (89.2% of cases). The incidence of hMPV infection was highest (5.1%) among the youngest age-group (0-4 years), where hMPV was a causative agent in 8.1 and 4.8% of bronchiolitis and pneumonia cases, respectively. Among the patients aged ≥5 years, hMPV was detected in 2.2 and 3.2% of cases of pneumonia and central nervous system infections, respectively. Phylogenetic analysis of the F gene showed that the sequenced hMPV strains belonged to the A2b, B1, and B2 genotypes. Numerous amino acid substitutions were identified compared with the NL00/1 prototype strain. CONCLUSION: This study revealed the significant role of hMPV as a causative agent of serious respiratory illnesses in early childhood, and also demonstrated year-to-year changes in hMPV prevalence and genetic diversity in circulating strains.

Predominance of ON1 and BA9 genotypes of respiratory syncytial virus (RSV) in Bulgaria, 2016-2018.

The objectives of this study were to investigate the prevalence of respiratory syncytial virus (RSV) infections in Bulgaria, to characterize the genetic diversity of the RSV strains, and to perform amino acid sequence analysis of the RSV G protein. Clinical, epidemiological data and nasopharyngeal swabs were prospectively collected from children aged less than 5 years presenting with acute respiratory infections from October 2016 to September 2018. Real-time polymerase chain reaction for 12 respiratory viruses, and sequencing, phylogenetic, and amino acid analyses of the RSV G gene/protein were performed. Of the 875 children examined, 645 (73.7%) were positive for at least one viral respiratory pathogen. RSV was the most commonly detected virus (26.2%), followed by rhinoviruses (15%), influenza A (H3N2) (9.7%), adenoviruses (9%), bocaviruses (7.2%), human metapneumovirus (6.1%), parainfluenza viruses 1/2/3 (5.8%), influenza type B (5.5%), and A(H1N1)pdm09 (3.4%). The detection rate for RSV varied across two winter seasons (36.7% vs 20.3%). RSV-B cases outnumbered those of the RSV-A throughout the study period. RSV was the most common virus detected in patients with bronchiolitis (45.1%) and pneumonia (24%). Phylogenetic analysis indicated that all the sequenced RSV-A strains belonged to the ON1 genotype and the RSV-B strains were classified as BA9 genotype. Amino acid substitutions at 15 and 22 positions of the HVR-2 were identified compared with the ON1 and BA prototype strains, respectively. This study revealed the leading role of RSV as a causative agent of serious respiratory illnesses in early childhood, year-on-year fluctuations in RSV incidence, the dominance of RSV-B, and relatively low genetic diversity in the circulating RSV strains.

Viral pathogens associated with acute lower respiratory tract infections in children younger than 5 years of age in Bulgaria.

Acute lower respiratory infections (ALRIs) are a leading cause of morbidity and hospital admissions in children. This study aimed to determine the viral etiology of these infections in children aged < 5 years during three successive epidemic seasons in Bulgaria. Nasopharyngeal and throat specimens were collected from children with bronchiolitis and pneumonia during the 2015/2016, 2016/2017, and 2017/2018 seasons. The viral etiology was determined by individual real-time PCR assays against 11 respiratory viruses. Of the 515 children examined, 402 (78.1%) were positive for at least one virus. Co-infections with two and three viruses were found in 64 (15.9%) of the infected children. Respiratory syncytial virus (RSV) was the predominant pathogen (37.5%), followed by rhinoviruses (13.8%), metapneumovirus (9.1%), adenoviruses (7%), bocaviruses (7%), influenza A(H1N1)pdm09 (4.9%), A(H3N2) (4.3%), type B (4.1%), and parainfluenza viruses 1/2/3 (2.9%). RSV-B were more prevalent than RSV-A during the three seasons. At least one respiratory virus was identified in 82.6% and 70.1% of the children with bronchiolitis and pneumonia, respectively. Respiratory viruses, especially RSV, are principal pathogens of ALRIs in children aged < 5 years. Diagnostic testing for respiratory viruses using molecular methods may lead to the reduced use of antibiotics and may assist in measures to control infection.

Predominance of influenza A(H3N2) viruses during the 2016/2017 season in Bulgaria.

PURPOSE: Influenza viruses are characterised by high variability, which makes them able to cause annual epidemics. The aim of this study is to determine the antigenic and genetic characteristics of influenza viruses circulating in Bulgaria during the 2016/2017 season. METHODOLOGY: The detection and typing/subtyping of influenza viruses were performed using real time RT-PCR. Results of antigenic characterisation, phylogenetic and amino acid sequence analyses of representative influenza strains are presented herein. RESULTS: The 2016/2017 season was characterised by an early start, an exclusive dominance of A(H3N2) viruses accounting for 93 % of total influenza virus detections, and a low circulation of A(H1N1)pdm09 (4.2 %) and type B (2.5 %) viruses. The analysed A(H3N2) viruses belonged to subclades 3C.2a (52 %) and 3C.2a1 (48 %); all studied A(H1N1)pdm09 and B/Victoria-lineage viruses belonged to subclades 6B.1 and 1A, respectively. The amino acid sequence analysis of 56 A(H3N2) isolates revealed the presence of substitutions in 18 positions in haemagglutinin (HA) as compared to the A/Hong Kong/4801/2014 vaccine virus, seven of which occurred in four antigenic sites, together with changes in 23 positions in neuraminidase (NA), and a number of substitutions in internal proteins PB2, PB1, PB1-F2, PA, NP and NS1. Despite the many amino acid substitutions, A(H3N2) viruses remained antigenically similar to the vaccine strain. Substitutions in HA and NA sequences of A(H1N1)pdm09 and B/Victoria-lineage strains were also identified, including in antigenic sites. CONCLUSION: The results of this study confirm the genetic variability of circulating influenza viruses, particularly A(H3N2), and the need for continued antigenic and molecular surveillance.