A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes.

PURPOSE: Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls. METHODS: The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing. RESULTS: The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient's whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens. CONCLUSION: Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

The correlation between middle schoolchildren allergic symptoms and airborne particle season: A cross-sectional study.

ABSTRACT: Limited studies correlate allergic symptoms and associated outdoor biological particle exposure among schoolchildren globally.This study aimed to investigate the relationship between the seasonality of symptoms of allergic diseases among middle schoolchildren and the annual variation of airborne pollen and fungal spore in a hot and humid geographical region (Qatar).During November 2017 to January 2018, a self-reported study of middle schoolchildren living in the Doha capital city of Qatar was conducted, and data gathered were evaluated in relation to the collected monthly pollen and fungal spores. Participants' data were collected by conducting a survey based on a modified questionnaire adopted from the International Study of Asthma and Allergy in Childhood (ISAAC). The airborne pollen and fungal spore in Doha's atmosphere were extracted from the Doha aerobiology project (2017-2020).Among the 1000 distributed questionnaires, 100 were excluded due to significant missing data and 644 middle schoolchildren living in Doha city responded and were included in the final analysis. The symptoms of allergic rhinitis (AR) pattern among the responders with positive symptoms were strongly linked with the higher airborne fungal spore incidence during the month of November. Out of 331 students with positive symptoms, the prevalence of AR, lifetime wheeze, and eczema was 62.8%, 28.1%, and 26.6%, respectively. Asthma was significantly higher in Qatari (39.8%) compared to non-Qatari (26.7%) middle schoolchildren (P = .02).Outdoor aeroallergen may be a contributing factor in addition to other environmental and genetic predisposing factors for childhood atopic diseases in the prevalence rate of allergic symptoms among middle schoolchildren in the peninsula of Qatar.

Aerobiological monitoring in a desert type ecosystem: Two sampling stations of two cities (2017-2020) in Qatar.

BACKGROUND: The increasing number of aerobiological stations empower comparative studies to determine the relationship between pollen concentrations in different localities and the appropriate distance, which should be established between sampling stations. In Qatar, this is basically the first aerobiological study for a continuous monitoring interval. OBJECTIVES: The study aimed to assess the abundance and seasonality of the most prevalent pollen types, plus identify potential differences between two sites within the country. METHODS: Airborne pollen data were collected during 2017-2020 by using Hirst-type volumetric samplers in Doha capital city and Al Khor city in Qatar, placed 50 km apart. RESULTS: Higher total pollen indexes were recorded in the Al Khor station (2931 pollen * day/m3) compared to the Doha station (1618 pollen * day/m3). Comparing the pollen spectrum between the sampling stations revealed that ten pollen types were found in common. Amaranthaceae and Poaceae airborne pollen constituted 73.5% and 70.9% of the total amount of pollen detected at the samplers of Al Khor station and Doha station. In both sampling sites, a very pronounced seasonality was shown; August-October appeared as the period with the most intense incidence of atmospheric herbaceous pollen, with 71% and 51% of the annual total counts in Al Khor and Doha stations, respectively. August (Al Khor, 21%; Doha, 9%), September (Al Khor, 33%; Doha, 26%), October (Al Khor, 17%; Doha, 16%) were the months in which the herbs pollen concentrations were highest. Significant statistical differences between the two stations were observed in specific pollen types with local distribution in each trap's vicinity. CONCLUSIONS: Comparison of data obtained by the two samplers running at a distance of 50 Km indicated that potential inter-site differences could be attributed to the vegetation surrounding the city having a decisive influence on data collected.

Sensitization to Common Allergens Among Children with Asthma and Allergic Rhinitis in Qatar.

BACKGROUND: Childhood asthma (A) and allergic rhinitis (AR) are common in Qatar. Aeroallergens sensitization is integral in disease pathogenesis and clinical presentation. Determining sensitization patterns assists clinicians in tailoring an efficient medical management. OBJECTIVE: To determine the aeroallergen sensitization pattern and relationship to clinical parameters. METHODS: A retrospective review of children (2-14-years) files with i) Pediatric Allergist/or Pulmonologist confirmed-diagnosis of A, and AR, and ii) positive skin prick test (SPT). RESULTS: Among 473 patients (69.1% males; 30.9% females), aged 7.6 years, family history was positive in 66.3%: 59.4% in A, 64.2% AR, and 78.2% A-AR. The number of allergens/patients was 2.1±1.7. Median eosinophil count was 400 cells/ul and IgE 287 KU/L. Rates of A, AR, and A-AR varied significantly in children ≤5 years compared to >10 years: A was 43.2% vs 17.8%, and AR 34.5% vs 16.4%. Two hundred and four children (43.1%) were mono-sensitized, 215 (45.5%) oligosensitized (2-3 allergens), and 54 (11.4%) polysensitized (≥4 allergens). A-AR ranked the top number of positive allergens. The commonest aeroallergen was Der p1 (38.1%), followed by Der f (29.0%), cat (22.6%), alternaria (18.8%), American cockroach (18.4%), and dog (14.0%). House dust mite (HDM) and American cockroach were commoner in ≤5 years than older >10-year children (52.5%, 24.1%), while cat and dog allergens were commoner in older ones (37.1%, 21.6%). CONCLUSION: Family history is quite positive in patients with A and AR. Common aeroallergens include HDM, cats, and alternaria in the young children, while animal allergens were commoner in the older children.

The association between airborne pollen monitoring and sensitization in the hot desert climate.

BACKGROUND: Pollen is a major cause of allergic respiratory diseases. In Qatar, data on the presence and prevalence of allergenic airborne types of pollen is quite limited. METHODS: The study aimed to determine and correlate the most frequently implicated airborne pollen detected by aerobiological monitoring samplers in respiratory allergy symptoms. An aerobiological survey was started on May 8, 2017. Airborne pollen was collected using two Hirst type seven-day recorder volumetric traps. Skin prick test in patients attending allergy clinics in Doha using commercial extracts was conducted. RESULTS: Twenty-five pollen types representing the native, as well as the introduced plants, with a relatively low daily mean concentration were observed from May 2017 to May 2019. The highest pollen concentrations were reached by Amaranthaceae (58.9%), followed by Poaceae (21.7%). SPT revealed a comparatively higher degree of sensitization to pollen. Among 940 patients, 204 were sensitized to pollen (54% female) with 135 (66.2%) and 114 (55.8%) to Amaranthaceae and Poaceae, respectively. Some patients had polysensitization. There was a statistically significant association between Amaranthaceae, and asthma (r = 0.169, P = 0.016) and allergic rhinitis (r = 0.177, P = 0.012). CONCLUSIONS: This is the first study to monitor airborne pollen in the state of Qatar. The main pollen detected were Amaranthaceae and Poaceae. Pollen may represent a possible exacerbating factor in adult patients with allergic diseases such as asthma and allergic rhinitis.

Effects of a DNA vaccine in an animal model of Alternaria alternata sensitivity.

Sensitivity to the fungus Alternaria is associated with asthma persistence and severity. Current therapeutic options for treating Alternaria-induced airway inflammation are limited. In this study, Brown Norway rats are used to study the effectiveness of a DNA-based vaccine delivered to the airway in attenuating the response to a major Alternaria allergen, rAlt a 2. Compared to untreated sensitized animals, or animals receiving an "out-of-frame" DNA-based vaccine, animals treated with "in-frame" DNA vaccine showed an attenuation in specific IgE antibody titers to rAlt a 2, an increase in IgG(2b) (a Th1 response), a reduction in spontaneous IL-13 release by peribronchial lymph node cell suspensions, and an attenuation in the decrease in total lung capacity 72 h post-allergen challenge. Further, histopathologic examination of the lung tissues revealed reduced pulmonary inflammation post-allergen challenge in the DNA-vaccine-treated compared to sensitized, untreated animals. We conclude that a DNA-based vaccine delivered to the airway significantly influences the immunologic, pulmonary physiologic, and histological alterations induced by challenge with a major Alternaria allergen, rAlt a 2, in sensitized animals.

Embedded esophageal foreign body. A diagnostic challenge.

Esophageal foreign body (EFB) ingestion is of ubiquitous occurrence in pediatric population. Diagnosis and precise localization of non-radio opaque FB poses considerable challenge. Delayed presentation, poor history, and inconclusive esophagoscopic findings often lead to diagnostic delay. Multidetector computed tomography (MDCT) could be a great option in these situations. We present a case of EFB in a child who presented with failure to thrive, had negative fibreoptic endoscopy, ultimately diagnosed conclusively on MDCT examination.

Effectiveness of palivizumab immunoprophylaxis in preterm infants against respiratory syncytial virus disease in Qatar.

OBJECTIVE: The primary objective of this study was to document the hospitalization rate due to respiratory syncytial virus (RSV) and compliance with palivizumab use in preterm infants receiving palivizumab immunoprophylaxis during 2009-2012 RSV seasons. DESIGN: This is a descriptive single-center cohort study. Infants who were ≤35-week gestational age were eligible for enrollment if they received the first palivizumab dose between November 1 and March 31 (2009-2010, 2010-2011, 2011-2012). Primary endpoint was defined as RSV hospitalization of duration 24 hours or longer. RESULTS: The cumulative RSV hospitalization rate in the registry (2009-2012) was 1.9%. The compliance rate was 85.7%. It showed steady increase across the 3 successive RSV seasons, 2009-2010, 2010-2011, and 2011-2012 (57.7% vs 92.6%, 94.2%, respectively, p<0.05). The RSV hospitalization rate decreased from 3.7% for 2009-2010 to 1.3% for 2010-2011 and 1.7% for 2011-2012 RSV seasons. No deaths and no side effects linked to palivizumab injections were reported for any subjects enrolled. CONCLUSION: Our study provides national data regarding characteristics, compliance rate, and hospitalization outcomes for preterm infants receiving palivizumab in Qatar. Our data is consistent with the previously reported efficacy and safety profile of palivizumab.

Contribution of airway closure to chronic postbronchiolitis airway dysfunction in rats.

Genetically susceptible Brown Norway rats develop a chronic asthmalike syndrome after recovering from viral bronchiolitis at an early age. We hypothesized that airway closure is an important mechanism of airflow obstruction in postbronchiolitis rats. Rats were studied 8-12 wk after inoculation with Sendai virus or sterile vehicle at 3-4 wk of age. Under light pentobarbital anesthesia, rats were instrumented with an orotracheal catheter and an esophageal pressure monitor and placed in a total body plethysmograph. Lung volumes and forced-expiratory maneuvers were measured using the Boyle's law method and software-controlled valving of positive and negative pressures to elicit lung inflations and rapid deflations; pulmonary resistance was measured during spontaneous tidal breathing; and quasi-static pressure-volume curves were obtained with passive inflations and deflations in fully anesthetized, paralyzed rats. Compared with controls, the postbronchiolitis rats had elevated pulmonary resistance and reduced forced-expiratory volume in 0.2 s. Most of the reduced forced-expiratory volume in 0.2 s was associated with reduced forced vital capacity, indicating premature airway closure as a prominent mechanism. The reduced airflow in postbronchiolitis rats was highly dependent on lung volume, being nearly normal at 70% lung capacity, but sevenfold less than normal at 30% lung capacity. Increased respiratory system hysteresis between functional reserve capacity and total lung capacity was evidence for increased airway closure at normal end-expiratory lung volumes in postbronchiolitis rats. We conclude that airway instability and closure is a prominent mechanism of the chronic airway dysfunction in rats that have recovered from viral bronchiolitis at an early age.

Effects of age, gender, and environmental exposures on exhaled nitric oxide level in healthy 12 to 18 years Qatari children.

CONTEXT: Fractional exhaled nitric oxide (FENO) is a useful noninvasive diagnostic tool for asthma and some other pediatric respiratory diseases. Factors affecting FENO level are variable in different populations and studies. AIMS: To estimate the normal values of exhaled nitric oxide for Qataris 12 to 18 years of age. Other objectives were to measure the correlation of anthropometric and other potential factors with FENO levels. SETTINGS AND DESIGN: Community-based, cross-sectional study. METHODS: A total of 438 Qatari national school children from both genders were randomly recruited in cross-sectional study. Of them, 203 were non-atopic and hence included in the statistical analysis. Questionnaires including personal data, demographic data, and other factors that may affect FENO level were distributed. STATISTICAL ANALYSIS USED: Comparison of means done using t-test. We performed Spearman's rho test to measure correlations. Data analysis was done using PASW 18.0 Release 18.0.0, 2009. RESULTS: The geometric mean of FENO levels for all subjects was 14.1 ppb (upper level CI 95% - 36.3 ppb). FENO was significantly higher in males (R(2) = -0.254, P<0.0001) and was negatively correlated with increasing age for the whole study population (P=0.036). This decline was interrupted by a significant upraise at the age of 15 years (P=0.0462) which seems to be driven by the males (P=0.0244). FENO levels were lower in subjects exposed to cats (P=0.019). We could not find significant correlation between FENO and other factors studied. CONCLUSIONS: Estimated FENO level with 95% CI in Qatari children, which is probably close to those in other Gulf countries, will be helpful clinically. The lower level of FENO with female gender, increasing age, and exposure to cats needs to be further studied to establish the association and to understand the underlying mechanisms.

Bilateral congenital lobar emphysema: A rare cause for respiratory distress in infancy.

We report a rare case of bilateral congenital lobar emphysema in a 2-month-old male infant who presented with severe respiratory distress leading to respiratory failure. Plain chest X-ray and later high-resolution CT scan of the chest revealed that both the right middle and the left upper lobes were emphysematous. Surgical excision of the affected lobes has been done successfully in two sequential operations of right middle lobectomy followed by left upper lobectomy which resulted in significant improvement of respiratory status. In this report, the presentation, diagnosis, and surgical management of this rare condition are discussed.

Attenuated innate mechanisms of interferon-gamma production in rats susceptible to postviral airway dysfunction.

After Sendai virus (SeV)-induced bronchiolitis as weanlings, BN, but not F344, rats develop a postbronchiolitis asthma-like phenotype, which can be prevented by supplemental interferon (IFN)-gamma treatment. We have shown that splenocytes from BN weanlings, compared with those from F344 weanlings, have a markedly reduced capacity for IFN-gamma production. We hypothesized that SeV-induced IFN-gamma production occurs via innate mechanisms that are attenuated in BN weanlings. Therefore, we investigated potential mechanisms of SeV-induced IFN-gamma production in BN and F344 weanlings. SeV-stimulated splenocytes secreted the IFN-gamma-inducing cytokines, interleukin (IL)-12 and IL-18. BN splenocytes produced significantly less IL-12 (P = 0.001) and IL-18 (P < 0.001) than did F344 splenocytes. Depletion studies demonstrated that natural killer cells were the primary source of SeV-induced IFN-gamma production. Anti-IL-12 antibody, IL-12 p40 homodimer, and IL-18 binding protein each inhibited SeV-induced IFN-gamma production by 82-94%, and the combination of IL-12 p40 homodimer and IL-18 binding protein abolished SeV-induced IFN-gamma production, demonstrating synergism between IL-12 and IL-18. Therefore, SeV-induced IFN-gamma production occurred via innate IL-12-, IL-18-, and natural killer cell-dependent mechanisms, which were attenuated in BN weanlings. Attenuation of innate IFN-gamma-producing responses to SeV in BN weanlings may be a critical factor in their susceptibility to postbronchiolitis chronic airway dysfunction.

Effects of a DNA vaccine in an animal model of Alternaria alternata sensitivity

La sensibilidad al hongo Alternaria se asocia con la persistencia y gravedad del asma. Las opciones terapéuticasactuales para el tratamiento de la inflamación de las vías aéreas inducida por Alternaria son limitadas.En este estudio se han utilizado ratas Brown Norway para estudiar la eficacia de una vacuna de ADN administradapor vía aérea para atenuar la respuesta al alérgeno mayor de Alternaria rAlt a 2. Comparados conlos animales sensibilizados sin tratar, o con los animales que recibieron una vacuna de ADN con un marcode lectura incorrecto, los animales tratados con una vacuna ADN con un marco de lectura correcto mostraronuna atenuación en los títulos de anticuerpos específicos IgE frente a rAlt a 2, un aumento en IgG2b (unarespuesta Th1), una reducción en la liberación espontánea de IL-13 por suspensiones celulares de nóduloslinfáticos peribronquiales y una atenuación en la diminución en la capacidad pulmonar total 72 h despuésde la administración del alérgeno. El examen histopatológico de los tejidos pulmonares reveló una inflamaciónpulmonar reducida tras la administración del alérgeno en los animales tratados con ADN comparadoscon los animales sensibilizados sin tratamiento. Se concluye que una vacuna de ADN administrada por víaaérea ejerce una influencia significativa sobre las alteraciones inmunológicas, fisiológicas pulmonares ehistológicas inducidas por el alérgeno mayor de Alternaria rAlt a 2 en animales sensibilizados(AU)

Sensitivity to the fungus Alternaria is associated with asthma persistence and severity. Current therapeuticoptions for treating Alternaria-induced airway inflammation are limited. In this study, Brown Norway ratsare used to study the effectiveness of a DNA-based vaccine delivered to the airway in attenuating theresponse to a major Alternaria allergen, rAlt a 2. Compared to untreated sensitized animals, or animalsreceiving an “out-of-frame” DNA-based vaccine, animals treated with “in-frame” DNA vaccine showed anattenuation in specific IgE antibody titers to rAlt a 2, an increase in IgG2b (a Th1 response), a reduction inspontaneous IL-13 release by peribronchial lymph node cell suspensions, and an attenuation in thedecrease in total lung capacity 72 h post-allergen challenge. Further, histopathologic examination of thelung tissues revealed reduced pulmonary inflammation post-allergen challenge in the DNA-vaccine-treatedcompared to sensitized, untreated animals. We conclude that a DNA-based vaccine delivered to the airwaysignificantly influences the immunologic, pulmonary physiologic, and histological alterations induced bychallenge with a major Alternaria allergen, rAlt a 2, in sensitized animals(AU)