IL-33 gene variants and protein expression in pediatric Tunisian asthmatic patients.

Interleukin-33 (IL-33) is one of the last discovered members of the human IL-1 family. It is involved in the pathogenesis of many inflammatory diseases. This study investigates the relationship between IL33 gene variants and serum protein levels with the development of childhood asthma. We analyzed in this case-control study the distribution of two IL33 polymorphisms, rs7044343 and rs1342326, within 200 Tunisian children, using predefined Taqman genotyping assays. IL-33 serum levels were assessed by commercial sandwich Enzyme-linked immunosorbent assay (ELISA). The presence of rs1342326 polymorphism was significantly associated with a lower risk of asthma development. The CC [OR=0.20, CI (0.08-0.50)] and AC [OR=0.24, CI (0.11-0.49)] genotypes, as well as the C-allele [OR=0.40; CI: 0.26-0.61, P=0.00001] were associated significantly with a decreased asthma risk. However, the C-allele was more frequent in severe asthma patients than in milder ones. No association was found between rs7044343 variant and asthma. The level of IL-33 in sera was significantly increased in asthmatic children [1.48±0.47pg/mL] compared to controls [0.70±0.18pg/mL; P<0.001]. Furthermore, this increase of IL-33 was associated with the presence of rs1342326 C allele. The IL33 rs1342326 polymorphism was associated with a lower childhood asthma risk in the Tunisian population and a higher IL-33 protein expression.

Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults' Asthma.

INTRODUCTION: Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function. OBJECTIVE: Study the relationship between vitamin D and the severity of asthma by targeting five SNPs of vitamin D metabolism gene pathway in a Tunisian adult asthmatics population. METHODS: Our case-control study includes 154 adult asthmatic patients and 154 healthy Tunisian subjects. We genotyped many variants in three human genes encoding key components of the vitamin D metabolism, CYP2R1, CYP27B1, GC. The GC gene rs4588 and rs7041 polymorphisms were analysed using the PCR-RFLP method, while rs10741657 and rs12794714 for CYP2R1 gene and rs10877012 of CYP27B1 gene were investigated using TaqMan PCR genotyping techniques. RESULTS: We found that the presence of at least one copy of the rs12794714 A, allele was associated with lower risk of developing asthma (OR 0.61). Further, the rs12794714 is a protector factor against asthma severity (OR 0.5). However, the presence of rs10877012 TG genotype is a risk factor related to asthma severity (OR 1.89). When we classified the population according to sex, our results showed that rs10877012 TT genotype was a risk factor for women subjects (OR 6.7). Moreover, the expression of TT genotype was associated with a higher risk of asthma in non-smoker patients (OR 7.13). We found a significant lower VD serum levels in asthmatics than controls but no impact of the polymorphisms on VD levels. CONCLUSIONS: We found that rs12794714 and rs10877012 SNPs were associated with asthma risk.

IL-8 Gene Variants and Expression in Childhood Asthma.

PURPOSE: To examine the IL-8 expression levels and association of genetic variants with the risk of childhood persistent asthma prognosis. METHODS: Overall, 170 asthmatic children and 170 healthy controls were included in this case-control study. The human IL-8 serum levels were measured using ELISA. The IL-8 mRNA expression levels were assessed by a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The IL-8 expression at both protein and mRNA levels was found to be significantly elevated in asthmatic children compared to healthy subjects (P < 0.0001, P = 0.004; respectively). Higher levels of IL-8 mRNA are detected in subjects with moderate to severe asthma. The presence of IL8-251 A/T (rs4073) and + 781C/T (rs2227306) polymorphisms was significantly associated with an increased risk of asthma (P = 0.002, P = 0.036, respectively). In addition, we noted a significant association between these polymorphisms and an elevated risk of atopic asthma (P < 0.05). For rs2227306 SNP, the highest median level of IgE was detected for the presence of TT genotype (865 ± 99.74 IU/mL). Although, the rs4073 polymorphism conferred a higher risk to develop asthma at an advanced stage of severity (P = 0.008). The rs4073 T and rs2227306 C alleles are considered as risk factors for asthma development. The rs4073 T allele is represented also as a risk factor for asthma severity in Tunisian children. CONCLUSIONS: Both IL-8 gene and protein expression may play a key role in asthma pathogenesis.

The role of the pathologic exam in the acute exacerbations of the interstitial pneumonia.

Acute exacerbation of interstitial pneumonia is a new terminology with recent debated criteria. Its prognosis is bad and its management remains non consensual. This lack of consensus seems to be due to the lack of knowledge concerning the physiopathologic phenomenon. This lack of knowledge results in few efficient therapeutics. The diagnosis of acute exacerbation is challenging for clinicians and the real place of the pathologic exam remains unknown. Our aim was to assess the different situations faced by the pathologists by emphasizing their real role.

Diagnostic value of the bronchoalveolar lavage in interstitial lung disease.

Background The bronchoalveolar lavage (BAL) cellular analysis is an invasive method of exploration of the lung. Its diagnostic value in interstitial lung disease (ILD) is integrated to a multi-disciplianry approach implicating clinicians, radiologists and pathologists. Aim We targeted to evaluate the diagnostic value of the BAL. Methods We reported a retrospective study about patients hospitalized for an ILD since the 1st January 2011 to the 31th December 2013. Thirty three patients were admitted in the Department of Pulmonology and the BAL analyses were studied in the Department of Pathology of the same hospital. The different cell patterns were compared to the final diagnostics. Results our study contained 4 non specific interstitial pneumonia (NSIP), 10 usual interstitial pneumoniae (UIP), 4 organizing pneumoniae (COP), 8 sarcoidosis, 2 hypersensitivity pneumonitis, 3 infectious pneumonitis, 1 lymphoma and a pulmonary adenocarcinoma. We considered positive results those that were compatible with the final diagnosis. The profile lavage was typical in 1 NSIP, 3 UIP, 3 COP, 1 hypersensitivity pneumonitis, 6 sarcoidosis, 3 infectious pneumonitis and 1 adenocarcinoma. Among the 17 cases with an atypical profile lavage, radiological features were diagnostic in 10 cases. This finding highlights the fact that 7 cases/ 33 presented simultaneously an atypical profile lavage and non specific radiological findings Conclusion Our results put emphasis on the diagnostic value of BAL especially when it is integrated to a multi-disciplinary approach. Its value in the follow up, the evaluation of the activity of the disease and the prognosis is being more and more reported.

Childhood tuberculosis: A descriptive study in a pneumo-pediatrics department in Tunisia.

Objective to assess the different localizations of tuberculosis (TB) in children in a pneumopediatric department in Tunisia and to describe its diagnosis tools since clinical investigations of childhood TB are challenged by the paucibacillary nature of the disease and the difficulties in obtaining specimens. Methods Forty-six cases of TB in children were studied between 2008 and 2013. Clinical history, examination and chest radiography were reported. Several investigations have been conducted to confirm the diagnosis of TB such as: tuberculin skin test (TST), bacteriological and histological investigations. Anti-tuberculosis treatment was prescribed according to the national guidelines. Results Cough and deterioration in general condition were the most frequent symptoms (47.8% and 43.7%). The other children presented cervical swelling (19.5%), chest pain (17.4%) and hemoptysis (4.3%). Abnormalities have been found in chest radiography in 35 cases (76%). TST was positive in 73% of cases. Diagnosis of TB was confirmed in 56.6% of cases by Mycobacterium tuberculosis (MT) isolation and/or biopsy. The diagnosis was made on presumptive arguments in 20 cases (43.4%) based on a history of TB contact, suggestive symptoms and a positive TST. A surgical biopsy was necessary for diagnosis in 17 cases (nasopharynx, bone, cervical, mediastinal and mesenteric lymph nodes). Pulmonary TB was diagnosed in 52% of cases. Two children were diagnosed with disseminated TB. A diagnosis delay was noted with an average of 20 days and a contact history was found in 52% of the children. All children were treated according to the national guidelines without major side effects. Healing without sequelae was achieved in 91% of cases. Conclusion Children represent a population at high risk for TB especially after a household contact with a higher frequency of multifocal forms compared to adults. The difficulty of the diagnosis in children may explain partially the diagnosis delay, but efforts must be done to improve prevention and diagnosis in our country.

Association of vitamin D receptor gene polymorphisms with asthma risk: systematic review and updated meta-analysis of case-control studies.

BACKGROUND: The association between vitamin D receptor (VDR) polymorphisms and asthma risk has been inconsistently investigated, but published studies demonstrated conflicting results. The aim of the current study was to investigate the impact of TaqI, BsmI, ApaI, and FokI VDR polymorphisms on asthma disease by using a meta-analysis approach. METHODS: Following the preferred reporting items for systematic reviews and meta-analyses guidelines, a systematic search and meta-analysis of the literature were conducted. Subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics. RESULTS: A total of 2,097 cases and 1,968 controls in eight case-control studies were included in meta-analyses. A significant association was found between TaqI polymorphisms and asthma risk [OR 1.488 (95 % CI 1.019-2.174); P = 0.040] in a codominant model. In the same way, BsmI was significantly associated with asthma risk [OR 2.017 (95 % CI 1.236-3.851); P = 0.017] in the codominant model. The homozygote BB BsmI genotype was found to confer significant asthma risk. FokI polymorphism was marginally associated with asthma risk [OR 1.187 (95 % CI 0.975-1.446); P = 0.088] in the codominant model. In contrast, no significant association was found between ApaI polymorphism and asthma risk. Subgroup analyses revealed that gender and age modified significantly the association between FokI polymorphisms and asthma risk (P = 0.035 and 0.013, respectively). Publication year and serum 25(OH) D level tended, marginally, to moderate the association between FokI polymorphism and asthma risk. CONCLUSION: TaqI, BsmI, and FokI VDR polymorphisms contribute to asthma susceptibility. The association between FokI polymorphism and asthma risk is influenced by study characteristics.

Brief original scientific report: a new surgical approach for the treatment of left pulmonary and hepatic hydatid disease.

BACKGROUND: The combination of pulmonary and hepatic hydatid cysts is frequently encountered, and poses a challenge in terms of surgical accessibility. The surgical treatment of the two locations by the same incision (thoracotomy with phrenotomy) has been proposed, but always from the right side. However, applying this technique to the left side seems to be more difficult and unusual. We herein describe a new left-sided technique that was used to treat two patients with pulmonary and hepatic hydatid cysts. METHODS: The first patient was 14-year-old; he had bilateral pulmonary hydatid cysts and one type I cyst of the left lobe of the liver. The second patient was a 10-year-old female who had a hydatid cyst of the upper left lobe with one type III cyst of hepatic segments 2 and 3. RESULTS: Both patients were operated on via a left lateral thoracotomy through the sixth intercostal space. They underwent cystectomy for the left pulmonary hydatid cysts, followed by padding, and then the hepatic cyst was treated by Lagrot's method via a radial phrenotomy. The postoperative course was uneventful in both cases, with postoperative hospital stays of 3 and 5 days, respectively. CONCLUSION: This combined treatment of pulmonary and hepatic hydatid cysts by the left-sided thoracic approach is feasible and provides a good outcome. It should be indicated under the same conditions of accessibility and feasibility applied for the right thoracic side.

Induced sputum levels of IL-33 and soluble ST2 in young asthmatic children.

OBJECTIVE: Interleukin-33 is an IL-1 family cytokine which signals via its T1/ST2 receptor, and acts as a key regulator of inflammation, notably the type-2 response implicated in asthma. This study aims to measure the expression of soluble ST2 (sST2) and IL-33 in asthmatic children, depending on disease activity. METHODS: Thirty-seven children with well-defined asthma (20 moderate and 17 mild asthmatics) were studied. IL-33 and sST2 were measured by ELISA in serum and induced sputum (IS) samples, and compared with 22 age- and sex-matched healthy controls. Real-time quantitative PCR was used to determine IL-33 and TNF-α mRNA expression in IS. RESULTS: sST2 and IL-33 levels in IS and serum were significantly higher in patients compared with healthy controls (p = 0.0001). The increase in sST2 and IL33 was significantly more important in moderate cases than in mild asthma. A significant correlation was observed between serum and IS IL-33 levels (r = 0.497; p = 0.0018). Higher levels of IL-33 mRNA were detected in IS from asthmatics than those observed in controls. A significant correlation was found between TNF-α and IL-33 mRNA expression in the asthmatic subjects (r = 0.772, p = 0.0001). CONCLUSIONS: Values of sST2 and IL-33 observed in IS were found to correlate with disease activity. Elevated IL-33 mRNA expression in IS and its correlation with TNF-α reflected the inflammatory process observed in the lung of young asthmatics.

Influence of socio-economic status on functional recovery after ARDS caused by SARS-CoV-2: the multicentre, observational RECOVIDS study.

PURPOSE: Survivors after acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) are at high risk of developing respiratory sequelae and functional impairment. The healthcare crisis caused by the pandemic hit socially disadvantaged populations. We aimed to evaluate the influence of socio-economic status on respiratory sequelae after COVID-19 ARDS. METHODS: We carried out a prospective multicenter study in 30 French intensive care units (ICUs), where ARDS survivors were pre-enrolled if they fulfilled the Berlin ARDS criteria. For patients receiving high flow oxygen therapy, a flow ≥ 50 l/min and an FiO2 ≥ 50% were required for enrollment. Socio-economic deprivation was defined by an EPICES (Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examens de Santé - Evaluation of Deprivation and Inequalities in Health Examination Centres) score ≥ 30.17 and patients were included if they performed the 6-month evaluation. The primary outcome was respiratory sequelae 6 months after ICU discharge, defined by at least one of the following criteria: forced vital capacity < 80% of theoretical value, diffusing capacity of the lung for carbon monoxide < 80% of theoretical value, oxygen desaturation during a 6-min walk test and fibrotic-like findings on chest computed tomography. RESULTS: Among 401 analyzable patients, 160 (40%) were socio-economically deprived and 241 (60%) non-deprived; 319 (80%) patients had respiratory sequelae 6 months after ICU discharge (81% vs 78%, deprived vs non-deprived, respectively). No significant effect of socio-economic status was identified on lung sequelae (odds ratio (OR), 1.19 [95% confidence interval (CI), 0.72-1.97]), even after adjustment for age, sex, most invasive respiratory support, obesity, most severe P/F ratio (adjusted OR, 1.02 [95% CI 0.57-1.83]). CONCLUSIONS: In COVID-19 ARDS survivors, socio-economic status had no significant influence on respiratory sequelae 6 months after ICU discharge.

Unusual bone localization of sarcoidosis mimicking metastatic lesions: case report and review of literature.

Sarcoidosis is a multisystem disease of unknown origin. Diagnosis remains challenging, based on organ site involvement, histological confirmation of non-caseating granuloma and an appropriate clinical syndrome. Granulomatous bone involvement is rare and may be ignored because it is usually asymptomatic. Vertebrae, ribs and skull localizations are rarely reported. We described an interesting case of a woman with chronic and multiorgan sarcoidosis with unusual bone localizations.

[Impact of tobacco on bronchopulmonary affections: magnitude of the problem]. / Impact du tabagisme sur les affections brochopulmonaires : ampleur du problème.

BACKGROUND: Tobacco smoking is frequent in the world affecting 20 à 50% of the population but with a decrease in occidental countries due to a huge effort based on sensiblisation and anti-tobacco decisions. AIM: To review the impact of tobacco on bronchopulmonary affections. METHODS: A narrative review of literature RESULTS: In the next future, yearly tobacco-related deaths could increase from 4.2 millions in 2000 to 10 millions in 2025-2030 making smoking as the main evitable cause of deaths by respiratory diseases. Lung cancer is the leading killer cancer. Tobacco is the most frequent cause of respiratory diseases. It is responsible of 80 to 90% of deaths by chronic obstructive pneumobronchopathiy (COPD) and 80 to 85% deaths by bronchopulmonary cancer. CONCLUSION: Tobacco is a « chronic disease ¼ necessitating management with advices and medical treatment.

Interleukin-26 is overexpressed in Behçet's disease and enhances Th17 related -cytokines.

Behçet's disease (BD) is a multi-systemic inflammatory disorder characterized by the "triple symptom complex". Several pro-inflammatory cytokines, mainly derived from the immune Th17 axis, seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. Here, we have analyzed the expression and role of IL-26 in active BD patients, an inflammatory disorder characterized by bronchoalveolar lavage fluid (BAL) and cerebrospinal fluid (CSF) inflammation. On this basis, the primary aim of our work was to study IL-26 levels in serum, BAL CSF) from active BD patients. Samples were collected from 95 BD patients (55 patients were in active stage) and 50 healthy controls (HC). They were investigated with ELISA for estimation of cytokines levels. Serum concentration of IL-26 resulted higher in both active [4.80±1.32] and inactive [2.77±1.026] BD than HC [0.31±0.14ng/ml; p<0.0001]. Level of IL-26 was associated with the BD clinical severity score from moderate to severe (P<0.0001). IL-26 was highly expressed in CSF [10.80±2.05ng/ml] and in BAL [12.89±3.03ng/ml] fluid from BD patients comparatively to their respective controls. IL-26 levels in CSF and in BAL fluid showed positive correlations with IL-17 level and an inversely correlation with IL-37. Interestingly, IL-26-stimulated CD4+ T cells and monocytes promote the generation of Th17 (IL-17A, IL-23) and suppress Treg (IL-10, TGF-ß) cytokines. Our findings may suggest a signature of IL-26 probably responsible for the inflammatory process to correlate positively with Th17 cytokines and inversely with Treg mediators. This evidence could contribute to improve the knowledge regarding the role of IL-26 in BD severity. For the first time, IL-26 expression is demonstrated in BAL and CSF, supporting a role for this cytokine in the pathogenesis of BD. IL-26 thereby appears as a novel proinflammatory cytokine favoring the generation of Th17 cytokines.

Anti-inflammatory activity of IL-37 in asthmatic children: Correlation with inflammatory cytokines TNF-α, IL-ß, IL-6 and IL-17A.

BACKGROUND: The aim of this study was to assess interleukin (IL)-37 production in asthmatic children in serum and induced sputum and to look to the impact of IL-37 on pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß and IL-17). METHODS: Forty children with well-controlled asthma (20 moderate and 20 mild asthmatics) were studied. IL-37 was measured by ELISA in serum and induced sputum (IS) samples, and compared with 22 age- and sex-matched healthy controls. Real-time quantitative PCR was used to determine IL-37 mRNA expression in induced sputum cells. Induced sputum mononuclear cells from 10 moderate asthmatics and 10 healthy controls were stimulated either with lipopolysaccharides (LPS) or LPS plus recombinant IL-37 (rIL-37) comparing pro-inflammatory cytokines production. TNF-α, IL-1ß, IL-6 and IL-17 were measured by RT-PCR and ELISA. FINDINGS: The expression of IL-37 mRNA in asthmatic patients was significantly lower than that observed in healthy controls (P=0.0001). IL37 mRNA expression depended on asthma severity. Serum and IS IL-37 levels were significantly lower in asthma patients compared to healthy controls. LPS-stimulated sputum cells from asthma patients produced higher levels of IL-1ß, IL-6, and TNF-α than those from HC. Adding rIL-37 suppressed TNF-α, IL-1ß and IL-6 production in IS cells. In the same way, stimulating IS CD4(+) T cells in the presence of rIL-37 inhibited IL-17 production both in asthma patients and HC. IL-37 effect on IL-17 was more pronounced in patients than controls. INTERPRETATION: The decrease in IL-37 level observed in IS was found to correlate with disease severity. The increased pro-inflammatory cytokines production from asthma IS cells was abrogated by the addition of rIL-37. IL-37 could be an important cytokine in the control of asthma by suppressing the production of inflammatory cytokines.

Increased expression of thymic stromal lymphopoietin in induced sputum from asthmatic children.

OBJECTIVE: Thymic stromal lymphopoietin (TSLP) plays a role in amplifying the inflammatory response in asthmatics. TSLP is also a critical factor in airway remodeling airways. The aim of this study was to assess the expression of TSLP in induced sputum from asthmatic children and to look to the impact of TNF-α and IL-37 on TSLP production in induced sputum from asthmatic children. METHODS: Forty children with well-controlled asthma (20 moderate and 20 mild asthmatics) were studied. TSLP was measured by enzyme-linked immunosorbent assay (ELISA) in induced sputum (IS) samples, and compared with 22 age- and sex-matched healthy controls. Real-time quantitative PCR was used to determine TSLP mRNA expression in induced sputum cells. Sputum cells (ISCs) from 5 moderate asthmatics and 5 healthy controls (HC) were stimulated either with TNF-α or TNF-α plus recombinant IL-37 (rIL-37) comparing the suppression on TSLP production. RESULTS: The expression of TSLP mRNA in asthmatic patients was significantly higher than that observed in healthy controls [P=0.0001]. Induced sputum fluid TSLP and TNF-α levels were significantly higher in asthmatic patients compared to healthy controls and their levels depend on asthma severity. Sputum cells produced high TSLP levels upon stimulation with TNF-α (10pg/ml) in asthmatics. TSLP is merely produced by bronchial epithelial cells. Addition of recombinant IL-37 suppressed partially TSLP production in sputum-cultured cells and in bronchial epithelial cultured cells. CONCLUSIONS: The increase in TSLP and TNF-α level observed in IS fluid was found to correlate with disease severity. The increased TSLP production from asthma sputum cells was abrogated by the addition of rIL-37. Regulation of TSLP pathway may be a therapeutic approach for asthma.

Link between vitamin D and airway remodeling.

In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.