ABSTRACT
Candida albicans chronically colonizes the respiratory tract of patients with Cystic Fibrosis (CF). It competes with CF-associated pathogens (e.g. Pseudomonas aeruginosa) and contributes to disease severity. We hypothesize that C. albicans undergoes specific adaptation mechanisms that explain its persistence in the CF lung environment. To identify the underlying genetic and phenotypic determinants, we serially recovered 146 C. albicans clinical isolates over a period of 30 months from the sputum of 25 antifungal-naive CF patients. Multilocus sequence typing analyses revealed that most patients were individually colonized with genetically close strains, facilitating comparative analyses between serial isolates. We strikingly observed differential ability to filament and form monospecies and dual-species biofilms with P. aeruginosa among 18 serial isolates sharing the same diploid sequence type, recovered within one year from a pediatric patient. Whole genome sequencing revealed that their genomes were highly heterozygous and similar to each other, displaying a highly clonal subpopulation structure. Data mining identified 34 non-synonymous heterozygous SNPs in 19 open reading frames differentiating the hyperfilamentous and strong biofilm-former strains from the remaining isolates. Among these, we detected a glycine-to-glutamate substitution at position 299 (G299E) in the deduced amino acid sequence of the zinc cluster transcription factor ROB1 (ROB1G299E), encoding a major regulator of filamentous growth and biofilm formation. Introduction of the G299E heterozygous mutation in a co-isolated weak biofilm-former CF strain was sufficient to confer hyperfilamentous growth, increased expression of hyphal-specific genes, increased monospecies biofilm formation and increased survival in dual-species biofilms formed with P. aeruginosa, indicating that ROB1G299E is a gain-of-function mutation. Disruption of ROB1 in a hyperfilamentous isolate carrying the ROB1G299E allele abolished hyperfilamentation and biofilm formation. Our study links a single heterozygous mutation to the ability of C. albicans to better survive during the interaction with other CF-associated microbes and illuminates how adaptive traits emerge in microbial pathogens to persistently colonize and/or infect the CF-patient airways.
Subject(s)
Biofilms , Candida albicans , Cystic Fibrosis , Fungal Proteins , Transcription Factors , Cystic Fibrosis/microbiology , Candida albicans/genetics , Candida albicans/metabolism , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Biofilms/growth & development , Fungal Proteins/genetics , Fungal Proteins/metabolism , Gain of Function Mutation , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/metabolism , Lung/microbiology , Candidiasis/microbiology , Adaptation, PhysiologicalABSTRACT
The incapacity to synthesize certain components of pulmonary surfactant causes a heterogeneous group of rare respiratory diseases called genetic disorders of surfactant dysfunction. We report a female full-term infant with neonatal respiratory distress of early onset due to inherited SP-B deficiency. The infant failed oxygen weaning at multiple trials. Chest computed tomography was performed on the 29th day of life revealing ground-glass opacities, regular interlobular septal thickening and fine interlobular reticulations. Analysis of genomic DNA showed homozygosity for an extremely rare SFTPB gene variant (c.620A>G, p.Tyr207Cys). Both parents were heterozygotes for the mutation. The diagnosis of congenital SP-B deficiency should be suspected whenever an early and acute respiratory failure in a term or near-term infant does not resolve after five days of age: diagnostic confirmation can be easily and rapidly obtained with the analysis of genomic DNA.
Subject(s)
Respiratory Distress Syndrome, Newborn , Infant , Infant, Newborn , Humans , Female , Respiratory Distress Syndrome, Newborn/etiology , Surface-Active Agents , DNAABSTRACT
INTRODUCTION: Children's Interstitial Lung Diseases (cHILD) are a heterogeneous group of rare respiratory diseases. Their common characteristics are gas exchange abnormalities and diffuse pulmonary infiltrates on chest imaging. This group includes inherited surfactant protein deficiency (ISPD), a little-known etiology in Tunisia. CASE PRESENTATION: A 22-month-old boy was referred to investigate recurrent respiratory infections. He had polypnea, cyanosis, finger clubbing, pectus carinatum, intercostal retraction, and bilateral crackles on pulmonary auscultation. The chest imaging revealed a diffuse ground-glass appearance consistent with cHILD. Lung biopsy was suggestive of ISPD. The infant was mainly treated with intravenous corticosteroids. At the age of nine, he was still dependent on oxygen but had better exercise tolerance. CONCLUSION: This case showed that recurrent respiratory infections can hide cHILD which may be related to ISPD, particularly in infants. A better knowledge of this disease was necessary to start specific treatment. Early management would lead to better prognosis.
Subject(s)
Lung Diseases, Interstitial , Protein Deficiency , Respiratory Tract Infections , Infant , Child , Male , Humans , Tunisia , Lung/pathology , Lung Diseases, Interstitial/etiology , Respiratory Tract Infections/complications , Respiratory Tract Infections/pathology , Protein Deficiency/complications , Protein Deficiency/pathology , Surface-Active AgentsABSTRACT
Introduction: Mediastinal teratomas are rare in children. Nevertheless, they represent the most frequent mediastinal germ cell tumor. Most often, they are discovered incidentally in older children or adolescents on chest X-ray. There are other signs of discovery but less frequent: chest pain, hemoptysis and signs of mediastinal compression. Rupture into pleural space, pericardium or tracheobronchial tree are exceptional. Case presentation: We report the case of 7-years old girl admitted for chest pain. The chest x-ray showed a mediastinal mass with calcifications and pleural effusion. Chest CT scan revealed a well limited heterogeneous anterior mediastinal mass with calcifications and a left pleural effusion. She underwent a median sternotomy and the tumor was completely excised. Histopathology confirmed the diagnosis of mature teratoma. Conclusion: Intrapleural rupture is a rare complication of mature teratoma. Calcifications on chest imaging in afebrile children with pleural effusion should be suspected of mediastinal teratoma.
Subject(s)
Mediastinal Neoplasms , Pleural Effusion , Teratoma , Female , Adolescent , Humans , Child , Mediastinal Neoplasms/complications , Mediastinal Neoplasms/pathology , Rupture, Spontaneous/complications , Pleural Effusion/complications , Teratoma/complications , Teratoma/pathology , Chest Pain/complicationsABSTRACT
BACKGROUND: Acute bronchiolitis management involves all pediatricians and primary care physicians. The national guidelines for bronchiolitis diagnosis and treatment were published in Tunisia to reduce excessive use of diagnostic tests and unify bronchiolitis management. OBJECTIVES: We aimed to assess the real impact of the national guidelines on acute bronchiolitis management in Tunisia. METHODS: We conducted an evaluative cross-sectional study. We randomly distributed anonymous questionnaires to physicians managing acute bronchiolitis during the period from 1st March 2014 to 30 November 2015. RESULTS: We analyzed 140 questionnaires. Ninety-three interviewed physicians (66.4%) were advised of the latest national guidelines, half of them (33.6%) declared they didn't follow these guidelines. Real and complete guidelines adherence was observed in only 1.4% of interviewed physicians. According to bronchiolitis diagnosis, appropriate Chest X-rays and blood tests were requested respectively by 57.8% and 59.3% of interviewed doctors. Regarding bronchiolitis therapeutic management, bronchodilators and epinephrine nebulization weren't prescribed by respectively 45.7% and 38.6% of them. Antibiotics were prescribed by 92.9% of interviewed doctors and chest physiotherapy was well indicated by 47.8% of them. CONCLUSIONS: There is a disconnect between the bronchiolitis guidelines and clinical practice. National strategies have to be developed to reduce excessive use of diagnostic tests and unrecommanded therapies.
Subject(s)
Bronchiolitis , Practice Patterns, Physicians' , Acute Disease , Bronchiolitis/diagnosis , Bronchiolitis/epidemiology , Bronchiolitis/therapy , Cross-Sectional Studies , Humans , Tunisia/epidemiologyABSTRACT
AIM: To establish a preliminary national report on clinical and genetic features of cystic fibrosis (CF) in Tunisian children as a first measure for a better health care organization. METHODS: All children with CF diagnosed by positive sweat tests between 1996 and 2015 in children's departments of Tunisian university hospitals were included. Data was recorded at diagnosis and during the follow-up from patients' medical records. RESULTS: In 12 departments, 123 CF children were collected. The median age at diagnosis was 5 months with a median diagnosis delay of 3 months. CF was revealed mostly by recurrent respiratory tract infections (69.9%), denutrition (55.2%), and/or chronic diarrhea (41.4%). The mean sweat chloride concentration was 110.9mmol/L. At least one mutation was found in 95 cases (77.2%). The most frequent mutations were Phe508del (n=58) and E1104X (n=15). Fifty-five patients had a Pseudomonas Aeruginosa chronic colonization at a median age of 30 months. Cirrhosis and diabetes appeared at a mean age of 5.5 and 12.5 years respectively in 4 patients each. Sixty-two patients died at a median age of 8 months. Phe508del mutation and hypotrophy were associated with death (p=0.002 and p<0.001, respectively). CONCLUSION: CF is life-shortening in Tunisia. Setting-up appropriate management is urgent.
Subject(s)
Cystic Fibrosis/epidemiology , Child , Cystic Fibrosis/complications , Diarrhea/etiology , Female , Humans , Infant , Male , Malnutrition/etiology , Respiratory Tract Infections/complications , Respiratory Tract Infections/etiology , Retrospective Studies , Tunisia/epidemiology , Young AdultABSTRACT
BACKGROUND: Due to the marked decline of maternal-fetal rhesus incompatibility, ABO alloimmunization has become the leading cause of the newborn hemolytic disease. It is estimated that 15-25 % of all pregnancies are concerned by ABO incompatibility. AIM: Neonatal blood group B seems to be more predisposing to acute hemolysis and severe hyperbilirubinemia. We propose to find if the newborn's blood group B represents a risk factor for severe hemolysis and/or severe hyperbilirubinemia. METHODS: We conducted a comparative study in the pediatrics department "B" of the Children Hospital of Tunis. We collected retrospectively the medical files of the newborn hospitalized for ABO alloimmunization (January 2011 - March 2014), then we compared two groups, OA group with OA alloimmunization and OB group with OB alloimmunization. A significant threshold was fixed to 0.05. RESULTS: We collected 98 cases of newborn ABO hemolytic disease. Both groups, OA and OB, were similar for the onset of jaundice, age of hospitalization, initial hemoglobin and indirect bilirubin levels. There were no statistically significant difference in the severity of hyperbilirubinemia and the use of exchange transfusion for the two groups. However, transfusion was statistically more frequent in the OB group compared to OA group (81.6 vs 10.2, p = 0,039, OR=2.9, 95% IC (1.1 - 7.8)). CONCLUSION: OB alloimmunization seems to induce more active hemolysis than OA one, with no difference for severe hyperbilirubinemia in both groups.
Subject(s)
ABO Blood-Group System/physiology , Blood Group Incompatibility/epidemiology , Blood Group Incompatibility/etiology , Erythroblastosis, Fetal/epidemiology , Erythroblastosis, Fetal/etiology , ABO Blood-Group System/adverse effects , ABO Blood-Group System/immunology , Blood Group Antigens/physiology , Blood Group Incompatibility/blood , Erythroblastosis, Fetal/blood , Female , Humans , Hyperbilirubinemia, Neonatal/epidemiology , Hyperbilirubinemia, Neonatal/etiology , Hyperbilirubinemia, Neonatal/immunology , Infant, Newborn , Infant, Premature, Diseases/blood , Infant, Premature, Diseases/epidemiology , Male , Retrospective Studies , Risk Factors , Sex RatioABSTRACT
Introduction and Objectives: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. Patients and methods: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. Results: We found a significant difference in the genotype frequencies between the two studied groups (chi2 = 9.855, P = 0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (chi2 = 9.610, P = 0.022). Conclusions: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia
No disponible
Subject(s)
Humans , Male , Infant , Child, Preschool , Child , Adolescent , Asthma/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genotype , Mutation/genetics , Gene Frequency , Genetic Association Studies , PhenotypeABSTRACT
INTRODUCTION AND OBJECTIVES: Asthma is a complex genetic disorder. Several genes have been found associated with asthma. The cystic fibrosis transmembrane conductance regulator (CFTR) gene is one of them. The aim of this study was to perform a comparative analysis of the genotype and allele frequency distributions of the biallelic marker M470V within the CFTR gene on mutant and wide chromosomes. PATIENTS AND METHODS: The molecular approach consists in the genotyping of the M470V marker by the PCR-RFLP technique in 105 asthmatic patients, aged between four months and 17 years, and 105 healthy subjects. RESULTS: We found a significant difference in the genotype frequencies between the two studied groups (χ2=9.855, P=0.007). The V/V genotype was over represented in the asthmatic group as compared to the controls (32.38% vs. 16.19%). Whereas, the M/V genotype is more frequent in healthy subjects (40.95% vs. 28.71%). We also noted a significant difference in allelic distribution of M470V with associated diseases (χ2=9.610, P=0.022). CONCLUSIONS: The present study is the first report on the distribution of the M470V polymorphism in asthmatic Tunisian patients. We noticed that the M470V variant could modulate the clinical phenotype of asthmatic patients. This preliminary study will establish the molecular basis of this disease in Tunisia.
Subject(s)
Asthma/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Genotype , Mutation/genetics , Adolescent , Child , Child, Preschool , Female , Gene Frequency , Genetic Association Studies , Humans , Infant , Male , Phenotype , Polymorphism, Genetic , TunisiaABSTRACT
BACKGROUND: Cystic fibrosis is rare in Tunisia. Its diagnosis requires experienced specialists. Its prognosis is poor in developing countries. OBJECTIVES: To study the epidemiologic, clinical, genetic features and the therapeutic challenges of cystic fibrosis in Tunisian children. METHODS: Covering a period of 21 years, this retrospective study included all patients with a definite diagnosis of cystic fibrosis from the Pediatrics Department B of The Children's Hospital of Tunis. RESULTS: Data from 32 children (14 boys and 18 girls) were collected. The diagnosis was made during the first year of life in 28 cases. Meconium ileus was found in 5 cases, respiratory manifestations in 22 cases, chronic diarrhea in 19 cases, faltering growth in 17 cases and a pseudo Barter syndrome in 2 cases. The sweat chloride test was positive in all cases. The most frequent mutation was F508del (56% of cases). Respiratory complications marked the outcome. Among our 32 patients, 15 patients (50%) died at an average age of 5 years and 3 months, mainly due to respiratory failure. The mean age of the surviving patients was 5 years. CONCLUSION: Cystic fibrosis prognosis is poor in our series compared to developed countries due to the longer diagnostic delay and the limited therapeutic options.
Subject(s)
Cystic Fibrosis/epidemiology , Child, Preschool , Cystic Fibrosis/genetics , Cystic Fibrosis/pathology , Cystic Fibrosis/therapy , Female , Humans , Male , Retrospective Studies , Tunisia/epidemiologyABSTRACT
Pseudo-Bartter syndrome (PBS) describes an uncommon complication of cystic fibrosis leading to hypochloraemic, hypokalaemic metabolic alkalosis. PBS as the sole manifestation of cystic fibrosis in children is extremely rare and has never been described in patients carrying 5T variant. We report a clinical, biochemical and genetic study of a four year-old boy presenting a pseudo-Bartter syndrome as the sole manifestation of cystic fibrosis. All 27 exons and the flanking intron regions of the CFTR gene were analysed by PCR and direct sequencing. Direct sequencing was also used to analyse TGmTn and M470V polymorphisms in the patient and his parents. Two sweat tests were abnormal with elevated chloride levels at 78 and 88 mmol/L. DNA sequencing revealed a heterozygous mutation 711+1 G>T and an IVS8-T5 allele. The mutation 711+1 G>T is in trans with the IVS8-T5-TG11 allele and the child carried M470/V470 genotype. To the best of our knowledge, the genotype 711+1 G>T /IVS8-5T found in our patient is described for the first time. The role of TG11-5T-V470 allele in cases of cystic fibrosis with PB syndrome remains to be determined.
Subject(s)
Bartter Syndrome/diagnosis , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/diagnosis , Cystic Fibrosis/genetics , Mutation , Bartter Syndrome/genetics , Child, Preschool , Cystic Fibrosis/complications , Diagnosis, Differential , Humans , Male , Polymorphism, GeneticABSTRACT
Background Community-acquired pleuropneumonia (CPP) is a common complication of pneumonia in children. It is serious given its high morbidity and significant mortality. Aim To study clinical and paraclinical features of CPP in children and to establish a common therapeutic strategy. Methods Our retrospective study included patients who were hospitalized for CPP between 2004 and 2012. All data were collected from patients' medical files. Statistical analysis was made by Epi-Info 6. Results One hundred and sixty four patients were registered. The mean age was 32 months (15 days - 14.5 years). The hospital incidence of CPP doubled between 2004 and 2012. The symptomatology was dominated by fever (93.9%), cough (56.7%) and dyspnea (48.1%). The pleural effusion was frequently moderately abundant and loculated. Pleural sample, performed in 53.6% of cases, was the most beneficial bacteriological examination (p=10-6 ). The bacteriological confirmation was attained in 44.5% of cases with the predominance of Staphylococcus aureus (59%) followed by Streptococcus pneumoniae (26%). The S. aureus occurred basically in most young infants (p=0.04) and was responsible for the most severe cases (p=0.01). The CPP management included heterogeneous intravenous antibiotics associated with a pleural drainage in 40% of cases. The quarter of our patients were transferred to an intensive care unit. Six patients died. Conclusion The bacteriological confirmation is difficult. Pleural aspiration is the key tool. S. aureus is the first microorganism followed by S. pneumoniae. A therapeutic strategy is proposed based on large spectrum intravenous antibiotics. The pleural drainage indication is limited.
Subject(s)
Community-Acquired Infections/epidemiology , Pleural Effusion/epidemiology , Pleuropneumonia/epidemiology , Adolescent , Animals , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Community-Acquired Infections/microbiology , Community-Acquired Infections/therapy , Cough/epidemiology , Cough/etiology , Drainage/methods , Dyspnea/epidemiology , Dyspnea/etiology , Female , Fever/epidemiology , Fever/etiology , Humans , Infant , Infant, Newborn , Male , Pleural Effusion/microbiology , Pleural Effusion/therapy , Pleuropneumonia/microbiology , Pleuropneumonia/therapy , Retrospective StudiesABSTRACT
OBJECTIVE: Our study aimed at assessing the role of flexible bronchoscopy (FB) in improving diagnosis and management of children's respiratory conditions in the pediatric unit of FB, newly created and unique in Tunisia. METHODS: Retrospective study including all the FB achieved in our pediatric unit from 2009 to 2014. RESULTS: We performed 365 FB in 333 patients aged 46 months on average (1 month - 15 years), often under conscious anesthesia (81.6%). FB was performed for diagnostic purposes in 341 cases and for therapeutic purposes in 24 cases. Eight anatomical abnormalities were revealed in 22 patients. An intraluminal bronchial obstruction was found in 71 FB, mainly due to a foreign body (n=36). A vascular anomaly was responsible for nine cases out of 17 extraluminal obstructions. Airways malacia was observed in 60 FB. Bronchoalveolar lavage was performed in 196 cases. It was determinant in 43.9% of the cases. FB was of great diagnostic value in 74.8% of the cases. It influenced the management of the patients in 58% of the cases. The FB for therapeutic purposes was beneficial in all cases. Few complications occurred (5.5%). CONCLUSION: FB is a safe tool providing precious diagnostic and/or therapeutic help for the clinician.