The First Case of a Homozygous CCNO NM 021147.4 Mutation Associated With Primary Ciliary Dyskinesia in Two Indian Siblings.

Primary ciliary dyskinesia (PCD) is a heterogeneous autosomal recessive disease marked by organ lateralization in 50% of patients, chronic sinopulmonary disease, infertility in men, and neonatal respiratory distress. Respiratory control cells contain CCNO in their apical cytoplasm, which is necessary for the development of multiciliate cells, basal body amplification, and migration. Reduced generation of multiple motile cilia, a rare form of PCD, has been linked to CCNO gene abnormalities. Individuals with CCNO mutations have been reported to suffer from severe lower respiratory infections that cause progressive impairment of lung function. For the first time, we describe the CCNO NM 021147.4 (c.258 262dup.p, Gln88argfs*8 Homozygous) gene mutation in an Indian consanguineous family that resulted in severe PCD.

Ultrastructure abnormalities of collagen and elastin in Arab patients with arterial tortuosity syndrome.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disease characterized by elongation and tortuosity of the large- and medium-sized arteries. ATS patients display features that are also found in Ehlers-Danlos syndrome (EDS) patients. ATS is caused by pathogenic mutations in the SLC2A10 gene, which encodes for the glucose transporter, GLUT10. This study aimed at examining the ultrastructure of skin for abnormalities that can explain the loose skin and arterial phenotypes of Arab patients with the p.S81R mutation in SLC2A10. Forty-eight patients with SLC2A10 mutation were recruited for this study. Skin biopsy specimens from three children with ATS and a healthy child were examined by electron microscopy to determine the ultrastructure of collagen and elastin. Histopathologic staining of sections from tissue biopsy specimens was also performed. Large spaces were observed among the collagen fibrils in the skin biopsy specimens obtained from ATS patients, suggesting disorganization of the collagen structures. Furthermore, elastin fiber contents and their thickness are reduced in the skin. In small muscular arteries in the skin from ATS patients, discontinuous internal elastic lamina, lack of myofilaments, and disorganized medial smooth muscle cells with vacuolated cytoplasm are present. The disorganization of collagen fibrils and reduced elastin contents in the skin may explain the loose skin phenotype of ATS patients similar to the EDS patients. The lack of elastin in small muscular arteries may have contributed to the development of arterial tortuosity in these patients.

Use of Intravenous Pulse Steroids to Treat Allergic Bronchopulmonary Aspergillosis in a Non-Compliant Asthmatic Adolescent.

Allergic bronchopulmonary aspergillosis (ABPA) is an immune-mediated inflammatory airway disease that predominantly affects patients with cystic fibrosis (CF) and, less commonly, patients with asthma. ABPA can lead to irreversible lung injury and bronchiectasis if not treated early and aggressively. Long-term oral steroids are the standard therapy of ABPA. However, it is associated with an increased risk of steroids side effects and possible medication noncompliance. Monthly intravenous pulse methylprednisolone (IV-PS) has been used as an alternative to oral steroids to treat CF-related ABPA with a reportedly similar clinical response and less steroid-related side effects. To our knowledge, the use of IV-PS in asthma-related ABPA has not been previously reported. We report the successful management of asthma-related ABPA in an adolescent using intravenous pulse methylprednisolone in addition to oral itraconazole with no significant steroid-related side effects.

Serum Cytokine Profile in Patients with Candidemia versus Bacteremia.

Bloodstream Candida infections constitute a major threat for hospitalized patients in intensive care units and immunocompromised hosts. Certain serum cytokines play a decisive role in anti-microbial host defense. Cytokines may act as discriminatory biomarkers that can significantly increase in candidemia compared to bacteremia patients. The concentration of secreted cytokine/chemokines was determined using a multiplexed cytometric bead array run on a cell analyzer. The cytokines tested during the study were interleukin (IL)-1ß, IL-6, IL-17A, IL-10, IFN-γ, IL-4, IL-2, IL-8, IL-12p70 and the tumor necrosis factor (TNF)-α. The cytokines of 51 candidemia patients were characterized and compared to the cytokine levels of 20 bacteremia patients. Levels were significantly elevated in patients with bloodstream infections compared to healthy controls. Cytokines comprising IL-2, IL-17A, IL-6 and IL-10 were significantly elevated in the patients with bloodstream Candida infection as compared to the patients having bloodstream bacterial infections. The levels were found to be promising as a potential diagnostic marker for bloodstream Candida infections.

First report of the cystic fibrosis transmembrane conductance regulator mutation c.1521_1523delCTT (p. Phe508del) in two Qatari patients with cystic fibrosis.

We report two cases of Qatari children with cystic fibrosis (CF) from different families presenting the homozygous CFTR 1521_1523delCTT (p. Phe508del) mutation with classic CF phenotypes. This gene mutation is considered the second CF mutation identified in Qatar. Herein, we review the frequency and distribution of this mutation in Arab countries.

Sputum and Plasma Neutrophil Elastase in Stable Adult Patients With Cystic Fibrosis in Relation to Chronic Pseudomonas Aeruginosa Colonization.

Background and purpose Neutrophil elastase (NE) has been implicated in the pathogenesis of airway inflammation in cystic fibrosis (CF) patients and it impairs defenses against Pseudomonas aeruginosa (PA) infection or colonization. Sputum NE may act as a biomarker of neutrophilic inflammation in CF patients. This study aimed to determine sputum and plasma total NE levels in clinically stable adult CF patients and control subjects, and their correlation to PA colonization and lung functions. Methods This is a cross-sectional study. Total NE was measured on spontaneously expectorated sputum and plasma obtained from 21 CF patients, aged 18-40 years, during routine visits to the adult CF clinic. This was compared to plasma obtained from 22 matching healthy controls. The levels of NE were measured by the magnetic bead-based multiplex assay. Results Sputum and plasma NE levels had a significant positive correlation (Pearson r=0.533, P=0.013) with PA colonization. Sixteen CF patients (76.2%) were chronically colonized with PA. Both median sputum and plasma NE were found to be higher in CF patients with PA as compared with non-PA patients, even though this difference was statistically insignificant. Sputum and plasma NE levels did not correlate with the percentage predicted forced expiratory volume in one second (FEV1), the forced vital capacity (FVC), and FEV1/FVC and no association with PA. Conclusion The findings suggest that clinically stable adult CF patients colonized with PA may have higher NE levels in both plasma and sputum as compared to non-PA CF patients and probably total NE does not influence lung functions.

Approaching two decades of cystic fibrosis research in Qatar: a historical perspective and future directions.

Cystic fibrosis (CF) is a genetic disease caused by a defect of CF transmembrane conductance regulator (CFTR) gene. CF affects multiple systems, predominantly with respiratory involvement. In Qatar, researchers have been exploring various aspects of the disease for almost 20 years. PubMed and Google Scholar were reviewed for articles related to CF in Qatar. The first publication appeared in the year 2000. Since then, several studies have been conducted on CF patients in Qatar considering a variety of topics. The presence of the CFTR I1234V mutation in a certain Arab tribe stands out as a distinguishing characteristic of CF patients in Qatar when compared to the larger Arab region or even worldwide. We aim here to summarize the existing CF research conducted in Qatar over the years as well as to introduce topics for future research.

A Rare Pediatric Case of Severe Bird Fancier's Lung Presented with Viral Pneumonitis-Like Picture.

Bird Fancier's Lung (BFL) is a rare, nonatopic immunologic response to repeated or intense inhalation of avian (bird) proteins/antigens found in the feathers or droppings of many species of birds, which leads to an immune-mediated inflammatory reaction in the respiratory system. Although this is the most common type of hypersensitivity pneumonitis (HP) reported in adults, it is one of the classifications of a rare subtype of interstitial lung disease that occurs in the pediatric age group of which few case reports are available in the literature. The pathophysiology of HP is complex; numerous organic and inorganic antigens can cause immune dysregulation, leading to an immune-related antigen⁻antibody response (immunoglobulin G-IgG- against the offending antigen). Diagnosing BFL in the pediatric age group is challenging due to the history of exposure usually being missed by health care providers, symptoms and clinical findings in such cases being nonspecific and often misdiagnosed during the acute illness with other common diseases such asthma or acute viral lower respiratory tract infection, and the lack of standardization of criteria for diagnosing such a condition or sensitive radiological or laboratory tests. Treatment, on the other hand, is also controversial. Avoidance of the offending antigen could be the sole or most important part of treatment, particularly in acute mild and moderate cases. Untreated cases can result in irreversible lung fibrosis. In this case report, we highlight how children presenting with an acute viral lower respiratory tract infection can overlap with the acute/subacute phase of HP. Early intervention with pulse steroids markedly improves the patient's clinical course.

Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar.

A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% for Candida albicans versus 69.8% for the other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild-type (non-WT) strains (strains for which MICs were above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) among strains of C. albicans and C. orthopsilosis contained FKS hot spot mutations, including heterozygous mutations in FKS1 For C. tropicalis, the Etest appeared to overestimate strains non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains, respectively, had values above the epidemiological cutoff value. However, no FKS mutations were identified in this species. For all other species, micafungin best reported the echinocandin non-WT strains relative to the FKS genotype, as anidulafungin tended to overestimate non-wild-type strains. Besides C. tropicalis, few strains were classified as non-WT for amphotericin B.

Serum Zinc Level in Asthmatic and Non-Asthmatic School Children.

Asthma is one of the most common chronic disorders among children. Zinc (Zn) is an essential dietary antioxidant and may have a special role in assisting the airways of asthmatic subjects. The primary objective of this study was to measure serum Zn levels among asthmatic school children and to compare this to the serum Zn level in non-asthmatic children. The secondary objective was to investigate the relationship between Zn levels and the degree of asthma control. A cross-sectional study following forty asthmatic children and forty matched non-asthmatic children of both genders was conducted. Weight, height, body mass index (BMI), BMI Z-scores, serum Zn, hemoglobin, total protein, and albumin concentrations were measured in both groups. Serum immunoglobulin E (IgE) levels, the forced expiratory volume in 1 second (FEV1), and dosage of inhaled steroids were measured in asthmatic school children. The results show the mean Zn level among asthmatic children was 12.78 ± 1.8 µmol/L. Hypozincemia was detected in four asthmatic children. Asthma and control groups were matched in age, gender, and BMI Z score (p > 0.05). No significant difference was observed in Zn levels, hemoglobin, albumin, and total protein between both groups (p > 0.05). Among asthmatics, Zn levels were not significantly associated with the degree of asthma control (well controlled, mean Zn = 12.9 ± 1.5, partially controlled, mean Zn = 11.9 ± 1.6, and uncontrolled, mean Zn = 3.62 ± 2.2) (p = 0.053). The Zn level was not correlated with the FEV1 Z score. There was no significant association between Zn level and the dosage of inhaled steroids or IgE concentrations (p > 0.05). The findings show that Zn may not play a major role in the degree of asthma control. Larger studies are needed to confirm these results.

The emergence of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis patients on inhaled antibiotics.

INTRODUCTION: Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is an important and growing issue in the care of patients with cystic fibrosis (CF), and a major cause of morbidity and mortality. OBJECTIVE: The objective of the study was to describe the frequency of MDR-PA recovered from the lower respiratory samples of pediatric and adult CF patients, and its antibiotic resistance pattern to commonly used antimicrobial agents including ß-lactams, aminoglycosides, and fluoroquinolones. MATERIALS AND METHODS: The lower respiratory isolates of P. aeruginosa were obtained from inpatients and outpatients CF clinics from a tertiary care teaching hospital for the period from October 2014 to September 2015. The identification and antimicrobial susceptibility for all the isolates were performed by using the BD Phoenix™ and E-test in compliance with Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: A total of 61 P. aeruginosa samples were isolated from thirty CF patients from twenty families. Twelve sputum samples were positive for MDR-PA (seven nonmucoid and five mucoid isolates) from five CF patients (five families) with moderate-to-very severe lung disease given MDR-PA frequency of 19.7%. The median age of the study group was 20 (range 10-30) years. Three CF patients were on chronic inhaled tobramycin and two on nebulized colistin. The antimicrobial patterns of isolates MDR-PA showed the highest rate of resistance toward each gentamycin, amikacin, and cefepime (100%), followed by 91.7% to ciprofloxacin, 75% to tobramycin, 58.3% to meropenem, and 50% to piperacillin-tazobactam. None of the isolates were resistant to colistin during the study period. CONCLUSION: The study results emphasize that the emergence of a significant problem in the clinical isolates of P. aeruginosa in CF patients that dictate appropriate attention to the antibiotic management after proper surveillance.

Persistence of Candida dubliniensis and lung function in patients with cystic fibrosis.

OBJECTIVES: Candida dubliniensis is an emerging yeast and demonstrated a high adherence property to cystic fibrosis respiratory tract. Therefore, it is important to determine the persistence of C. dubliniensis and to assess the possible relationship to the body mass index (BMI) and forced expiratory volume in 1st second (FEV1). RESULTS: Candida isolates were identified by MALDI-TOF MS to species level from 40/52 (76.9%) cystic fibrosis patients. C. dubliniensis was the most common organism isolated from 50/77 (65%) lower respiratory specimens of 29 patients. Patients with persistent C. dubliniensis isolates have higher mean BMI in comparison to intermittent C. dubliniensis group. However, this difference did not reach statistical significance (P = 0.539). In contrast, patients with persistent C. dubliniensis isolates have significantly lower FEV1% mean in comparison to intermittent C. dubliniensis group particularly at initial two visits (P < 0.05); however, at subsequent visit the difference observed was not statistically significant (P = 0.456). The persistence of C. dubliniensis is more frequent in adults having more advanced disease, co-infections with chronic P. aeruginosa, cystic fibrosis related diabetes, long-term nebulized tobramycin and oral Zithromax therapy than patients with intermittent C. dubliniensis. Patients with persistent C. dubliniensis have lower FEV1 percentage and higher BMI than the intermittent C. dubliniensis.

Serum zinc concentration in cystic fibrosis patients with CFTR I1234V mutation associated with pancreatic sufficiency.

OBJECTIVE: To determine serum zinc (Zn) level among cystic fibrosis (CF) patients with homozygous CFTR I1234V mutation associated with pancreatic sufficiency (PS). METHODS: A cross-sectional study was conducted including both pediatric and adult CF patients. Data on age, weight, height, body mass index (BMI), BMI Z-score, FEV1, and chronic Pseudomonas aeruginosa infection were collected. Serum Zn, albumin, and total proteins were measured and analyzed. RESULTS: Forty-five CF patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred tribe and eight CF patients with other mutations associated with pancreatic insufficiency (PI). Patient's age ranged from 2 to 49 years with a mean age of 15.1 ± 9.1 years and mean plasma Zn of 0.78 ± 0.15 mcg/mL. Seven (13.2%) patients with CFTR I1234V and PS had low Zn levels (<0.6 mcg/mL). Mean age among Zn deficient group was significantly older. The mean FEV1 in the deficient group was found to be insignificant low. Persistent P. aeruginosa colonization was more prevalent in Zn deficient group. BMI Z-scosre of CF patients were positively correlated with Zn levels. Forty-five healthy subjects belonging to the same Arab tribe were selected in order to assess their Zn levels and their mean plasma Zn of 0.84 ± 0.11 mcg/mL (range 0.65-1.1 mcg/mL) with mean age 20.4 ± 10.1 years (range 6-40 years). CONCLUSION: These findings suggest that Zn deficiency can occur in CF patients with PS. The association of Zn levels and the frequency of P. aeruginosa isolated in CF patients need further investigation.

Discrepancy in MALDI-TOF MS identification of uncommon Gram-negative bacteria from lower respiratory secretions in patients with cystic fibrosis.

INTRODUCTION: Early identification of microbial organisms from respiratory secretions of patients with cystic fibrosis (CF) is important to guide therapeutic decisions. The objective was to compare the accuracy of matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) relative to the conventional phenotypic method in identifying common bacterial isolates, including nonfermenting Gram-negative bacteria, in a cohort of patients with CF. METHODS: A total of 123 isolates from 50 patients with CF representing 14 bacterial species from respiratory specimens were identified using MALDI-TOF MS in parallel with conventional phenotypic methods. Discrepancies were confirmed by 16S ribosomal RNA (rRNA) gene sequencing in five Gram-negative isolates. RESULTS: The MALDI-TOF MS managed to identify 122/123 (99.2%) bacterial isolates to the genus level and 118/123 (95.9%) were identified to the species level. The MALDI-TOF MS results were 100% consistent to the species level with conventional phenotypic identification for isolates of Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pyogenes, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and other uncommon organisms such as Chryseobacterium gleum and Enterobacter cloacae. The 5/123 (4.6%) isolates misidentified were all Gram-negative bacteria. The isolation of E. cloacae and Haemophilus paraphrohaemolyticus may extend the potentially pathogenic list of organisms isolated from patients with CF. CONCLUSION: Although the technique provides an early identification and antimicrobial therapy approach in patients with CF, limitation in the diagnosis of uncommon Gram-negative bacteria may exist.

Genetic relatedness and host specificity of Pseudomonas aeruginosa isolates from cystic fibrosis and non-cystic fibrosis patients.

BACKGROUND: Pseudomonas aeruginosa is one of the primary pathogens isolated more frequently in cystic fibrosis (CF) and it exhibits innate resistance to a wide range of antibiotics. PURPOSE: We sought to determine whether the highly prevalent genotypes of P. aeruginosa are specifically linked to CF patients and have any related multidrug antibiotic resistance. Isolates from hospitalized non-CF patients and from environmental sources were also genotypically analyzed. METHODS: Collections of P. aeruginosa from lower respiratory secretions (n=45) were genotyped using pulsed-field gel electrophoresis (PFGE). Phenotypic screening for antibiotic susceptibility was performed for the common antimicrobial agents by E-test and automated Phoenix method. RESULTS: P. aeruginosa isolates from CF (n=32), hospitalized non-CF patients (n=13), and environment sources (n=5) were analyzed. The population structure of P. aeruginosa is highly diverse and population-specific. All PFGE results of P. aeruginosa isolates fall among four major clusters. Cluster 1 contained 16 P. aeruginosa isolates from CF patients and two from environmental sources; cluster 2 contained 11 P. aeruginosa isolates from CF and one each from non-CF and environmental sources; cluster 3 contained 12 P. aeruginosa isolates from hospitalized non-CF patients and two P. aeruginosa isolates from one CF patient and one environmental source; and cluster 4 consisted of three isolates from CF patients and one from the environment. The majority of multidrug-resistant P. aeruginosa isolates were in clusters 3 and 4. P. aeruginosa isolates from CF patients were resistant to ciprofloxacin (34.4%) followed by resistance to amikacin and gentamicin (each 28%), whereas the majority of isolates from non-CF patients were resistant to meropenem (69%) and were grouped in cluster 3. CONCLUSION: PFGE of P. aeruginosa isolates from CF patients shows a high degree of similarity, suggesting specific adaptation of these clones to CF-affected lungs. The hospitalized non-CF cluster has a different clonal origin, indicating specific clustering in a specific location, suggesting hospital-acquired P. aeruginosa infections.

Uncommon opportunistic yeast bloodstream infections from Qatar.

Eleven uncommon yeast species that are associated with high mortality rates irrespective of antifungal therapy were isolated from 17/187 (201 episodes) pediatric and elderly patients with fungemia from Qatar. The samples were taken over a 6-year period (January 2004-December 2010). Isolated species included Kluyveromyces marxianus, Lodderomyces elongisporus, Lindnera fabianii, Candida dubliniensis, Meyerozyma guilliermondii, Candida intermedia, Pichia kudriavzevii, Yarrowia lipolytica, Clavispora lusitaniae, Candida pararugosa, and Wickerhamomyces anomalus. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry provided correct identifications compared with molecular analysis testing of the same isolates. Low minimal inhibitory concentrations were found when isavuconazole and voriconazole were used for all uncommon yeast species evaluated in this study. Resistance to antifungal drugs was low and remained restricted to a few species.