Nagehan Emiralioglu

Crucial role of posttranslational modifications of integrin α3 in interstitial lung disease and nephrotic syndrome

Interstitial lung disease, nephrotic syndrome and junctional epidermolysis bullosa is an autosomal recessive multiorgan disorder caused by mutations in the gene for the integrin α3 subunit (ITGA3). The full spectrum of manifestations and genotype-phenotype correlations is still poorly characterized. Here, we uncovered the disease-causing role and the molecular mechanisms underlying a homozygous ITGA3 mutation leading to the single amino acid substitution, p.R463W. The patient suffered from respiratory distress and episodes of cyanosis with onset in the first week of life and had a nephrotic syndrome. Although there was no clinical evidence for cutaneous fragility, the analysis of a skin sample and of skin epithelial cells enabled the direct assessment of the authentic mutant protein. We show that the mutation altered the conformation of the extracellular β-propeller domain of the integrin α3 subunit preventing correct processing of N-linked oligosaccharides, heterodimerization with β1 integrin and maturation through cleavage into heavy and light chains in the Golgi. Confocal microscopy demonstrated that the mutant protein accumulated intracellularly, but it was not present in focal adhesions or on the cell membrane as shown by flow cytometry. These findings highlight that single amino acid changes in the integrin α3 subunit may crucially alter the structure and complex processing of this integrin, completely preventing its functionality. The present report also underscores that ITGA3 mutations may account for atypical cases solely with early onset respiratory and renal involvement.

Use of serial rigid bronchoscopy in the treatment of plastic bronchitis in children

AIM Plastic bronchitis (PB) is a rare disorder characterized by formation of bronchial casts (BC) in the tracheobronchial tree with partial or complete airway obstruction. Although lysis of casts with several fibrinolytic agents has been reported, removal of BC with bronchoscope provides better clearance of airways. A retrospective study was performed to evaluate the use of serial rigid bronchoscopy (RB) in the treatment of PB in children. PATIENTS AND METHODS Between 2011 and 2015, children with partial or complete airway obstruction with PB were evaluated for age, gender, underlying disease, clinical findings, results of bronchoscopic interventions and histopathologic findings. RESULTS Five patients with 14 RB interventions were evaluated. The mean age of the patients was 7.8years (min: 3years - max: 14years) and male-female ratio was 4:1. All of the patients were diagnosed as asthma and none of them had underlying cardiac disease. Suction of mucus plaques and bronchoalveolar lavage were performed in all patients with flexible bronchoscopy. Also, aerosolized tissue plasminogen activator was used in two patients. During follow-up serial RB was indicated in patients with persistent atelectasis and severe airway obstruction. The most common localization of BC was left main stem bronchus and bilateral cast formation was detected in 7 interventions. Although, removal of BC was challenging in two patients because of cast friability and fragmentation, most of the plugs were successfully removed with optical forceps and rigid suctioning. Two patients underwent repeated RB (min: 3 - max: 8) for recurrent symptoms. Histopathologic evaluation of BC revealed Charcot-Leyden crystals with inflammatory cells in all patients. The time interval between RB interventions was one to five months. CONCLUSION BC are tenacious mucus plugs which are firmly wedged to the tracheobronchial tree. The use of optical forceps with rigid suction provides adequate removal of BC during RB. Because of underlying disease, it is difficult to cure cast formation. Therefore, most of the patients require serial RB when they become unresponsive to standard therapy or develop partial or complete airway obstruction.

International management platform for children’s interstitial lung disease (chILD-EU)

Background Children’s interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register. Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. Methods A web-based chILD management platform with a registry and biobank was successfully designed and implemented. Results Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%). The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the ‘wrong’ answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. Conclusions We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. Trial registration number Results, NCT02852928.

Omalizumab Treatment for Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis

Background: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) is characterized by destructive changes in the airways. Long-term treatment with oral corticosteroids is often required for repeated exacerbations. Because elevated total IgE is a cardinal abnormality of ABPA, omalizumab has been used sporadically to decrease corticosteroid dose or totally replace corticosteroids. Objective: The aim of this report is to describe our experience with omalizumab treatment in patients with CF and ABPA. Methods: We conducted a review of 6 CF patients with ABPA receiving omalizumab. All patients were treated with oral prednisolone and itraconazole. Omalizumab was started if the patient was not responding to steroid treatment, which was determined according to serum IgE levels and/or clinical findings or depending on if there were side effects caused by steroid treatment. Results: The mean age of patients at the beginning of omalizumab treatment was 16.1 years. One patient had a new diagnosis of ABPA; however, the others had the first to third exacerbation when treated with omalizumab. The mean duration of ABPA by the time that treatment with omalizumab started was 13 ± 12.4 months (range = 2-29 months). With omalizumab treatment, IgE levels were decreased in all patients, and Aspergillus-specific IgE levels were decreased in 4 patients; however, FEV1(% predicted) improved only in 2 patients who had mild disease. Corticosteroids were reduced in the first, second, and third months of omalizumab treatment in 2, 1, and 3 patients, respectively. In 2 patients, steroid treatment was stopped. None of the patients suffered from side effects of omalizumab. The mean duration of omalizumab treatment was 12.5 months (range = 6-18 months). Conclusions: This study showed steroid-sparing effect, decreasing IgE levels, and improvement in respiratory symptoms in 6 CF patients with omalizumab treatment. Although this is a small sample of the population, omalizumab may be an alternative therapy for ABPA in CF patients who fail to respond to systemic corticosteroids or have serious adverse effects.

Diagnosis and treatment of pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare genetic disease caused by mutations in sodium–phosphate co‐transporter (SLC34A2), which encodes a type 2b sodium phosphate co‐transporter. Disease is characterized by intra‐alveolar microlith formation of phosphate. Turkey has a high prevalence of PAM. Herein, we report the clinical and radiological findings of three patients diagnosed with PAM and treated with disodium etidronate.

Successful treatment of pulmonary hemangioma with propranolol

Pulmonary hemangioma is a rare benign tumor of the lungs. Airway hemangiomas in particular may lead to feeding difficulties, barking cough, stridor, respiratory distress, and even acute airway obstruction. Hence, such hemangiomas usually require early and aggressive treatment; however, the treatment modalities employed so far have been associated with their own co‐morbidities and potential long‐term adverse effects for the developing child. Here, we report a case of 9‐month‐old girl who presented with dyspnea and diagnosed pulmonary hemangioma in the lower lobe of left lung. Propranolol is now used as a first line treatment for infantile hemangiomas by many practitioners so we experienced propranolol treatment. This case report argues the first case of pulmonary hemangioma treated with propranolol successfully. Pediatr Pulmonol. 2014; 49:829–833.

Diagnosis of Interstitial Lung Disease Caused by Possible Hypersensitivity Pneumonitis in a Child: Think CGD

Interstitial lung disease (ILD) is a rare and heterogeneous group of disorder affecting the lung parenchyma and has a detrimental effect on gas exchange. Chronic granulomatous disease (CGD), when it affects primarily lungs, may cause ILD. We report a 16-year-old patient with CGD caused by homozygous deletion of NCF1 who atypically presented with ILD. The patient had many pigeons and was a pigeon breeder. Exacerbated clinical symptoms were linked to hypersensitivity pneumonitis (HP), and the patient was suggested to keep away from pigeons. In addition to allergen avoidance and prophylactic antibacterial therapy, treatment with corticosteroids and hydroxychloroquine was started for mainly obstructive and persistant symptoms of ILD. CGD is known to cause a hyperinflammatory state and the patients present with excessive granuloma formation and HP. Control of inflammation either by avoidance of allergen exposure and by anti-inflammatory drugs is necessary for the relief of symptoms.

Congenital Tuberculosis after in-vitro Fertilization in a Woman Previously Undiagnosed with Tuberculosis Salpingitis

Congenital tuberculosis (TB) is rarely seen with only several hundred cases reported in the literature. Because genitourinary TB causes infertility, rates of congenital TB have been low. However, the increased availability of assisted reproductive technology allows emergence of congenital TB if mothers are not properly evaluated and treated before implantation of the embryos. Diagnosis of congenital TB is difficult due to nonspecific symptoms, and a high index of suspicion is required for early diagnosis in infants. Here we present a 3-month-old infant with congenital tuberculosis after in vitro fertilization (IVF).

The success of the different eradication therapy regimens for Pseudomonas aeruginosa in cystic fibrosis

Antibiotic therapy aimed at eradicating Pseudomonas aeruginosa (Pa), and improved regimens to treat chronic Pa infection have played a major role in increasing the median survival of patients with cystic fibrosis (CF). However, different clinical centres use varying eradication regimens. The aim of this study was to evaluate the efficacy of multiple eradication treatments against initial Pa infection and to determine the factors affecting the treatment success.

Pneumomediastinum, pneumorrhachis and subcutaneous emphysema associated with viral infections: Report of three cases

Spontaneous pneumomediastinum is usually secondary to alveolar rupture in the pulmonary interstitium, associated with subcutaneous emphysema and occasionally with pneumothorax, but is rarely associated with pneumorrhachis. The leaked air into the pulmonary perivascular interstitium follows the path of least resistance from the mediastinum to the fascial planes of the neck. Air freely communicates via the neural foramina and collects in the epidural space. Pneumorrhachis is defined as the presence of air in the spinal canal, either in the intradural and/or extradural spaces. It is a very rare clinical entity and mostly asymptomatic, hence most probably underdiagnosed. Many pathological and physiological events can lead to alveolar rupture, and these clinical findings can be related to various, mainly traumatic and iatrogenic etiologies. Herein we report three cases of pneumomediastinum, subcutaneous emphysema, interstitial emphysema and pneumorrhachis in two cases, which were related to rhinovirus, human bocavirus and respiratory syncytial virus infection.