Chronic respiratory disorders due to aberrant innominate artery: a case series and critical review of the literature.

BACKGROUND: Tracheal compression (TC) due to vascular anomalies is an uncommon, but potentially serious cause of chronic respiratory disease in childhood. Vascular slings are congenital malformations resulting from abnormal development of the great vessels; in this group of disorders the most prevalent entity is the aberrant innominate artery (AIA). Here we provide a report on diagnosis and treatment of AIA in nine children with unexplained chronic respiratory symptoms. We describe the cases, perform a literature review, and provide a discussion on the diagnostic workup and treatment that can help manage AIA. METHODS: Clinical history, diagnostic procedures and treatment before and after the AIA diagnosis were retrospectively reviewed in nine children (5 boys and 4 girls), who were referred for recurrent-to-chronic respiratory manifestations over 10 years (2012-2022). We performed a comprehensive report on the ongoing clinical course and treatment as well as an electronic literature search on the topic. RESULTS: Diagnoses at referral, before AIA was identified, were chronic dry barking cough associated with recurrent pneumonia (n = 8, 89%), lobar/segmental atelectasis (n = 3, 33%), atopic/non atopic asthma (n = 3, 33%); pneumomediastinum with subcutaneous emphysema complicated the clinical course in one case. When referred to our Unit, all patients had been previously treated with repeated antibiotic courses (n = 9, 100%), alone (n = 6, 67%) or combined with prolonged antiasthma medications (n = 3, 33%) and/or daily chest physiotherapy (n = 2, 22%), but reported only partial clinical benefit. Median ages at symptom onset and at AIA diagnosis were 1.5 [0.08-13] and 6 [4-14] years, respectively, with a relevant delay in the definitive diagnosis (4.5 years). Tracheal stenosis at computed tomography (CT) was ≥ 51% in 4/9 cases and ≤ 50% in the remaining 5 subjects. Airway endoscopy was performed in 4 cases with CT evidence of tracheal stenosis ≥ 51% and confirmed CT findings. In these 4 cases, the decision of surgery was made based on endoscopy and CT findings combined with persistence of clinical symptoms despite medical treatment. The remaining 5 children were managed conservatively. CONCLUSIONS: TC caused by AIA may be responsible for unexplained chronic respiratory disease in childhood. Early diagnosis of AIA can decrease the use of expensive investigations or unsuccessful treatments, reduce disease morbidity, and accelerate the path toward a proper treatment.

Posterior Tracheopexy for Tracheomalacia: A Study of Clinical and Radiological Consequences on Esophagus.

INTRODUCTION: Posterior tracheopexy (PT) directly addresses the posterior trachealis membrane intrusion in severe tracheomalacia. During PT, the esophagus is mobilized and membranous trachea is sutured to the prevertebral fascia. Although dysphagia has been reported as a possible complication of PT, in the literature there are no data investigating postoperative esophageal anatomy and digestive symptoms. Our aim was to study clinical and radiological consequences of PT on esophagus. METHODS: Patients with symptomatic tracheobronchomalacia scheduled for PT between May 2019 and November 2022 underwent pre- and postoperative esophagogram. For each patient, we analyzed radiological images and measured esophageal deviation providing new radiological parameters. RESULTS: All 12 patients underwent thoracoscopic PT (n = 3) or robot-assisted thoracoscopic PT (n = 9). For all patients, the postoperative esophagogram showed a right dislocation of the thoracic esophagus (median postoperative deviation = 27.5 mm). We report an esophageal perforation at postoperative day 7 in a patient affected by esophageal atresia, who underwent several surgical procedures before. A stent was placed and esophagus healed. Another patient with severe right dislocation referred transient dysphagia to solids, which resolved gradually in the first postoperative year. All the other patients did not present any esophageal symptoms. CONCLUSION: For the first time, we demonstrate the right dislocation of the esophagus after PT and we propose an objective method to measure it. In most patients, PT is a procedure not affecting esophageal function, but dysphagia can occur if dislocation is important. Esophagus mobilization during PT should be cautious, especially in patients who underwent previous thoracic procedures.

[Recent updates on the antibacterial clofoctol.] / Recenti aggiornamenti sull'antibatterico clofoctolo.

Due to the worry growing increase in bacterial antibiotic resistance and the scanty availability of new antibiotics, it is highly recommended to use not recently synthesized, but still active molecules. Clofoctol is a synthetic chemotherapeutic agent with a different mechanism of action, as compared with the other antibacterial molecules currently available. By reducing intracellular ATP, clofoctol inhibits the synthesis of bacterial cytoplasmic membrane peptidoglycans, inducing the arrest of cell wall synthesis, thus characterizing the molecule as a "membrane-acting agent". More recently, however, it has been shown that clofoctol is also able to induce apoptosis by inhibiting the translation of intracellular proteins. An important property of clofoctol is the rapidity of the antimicrobial effect, which allows the complete eradication of the pathogen and makes the development of resistance unlikely. Administered rectally, the drug rapidly accumulates in the tissues. Most of the clinical studies conducted on clofoctol concern the treatment of respiratory diseases in children. The drug appears to be more active in upper rather than in lower respiratory tract infections. Tolerability was reported to be good, with a low incidence of side effects.

Primary ciliary dyskinesia: A multicenter survey on clinical practice and patient management in Italy.

INTRODUCTION: There are no recent data on primary ciliary dyskinesia (PCD) distribution, diagnosis and treatment in Italy. METHODS: A descriptive study based on a survey questionnaire. It consisted of three sections (patients, diagnosis, and treatment), and sent to all the Italian PCD Centers. RESULTS: Questionnaires obtained from 20/22 centers in 12/20 regions showed that the total number of PCD patients treated at the participating centers was of 416. Out of all centers, 55% follow <20 patients, two centers have >40 patients, and 75% follow both pediatric and adults. Age at diagnosis was between 4 and 8 years in 45% of the centers, <3 years in three centers. Nasal nitric oxide, transmission electron microscopy and ciliary high-speed video microscopy are performed in 75%, 90%, and 40% of centers, respectively. Immunofluorescence is available in five centers. Genetic analysis is offered in 55% of the centers, and in seven centers >50% of the patients have a known genetic profile. Patients treated at all centers receive inhaled saline solutions, corticosteroids and chest physiotherapy. Prophylactic antibiotics and mucolytics are prescribed in 95% and 50% of the centers, respectively. Pseudomonas infection is treated with oral or inhaled antibiotics. CONCLUSIONS: Many Italian centers care for a small number of pediatric and adult patients, and diagnosis is often delayed. We found a great variability in the available diagnostic procedures, as well in the prescribed therapies. Our study will help to uniform diagnostic algorithm and share treatments protocols for PCD in Italy and allowed to set specific national goals.

How has the SARS-CoV-2 pandemic changed the epidemiology and management of acute bronchiolitis?

OBJECTIVE: SARS-COV-2 pandemic profoundly impacted acute bronchiolitis epidemiology worldwide, especially respiratory syncytial virus (RSV) diffusion and the burden of disease, with remarkable implications on the management of health resources. We aimed to study the epidemiology and clinical course of bronchiolitis in the past 5 years in our region and to assess the trends that occurred during and after the SARS-COV-2 pandemic. METHODS: We conducted an observational study including all children aged 0-2 years with bronchiolitis admitted to a tertiary children's hospital during the last 5 years. Demographic, clinical, and microbiological data were collected. Comparisons between patient subgroups were carried out. RESULTS: A total of 647 patients admitted for bronchiolitis were included (median age 78 days). Molecular diagnostic tests were performed in 617 patients (95.4%) with RSV detected in 51.5% of patients in prepandemic years and 74.5% in pandemic years. Through the study period, we observed a progressive increase in the number of children requiring respiratory support, RSV infections, and children with a history of prematurity. Conversely, this was not true for mechanical ventilation, duration of respiratory support, intensive care unit admission, and length of stay. CONCLUSIONS: Clinical course and epidemiology of bronchiolitis showed a significant change through the study years with a heavy impact during the 2021-2022 season. The increase in the number of patients requiring respiratory support, although not associated with an increase in mechanical ventilation, may be explained by the higher prevalence of RSV. The change in epidemiology highlights the importance of surveillance systems to monitor RSV circulation, to plan prophylactic strategies, and prepare healthcare systems.

Lateral Thoracic Expansion for Jeune's Syndrome, Surgical Approach, and Technical Details.

INTRODUCTION: Jeune's syndrome, or asphyxiating thoracic dystrophy (ATD), is a rare autosomal recessive disorder characterized by skeletal dysplasia. Ribs are typically short and horizontal resulting-in lethal variant-in severe lung hypoplasia, progressive respiratory failure, and death. Lateral thoracic expansion (LTE) consists in staggered bilateral ribs osteotomy leading to chest expansion and lung development. Studies on LTE in ATD patients report encouraging data, but the rarity of ATD implies the lack of a standardized surgical path. The aim of this report is to present our experience with LTE, the technical modification we adopted, and patients' clinical outcome. MATERIALS AND METHODS: We retrospectively reviewed data of 11 LTE performed in 7 ATD patients with lethal variant. Information regarding pre- and postoperative clinical conditions and surgical details was collected. We adopted a single-stage or a two-stage approach based on patient clinical condition. Computed tomography (CT) scan was performed before and after surgery and lung volume was calculated. RESULTS: Five patients are alive, while two died in intensive care unit for other than respiratory cause (sepsis). Most patients experienced clinical improvement in terms of decreased respiratory infections rate, need for ventilation, and improved exercise tolerance. Postoperative CT scan demonstrated a median lung volume increase of 88%. CONCLUSION: Mortality in ADT patients is high. However, LTE is a feasible and safe surgical approach, which could improve clinical conditions and survival rate. Survived patients showed postoperatively less oxygen requirement and improved clinical conditions.

Can bacterial lysates be useful in prevention of viral respiratory infections in childhood? The results of experimental OM-85 studies.

Respiratory tract infections (RTI) are mainly viral in origin and among the leading cause of childhood morbidity globally. Associated wheezing illness and asthma are still a clear unmet medical need. Despite the continuous progress in understanding the processes involved in their pathogenesis, preventive measures and treatments failed to demonstrate any significant disease-modifying effect. However, in the last decades it was understood that early-life exposure to microbes, may reduce the risk of infectious and allergic disorders, increasing the immune response efficacy. These results suggested that treatment with bacterial lysates (BLs) acting on gut microbiota, could promote a heterologous immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. This hypothesis has been supported by clinical and experimental studies showing the reduction of RTI frequency and severity in childhood after oral BL prophylaxis and elucidating the involved mechanisms. OM-85 is the product whose anti-viral effects have been most extensively studied in vitro, animal, and human cell studies and in translational animal infection/disease models. The results of the latter studies, describing the potential immune training-based activities of such BL, leading to the protection against respiratory viruses, will be reported. In response to human rhinovirus, influenza virus, respiratory syncytial virus and severe acute respiratory coronavirus-2, OM-85 was effective in modulating the structure and the functions of a large numbers of airways epithelial and immune cells, when administered both orally and intranasally.

Alarmins and innate lymphoid cells 2 activation: A common pathogenetic link connecting respiratory syncytial virus bronchiolitis and later wheezing/asthma?

Severe respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of recurrent wheezing in childhood. Both acute and long-term alterations in airway functions are thought to be related to inefficient antiviral immune response. The airway epithelium, the first target of RSV, normally acts as an immunological barrier able to elicit an effective immune reaction but may also be programmed to directly promote a Th2 response, independently from Th2 lymphocyte involvement. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells brings about release of TSLP, IL-33, HMGB1, and IL-25, dubbed "alarmins." These epithelial cell-derived proteins are particularly effective in stimulating innate lymphoid cells 2 (ILC2) to release IL-4, IL-5, and IL-13. ILC2, reflect the innate counterparts of Th2 cells and, when activate, are potent promoters of airway inflammation and hyperresponsiveness in RSV bronchiolitis and childhood wheezing/asthma. Long-term epithelial progenitors or persistent epigenetic modifications of the airway epithelium following RSV infection may play a pathogenetic role in the short- and long-term increased susceptibility to obstructive lung diseases in response to RSV in the young. Additionally, ILC2 function may be further regulated by RSV-induced changes in gut microbiota community composition that can be associated with disease severity in infants. A better understanding of the alarmin-ILC interactions in childhood might provide insights into the mechanisms characterizing these immune-mediated diseases and indicate new targets for prevention and therapeutic interventions.

Is secondary tracheomalacia associated with airway inflammation and infection?

BACKGROUND: Recurrent lower respiratory tract infections are among the most prevalent symptoms in secondary tracheomalacia due to mediastinal vascular anomalies (MVAs). It is not known whether this condition could result in persistent lower respiratory tract inflammation and subclinical infection. METHODS: A retrospective study was performed on records of children with tracheomalacia due to MVAs and recurrent respiratory infections who underwent computed tomography scan, bronchoscopy, and bronchoalveolar lavage (BAL) as part of their clinical evaluation. RESULTS: Thirty-one children were included in the study: 21 with aberrant innominate artery, four with right aortic arch, one with double aortic arch, and five with aberrant innominate artery associated with right aortic arch. Cytological evaluation of bronchoalveolar lavage fluid showed increased neutrophil percentages and normal lymphocyte and eosinophil proportions. Microorganism growth was detected in 13 BAL samples, with a bacterial load ≥104 colony-forming units/mL in eight (25.8%) of them. Most isolates were positive for Haemophilus influenzae. Bronchiectasis was detected in four children, all with BAL culture positive for H. influenzae. Four patients underwent MVA surgical correction and 27 conservative management, i.e., respiratory physiotherapy in all and high-dose amoxicillin/clavulanic acid (40 mg/kg/day) for 2-4 weeks in those with significant bacterial growth. There was an excellent outcome in most of them. CONCLUSIONS: Neutrophilic alveolitis is detectable in secondary tracheomalacia but is associated with a clinically significant bacterial load only in a quarter of the patients. Caution should be used regarding inappropriate antibiotic prescriptions to avoid the emergence of resistance, whilst airway clearance maneuvers and infection preventive measures should be promoted.

Tracheobronchography for pediatric airway disease is still a valuable technique?

BACKGROUND: Congenital and acquired airway anomalies represent a relatively common albeit diagnostic and therapeutic challenge. Obtaining maximum definition of the abnormality is imperative prior to attempting surgical procedure because some tracheal lesions have a significant risk of mortality. Are Tracheobronchography (TBG) and Tracheobronchofluoroscopy (TBF) valuable or obsolete tecniques? METHODS: We retrospectively reviewed all the diagnostic and interventional TBG-TBF requested by the multidisciplinary conference, during the last 10 years in a tertiary care hospital exclusively dedicated to pediatric patients. RESULTS: A total of 268 procedures performed in 60 pediatric patients (68% male, mean age 4,8 years), were reviewed. 41 diagnostic TBG-TBF were performed in a group of 34 patients with excellent result, without complications. A total of 175 procedures of tracheobronchoplasty guided by TBG-TBF were completed in a group of 25 patients. Seven bioabsorbable self-expanding stents were placed in the airway of 6 children. CONCLUSIONS: Diagnostic TBG and TBF are still irreplaceable tools to evaluate pediatric airway disease, with many advantages over the newest imaging techniques. Interventional procedures of pediatric airways under the guide of TBGTBF represent safe and effective treatment options in selected patients, with positive clinical impact.

Steroid-sparing effect of mepolizumab in children with severe eosinophilic nonallergic asthma.

BACKGROUND: Asthma is characterized by a chronic airway inflammation, usually sustained by type 2 immunity. Bronchial and peripheral eosinophilia are biomarkers for type 2 asthma. Biologicals are the most effective treatment for severe asthma at present. Mepolizumab is an antagonist of interleukin-5 (IL-5), the most relevant cytokine involved in eosinophilia. OBJECTIVE: This case report evaluated the effectiveness of mepolizumab in two girls with severe eosinophilic non-allergic asthma. MATERIALS AND METHODS: Two female children with severe eosinophilic nonallergic asthma were treated with mepolizumab for two years. Clinical findings, lung function, peripheral eosinophils, asthma control, and bronchial endoscopy were performed. RESULTS: Biologicals reduced the eosinophilia, asthma exacerbations, and improved lung function in both patients. The treatment was also safe and well-tolerated. CONCLUSION: Mepolizumab represents an effective therapeutic option in the management of severe pediatric asthma.

ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype-phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.

Can Resveratrol-Inhaled Formulations Be Considered Potential Adjunct Treatments for COVID-19?

The pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has led to an extraordinary threat to the global healthcare system. This infection disease, named COVID-19, is characterized by a wide clinical spectrum, ranging from asymptomatic or mild upper respiratory tract illness to severe viral pneumonia with fulminant cytokine storm, which leads to respiratory failure. To improve patient outcomes, both the inhibition of viral replication and of the unwarranted excessive inflammatory response are crucial. Since no specific antiviral drug has been proven effective for the treatment of patients and the only upcoming promising agents are monoclonal antibodies, inexpensive, safe, and widely available treatments are urgently needed. A potential anti-inflammatory molecule to be evaluated, which possesses antiviral activities in several experimental models, is the polyphenol resveratrol. This compound has been shown to inhibit SARS-CoV-2 replication in human primary bronchial epithelial cell cultures and to downregulate several pathogenetic mechanisms involved in COVID-19 severity. The use of resveratrol in clinical practice is limited by the low bioavailability following oral administration, due to the pharmacokinetic and metabolic characteristics of the molecule. Therefore, topical administration through inhaled formulations could allow us to achieve sufficiently high concentrations of the compound in the airways, the entry route of SARS-CoV-2.

Working as a team in airway surgery: History, present and perspectives.

Teamwork is one of the most important trend in modern medicine. Airway team were created in many places to respond in a multidisciplinary and coordinated way to challenging clinical problems which were beyond the possibility of an individual management. In this chapter, we illustrate the historical steps leading to the development of an airway team in a pediatric referral hospital, describe the present teamwork activity defining the key points for the creation of a team and discussing different organization models; finally we delineate possible future directions for the airway teams in the globalized world.

Respiratory syncytial virus and airway microbiota - A complex interplay and its reflection on morbidity.

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease-induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder.

Description of a novel chest wall anomaly: The postprematurity thoracic dysplasia.

BACKGROUND/PURPOSE: Many studies on ex-preterm babies were conducted to evaluate their respiratory sequelae, but, to our knowledge, the condition described in this paper was never reported before and is not included in the classifications of thoracic anomalies proposed so far. METHODS: Clinical data and images of a novel thoracic deformity observed in the last 10 years are shown. This anomaly is characterized by an indentation of the ribs on both (less frequently one) anterolateral parts of the chest wall. All our patients with this condition were ex-preterm babies. We named this novel thoracic anomaly as "postprematurity thoracic dysplasia" (PPTD). Possible etiopathogenetic mechanisms and treatment options are discussed. RESULTS: We observed 8 patients with variable range of respiratory symptoms. In 2 cases the malformation caused a severe functional restriction of lung volumes and surgery was performed to improve respiratory symptoms; in other cases the symptoms were mild or absent and the malformation was a matter of concern only for cosmesis. CONCLUSIONS: PPTD is a novel thoracic anomaly typical of ex-preterms. Clinical relevance is variable. In severe cases surgery can be considered. LEVEL OF EVIDENCE: IV.

Differences and similarities between SARS-CoV and SARS-CoV-2: spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases.

Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) became pandemic by the end of March 2020. In contrast to the 2002-2003 SARS-CoV outbreak, which had a higher pathogenicity and lead to higher mortality rates, SARSCoV-2 infection appears to be much more contagious. Moreover, many SARS-CoV-2 infected patients are reported to develop low-titer neutralizing antibody and usually suffer prolonged illness, suggesting a more effective SARS-CoV-2 immune surveillance evasion than SARS-CoV. This paper summarizes the current state of art about the differences and similarities between the pathogenesis of the two coronaviruses, focusing on receptor binding domain, host cell entry and protease activation. Such differences may provide insight into possible intervention strategies to fight the pandemic.

Ectopic Thymus: An Unusual Case of Subglottic Mass.

OBJECTIVES: The aim of our study is to report a case of a child with subglottic thymus that was suspected during diagnostic work-up for severe airway obstruction, excised surgically and confirmed with final histopathological examination. Moreover, we performed a narrative literature review to outline clinical and diagnostic features of this rare condition and to report suggestions for the management of subglottic masses. METHODS: We report the case of a 7-month-old boy who was admitted to our Pediatric Airway Team Unit due to a history of worsening biphasic stridor and recurrent episodes of upper airway obstruction. The successful diagnostic work-up and a narrative literature of analogous cases of subglottic thymus were reported. RESULTS: Ectopic thymus is a very rare condition in which thymic tissue is found outside the normal pathway of its embryonic migration. It usually presents as a cystic or, more rarely, solid mass, showing an indolent course toward spontaneous involution. In some cases, however, it becomes symptomatic exerting compression on surrounding vital structures. Due to its rarity, the initial diagnosis is normally mistaken with inflammatory diseases or malignancies and the definitive diagnosis is only achieved after histological examination of the excised specimen. To our knowledge, only four other cases of subglottic ectopic thymic tissue have been reported in the English literature so far and the diagnosis has never been suspected preoperatively. CONCLUSION: It is mandatory to consider ectopic thymic tissue in the differential diagnosis in children presenting with airways obstruction in order to prevent unnecessary, extensive, and exploratory surgery.

Epileptic Encephalopathy, Myoclonus-Dystonia, and Premature Pubarche in Siblings with a Novel C-Terminal Truncating Mutation in ATRX Gene.

The X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus-dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.