Current Respiratory Medicine Reviews - Volume 15, Issue 3, 2019

In the last decade, extensive research has provided consistent advances in molecular biology and “omics” science (genomics, metabolomics, proteomics, and transcriptomics), which have led to the detailed characterization of the etiology, pathophysiological mechanisms, and subtypes of many diseases. Based on these developments, the concept of precision medicine was established. About a quarter of medical consultations related to primary care in children involves respiratory problems. About 10% of the cases are asthma, while the other most important respiratory diseases includes bronchiolitis, acute bronchitis and respiratory infections. Today, beyond the most common respiratory pathology, it is appropriate to discuss what are the novelties in the management of more complex, frequent and infrequent, pathologies because they are those in which it is possible to implement the concept of precision medicine.

In recent decades, scientific studies of chemical processes involving metabolites have been steadily increasing, indicating that we are well into the metabolomics era. This has resulted in numerous studies that explore the field of biomarkers. One of the medical areas most concerned with these innovations is certainly that of childhood respiratory disorders, including asthma and cystic fibrosis. This current study is a review of the literature about biomarkers used or studied in the field of pediatric pulmonology, including asthma and cystic fibrosis.

Since the identification of Cystic Fibrosis (CF) as a disease in 1938 until 2012, only therapies to treat symptoms rather than etiological therapies have been used to treat the disease. Over the last few years, new technologies have been developed, and gene editing strategies are now moving toward a one-time cure. This review will summarize recent advances in etiological therapies that target the basic defect in the CF Transmembrane Receptor (CFTR), the protein that is mutated in CF. We will discuss how newly identified compounds can directly target mutated CFTR to improve its function. Moreover, we will discuss how proteostasis regulators can modify the environment in which the mutant CFTR protein is synthesized and decayed, thus restoring CFTR function. The future of CF therapies lies in combinatory therapies that may be personalized for each CF patient.

Pediatric severe asthma is actually considered a rare disease with a heterogeneous nature. Recent cohort studies focusing on children with severe asthma identified different clinical presentations (phenotypes) and underlying pathophysiological mechanisms (endotypes). Phenotyping and endotyping asthma represent the current approach to patients with severe asthma and consist in characterizing objectively measurable and non-invasive indicators (biomarkers) capable of orienting diagnosis, management and personalized treatment, as advocated by the Precision Medicine approach. The aim of this review is to provide a practical overview of current and emerging biomarkers in pediatric severe asthma.

Estimated to represent less than 5% of all asthmatic patients, children with severe asthma experience troublesome persistent symptoms, life-threatening attacks and side effects by oral corticosteroid treatment, that significantly impact on the quality of life and on economic costs. An accurate understanding of the mechanisms of the disease has been crucial for the discovery and development of biological therapies, for which children with severe asthma are candidates. The aim of this review is to discuss the use of approved biologics for severe asthma, providing updated evidence of novel targeted therapies in the pediatric age range.

Respiratory Syncytial Virus (RSV), an enveloped, non-segmented, negative-sense RNA virus of the Paramyxoviridae family, is the most common respiratory pathogen in infants and young children worldwide, also leading to lower respiratory tract infections during infancy and subsequent development of recurrent wheezing and asthma in childhood. Despite many years of research, we still lack reliable biomarkers of the disease activity as well as effective vaccines and therapeutic strategies. Recent studies have directed attention toward High Mobility Group Box-1 (HMGB1), a 30 kDa nuclear and cytosolic ubiquitous protein, belonging to the alarmins family and promoting an immediate activation of the innate immune response, as a biomarker potentially able to elucidate the link between the RSV and chronic airway dysfunction. Herein, we aimed to summarize what is known on RSV-HMGB1 link, also describing recent findings coming from our experimental studies.

Pulmonary surfactant is a heterogeneous combination of lipids and proteins, which prevents alveolar collapse at the end of expiration cycle by decreasing the alveolar surface tension at the air-liquid interface. At birth, the expression of surfactant is very important for normal lung function and it is strictly correlated to gestational age. The best known genetic mutations associated with the onset of respiratory distress in preterm and full-term newborns and with interstitial lung disease later in childhood are those involving the phospholipid transporter (ABCA3) or surfactant proteins C and B (SP-C and SP-B) genes. In particular, mutations in the SP-B gene induce respiratory distress in neonatal period, while alterations on gene encoding for SP-C are commonly associated with diffuse lung disease in children or in adults. Both clinical phenotypes are present, if genetic mutations interest even the phospholipid transporter ABCA3 ambiguity in the sentence. Interstitial lung disease in children (chILD) is defined as a mixed category of mainly chronic and rare respiratory disorders with increased mortality and morbidity. Although genetic alterations are mainly responsible for the onset of these diseases, however, there are also other pathogenic factors that contribute to increase the severity of clinical presentation. In this review, we analyze all clinical features of these rare pulmonary diseases in neonatal and in pediatric age.

Hereditary lung diseases can affect the airways, parenchyma and vasculature of the lung. Such diseases comprehend simple monogenic disorders such as Kartagener syndrome and α1-antitrypsin deficiency, in which mutations of critical genes are sufficient to induce well128;defined disease phenotypes. A major comprehension of the genetic basis of pulmonary diseases has produced new investigations into their underlying pathophysiology and contributed sometimes to clarify on more frequent sporadic forms. The presence of these structural abnormalities of the respiratory tract can be fatal, so that the identification of causative genes has allowed prenatal diagnosis for many diseases giving a greater hope of survival thanks to a more adequate and prompt management.

The mucosal-associated lymphoid tissues of the upper respiratory tract, including adenoids and palatine tonsils, are considered as the first line of defense against respiratory infections, being important effector organs in both mucosal-type and systemic-type adaptive immunity. They are strategically located for mediating both local and regional immune functions, as they are exposed to antigens from both the inhaled air (allergens and pathogens) and the alimentary tract. Adenoids play a major role in the early and effective immune responses against viral and bacterial upper airway infections, as well as in the development of allergic reactions to respiratory allergens, being influenced by several environmental antigens and pollutants, such as tobacco smoke. In addition, recent studies have focused on new immune-modulating strategies for adenoidal cells as a preventive and therapeutic approach for chronic upper airways inflammation. Herein, we aimed to summarize what is known about the cellular and molecular mechanisms regulating adenoidal immune responses in the context of inflammation and allergy, with particular reference to scientific literature published within the last five years.

The growing interest in the new role of vitamin D, particularly as an immunomodulatory factor, has spurred basic research and the development of clinical trials to better understand the influence of supplementation on various diseases. Vitamin D is an important nutrient factor in human health due to its role in calcium metabolism regulation, cellular growth, differentiation and its fundamental discovered activity in immune functions. It has influenced different diseases, particularly inflammatory and autoimmune diseases, through immune response regulation, modulating innate and adaptive immunity. The aim of this review was to explore the role of vitamin D in the main respiratory diseases in children such as asthma, chronic rhinosinusitis, cystic fibrosis and recurrent respiratory infections.