The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis.

In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders.

Spirometric Changes After Initiation of Hydroxyurea in Children With Sickle Cell Anemia.

Individuals with sickle cell disease (SCD) develop a decline in lung function over time. Hydroxyurea (HU) is the most common disease-modifying therapy used in SCD. We hypothesized that children with SCD treated with HU will have a slower decline in pulmonary function. We performed a retrospective chart review of children with HbSS and HbS-beta zero thalassemia referred to pulmonology for respiratory symptoms. We compared the spirometry results at 2 time points between children on HU (HU group) and not on HU (control group). For the HU group, these endpoints were evaluated before and after being on HU. The mean time interval between 2 spirometry studies was not significantly different between the groups (2.6±1.5 y for HU group vs. 3.0±1.8 y for the control group; P =0.33). The mean age of patients in the HU group was 9.8±3.8 years (55% male) and 10.7±4.9 years (50% male) in the control group. The spirometry data was compared within and between the groups using t test. There was a significant increase in forced vital capacity in HU group during follow-up, while children in the control group showed a decline (7.2±17.1 vs. -3.4±18.2; P <0.01). Our study suggests that HU therapy may help preserve lung function over time in children with SCD.

Inflammation in children with cystic fibrosis: contribution of bacterial production of long-chain fatty acids.

BACKGROUND: Cystic fibrosis (CF) affects >70,000 people worldwide, yet the microbiologic trigger for pulmonary exacerbations (PExs) remains unknown. The objective of this study was to identify changes in bacterial metabolic pathways associated with clinical status. METHODS: Respiratory samples were collected at hospital admission for PEx, end of intravenous (IV) antibiotic treatment, and follow-up from 27 hospitalized children with CF. Bacterial DNA was extracted and shotgun DNA sequencing was performed. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance, while DESeq2 was used to evaluate differential abundance based on clinical status. RESULTS: The mean age of study participants was 10 years; 85% received combination IV antibiotic therapy (beta-lactam plus a second agent). Long-chain fatty acid (LCFA) biosynthesis pathways were upregulated in follow-up samples compared to end of treatment: gondoate (p = 0.012), oleate (p = 0.048), palmitoleate (p = 0.043), and pathways of fatty acid elongation (p = 0.012). Achromobacter xylosoxidans and Escherichia sp. were also more prevalent in follow-up compared to PEx (p < 0.001). CONCLUSIONS: LCFAs may be associated with persistent infection of opportunistic pathogens. Future studies should more closely investigate the role of LCFA production by lung bacteria in the transition from baseline wellness to PEx in persons with CF. IMPACT: Increased levels of LCFAs are found after IV antibiotic treatment in persons with CF. LCFAs have previously been associated with increased lung inflammation in asthma. This is the first report of LCFAs in the airway of persons with CF. This research provides support that bacterial production of LCFAs may be a contributor to inflammation in persons with CF. Future studies should evaluate LCFAs as predictors of future PExs.

The airway epithelium during infancy and childhood: A complex multicellular immune barrier. Basic review for clinicians.

The airway epithelium is a complex multicellular layer that extends from the nasopharynx to the small airways. It functions as an immune respiratory barrier during early life that develops, matures, and regenerates to adapt to the changes in the environment. While airway epithelial abnormalities have been identified in several clinical disorders, there is increasing interest in understanding its basic regulation and structure in humans. Indeed, recent advances in technology (e.g. single-cell analysis and new human airway epithelial cell models) have allowed us to identify additional cellular subtypes and functions that overall have greatly improved our understanding of the airway epithelium during health and disease. In this review we summarize key features of the airway epithelium including: 1) multilayer structure and cell heterogeneity; 2) adaptability to different environmental and developmental stimuli; 3) innate recognition; and 4) orchestration of immune responses. We discuss these features with a translational and clinical prospective focusing on the development of human respiratory immunity, particularly during early life.

The interplay between airway epithelium and the immune system - A primer for the respiratory clinician.

The respiratory epithelium is one of the primary interfaces between the body's immune system and the external environment. This review discusses the innate and adaptive immunomodulatory effects of the respiratory epithelium, highlighting the physiologic immune responses associated with health and the disease-causing sequelae when these physiologic responses go awry. Airway macrophages, dendritic cells, and innate lymphoid cells are discussed as orchestrators of physiological and pathological innate immune responses and T cells, B cells, mast cells, and granulocytes (eosinophils and neutrophils) as orchestrators of physiologic and pathologic adaptive immune responses. The interplay between the airway epithelium and the varied immune cells as well as the interplay between these immune cells is discussed, highlighting the importance of the dose of noxious stimuli and pathogens in immune programming and the timing of their interaction with the immune cells that determine the pattern of immune responses. Although each cell type has been researched individually, this review highlights the need for simultaneous temporal investigation of immune responses from these varied cells to noxious stimuli and pathogens.

Pectus deformities and their impact on pulmonary physiology.

Pectus excavatum (PE) and pectus carinatum (PC) are the most common anomalies of the thoracic cage and they have been recognized since ancient times [1-3]. The two conditions differ in their appearance, and their effect on lung function. There is no direct correlation between the appearance of the deformities and the clinical symptoms. Whether, and when these deformities should be corrected as well as with which method (surgical or conservative) remain controversial. The following article reviews the current concepts regarding the pathophysiology of both conditions as well as the advances in their evaluation and management.

Lung function in sickle cell disease.

Although some of the most severe complications of Sickle Cell Disease (SCD) tend to be acute and severe (e.g. acute chest syndrome, stroke etc.), the chronic ones can be equally debilitating. Prominent among them is the effect that the disease has on lung growth and function. For many years the traditional teaching has been that SCD is associated with the development of a restrictive lung defect. However, there is increasing evidence that this is not a universal finding and that at least during childhood and adolescence, the majority of the patients have a normal or obstructive pattern of lung function. The following article reviews the current knowledge on the effects of SCD on lung growth and function. Special emphasis is given to the controversies among the published articles in the literature and discusses possible causes for these discrepancies.

Chest wall abnormalities and their clinical significance in childhood.

The thorax consists of the rib cage and the respiratory muscles. It houses and protects the various intrathoracic organs such as the lungs, heart, vessels, esophagus, nerves etc. It also serves as the so-called "respiratory pump" that generates the movement of air into the lungs while it prevents their total collapse during exhalation. In order to be performed these functions depend on the structural and functional integrity of the rib cage and of the respiratory muscles. Any condition (congenital or acquired) that may affect either one of these components is going to have serious implications on the function of the other. Furthermore, when these abnormalities occur early in life, they may affect the growth of the lungs themselves. The following article reviews the physiology of the respiratory pump, provides a comprehensive list of conditions that affect the thorax and describes their effect(s) on lung growth and function.

Somatic growth and lung function in sickle cell disease.

Somatic growth is a key indicator of overall health and well-being with important prognostic implications in the management of chronic disease. Worldwide studies of growth in children and adults with SCD have predominantly shown delayed growth (especially in terms of body weight) that is gradual and progressive in nature. However, more recent studies have shown that a substantial number of patients with SCD have normal weight gain whereas some are even obese. Height in patients with SCD is not universally affected even among those with suboptimal weight gain, whereas some achieve the same or greater height than healthy controls. The relationship between somatic growth and lung function in SCD is not yet clearly defined. As a group, patients with SCD tend to have lower lung volumes compared with healthy controls. These findings are similar across the age spectrum and across ethnic/racial lines regardless of the differences in body weight. Several mechanisms and risk factors have been proposed to explain these findings. These include malnutrition, racial differences and socioeconomic status. In addition, there are structural changes of the thorax (specifically the anterio-posterior chest diameter and anterio-posterior to lateral chest ratio) specific to sickle cell disease, that potentially interfere with normal lung growth. Although, caloric and protein intake have been shown to improve both height and weight, the composition of an optimal diet remains unclear. The following article reviews the current knowledge and controversies regarding somatic growth and its relationship with lung function in sickle cell disease (SCD) as well as the role of specific deficiencies of certain micronutrients.

Systemic corticosteroids in acute chest syndrome: friend or foe?

Acute chest syndrome(ACS) is the most common pulmonary complication of sickle cell disease (SCD), the second most common cause of hospitalization and the primary cause of death in patients with sickle cell disease. Its highest prevalence is in early childhood. The pathogenesis of ACS is unknown but many predisposing conditions and mechanisms have been implicated including infections, pulmonary fat embolism, asthma and ischemic reperfusion injury. These conditions are associated with inflammation and therefore, the use of corticosteroids has been advocated because of their anti-inflammatory properties. Although, significant benefits from their use have been shown, there is great reluctance in using them because of reports of serious adverse effects, such as readmission to the hospital due rebound pain crisis, stroke, renal infarction, coma and even death. The current article reviews the evidence in favor and against the use of corticosteroids in ACS. Emphasis is given on the potential benefits vs. risks among the different types of corticosteroids, the importance of the dosing regimen and the role of underlying co-morbidities.

Time to re-set our thinking about airways disease: lessons from history, the resurgence of chronic bronchitis / PBB and modern concepts in microbiology.

In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary disease' (COPD) has minimally changed in recent decades while 'the incidence of bronchiectasis' is on the rise. The current focus on producing guidelines for these two airway 'diseases' has hindered progress in both treatment and prevention. The elephant in the room is that neither COPD nor bronchiectasis is a disease but rather a consequence of progressive untreated airway inflammation. To make this case, it is important to review the evolution of our understanding of airway disease and how a pathological appearance (bronchiectasis) and an arbitrary physiological marker of impaired airways (COPD) came to be labelled as 'diseases'. Valuable insights into the natural history of airway disease can be obtained from the pre-antibiotic era. The dramatic impacts of antibiotics on the prevalence of significant airway disease, especially in childhood and early adult life, have largely been forgotten and will be revisited as will the misinterpretation of trials undertaken in those with chronic (bacterial) bronchitis. In the past decades, paediatricians have observed a progressive increase in what is termed 'persistent bacterial bronchitis' (PBB). This condition shares all the same characteristics as 'chronic bronchitis', which is prevalent in young children during the pre-antibiotic era. Additionally, the radiological appearance of bronchiectasis is once again becoming more common in children and, more recently, in adults. Adult physicians remain sceptical about the existence of PBB; however, in one study aimed at assessing the efficacy of antibiotics in adults with persistent symptoms, researchers discovered that the majority of patients exhibiting symptoms of PBB were already on long-term macrolides. In recent decades, there has been a growing recognition of the importance of the respiratory microbiome and an understanding of the ability of bacteria to persist in potentially hostile environments through strategies such as biofilms, intracellular communities, and persister bacteria. This is a challenging field that will likely require new approaches to diagnosis and treatment; however, it needs to be embraced if real progress is to be made.

Tolerance & resistance to ß2-agonist bronchodilators.

For the past half-century, ß2-agonists have been the mainstay of treatment of the bronchoconstriction associated with asthma. Although their usefulness in reversing acute bronchospasm remains undiminished, there is increasing evidence that chronic use may lead to development of tolerance and thus, potentially increasing morbidity and even mortality. In addition, genetic studies have shown that certain individuals carrying specific mutations may be prone to developing resistance to ß2-agonists regardless of the duration of treatment. This article reviews the current evidence regarding the underlying mechanisms that cause or contribute to the development of the resistance, as well as the strategies for the evaluation and management of patients who are at risk for or have developed tolerance to ß2-agonists.

Therapeutic beta-lactam dosages and broad-spectrum antibiotics are associated with reductions in microbial richness and diversity in persons with cystic fibrosis.

Persons with cystic fibrosis (PwCF) suffer from pulmonary exacerbations (PEx) related in part to lung infection. While higher microbial diversity is associated with higher lung function, the data on the impact of short-term antibiotics on changes in microbial diversity is conflicting. Further, Prevotella secretes beta-lactamases, which may influence recovery of lung function. We hypothesize that sub-therapeutic and broad spectrum antibiotic exposure leads to decreasing microbial diversity. Our secondary aim was to evaluate the concerted association of beta-lactam pharmacokinetics (PK), antibiotic spectrum, microbial diversity, and antibiotic resistance on lung function recovery using a pathway analysis. This was a retrospective observational study of persons with CF treated with IV antibiotics for PEx between 2016 and 2020 at Children's National Hospital; respiratory samples and clinical information were collected at hospital admission for PEx (E), end of antibiotic treatment (T), and follow-up (F). Metagenomic sequencing was performed; PathoScope 2.0 and AmrPlusPlus were used for taxonomic assignment of sequences to bacteria and antibiotic resistance genes (ARGs). M/W Pharm was used for PK modeling. Comparison of categorical and continuous variables and pathway analysis were performed in STATA. Twenty-two PwCF experienced 43 PEx. The study cohort had a mean age of 14.6 years. Only 12/43 beta-lactam courses had therapeutic PK, and 18/43 were broad spectrum. A larger decrease in richness between E and T was seen in the therapeutic PK group (sufficient - 20.1 vs. insufficient - 1.59, p = 0.025) and those receiving broad spectrum antibiotics (broad - 14.5 vs. narrow - 2.8, p = 0.030). We did not detect differences in the increase in percent predicted forced expiratory volume in one second (ppFEV1) at end of treatment compared to PEx based on beta-lactam PK (sufficient 13.6% vs. insufficient 15.1%) or antibiotic spectrum (broad 11.5% vs. narrow 16.6%). While both therapeutic beta-lactam PK and broad-spectrum antibiotics decreased richness between PEx and the end of treatment, we did not detect longstanding changes in alpha diversity or an association with superior recovery of lung function compared with subtherapeutic PK and narrow spectrum antimicrobials.

Bacteriophage Therapy for Pan-Drug-Resistant Pseudomonas aeruginosa in Two Persons With Cystic Fibrosis.

Cystic fibrosis (CF) is an important monogenic disease that affects more than 70 000 people worldwide. Defects of the CF transmembrane conductance regulator gene lead to dehydrated viscous secretions that result in chronic bacterial colonization. This leads to frequent recurrent lung infections called pulmonary exacerbations, lung inflammation, and resulting structural lung damage called bronchiectasis. Pseudomonas aeruginosa in particular is a common pathogen in persons with CF associated with increased pulmonary exacerbations, long-term lung function decline, and reduced survival. In addition, P. aeruginosa commonly develops antibiotic resistance and forms biofilms, making it difficult to treat. Here, we report the details of two patients with CF with pan-drug-resistant P. aeruginosa who were treated with a novel therapeutic strategy, bacteriophages. These cases highlight the need for further research and development of this treatment modality, including pediatric clinical trials.

The International Network on Oesophageal Atresia (INoEA) consensus guidelines on the transition of patients with oesophageal atresia-tracheoesophageal fistula.

Oesophageal atresia-tracheoesophageal fistula (EA-TEF) is a common congenital digestive disease. Patients with EA-TEF face gastrointestinal, surgical, respiratory, otolaryngological, nutritional, psychological and quality of life issues in childhood, adolescence and adulthood. Although consensus guidelines exist for the management of gastrointestinal, nutritional, surgical and respiratory problems in childhood, a systematic approach to the care of these patients in adolescence, during transition to adulthood and in adulthood is currently lacking. The Transition Working Group of the International Network on Oesophageal Atresia (INoEA) was charged with the task of developing uniform evidence-based guidelines for the management of complications through the transition from adolescence into adulthood. Forty-two questions addressing the diagnosis, treatment and prognosis of gastrointestinal, surgical, respiratory, otolaryngological, nutritional, psychological and quality of life complications that patients with EA-TEF face during adolescence and after the transition to adulthood were formulated. A systematic literature search was performed based on which recommendations were made. All recommendations were discussed and finalized during consensus meetings, and the group members voted on each recommendation. Expert opinion was used when no randomized controlled trials were available to support the recommendation. The list of the 42 statements, all based on expert opinion, was voted on and agreed upon.

Steroid-resistant asthma.

Steroid-resistant asthma (SRA) refers to patients with symptoms consistent with asthma who show very poor or no response at all to high doses of inhaled or even of systemic corticosteroids. The current article reviews the SRA related literature focusing on the problems associated with the definition of SRA (especially its association with difficult to control, or severe asthma), its various phenotypes, its molecular basis, and the potential treatment options. The article also discusses the limitations of some of the key criteria used for the determination of SRA and proposes a modified set of criteria that are more applicable to children.