Inhaled endotoxin induces a systemic neutrophil response without affecting cardiovascular measures in a randomized cross-over exposure study.

OBJECTIVE: The gram-negative bacterial cell wall component endotoxin (lipopolysaccharide, LPS) is a key component of particulate matter (PM). PM exposure is associated with cardiovascular morbidity and mortality. However, the contribution of individual components of PM to acute and chronic cardiovascular measures is not clear. This study examines whether systemic inflammation induced by LPS inhalation causes acute changes in cardiovascular physiology measures. MATERIALS AND METHODS: In this double blinded, placebo-controlled crossover study, fifteen adult volunteers underwent inhalation exposure to 20,000 EU Clinical Center Reference Endotoxin (CCRE). Peripheral blood and induced sputum neutrophils were obtained at baseline and six hours post-exposure. Blood pressure, measures of left ventricular function (ejection fraction (LVEF) and global longitudinal strain (LVGLS)), and indices of endothelial function (flow mediated dilation (FMD) and velocity time integral during hyperemia (VTIhyp)) were measured before and after treatment. Wilcoxon sign-rank tests and linear mixed models were used for statistical analysis. RESULTS: In comparison with normal saline, LPS inhalation resulted in significant increases in peripheral blood and sputum neutrophils but was not associated with significant alterations in blood pressure, LVGLS, LVEF, FMD, or VTIhyp. DISCUSSION AND CONCLUSIONS: In healthy adults, systemic inflammation after LPS inhalation was not associated with acute changes in cardiovascular physiology. Larger studies are needed to investigate the effects of other PM components on inflammation induced cardiovascular dysfunction.

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

Systemic Type I IFN Inflammation in Human ISG15 Deficiency Leads to Necrotizing Skin Lesions.

Most monogenic disorders have a primary clinical presentation. Inherited ISG15 deficiency, however, has manifested with two distinct presentations to date: susceptibility to mycobacterial disease and intracranial calcifications from hypomorphic interferon-II (IFN-II) production and excessive IFN-I response, respectively. Accordingly, these patients were managed for their infectious and neurologic complications. Herein, we describe five new patients with six novel ISG15 mutations presenting with skin lesions who were managed for dermatologic disease. Cellularly, we denote striking specificity to the IFN-I response, which was previously assumed to be universal. In peripheral blood, myeloid cells display the most robust IFN-I signatures. In the affected skin, IFN-I signaling is observed in the keratinocytes of the epidermis, endothelia, and the monocytes and macrophages of the dermis. These findings define the specific cells causing circulating and dermatologic inflammation and expand the clinical spectrum of ISG15 deficiency to dermatologic presentations as a third phenotype co-dominant to the infectious and neurologic manifestations.

Systemic inflammatory response to inhaled endotoxin does not correlate with airway response.

BACKGROUND: Endotoxin is a component of particulate matter linked to respiratory disease. Our group has shown that experimental endotoxin inhalation challenge reproducibly triggers neutrophilic inflammation in the airways and in peripheral blood. Sputum induction is currently the only available method for assessing airway neutrophilia but is laborious and time-consuming. This analysis examined the correlation between systemic and airway inflammatory responses to endotoxin to determine if peripheral blood could serve as a surrogate marker for neutrophilic airway inflammation. METHODS: We conducted a retrospective study of 124 inhaled endotoxin challenges conducted at our center using 20,000 endotoxin units (EU) of Clinical Center Reference Endotoxin (CCRE). Venipuncture and induced sputum samples were obtained at baseline and 6 hours after completion of endotoxin challenge. The relationship between change in sputum neutrophils (post-challenge - baseline) and change in peripheral blood neutrophils (post-challenge - baseline) was assessed using Spearman's correlation analyses. RESULTS: Inhaled endotoxin induced a significant increase in mean sputum percent neutrophils and peripheral blood absolute neutrophil counts in healthy adults with or without mild asthma, but no significant correlation was found between airway and systemic neutrophilia (r = 0.13, p = 0.18). Stratification by degree of airway neutrophil response and by atopic or asthmatic status did not change the results. CONCLUSIONS: Inhalation challenge with endotoxin safely and effectively induces airway neutrophilic inflammation in most individuals. Increases in endotoxin-induced peripheral blood neutrophils do not correlate well with airway responses and should not be used as a surrogate marker of airway inflammation.

Electronic cigarettes: One size does not fit all.

Electronic cigarettes (ECs) have been growing rapidly in popularity among youth and adults in the United States over the last decade. This increasing prevalence is driven partially by the ability to customize devices, flavors, and nicotine content and the general notion that ECs are harmless, particularly in comparison with conventional cigarettes. In vitro and in vivo murine models have demonstrated a number of harmful biological effects of e-liquids and their aerosols. However, limited clinical data exist on whether these effects translate into detrimental long-term outcomes in human subjects. The short-term harmful respiratory effects of EC use demonstrated in nonsmokers argue against their use. However, slightly more favorable data exist for the respiratory benefits of substituting conventional cigarettes with ECs and the short-term efficacy of ECs as smoking cessation tools. Nonetheless, available research is severely limited in regard to long-term outcomes and by study designs fraught with bias, pointing to the need for additional research efforts with well-designed longitudinal studies to guide US Food and Drug Administration regulatory efforts. The hurdle presented by diverse device designs and e-liquid permutations, which contribute to the inconsistency of available data, also highlights the need for legislative standardization of ECs.

Granulomatous-Lymphocytic Interstitial Lung Disease in 22q11.2 Deletion Syndrome: a Case Report and Literature Review.

PURPOSE OF REVIEW: Granulomatous-lymphocytic interstitial lung disease (GLILD) has classically been associated with common variable immune deficiency (CVID), but is increasingly being reported in other immunodeficiencies. We describe the second reported case of GLILD in a patient with 22q11.2 deletion syndrome (22q11.2DS) and review the recent literature surrounding GLILD. RECENT FINDINGS: GLILD is characterized by granulomata and lymphoproliferation. Consensus statements and retrospective and case-control studies have better elucidated the clinicopathological and radiographic manifestations of GLILD, allowing for its differentiation from similar conditions like sarcoidosis. Gaps of knowledge remain, however, particularly regarding optimal management strategies. Combination therapies targeting T and B cell populations have recently shown favorable results. GLILD is associated with poorer outcomes in CVID. Its recognition as a rare complication of 22q11.2DS and other immunodeficiencies therefore has important therapeutic and prognostic implications. Additional research is needed to better understand the natural history and pathogenesis of GLILD and to develop evidence-based practice guidelines.

Environmental determinants of allergy and asthma in early life.

Allergic disease prevalence has increased significantly in recent decades. Primary prevention efforts are being guided by study of the exposome (or collective environmental exposures beginning during the prenatal period) to identify modifiable factors that affect allergic disease risk. In this review we explore the evidence supporting a relationship between key components of the external exposome in the prenatal and early-life periods and their effect on atopy development focused on microbial, allergen, and air pollution exposures. The abundance and diversity of microbial exposures during the first months and years of life have been linked with risk of allergic sensitization and disease. Indoor environmental allergen exposure during early life can also affect disease development, depending on the allergen type, dose, and timing of exposure. Recent evidence supports the role of ambient air pollution in allergic disease inception. The lack of clarity in the literature surrounding the relationship between environment and atopy reflects the complex interplay between cumulative environmental factors and genetic susceptibility, such that no one factor dictates disease development in all subjects. Understanding the effect of the summation of environmental exposures throughout a child's development is needed to identify cost-effective interventions that reduce atopy risk in children.