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Hannah H Walford,1,2 Taylor A Doherty11Department of Medicine, 2Department of Pediatrics, University of California, La Jolla, CA, USAAbstract: Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma.Keywords: asthma, eosinophil, allergy, Th2, IL-4, IL-13

OBJECTIVE: To explore how the human immunodeficiency virus (HIV) epidemic has affected the infant-feeding experiences of HIV-positive mothers in South Africa. METHODS: This was a qualitative interview study within a prospective cohort study. We purposively selected a subsample of 40 women from a larger cohort of 650 HIV-positive mothers for in-depth interviews. FINDINGS: The HIV epidemic has changed the context in which infant-feeding choices are made and implemented. HIV-positive mothers in this study - who were predominantly young, single and unemployed - were struggling to protect their decision-making autonomy. Uncertainty about the safety of breastfeeding has increased the power and influence of health workers, who now act as gatekeepers to not only this new knowledge but also to essential resources such as formula milk. Fear of disclosure of HIV status and stigma has also weakened the ability of mothers to resist entrenched family and community norms that encourage early introduction of fluids and foods and that question non-breastfeeding. Women who chose to exclusively formula feed had difficulties accessing formula milk because of inflexible policies and a lack of supplies at clinics. Limited postpartum support led to social isolation and mothers doubting their ability to care for their children. CONCLUSION: The infant-feeding experiences of HIV-positive mothers have serious implications for the operational effectiveness of programmes that aim to prevent HIV transmission from mother to child. A better understanding of how HIV is changing infant-feeding practices can inform the development of interventions to improve infant-feeding counselling and postpartum support.

Abstract Background Globally, 40% of the 7.6 million deaths of children under five every year occur in the neonatal period (first 28 days after birth). Increased and earlier recognition of illness facilitated by community health workers (CHWs), coupled with effective referral systems can result in better child health outcomes. This model has not been tested in a peri-urban poor setting in Africa, or in a high HIV context. Methods The Good Start Saving Newborn Lives (SNL) study (ISRCTN41046462) conducted in Umlazi, KwaZulu-Natal, was a community randomized trial to assess the effect of an integrated home visit package delivered to mothers by CHWs during pregnancy and post-delivery on uptake of PMTCT interventions and appropriate newborn care practices. CHWs were trained to refer babies with illnesses or identified danger signs. The aim of this sub-study was to assess the effectiveness of this referral system by describing CHW referral completion rates as well as mothers’ health-care seeking practices. Interviews were conducted using a structured questionnaire with all mothers whose babies had been referred by a CHW since the start of the SNL trial. Descriptive analysis was conducted to describe referral completion and health seeking behaviour of mothers. Results Of the 2423 women enrolled in the SNL study, 148 sick infants were referred between June 2008 and June 2010. 62% of referrals occurred during the first 4 weeks of life and 22% between birth and 2 weeks of age. Almost all mothers (95%) completed the referral as advised by CHWs. Difficulty breathing, rash and redness/discharge around the cord accounted for the highest number of referrals (26%, 19% and 17% respectively). Only16% of health workers gave written feedback on the outcome of the referral to the referring CHW. Conclusions We found high compliance with CHW referral of sick babies in an urban South African township. This suggests that CHWs can play a significant role, within community outreach teams, to improve newborn health and reduce child mortality. This supports the current primary health care re-engineering process being undertaken by the South African National Department of Health which involves the establishment of family health worker teams including CHWs. Trial registration number ISRCTN41046462

Abstract Background Child cash transfers are increasingly recognised for their potential to reduce poverty and improve health outcomes. South Africa‘s child support grant (CSG) constitutes the largest cash transfer in the continent. No studies have been conducted to look at factors associated with successful receipt of the CSG. This paper reports findings on factors associated with CSG receipt in three settings in South Africa (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal). Methods This study used longitudinal data from a community-based cluster-randomized trial (PROMISE EBF) promoting exclusive breastfeeding by peer-counsellors in South Africa (ClinicalTrials.gov: NCT00397150). 1148 mother-infant pairs were enrolled in the study and data on the CSG were collected at infant age 6, 12, 24 weeks and 18–24 months. A stratified cox proportional hazards regression model was fitted to the data to investigate factors associated with CSG receipt. Results Uptake of the CSG amongst eligible children at a median age of 22 months was 62% in Paarl, 64% in Rietvlei and 60% in Umlazi. Possessing a birth certificate was found to be the strongest predictor of CSG receipt (HR 3.1, 95% CI: 2.4 -4.1). Other factors also found to be independently associated with CSG receipt were an HIV-positive mother (HR 1.2, 95% CI: 1.0-1.4) and a household income below R1100 (HR1.7, 95% CI: 1.1 -2.6). Conclusion Receipt of the CSG was sub optimal amongst eligible children showing administrative requirements such as possessing a birth certificate to be a serious barrier to access. In the spirit of promoting and protecting children’s rights, more efforts are needed to improve and ease access to this cash transfer program.

Abstract Background HIV counselling and testing (HCT) is a critical gateway for addressing HIV prevention and linking people to treatment, care, and support. Since national testing rates are often less than optimal, there is growing interest in expanding testing coverage through the implementation of innovative models such as home-based HIV counselling and testing (HBHCT). With the aim of informing scale up, this paper discusses client characteristics and acceptability of an HBHCT intervention implemented in rural South Africa. Methods Trained lay counsellors offered door-to-door rapid HIV testing in a rural sub-district of KwaZulu-Natal, South Africa. Household and client data were captured on cellular phones and transmitted to a web-based data management system. Descriptive analysis was undertaken to examine client characteristics, testing history, HBHCT uptake, and reasons for refusal. Chi-square tests were performed to assess the association between client characteristics and uptake. Results Lay counsellors visited 3,328 households and tested 75% (5,086) of the 6,757 people met. The majority of testers (73.7%) were female, and 57% had never previously tested. With regard to marital status, 1,916 (37.7%), 2,123 (41.7%), and 818 (16.1%) were single, married, and widowed, respectively. Testers ranged in age from 14 to 98 years, with a median of 37 years. Two hundred and twenty-nine couples received couples counselling and testing; 87.8%, 4.8%, and 7.4% were concordant negative, concordant positive, and discordant, respectively. There were significant differences in characteristics between testers and non-testers as well as between male and female testers. The most common reasons for not testing were: not being ready/feeling scared/needing to think about it (34.1%); knowing his/her status (22.6%), being HIV-positive (18.5%), and not feeling at risk of having or acquiring HIV (10.1%). The distribution of reasons for refusal differed significantly by gender and age. Conclusions These findings indicate that HBHCT is acceptable in rural South Africa. However, future HBHCT programmes should carefully consider community context, develop strategies to reach a broad range of clients, and tailor intervention messages and services to meet the unique needs of different sub-groups. It will also be important to understand and address factors related to refusal of testing.

Abstract Background Breastfeeding is a critical component of interventions to reduce child mortality. Exclusive breastfeeding practice is extremely low in South Africa and there has been no improvement in this over the past ten years largely due to fears of HIV transmission. Early cessation of breastfeeding has been found to have negative effects on child morbidity and survival in several studies in Africa. This paper reports on determinants of early breastfeeding cessation among women in South Africa. Methods This is a sub group analysis of a community-based cluster-randomized trial (PROMISE EBF) promoting exclusive breastfeeding in three South African sites (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal) between 2006 and 2008 (ClinicalTrials.gov no: NCT00397150). Infant feeding recall of 22 food and fluid items was collected at 3, 6, 12 and 24 weeks postpartum. Women’s experiences of breast health problems were also collected at the same time points. 999 women who ever breastfed were included in the analysis. Univariable and multivariable logistic regression analysis adjusting for site, arm and cluster, was performed to determine predictors of stopping breastfeeding by 12 weeks postpartum. Results By 12 weeks postpartum, 20% of HIV-negative women and 40% of HIV-positive women had stopped all breastfeeding. About a third of women introduced other fluids, most commonly formula milk, within the first 3 days after birth. Antenatal intention not to breastfeed and being undecided about how to feed were most strongly associated with stopping breastfeeding by 12 weeks (Adjusted odds ratio, AOR 5.6, 95% CI 3.4 – 9.5 and AOR 4.1, 95% CI 1.6 – 10.8, respectively). Also important was self-reported breast health problems associated with a 3-fold risk of stopping breastfeeding (AOR 3.1, 95%CI 1.7 – 5.7) and the mother having her own income doubled the risk of stopping breastfeeding (AOR 1.9, 95% CI 1.3 – 2.8). Conclusion Early cessation of breastfeeding is common amongst both HIV-negative and positive women in South Africa. There is an urgent need to improve antenatal breastfeeding counselling taking into account the challenges faced by working women as well as early postnatal lactation support to prevent breast health problems.

Abstract Background We sought to investigate infant feeding practices amongst HIV-positive and -negative mothers (0-9 months postpartum) and describe the association between infant feeding practices and HIV-free survival. Methods Infant feeding data from a prospective observational cohort study conducted at three (of 18) purposively-selected routine South African PMTCT sites, 2002-2003, were analysed. Infant feeding data (previous 4 days) were gathered during home visits at 3, 5, 7, 9, 12, 16, 20, 24, 28, 32 and 36 weeks postpartum. Four feeding groups were of interest, namely exclusive breastfeeding, mixed breastfeeding, exclusive formula feeding and mixed formula feeding. Cox proportional hazards models were fitted to investigate associations between feeding practices (0-12 weeks) and infant HIV-free survival. Results Six hundred and sixty five HIV-positive and 218 HIV-negative women were recruited antenatally and followed-up until 36 weeks postpartum. Amongst mothers who breastfed between 3 weeks and 6 months postpartum, significantly more HIV-positive mothers practiced exclusive breastfeeding compared with HIV-negative: at 3 weeks 130 (42%) versus 33 (17%) (p < 0.01); this dropped to 17 (11%) versus 1 (0.7%) by four months postpartum. Amongst mothers practicing mixed breastfeeding between 3 weeks and 6 months postpartum, significantly more HIV-negative mothers used commercially available breast milk substitutes (p < 0.02) and use of these peaked between 9 and 12 weeks. The probability of postnatal HIV or death was lowest amongst infants living in the best resourced site who avoided breastfeeding, and highest amongst infants living in the rural site who stopped breastfeeding early (mean and standard deviations: 10.7% ± 3% versus 46% ± 11%). Conclusions Although feeding practices were poor amongst HIV-positive and -negative mothers, HIV-positive mothers undertake safer infant feeding practices, possibly due to counseling provided through the routine PMTCT programme. The data on differences in infant outcome by feeding practice and site validate the WHO 2009 recommendations that site differences should guide feeding practices amongst HIV-positive mothers. Strong interventions are needed to promote exclusive breastfeeding (to 6 months) with continued breastfeeding thereafter amongst HIV-negative motherswho are still the majority of mothers even in high HIV prevalence setting like South Africa.

Abstract Background The low uptake of facility-based HIV counseling and testing (HCT) in South Africa, particularly amongst men and youth has hindered attempts to increase access to effective treatment and prevention strategies. Many barriers to HIV testing have been described including long waiting times, transport to reach facilities, fear of lack of confidentiality and health systems factors such as stock outs of HIV test kits. The aim of this study was to undertake a community survey to determine rates of HCT in a rural area in order to plan a community intervention. Methods A community-based survey was undertaken in 16 communities in Sisonke district, KwaZulu-Natal between September and November 2008. A total of 5821 individuals participated in the survey of which 66% were females. Gender specific mixed effects logistic regression models were used to describe differences in socio-economic characteristics, and their association with HIV testing histories. Results Overall 1833 (32%) individuals in this rural area knew their HIV status. Prior testing was higher amongst women (39%) than amongst men (17%). Older men (> 24 years) were more likely to report having tested for HIV previously, with the highest likelihood (adjusted OR = 4.02; 95% CI: 2.71-5.99) among men in age group, 35-49 years. For women, age group 25-34 years had the highest likelihood of having been previously tested (adjusted OR = 1.30; 95% CI: 1.05-1.66). Being currently pregnant (adjusted OR 3.31; 95% CI: 2.29 - 4.78) or having a child under five (adjusted OR 7.00; 95% CI: 5.84 - 8.39) were also associated with prior HIV testing amongst women. Conclusions Overall, knowledge of HIV status in this rural sub-district is low. The relatively higher uptake of HIV testing among women is encouraging as it shows that PMTCT services are well functioning. However, these data suggest that there is an urgent need for scaling up HIV testing services in rural communities specifically targeting men and youth.

Abstract Background Progress towards MDG4 in South Africa will depend largely on scaling up effective prevention against mother to child transmission (PMTCT) of HIV and also addressing neonatal mortality. This imperative drives increasing focus on the neonatal period and particularly on the development and testing of appropriate models of sustainable, community-based care in South Africa in order to reach the poor. A number of key implementation gaps affecting progress have been identified. Implementation gaps for HIV prevention in neonates; implementation gaps for neonatal care especially home postnatal care; and implementation gaps for maternal mental health support. We have developed and are evaluating and costing an integrated and scaleable home visit package delivered by community health workers targeting pregnant and postnatal women and their newborns to provide essential maternal/newborn care as well as interventions for Prevention of Mother to Child Transmission (PMTCT) of HIV. Methods The trial is a cluster randomized controlled trial that is being implemented in Umlazi which is a peri-urban settlement with a total population of 1 million close to Durban in KwaZulu Natal, South Africa. The trial consists of 30 randomized clusters (15 in each arm). A baseline survey established the homogeneity of clusters and neither stratification nor matching was performed. Sample size was based on increasing HIV-free survival from 74% to 84%, and calculated to be 120 pregnant women per cluster. Primary outcomes are higher levels of HIV free survival and levels of exclusive and appropriate infant feeding at 12 weeks postnatally. The intervention is home based with community health workers delivering two antenatal visits, a postnatal visit within 48 hours of birth, and a further four visits during the first two months of the infants life. We are undertaking programmatic and cost effectiveness analysis to cost the intervention. Discussion The question is not merely to develop an efficacious package but also to identify and test delivery strategies that enable scaling up, which requires effectiveness studies in a health systems context, adapting and testing Asian community-based studies in various African contexts. Trial registration ISRCTN: ISRCTN41046462

Abstract Background Despite free healthcare to pregnant women and children under the age of six, access to healthcare has failed to secure better child health outcomes amongst all children of the country. There is growing evidence of socioeconomic gradient on child health outcomes Methods The objectives of this study were to measure inequalities in child mortality, HIV transmission and vaccination coverage within a cohort of infants in South Africa. We also used the decomposition technique to identify the factors that contribute to the inequalities in these three child health outcomes. We used data from a prospective cohort study of mother-child pairs in three sites in South African. A relative index of household socio-economic status was developed using principal component analysis. This paper uses the concentration index to summarise inequalities in child mortality, HIV transmission and vaccination coverage. Results We observed disparities in the availability of infrastructure between least poor and most poor families, and inequalities in all measured child health outcomes. Overall, 75 (8.5%) infants died between birth and 36 weeks. Infant mortality and HIV transmission was higher among the poorest families within the sample. Immunisation coverage was higher among the least poor. The inequalities were mainly due to the area of residence and socio-economic position. Conclusion This study provides evidence that socio-economic inequalities are highly prevalent within the relatively poor black population. Poor socio-economic position exposes infants to ill health. In addition, the use of immunisation services was lower in the poor households. These inequalities need to be explicitly addressed in future programme planning to improve child health for all South Africans.

Abstract Background In this study we examined the role of Siglec-F, a receptor highly expressed on eosinophils, in contributing to mucus expression, airway remodeling, and Siglec-F ligand expression utilizing Siglec-F deficient mice exposed to chronic allergen challenge. Methods Wild type (WT) and Siglec-F deficient mice were sensitized and challenged chronically with OVA for one month. Levels of airway inflammation (eosinophils), Siglec-F ligand expresion and remodeling (mucus, fibrosis, smooth muscle thickness, extracellular matrix protein deposition) were assessed in lung sections by image analysis and immunohistology. Airway hyperreactivity to methacholine was assessed in intubated and ventilated mice. Results Siglec-F deficient mice challenged with OVA for one month had significantly increased numbers of BAL and peribronchial eosinophils compared to WT mice which was associated with a significant increase in mucus expression as assessed by the number of periodic acid Schiff positive airway epithelial cells. In addition, OVA challenged Siglec-F deficient mice had significantly increased levels of peribronchial fibrosis (total lung collagen, area of peribronchial trichrome staining), as well as increased numbers of peribronchial TGF-β1+ cells, and increased levels of expression of the extracellular matrix protein fibronectin compared to OVA challenged WT mice. Lung sections immunostained with a Siglec-Fc to detect Siglec-F ligand expression demonstrated higher levels of expression of the Siglec-F ligand in the peribronchial region in OVA challenged Siglec-F deficient mice compared to WT mice. WT and Siglec-F deficient mice challenged intranasally with IL-4 or IL-13 had significantly increased levels of airway epithelial Siglec-F ligand expression, whereas this was not observed in WT or Siglec-F deficient mice challenged with TNF-α. There was a significant increase in the thickness of the peribronchial smooth muscle layer in OVA challenged Siglec-F deficient mice, but this was not associated with significant increased airway hyperreactivity compared to WT mice. Conclusions Overall, this study demonstrates an important role for Siglec-F in modulating levels of chronic eosinophilic airway inflammation, peribronchial fibrosis, thickness of the smooth muscle layer, mucus expression, fibronectin, and levels of peribronchial Siglec-F ligands suggesting that Siglec-F may normally function to limit levels of chronic eosinophilic inflammation and remodeling. In addition, IL-4 and IL-13 are important regulators of Siglec-F ligand expression by airway epithelium.

Abstract Background Recent years have seen a re-emergence of community health worker (CHW) interventions, especially in relation to HIV care, and in increasing coverage of child health interventions. Such programmes can be particularly appealing in the face of human resource shortages and fragmented health systems. However, do we know enough about how these interventions function in order to support the investment? While research based on strong quantitative study designs such as randomised controlled trials increasingly document their impact, there has been less empirical analysis of the internal mechanisms through which CHW interventions succeed or fail. Qualitative process evaluations can help fill this gap. Methods This qualitative paper reports on the experience of three CHW supervisors who were responsible for supporting infant feeding peer counsellors. The intervention took place in three diverse settings in South Africa. Each setting employed one CHW supervisor, each of whom was individually interviewed for this study. The study forms part of the process evaluation of a large-scale randomized controlled trial of infant feeding peer counselling support. Results Our findings highlight the complexities of supervising and supporting CHWs. In order to facilitate effective infant feeding peer counselling, supervisors in this study had to move beyond mere technical management of the intervention to broader people management. While their capacity to achieve this was based on their own prior experience, it was enhanced through being supported themselves. In turn, resource limitations and concerns over safety and being in a rural setting were raised as some of the challenges to supervision. Adding to the complexity was the issue of HIV. Supervisors not only had to support CHWs in their attempts to offer peer counselling to mothers who were potentially HIV positive, but they also had to deal with supporting HIV-positive peer counsellors. Conclusions This study highlights the need to pay attention to the experiences of supervisors so as to better understand the components of supervision in the field. Such understanding can enhance future policy making, planning and implementation of peer community health worker programmes.

Abstract Background To investigate the feasibility, the ease of implementation, and the extent to which community health workers with little experience of data collection could be trained and successfully supervised to collect data using mobile phones in a large baseline survey Methods A web-based system was developed to allow electronic surveys or questionnaires to be designed on a word processor, sent to, and conducted on standard entry level mobile phones. Results The web-based interface permitted comprehensive daily real-time supervision of CHW performance, with no data loss. The system permitted the early detection of data fabrication in combination with real-time quality control and data collector supervision. Conclusions The benefits of mobile technology, combined with the improvement that mobile phones offer over PDA's in terms of data loss and uploading difficulties, make mobile phones a feasible method of data collection that needs to be further explored.

Abstract Background Despite several years of implementation, prevention of mother-to-child transmission (PMTCT) programmes in many resource poor settings are failing to reach the majority of HIV positive women. We report on a data driven participatory quality improvement intervention implemented in a high HIV prevalence district in South Africa. Methods A participatory quality improvement intervention was implemented consisting of an initial assessment undertaken by a team of district supervisors, workshops to assess results, identify weaknesses and set improvement targets and continuous monitoring to support changes. Results The assessment highlighted weaknesses in training and supervision. Routine data revealed poor coverage of all programme indicators except HIV testing. Monthly support to all facilities took place including an orientation to the PMTCT protocol, review of local data and identification of bottlenecks to optimal coverage using a continuous quality improvement approach. One year following the intervention large improvements in programme indicators were observed. Coverage of CD4 testing increased from 40 to 97%, uptake of maternal nevirapine from 57 to 96%, uptake of infant nevirapine from 15 to 68% and six week PCR testing from 24 to 68%. Conclusion It is estimated that these improvements in coverage could avert 580 new infant infections per year in this district. This relatively simple participatory assessment and intervention process has enabled programme managers to use a data driven approach to improve the coverage of this important programme.

Abstract Background The objective of this study was to examine missed opportunities for participation in a prevention of mother-to-child transmission (PMTCT) programme in three sites in South Africa. A rapid anthropological assessment was used to collect in-depth data from 58 HIV-positive women who were enrolled in a larger cohort study to assess mother-to-child HIV transmission. Semi-structured interviews were conducted with the women in order to gain an understanding of their experiences of antenatal care and to identify missed opportunities for participation in PMTCT. Results 15 women actually missed their nevirapine not because of stigma and ignorance but because of health systems failures. Six were not tested for HIV during antenatal care. Two were tested but did not receive their results. Seven were tested and received their results, but did not receive nevirapine. Health Systems failure for these programme leakages ranged from non-availability of counselors, supplies such as HIV test kits, consent forms, health staff giving the women incorrect instructions about when to take the tablet and health staff not supplying the women with the tablet to take. Conclusion HIV testing enables access to PMTCT interventions and should therefore be strengthened. The single dose nevirapine regimen is simple to implement but the all or nothing nature of the regimen may result in many missed opportunities. A short course dual or triple drug regimen could increase the effectiveness of PMTCT programmes.

Sensory neurons sense pathogenic infiltration to drive innate immune responses, but their role in humoral immunity is unclear. Here, using mouse models of Streptococcus pneumoniae infection and Alternaria alternata asthma, we show that sensory neurons are required for B cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion increases bacterial burden and reduces B cell numbers, IgG release, and neutrophil stimulation. Meanwhile, during A. alternata-induced airway inflammation, sensory neuron depletion decreases B cell population sizes, IgE levels, and asthmatic characteristics. Mechanistically, during bacterial infection, sensory neurons preferentially release vasoactive intestinal polypeptide (VIP). In response to asthma, sensory neurons release substance P. Administration of VIP into sensory neuron-depleted mice suppresses bacterial burden, while VIPR1 deficiency increases infection. Similarly, exogenous substance P delivery aggravates asthma in sensory neuron-depleted mice, while substance P deficiency ameliorates asthma. Our data, thus demonstrate that sensory neurons release select neuropeptides which target B cells dependent on the immunogen., (© 2024. The Author(s).)

Innate lymphoid cells (ILCs) are a heterogeneous population that play diverse roles in airway inflammation after exposure to allergens and infections. However, how ILCs respond after exposure to environmental toxins is not well understood. Here we show a novel method for studying the heterogeneity of rare lung ILC populations by magnetic enrichment for lung ILCs followed by particle-templated instant partition sequencing (PIP-seq). Using this method, we were able to identify novel group 1 and group 2 ILC subsets that exist after exposure to both fungal allergen and burn pit-related constituents (BPC) that include dioxin, aromatic hydrocarbon, and particulate matter. Toxin exposure in combination with fungal allergen induced activation of specific ILC1/NK and ILC2 populations as well as promoted neutrophilic lung inflammation. Oxidative stress pathways and downregulation of specific ribosomal protein genes (Rpl41 and Rps19) implicated in anti-inflammatory responses were present after BPC exposure. Increased IFNγ expression and other pro-neutrophilic mediator transcripts were increased in BPC-stimulated lung innate lymphoid cells. Further, the addition of BPC induced Hspa8 (encodes HSC70) and aryl hydrocarbon transcription factor activity across multiple lung ILC subsets. Overall, using an airway disease model that develops after occupational and environmental exposures, we demonstrate an effective method to better understand heterogenous ILC subset activation., (© 2024. The Author(s).)

Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity.

Introduction: While localized inflammation has been implicated in the pathophysiology of acute coronavirus disease of 2019 (COVID-19) olfactory dysfunction (OD), persistent COVID-19 OD remains poorly understood with limited therapeutics. Our prospective study evaluated olfactory cleft (OC) biomarkers as predictors of persistent OD in mucus sampling., Methods: COVID-19 subjects with persistent OD >3 months confirmed by psychophysical olfaction tests were compared to COVID-19 subjects with no OD and those with no prior infection. OC mucus samples were evaluated for 13 anti-viral and inflammatory biomarkers. Cohorts were compared using analysis of variance (ANOVA) and Mann-Whitney tests with multi-comparison adjustment. Viral RNA was assessed through RT-PCR using the COVID-19 N2 primer., Results: Thirty-five samples were collected (20 COVID persistent OD, 8 COVID no OD, and 7 non-COVID no OD). Significant differences in IFN-λ1 (p = 0.007) and IFN-γ (p = 0.006) expression in OC mucus were found across all three groups, with the highest cytokine concentrations corresponding to COVID OD. IFN-α2 levels were elevated in COVID OD versus no OD (p = 0.026). Mean IFN-γ levels were the highest in COVID OD, but there were higher levels found in COVID no OD compared to non-COVID no OD (p = 0.008). No difference was seen in IL6. No N2 gene expression was detected in all cohorts., Conclusion: IFN pathway cytokines were found elevated in the olfactory microenvironment of COVID-19 persistent OD compared to those with no OD and no prior history of COVID-19 infection., (© 2023 ARS‐AAOA, LLC.)

Aims: Despite recent investigations on the role of chitinase in asthma, its role in obesity-induced asthma has not been evaluated. Therefore, we investigated the roles of chitin, chitinase-1, and a chitinase-1 inhibitor (compound X, CPX) in a murine model., Main Methods: We assigned C57BL/6 mice to the ovalbumin (OVA) model or obesity model group. In the OVA model, mice received intraperitoneal OVA twice within a 2-week interval and intranasal OVA for 3 consecutive days. Additionally, chitin was intranasally administered for 3 consecutive days, and CPX was intraperitoneally injected three times over 5 days. In the obesity model, a high-fat diet (HFD) was maintained for 13 weeks, and CPX was intraperitoneally injected eight times over 4 weeks., Key Findings: In the OVA model, chitin aggravated OVA-induced airway hyper-responsiveness (AHR), increased bronchoalveolar lavage fluid (BALF) cell proliferation, increased fibrosis, and increased the levels of various inflammatory cytokines (including chitinase-1, TGF-β, TNF-α, IL-1 β, IL-6, IL-4, and IL-13). CPX treatment significantly ameliorated these effects. In the obesity model, HFD significantly increased AHR, BALF cell proliferation, fibrosis, and the levels of various inflammatory cytokines. Particularly, compared to the control group, the mRNA expression of chitinase, chitinase-like molecules, and other molecules associated with inflammation and the immune system was significantly upregulated in the HFD and HFD/OVA groups. Immunofluorescence analysis also showed increased chitinase-1 expression in these groups. CPX significantly ameliorated all these effects in this model., Significance: This study showed that CPX can be an effective therapeutic agent in asthma, especially, obesity-induced and -aggravated asthma to protect against the progression to airway remodeling and fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Millions of veterans have been exposed to burn pit smoke during combat deployments throughout the last three decades. Toxic compounds present in burn pit fumes that may cause or exacerbate upper and lower airway diseases include dioxins, polyaromatic hydrocarbons, and particulate matter, among others. There have been several observational studies evaluating the potential role of burn pit exposure in the development of a multitude chronic health conditions, and the veterans Administration has established the Airborne Hazards and Open Burn Pit Registry in 2014. However, specific causality of airway disease from burn pits has been difficult to prove, and there are multiple barriers toward etiologic research. Preclinical models have demonstrated airway dysfunction and inflammation but modeling human exposures remains challenging. Here, we review the current literature on the potential impact of burn pit exposure on chronic airway disease., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D 2 , and low levels of prostaglandin E 2 . Further, 15-hydroxyeicosatetraenoic acid (15-HETE) levels may have predictive value in therapeutic outcomes of aspirin desensitization. Accumulation of nasal group 2 innate lymphoid cells (ILC2s) has been demonstrated during COX-1 inhibition in AERD, although the relationships between tissue ILC2 accumulation, reaction symptom severity, and novel lipid biomarkers are unknown., Objective: We sought to determine whether novel lipid mediators are predictive of nasal ILC2 accumulation and symptom scores during COX-1 inhibitor challenge in patients with AERD., Methods: Blood and nasal scraping samples from patients with AERD were collected at baseline and COX-1 inhibitor reaction and then processed for flow cytometry for nasal ILC2s and serum for lipidomic analysis., Results: Eight patients with AERD who were undergoing aspirin desensitization were recruited. Of the 161 eicosanoids tested, 42 serum mediators were detected. Baseline levels of 15-HETE were negatively correlated with the change in numbers of airway ILC2s (r = -0.6667; P = .0428). Docosahexaenoic acid epoxygenase metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) was positively correlated with both changes in airway ILC2s (r = 0.7143; P = .0305) and clinical symptom scores (r = 0.5000; P = .0081)., Conclusion: Low levels of baseline 15-HETE predicted a greater accumulation of airway ILC2s in patients with AERD who were receiving COX-1 inhibition. Further, increases in the cytochrome P pathway metabolite 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20-diHDPA) were associated with increased symptoms and nasal ILC2 accumulation. Future studies to assess how these mediators might control ILC2s may improve the understanding of AERD pathogenesis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Innate lymphoid cells (ILCs) are a rare cell population subdivided into ILC1s, ILC2s, and ILC3s, based on transcription factor expression and cytokine production. In models of lung inflammation, the release of alarmins from the epithelium activates ILC2s and promotes the production of Th2-cytokines and the proliferation and migration of ILC2s within the lung. ILC2s are the innate counterpart to CD4 + Th2s and, as such, express Gata-3 and produce IL-4, IL-5, and IL-13. Due to the low number of ILCs and the lack of specific surface markers, flow cytometry is the most reliable technique for the identification and characterization of ILCs. In this protocol, multicolor flow cytometry is utilized to identify Lineage- Thy1.2+ ILCs. Intracellular cytokine staining further identifies ILC2s within the lung. This protocol presents a reliable method for promoting ILC2-mediated lung inflammation and for monitoring ILC2 biology. Key features In this protocol, ILC2s are expanded via intranasal challenges with Alternaria alternata , a fungal allergen, or recombinant IL-33. Bronchoalveolar lavage (BAL) and lung are collected and processed into single-cell suspension for multicolor flow cytometric analysis, including intracellular staining of transcription factors and cytokines. During lung inflammation, the percentage of ILC2s and eosinophils increases. ILC2s express greater levels of Gata-3 and Ki-67 and produce greater amounts of IL-5 and IL-13. Graphical overview., Competing Interests: Competing interestsThere are no conflicts of interest or competing interests., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY license.)

In an era of rapid identification of inborn errors of immunity, Sharma et al. 1 report novel heterozygous gain-of-function variants in the signal transducer and activator of transcription 6 (STAT6) gene in individuals with severe and early onset multi-systemic allergic disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3 -/- and Rbm3 -/- Rag2 -/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3 -/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3 -/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3 -/- Cyslt1r -/- mice show dependence on CysLT1R for accumulation of ST2 + IL-17 + ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R., (© 2022. The Author(s).)

ILC2s are key players in the emergence of type 2 inflammation in many pulmonary diseases. While several phenotypic markers can be used to identify ILC2s, our method utilizes the surface markers CD127 and ST2 to classify a group of type 2 cytokine-producing ILC2s upon activation by the fungal allergen Alternaria alternata . Here, we provide our protocol for the detection and isolation of a highly pure population of pulmonary mouse ILCs via flow cytometry and cell sorting. We also describe the methods for in vitro stimulation to assess the functionality of ILC2s., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti-IL-5/IL-5 receptor, anti-IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D 2 antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

ORM1-like 3 (ORMDL3) has strong genetic linkage to childhood onset asthma. To determine whether ORMDL3 selective expression in airway smooth muscle (ASM) influences ASM function, we used Cre-loxP techniques to generate transgenic mice (hORMDL3Myh11eGFP-cre), which express human ORMDL3 selectively in smooth muscle cells. In vitro studies of ASM cells isolated from the bronchi of hORMDL3Myh11eGFP-cre mice demonstrated that they developed hypertrophy (quantitated by FACS and image analysis), developed hyperplasia (assessed by BrdU incorporation), and expressed increased levels of tropomysin proteins TPM1 and TPM4. siRNA knockdown of TPM1 or TPM4 demonstrated their importance to ORMDL3-mediated ASM proliferation but not hypertrophy. In addition, ASM derived from hORMDL3Myh11eGFP-cre mice had increased contractility to histamine in vitro, which was associated with increased levels of intracellular Ca2+; increased cell surface membrane Orai1 Ca2+ channels, which mediate influx of Ca2+ into the cytoplasm; and increased expression of ASM contractile genes sarco/endoplasmic reticulum Ca2+ ATPase 2b and smooth muscle 22. In vivo studies of hORMDL3Myh11eGFP-cre mice demonstrated that they had a spontaneous increase in ASM and airway hyperreactivity (AHR). ORMDL3 expression in ASM thus induces changes in ASM (hypertrophy, hyperplasia, increased contractility), which may explain the contribution of ORMDL3 to the development of AHR in childhood onset asthma, which is highly linked to ORMDL3 on chromosome 17q12-21.

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cavagnero, Badrani, Naji, Amadeo, Leng, Lacasa, Strohm, Renusch, Gasparian and Doherty.)

Purpose of Review: The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD., Recent Findings: In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients., Summary: Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To synthesize investigations into the role of lipid-mediated recruitment and activation of group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease (AERD)., Data Sources: A comprehensive literature review of reports pertaining to cellular mechanisms, cytokine, and lipid mediators in AERD, as well as ILC2 activation and recruitment, was performed using PubMed and Google Scholar., Study Selections: Selections of studies were based on reports of lipid mediators in AERD, cytokine mediators in AERD, type 2 effector cells in AERD, platelets in AERD, AERD treatment, ILC2s in allergic airway disease, and ILC2 activation, inhibition, and trafficking., Results: The precise mechanisms of AERD pathogenesis are not well understood. Greater levels of proinflammatory lipid mediators and type 2 cytokines are found in tissues derived from patients with AERD relative to controls. After pathognomonic cyclooxygenase-1 inhibitor reactions, proinflammatory mediator concentrations (prostaglandin D2 and cysteinyl leukotrienes) are rapidly increased, as are ILC2 levels in the nasal mucosa. The ILC2s, which potently generate type 2 cytokines in response to lipid mediator stimulation, may play a key role in AERD pathogenesis., Conclusion: Although the literature suggests that lipid-mediated ILC2 activation may occur in AERD, there is a dearth of definitive evidence. Future investigations leveraging novel next-generation single-cell sequencing approaches along with recently developed AERD murine models will better define lipid mediator-induced ILC2 trafficking in patients with AERD., (Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Predicting the factors that increase the risk of immune-related pneumonitis, a potentially life-threatening complication of treatment with immune checkpoint inhibitors for cancer, is a clinical challenge. Baseline clinical factors such as asthma may portend the development of pneumonitis due to pre-existing airway inflammation prior to immunotherapy., Objective: The purpose of the study was to investigate whether a prior diagnosis of asthma is associated with an increased risk of immune-related pneumonitis in patients undergoing cancer immunotherapy., Methods: Patients at the Moores Cancer Center at UC San Diego Health undergoing immunotherapy were identified on an IRB-approved protocol. Clinical charts were reviewed for asthma documented in the medical records and CT scans were reviewed during and after treatment. Pneumonitis was defined as the onset of new pulmonary symptoms with characteristic imaging findings during or after a patient's first course of immunotherapy that could not be readily explained as infection or a progression of malignancy. It was graded according to the Common Terminology Criteria for Adverse Events., Results: A total of 187 patients were included. A diagnosis of asthma was found in the records of 26 cases (13.9%). Pneumonitis was found in 10 cases (5.35%); 50% were grade 2 and 50% were grade 3-4. Two of the grade 3-4 cases (40%) occurred in patients with non-small-cell lung cancer. Three patients with asthma developed pneumonitis (11.5% of patients with asthma), all grade 3-4. Only 28.6% of the non-asthma-pneumonitis cases were grade 3-4. All (100%) of the asthma-pneumonitis patients were former smokers, while 71.4% of the non-asthma-pneumonitis patients were former smokers., Conclusion: A history of asthma may be associated with a higher grade of pneumonitis if it develops, and a history of smoking may augment this relationship., (© 2019 S. Karger AG, Basel.)

The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Though a sizeable amount of data connects mast cell activity to the neurologic system, less is known about the true clinical implications of this relationship. Even less is understood about treatment strategies in those with both allergic and neurologic complaints. This is particularly true in postural orthostatic tachycardia syndrome (POTS), a common type of dysautonomia, where patients are burdened by symptoms of orthostatic cerebral hypoperfusion and several other comorbidities that are likely influenced by autonomic tone. Some patients describe characteristic allergic symptoms, in the absence of typical IgE mediated triggers, and also improvement with traditional mast cell directed medications. Further work is necessary to determine whether these anecdotal observations are valid. The answer to this question will likely be addressed as the mechanisms of POTS are better characterized, which may include a phenotype with distinct mast cell involvement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Postural orthostatic tachycardia syndrome (POTS) is a debilitating disease that predominantly affects young women. It is a multifactorial disorder that is characterized by severe tachycardia and orthostatic intolerance. Patients with POTS experience a variety of cardiac, neurological, and immunological symptoms that significantly reduce quality of life. In this review, a comprehensive framework is provided to aid in helping identify and treat patients with POTS. Given its heterogenous nature, it is crucial to understand each component of POTS in relation to one another instead of distinct parts. The framework highlights the overlap among the five main subtypes of POTS based on its pathophysiology (neuropathic, hypovolemic, primary hyperadrenergic, joint-hypermobility-related, and immune-related). Emphasis is placed on incorporating a multidisciplinary approach when treating patients with POTS, especially with a new focus towards immunotherapy. Although research has advanced our knowledge of POTS, there is still a critically unmet need to further our understanding and provide patients with the relief they need.

Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic nasal polyps, asthma, and airway reactions upon cyclooxygenase (COX) 1 inhibition. AERD is present in up to 7% of adult patients with asthma and the underlying pathogenesis remains largely elusive but prostaglandin D2, cysteinyl leukotrienes, mast cells, and type 2 cytokines are thought to contribute. A wealth of studies have recently implicated group 2 innate lymphoid cells (ILC2), a novel lineage-negative lymphocyte population that produces type 2 cytokines, in human allergic disease pathogenesis. Importantly, our recent work identified that ILC2s are recruited to the nasal mucosa of patients on AERD after COX-1 inhibitor administration. Here, we review the potential impact of ILC2s in the development and propagation of type 2 inflammation in AERD.

Background: Group 2 innate lymphoid cells (ILC2s) expand in the lungs of mice during type 2 inflammation induced by the fungal allergen Alternaria alternata. The increase in ILC2 numbers in the lung has been largely attributed to local proliferation and whether ILC2s migrate from the circulation to the lung after Alternaria exposure is unknown., Objective: We examined whether human (lung, lymph node, and blood) and mouse lung ILC2s express β 1 and β 2 integrin adhesion molecules and whether these integrins are required for trafficking of ILC2s into the lungs of mice., Methods: Human and mouse ILC2s were assessed for surface expression of β 1 and β 2 integrin adhesion molecules by using flow cytometry. The role of β 1 and β 2 integrins in ILC2 trafficking to the lungs was assessed by in vivo blocking of these integrins before airway exposure to Alternaria in mice., Results: Both human and mouse lung ILC2s express high levels of β 1 and β 2 integrin adhesion receptors. Intranasal administration of Alternaria challenge reduced ILC2 numbers in the bone marrow and concurrently increased blood and lung ILC2 numbers. In vivo blocking of β 2 integrins (CD18) significantly reduced ILC2 numbers in the lungs but did not alter ILC2 proliferation, apoptosis, and function. In contrast, in vivo blocking of β 1 integrins or α 4 integrins did not affect lung ILC2 numbers., Conclusion: ILC2 numbers increase in the mouse lung not only through local proliferation but also through trafficking from the circulation into the lung using β 2 rather than β 1 or α 4 integrins., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The recent discovery of group 2 innate lymphoid cells (ILC2s) has caused a paradigm shift in the understanding of allergic airway disease pathogenesis. Prior to the discovery of ILC2s, Th2 cells were largely thought to be the primary source of type 2 cytokines; however, activated ILC2s have since been shown to contribute significantly, and in some cases, dominantly to type 2 cytokine production. Since the discovery of ILC2s in 2010, many mediators have been shown to regulate their effector functions. Initial studies identified the epithelial derived cytokines IL-25, IL-33, and TSLP as activators of ILC2s, and recent studies have identified many additional cytokine and lipid mediators that are involved in ILC2 regulation. ILC2s and their mediators represent novel therapeutic targets for allergic airway diseases and intensive investigation is underway to better understand ILC2 biology and upstream and downstream pathways that lead to ILC2-driven airway pathology. In this review, we will focus on the cytokine and lipid mediators that regulate ILC2s in human allergic airway disease, as well as highlight newly discovered mediators of mouse ILC2s that may eventually translate to humans.