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Tuesday, February 14, 2017

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

The immune system is very complicated, and sometimes, a mutation in a single protein can cause major problems.  One such protein is Phosphoinositide 3-kinase (PI3Kδ), which, may interfere with the body’s ability to fight off disease upon activation.  In this month’s issue of JACI, Coulter and colleagues look at 53 patients with Activated PI3Kδ Syndrome (APDS) (J Allergy Clin Immunol 2017; 139(2): 597-606).

These 53 patients were found worldwide, and the diagnosis was confirmed by genetic sequencing.  They then looked at the laboratory findings, radiographs, and other clinical features to better understand the presentation of APDS. 

All in all, the presentation of APDS was highly variable.  Some were asymptomatic through adulthood while others developed infections early in childhood, leading to death.  Three required a bone marrow transplantation.  The most common infectious complication was recurrent respiratory tract infections.  Much like other antibody deficiency syndromes, there was a high rate of bronchiectasis.  Almost half of patients had difficulty fighting viruses like herpes, EBV, and CMV.  Swollen lymph nodes and hepato-splenomegaly were also very common.

Interestingly, PI3K mutations didn’t just effect the ability to fight infections.  Eighteen also had inflammatory/autoimmune diseases, most commonly autoimmune cytopenias. Seventeen had nodular mucosal lymphoid hyperplasia and seven developed lymphoma.  Since PI3K3D is associated with the central nervous system, there was also noted to be a high rate of neurodevelopmental morbidity, ranging from speech delays to global developmental delay.

This study provides a description of APDS, a newly recognized form of immunodeficiency.  It can present in so many different ways, so physicians should keep an eye out in patients who have recurrent infections, especially those involving the respiratory tract or those due to herpes viruses.  Treatment with hematopoietic stem cell transplant may be curative, and clinical trials for selective PI3Kδ inhibitors are currently underway.

Factors influencing the infant gut microbiome at age 3-6 months: Findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART)

In the gut, there are millions of bacteria and other micro-organisms, collectively called the gut microbiome.  Microbes in the gut are known to be important modulators of the developing immune system.   In this month’s issue of JACI, Sordillo and colleagues look at predictors of the gut microbiome in infancy (J Allergy Clin Immunol 2017; 139(2): 482-491).  Microbes present in this early life window may ultimately affect the risk of allergic disease later in childhood. 

They looked at stool samples in over 300 infants born to mothers in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a trial in which pregnant women took vitamin D to see how it would impact their children’s health.  In the stool, they looked at the bacterial genes to see what bacteria were present.

They found that race, mode of delivery, and formula-feeding are associated with different composition of gut bacteria.  Black race and caesarean section were independent predictors of having lower levels of Bacteroides.  This is important because lower Bacteroides abundance has already been associated with immune changes predisposing to asthma and allergic disease.  In addition, formula feeding was linked to higher levels of Clostridia.  Previous studies have suggested a link between Clostridia and development of atopic dermatitis, wheezing and allergic sensitization.

This study points out that factors with the potential to increase allergic disease risk are also associated with alterations in the infant gut microbiome, but there are still a lot of unanswered questions.  Do these factors (race, mode of delivery, formula feeding) act via changes in the infant gut microbiome to increase allergic disease risk?  Do these changes in the gut microbiome persist through childhood?  Can breastfeeding change the microbiome and reduce the risk of allergic disease?  Finally, can we figure out which species and subspecies are most closely associated with these risks?  Further research is needed, but this study provides a meaningful step towards providing answers.


Tuesday, December 20, 2016

Care transition interventions for children with asthma in the emergency department

Childhood asthma is a common and costly chronic medical condition, affecting 7 million children and leading to more than 50 billion dollars in direct healthcare costs every year.  It is particularly burdensome for non-Hispanic black and Puerto Rican children, who are four times as likely to visit the Emergency Department (ED) as non-Hispanic white children.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Martin and colleagues review strategies to bridge care from the ED to home and ambulatory settings, like primary care providers (J Allergy Clin Immunol 2016; 138(6): 1518-1525).   They divide these strategies into two domains: care coordination and self-management education.

Five studies were identified regarding care coordination.  Three involved improved scheduling for follow up appointments, one involved allergen skin testing in the ED, and one involved use of a template to improve adherence to guidelines in the ED.  In all five studies, there were mixed results in the improvement in asthma care.  Only one of the four interventions for self-management education showed improvement in asthma care.  An ongoing project, the CHICAGO Plan, attempts to improve asthma outcomes by taking a patient-centered approach toward asthma care coordination and self-management education in the ED.

Everyone agrees that the goal is to avoid ED visits but how exactly we can best achieve that is, as of yet, unknown. Interventions that link care coordination across the health and community sectors may be one way.  Indeed, there’s still a lot of work to be done in order to determine whether such programs are effective, but this review provides a solid basis for further progress.  

Patient-centered outcomes research to improve asthma outcomes

Asthma is a devastating chronic disease that affects up to 24 million Americans.  It is more severe and prevalent among African Americans and Hispanics, especially Puerto Ricans.  There’s a two-fold increase in asthma mortality in Hispanic children and three-fold among African Americans, compared to Whites.  The causes of these disparities are complex, but are undoubtedly worsened by the observation that they are less likely to be treated according to the National Asthma Education Prevention Program (NAEPP) guidelines, which have been widely available for the past 20 years.  To address these issues, the Patient-Centered Outcomes Research Institute (PCORI) funded 8 studies to help patients and clinicians adhere to the guidelines.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Anise and colleagues review these 8 randomized control trials (J Allergy Clin Immunol 2016; 138(6): 1503-1510).

Among the approaches being used are (1) clinician education, (2) clinical decision support, (3) patient education in the ER and clinic, (4) use of community health workers, and (5) use of long-term and quick-relief medications.    While each study has a distinct focus, all of them overlap in incorporating relevant stakeholders into the projects, and aligning local resources towards overarching, generalizable goals. 

The research projects are still underway, and results will not be available for at least two more years.  But these research projects are pioneering in the way that they are putting research in action in local communities, and embracing multi-faceted approaches with the understanding that single interventions may not be effective.

Home visits are needed to address asthma health disparities in adults

Asthma is a huge public health problem in the United States today.  But all asthmatics are not affected equally – there are a lot of disparities in asthma care.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Bryant-Stephens and colleagues describe the need for home visits to address these asthma health disparities (J Allergy Clin Immunol 2016; 138(6): 1526-1530).  They note that most of the research on asthma so far has been on patients who go to clinics.  This has meant that people who have problems getting to the clinic, like the elderly, disabled, and those with other chronic conditions are often left out.  To help prevent overlooking these blindspots, they advocate for the involvement of community health workers.  In particular, they describe the experiences of three community health workers when they visited patients.  They found that the challenges at home are often overwhelming.  Social stressors in patients’ lives can be major problems interfering with their ability to take care of their asthma and other health problems. Community health workers may be used to provide resources to overcome these barriers and to encourage patients to adopt healthier habits, such as smoking reduction, and better communication with providers.   Even though home visits are not routine in clinical practice and are only rarely used in research settings, Bryant and colleagues suggest that there may be greater room for community health workers.  They recommend examination of the costs as well as benefits, and identifying vulnerable patients who would be best managed in this way.  They conclude that there needs to be better understanding of the barriers to optimal asthma management, so that these disparities can be addressed directly.

Monday, November 28, 2016

Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity

Over the past 25 years, the rates of both obesity and asthma have increased dramatically.  These are related to one another, with a 92% increased risk of asthma in people whose body mass index (BMI) exceeds 30 kg/m2. People who do lose weight through bariatric surgery or dietary restriction, tend to show improvement in their bronchial hyperresponsiveness, the major feature of asthma.  The reason for this correlation is not well understood.  IL-33, a intercellular messenger that skews helper T cells towards allergies, is produced by fat cells.  IL33 also induces type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), two more recently identified sets of immune cells in fat and the lungs. 

In this month’s issue of the Journal of Allergy and Clinical Immunology, Everaere and colleagues use mouse models to investigate the roles of innate lymphoid cells in the correlation between asthma and obesity (J Allergy Clin Immunol 2016; 138(5): 1309-1318).  The mice were given a high-fat diet to induce obesity and were then sensitized to dust mites.  Their lung secretions were isolated by bronchoaveolar lavage (BAL) and checked for various proteins, RNA, and cell types by histology and flow cytometry. 

They found that nonsensitized obese mice had increased ILC counts and tissue eosinophils, cells that mediate damage in asthma, compared to lean mice.  These mice also had high IL33 and IL-1-Beta levels.  When ILCs were depleted using an anti-CD90 antibody, there was decreased infiltration by cells that prompt allergic inflammation, such as TH2 and TH17 cells.

Altogether, these results suggest that ILC2s and ILC3s mediate and exacerbate airway inflammation in obese mice.  This opens the possibility of using anti-IL5 antibodies in treating asthma for obese patients.

Wednesday, November 23, 2016

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice

Eosinophilic esophagitis (EoE) is an allergic disorder seen in approximately 1 out of 2000 people in the United States.  Young children often present with vomiting and failure to thrive, while older children and adults may have difficulties swallowing, food impaction, or strictures in their esophagus.  Despite increasing awareness and diagnosis, the etiology remains unclear.  Past studies support the role of a subset of Helper T-cells, called TH2 cells, which are also present in many other allergic diseases, including atopic dermatitis (AD).  In fact, approximately half of patients with EoE have AD.  But why is that so?

In this month’s issue of the Journal of Allergy and Clinical Immunology, Venturelli and colleagues investigate the role of abnormal skin barriers in the development of EoE, and, in particular, the role of IL-33, a chemical messenger whose levels are elevated in both EoE and AD (J Allergy Clin Immunol 2016; 138(5): 1367-1380).  They also investigated the role of ST2, an IL-33 receptor found on basophils using a mouse model. They applied ovalbumin to the mechanically injured skin of wild-type mice, and then to the skin of mice lacking filaggrin (ft/ft), which tend to develop AD-like skin lesions.  They then challenged both strains of mice with intra-nasal ovalbumin.  The esophagi of these mice were then examined microscopically and through advanced genetic analytic techniques. 

They found that a disrupted skin barrier (by tape stripping or a Filaggrin gene mutation) promotes the development of EoE, and that this is mediated by IL-33, ST2, and basophils.  They also reported that patients with EoE have increased ST2 in their esophagus. Their findings suggest that IL-33 could be a potential link between AD and EoE.  This is an important step in understanding how patients with AD and filaggrin deficiency tend to develop EoE.  Just as importantly, it may prompt development of new medications that block IL-33 or ST2, which could be effective targets for EoE.