Thursday, July 13, 2017
Features of the bronchial bacterial microbiome associated with atopy, asthma and responsiveness to inhaled corticosteroid treatment
It’s been known that asthmatic lungs are different from healthy lungs in many aspects, including housing different strains of bacteria. So far, studies haven’t been able to tell whether these differences are due to asthma, associated allergies (atopy), or treatment with different drugs. They also haven’t been able to determine how these differences affect the way asthma manifests itself and how asthma can be treated. In this month’s issue of JACI, Durack and colleagues aim to answer these pressing questions (J Allergy Clin Immunol 2017; 140(1): 63-75).
Durack and other investigators looked at the bacterial communities in 84 individuals, split into three groups: (1) 42 atopic asthmatic subjects, (2) 21 atopic non-asthmatic subjects, and (3) 21 non-atopic non-asthmatic, otherwise healthy, subjects. They also looked at inflammatory markers and changes in bronchial hyperresponsiveness after 6 weeks of treatment with fluticasone, an inhaled steroid commonly used for asthma treatment.
What they found is that the types of bacteria in each of the three groups were significantly different. This included the group with atopy without asthma, suggesting that atopy itself is associated with different patterns of bacterial colonization of the bronchi, but these patterns also differed from those in the subjects with atopic asthma. The bacteria seen in the asthmatic patients expressed genes for different metabolic pathways that result in products previously linked to risks for asthma development. And subjects with high levels of allergy/atopy-related inflammation markers in their bronchial epithelium (“T2-high asthma”) had overall lower amounts of bacteria. Differences were also found in the asthmatic subjects who responded to fluticasone, in that their bronchial bacteria were less different from those in healthy subjects than were the bronchial bacteria in the non-responsive asthmatics.
Overall these findings suggest that bacterial composition in the lungs is associated with various immunologic and clinical features of the disease. It also suggests that targeting these bacteria may be a way to help prevent, or even treat, asthma in the future.
Monday, July 10, 2017
Allergies and asthma are growing public health problems, as rates have continued to increase over the past 50 years. In that same time period, there has been a dramatic movement of people away from farms into cities and towns. Previous studies have suggested that these may be related and data do exist to show childhood farm animal exposures and consumption of unpasteurized milk reduces the risk of childhood asthma and allergies. But what about early-life farm exposures and adult asthma and allergic sensitization? In this month’s issue of JACI, House and colleagues studied more than 3000 farmers and their spouses to help answer this question (J Allergy Clin Immunol 2017; 140(1): 249-256).
Specifically, they looked at 1746 farmers and 1555 spouses from Iowa and North Carolina enrolled in the Agricultural Lung Health Study. They used questionnaires to identify current asthma and early-life farming exposure, and then measured blood levels of allergen-specific IgE, the type of antibody that suggests allergic sensitization to a given allergen.
After analyzing all the data, they found that exposure to a farming environment when still in the womb, living on a farm when born, exposure to farm animals before the age of 6 years, and drinking raw milk were all associated with a decreased risk of allergic sensitization. Among these, the strongest association was between the mother performing farm activities while pregnant and future atopy. There was little correlation between these factors and asthma development in adulthood.
This study builds upon previous research supporting “the hygiene hypothesis,” that is, exposures to diverse types of germs early in life promotes immune tolerance and reduces the risk of allergies throughout life. This information can guide further research in the prevention and treatment of allergies.
Monday, June 5, 2017
Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma
Omalizumab is a potent medication approved to treat asthma, which has been shown to improve symptoms as well as decrease flares and use of rescue medications. When it first became available, its long-term safety was not solidly clarified. In the May 2017 issue of JACI, Iribarren and colleagues discuss the results of the post-marketing observational study called EXCELS, which followed patients for five years to determine the long-term effects of omalizumab, with a particular focus on cardiovascular (CV) and cerebrovascular (CBV) events, such as heart attacks and strokes (J Allergy Clin Immunol 2017; 139(5): 1489-1495). Pooled results from previous studies showed a higher incidence of these events, but no clear association with omalizumab use was found.
Iribarren and colleagues looked at nearly 5000 patients on omalizumab and compared them to nearly 3000 that were not on omalizumab. They found that omalizumab is effective for moderate-to-severe asthma. Because more severe asthma, for which omalizumab would be indicated, is both directly and indirectly associated with risks for CV/CBV events, it was expected that there would be a higher rate of CV/CBV adverse events in the omalizumab group. The results showed that patients were 32% more likely to have a CV/CBV event after controlling for other factors.
However, this doesn’t mean that omalizumab causes CV/CBV events. Due to asthma severity and other risk factors, such as the presence of other diseases, the authors conclude that an increased risk cannot be ruled out. Healthcare professionals should be aware of this potential association when counseling patients about starting omalizumab.
It has long been known that many diseases, like asthma, are the result of complex interactions between genes and the environment. But how exactly do these two factors contribute to atopic asthma? In the May 2017 issue of JACI, Yang and colleagues discuss the epigenetic factors involved in the development of childhood asthma (J Allergy Clin Immunol 2017; 139(5): 1478-1488). They looked at nasal brushings from 36 inner-city children with asthma between the ages of 10 and 12 and compared them with nasal brushings from 36 children without asthma. They then looked at patterns of methylation, a way that genes can be chemically modified in order to change their expression. They found that 186 genes were modified in this way. The median percentage in methylation changes between allergic patients and non-allergic patients was 6.8%. This is in line with previous research that shows that there are significant changes in methylation in other airway diseases like chronic obstructive pulmonary disease (COPD) and with cigarette smoking exposure.
This research is important, because it opens up new targets for research, diagnosis, and perhaps even treatment. Future research can focus on what specific environmental changes lead to differences in genetic expression. Additionally, because the normal bacteria in the nose affect methylation patterns, researchers may be able to look at which specific bacterial species impact gene expression. The authors speculate that the methylation markers can be checked to determine disease activity in the future.
Wednesday, May 31, 2017
Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: Cohort study
Atopic dermatitis is a chronic skin disorder in which the skin becomes dry, itchy and thickened. Even though it is very common in children, its exact causes are not well-known. Because water is a known skin irritant and the skin of infants are very sensitive, it has been thought that hard water, that is water that contains high calcium carbonate, may be a risk factor. In this month’s issue of JACI, Engebretsen and colleagues investigate whether early exposure to hard domestic water is associated with the prevalence of atopic dermatitis (J Allergy Clin Immunol 2017; 139(5): 1568-1574).
To do this, they looked at the Danish National Birth Cohort study which collected nearly 100,000 children born between 1996 and 2002. Out of these, the mothers of 55,092 children completed an interview at 6 and 18 months to get more information on atopic dermatitis. What the authors found was that hard water is associated with a higher incidence of atopic dermatitis. This effect was dose-dependent, and they attribute a 2% risk for atopic dermatitis on hard domestic water. In addition, they found that children born in autumn and winter had a higher incidence as well. However, combined evaluation of these two effects did not cause an even greater incidence on atopic dermatitis.
The reasons for this association are unclear. The authors suggest that hard water may change the acidity of skin and thus change the activity of skin enzymes, or maybe that it requires more irritant soap for lather production with hard water. It may even be that hard water changes the growth of bacteria on the skin that may modulate risks for atopic dermatitis. It also opens a lot of other questions that have not yet been explored. Can water softening reduce the risk of developing AD? What role do skin moisturizers and other emollients have in preventing hard water-induced skin damage? Does this effect extend to infants outside of Denmark and other Nordic countries? Although these are all unanswered, this study opens a new window for research and helps point the way for further directions.
Monday, April 10, 2017
Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: clinical and histopathological correlations
Asthma is a disease in which the airways of the lung become very sensitive to certain triggers, leading to spasms, in turn causing shortness of breath, coughing and wheezing. The ultimate cause of asthma is unclear, but it has been shown in previous studies that there is remodeling of the airways in severe asthma. Airway smooth muscle (ASM) increases, along with fibrosis, infiltration of new blood vessels, and growth of cells that line the airways. Recently, a procedure called bronchial thermoplasty (BT) has been developed, in which an endoscope is inserted into the airways. This endoscope then delivers a temperature-controlled radio frequency to the airway wall. In this month’s issue of JACI, Pretolani and colleagues look at bronchial thermoplasty and its effect on various clinical and histopathological findings (J Allergy Clin Immunol 2017; 139(4): 1176-1185).
In order to do this, they recruited 15 patients with severe uncontrolled asthma that did not respond to medications. They looked at the symptoms through the Asthma Control Test (ACT) and the Asthma Quality of Life Questionnaire (AQLQ), as well as breathing patterns via spirometry and biopsy samples. Bronchial thermoplasty was then performed. At 3 and 12 months, the clinical and airway effects were examined.
What they found is that asthma control and quality of life increased considerably. Exacerbations requiring oral steroids, emergency room visits, and hospitalizations were also decreased by approximately 90%. Biopsy samples from 3 months showed a decrease in ASM size, as well as nerve fibers and neuroendocrine cells.
Based on these results, Pretolani and colleagues conclude that bronchial thermoplasty is an option for severe, uncontrolled, treatment refractory asthma. Bronchial thermoplasty seems to affect the structure of airways, especially muscle size and nerve connections. Targeting these structures, through thermoplasty or other means may be an effective way to help control these difficult-to-control cases.
Thursday, April 6, 2017
A prospective study on the natural history of patients with profound combined immunodeficiency (P-CID): an interim analysis
The immune system is complex, composed of numerous cells, proteins, and other components. Among them, the T-cells are essential in fighting off infectious agents and regulating the functions of the immune system. People with reduced or dysfunctional T-cells can have life-threatening complications, and may require interventions like hematopoietic stem cell transplant (HSCT), gene therapy, or enzyme replacement. If a T cell deficiency is severe (severe combined immunodeficiency, SCID), these treatment decisions are clear. However, in patients with moderate T cell deficiency (profound combined immunodeficiency, P-CID), prognosis is unclear and transplant decisions are difficult. These patients have so far received little attention. In this month’s issue of JACI, Speckmann and colleagues report the first 51 P-CID patients enrolled in a long-term prospective study (J Allergy Clin Immunol 2017; 139(4): 1302-1310). The patients suffer from heterogenous T cell deficiencies including: (1) ‘bona fide’ CID, where deficiencies are typically associated with profound T-cell deficiencie, (2) atypical severe combined immunodeficiency (SCID), in which T-cell dysfunction is due to less life-threatening mutations in SCID-associated genes, and (3) T cell deficiencies with genetically unidentified cause. They analyzed the clinical and molecular characteristics at study entry to determine disease severity. Ultimately, the aim is to identify parameters predicting when the risks of untreated disease outweigh the risks of performing HSCT.
They found that patients with P-CID have a high rate of morbidity and mortality as well as a lower quality of life. One-third of patients underwent HSCT within the first year of inclusion into the study, 5 patients died. The genetic diagnosis has limited value as a predictor of disease evolution and thus as a guidance for HSCT decisions, with the age of onset, quality of life, and severity of disease not significantly different between patients with atypical SCID, bona fide CVID, or genetically undefined disease. This was in line with the authors’ expectations, but what they didn’t expect was that basic measures of T-cell immunity also did not predict the prognosis and course of their disease.
Speckmann and colleagues continue to enroll patients and hope to eventually reach their target of 120. Parallel long-term follow-up of transplanted and of non-transplanted patients will better identify predictors for the natural progress of P-CID, and, in turn, give better guidance about how, and when, to treat with HSCT.