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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.

The nasal methylome and childhood atopic asthma

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.

Thursday, March 23, 2017

Omalizumab facilitates rapid oral desensitization for peanut allergy

Food allergy is the leading cause of anaphylaxis, a serious and life-threatening systemic allergic reaction, among American children today.  Although it can be managed by avoidance and supportive management, there are few options for disease modification.  Oral immunotherapy (OIT) whereby increasing doses of an allergen are given, has been a promising investigational treatment, but the high rates of adverse reactions and intolerance of symptoms lead to high drop-out rates. In this month’s issue of JACI, MacGinnitie et al look at the use of omalizumab, an anti-IgE medication used in asthma, in helping to facilitate OIT (J Allergy Clin Immunol 2017; 139(3): 873-881).

To do this, they randomized 37 participants to receive either omalizumab or a placebo for 19 weeks, in addition to oral immunotherapy.  Neither the patients nor the researchers knew the assignment of the groups.  6 weeks after stopping the omalizumab, it was found that a majority (79%) of the omalizumab group was able to achieve the 2000-mg maintenance dose.  Even 12 weeks after stopping the omalizumab, 76% were able to tolerate even higher doses of peanut protein (4000mg).  Even though the reaction rates were not statistically different between the two groups, the omalizumab group was also exposed to higher doses of peanut proteins.

Despite the small number of participants, this is encouraging news for the use of omalizumab as an adjunct for peanut oral desensitization.  The authors suggest that the benefits of omalizumab-enabled OIT may outweigh the downsides of its expense, repeat injections, and risk of hypersensitivity reactions.

Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age

Obesity and asthma are two of the most common childhood chronic diseases, seen in 25% and 10% of children, respectively.  There are increasing lines of evidence suggesting that they may be inter-dependent : fat may be the source of proinflammatory mediators and may change the mechanics of lung function. 

However, not all fat is considered equal.  The android distribution of fat along the abdomen, compared to gynoid distribution along the hips, is more closely associated with a variety of cardiometabolic diseases.  Similarly, visceral fat, situated just above the guts in the belly, is considered a marker of inflammatory status, compared to more superficial subcutaneous fat deposits.  In this month’s issue of JACI, den Dekker and colleagues discuss the effect of body fat mass distribution on asthma and airway function in children (J Allergy Clin Immunol 2017; 139(3): 810-816).

To do this, they looked at the medical histories and physical characteristics of 6178 children.  They focused on body-mass index (BMI), total and abdominal fat measures using ultrasonography and dual energy x-ray absorptiometry (DEXA), respiratory resistance (Rint), fractional exhaled nitric oxide (FENO), wheezing, and asthma.   They found that a higher BMI was associated with increased respiratory resistance and current wheezing.  They also noted that more visceral fat was associated with a higher FENO, while a higher android (belly)/gynoid (hip) ratio was associated with a lower FENO. 

Altogether, these results suggest that local fat deposition, especially visceral fat, is more closely related to asthma.  Even though the reasons for this are unclear, the authors speculate that maybe the different metabolic profiles of visceral vs. subcutaneous fat and the mechanical effects may be responsible for these differences.  Regardless, understanding the finer details of fat composition and distribution may help to explain part of the increased prevalence of childhood asthma.