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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.

Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy

Food allergy is a huge problem affecting 3 to 8% of school-age children.  So far, avoidance and supportive management have been the mainstays of therapy, but this is rapidly changing with studies showing the efficacy of oral immunotherapy (OIT), especially for peanut allergies.  In peanut OIT, gradually increasing doses of peanut are given as part of the buildup, with steady doses given during maintenance.  The hope is to desensitize the immune system so that reactions are not as severe.  In this month’s issue of JACI, Virkud and colleagues discuss the safety of oral immunotherapy to peanut by examining 104 patients from 3 peanut OIT trials (J Allergy Clin Immunol 2017; 139(3): 882-888).  They look at the past medical history, parental reports, daily symptom diaries, and relationship to dose escalations to determine the risks and predictors of adverse effects (AEs). 

The rate of AEs was high, with 80% experiencing at least 1 episode, and over 90% of these occurring at home.  42% of AEs were systemic reactions, but fewer than 50% received epinephrine, indicating a need for better patient education.  About half of these AEs were gastrointestinal, and half of the patients who dropped out did so due to these gastrointestinal AEs; this amounted to 10% of all enrolled patients.

Overall, allergic rhinitis and the wheal size on peanut skin prick testing (SPT) were significant predictors of AEs.  Allergic rhinitis approximately doubled the likelihood of having an AE, and seemed to explain why there was a higher rate of AEs during the spring and the fall.  Asthma was also predictive of AEs during maintenance, but not in the buildup phase.  Gastrointestinal AEs, like abdominal pain, nausea, vomiting, difficulty swallowing, and diarrhea, were also associated with the peanut SPT wheal size. 

While there remains a lot to be learned about oral immunotherapy, this study helps to determine who would be the best candidates for this promising means of treating food allergies.  Virkud and colleagues conclude that until there are rigorous well-designed and controlled trials, avoidance should remain the current standard of care.

Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening

Severe Combined Immunodeficiency (SCID) is a set of fatal immune disorders in which infants are born without proper functioning immune systems needed to fight off infections.  Fortunately, in recent years, there has been a push in several states for newborn screening (NBS) for early identification and life-saving treatment of these children.  In this month’s issue of JACI, Dorsey and colleagues describe the protocol that they use in California, which has successfully identified 32 SCID patients and 46 non-SCID patients with decreased levels of T-cells (J Allergy Clin Immunol 2017; 139(3): 733-742).

Newborn screening is performed by measuring TRECs (T-cell receptor excision circles) which are formed upon gene rearrangement of the T-cell receptor.  Peripheral blood count with differential and flow cytometry is the first follow up testing to determine the number of lymphocytes. This is followed by functional lymphocyte testing. If SCID is suspected, then children are placed in protective isolation and aggressively treated with antibiotics if needed.  A SCID social worker coordinates with family in order to manage workup and identify needs for support, including emotional support. 

 Because allogenic and autologous hematopoietic stem cell (HSC) transplant is life-saving, Dorsey and colleagues relay that they apply three principles: (1) use of a donor with the least likelihood of graft-versus-host disease (GVHD), (2) minimize the duration of waiting for the SCT, and (3) use the least amount of chemotherapy necessary.  Adherence to these principles has led to good outcomes: among the 32 that underwent transplant, 29 (94%) are alive and well. 

Among the non-SCID patients, the protocol is more reliant on the degree of immunodeficiency, but nevertheless, they are followed up very closely by immunologists in the coming years to identify the status of their immune dysfunction.  There remains a lot of work to be done in order to find out the best way to identify and treat SCID, but nationwide screening promises to accelerate our reaching that goal.

Tuesday, February 28, 2017

Humoral and cellular responses to casein in patients with food protein–induced enterocolitis to cow's milk

Food protein-induced enterocolitis syndrome (FPIES) is a type of food allergy in which children who eat milk, soy, or other foods develop repetitive vomiting and sometimes diarrhea.  This can lead to dehydration, and, in the longer run, failure to thrive.  But unlike more typical food allergies, FPIES isn’t mediated by IgE antibodies.  In fact, what causes FPIES is still a bit of a mystery.  In this month’s issue of JACI, Caubet and colleagues discuss results of their study on the immune responses seen in FPIES due to cow milk (CM-FPIES) (J Allergy Clin Immunol 2017; 139(2): 572-583).

To do this, they looked that the levels of antibodies, cytokines (chemical messengers), cell counts, and tryptase levels in 38 patients with active and resolved CM-FPIES.  Oral food challenges (OFCs) were performed, and the results from positive OFCs were compared to those from negative OFCs.

What they found is that neutrophils could be responsible cells, which were found to be higher in patients with positive oral food challenges.  The high levels of IL-8, a chemoattractant for neutrophils, also supported their conclusion.  Mast cells may also participate, since IL-9 that was also high is produced by mast cells, and baseline tryptase levels were elevated.  But interestingly, tryptase levels didn’t increase with the positive oral food challenge, meaning that mast cells weren’t activated during a challenge.  Regulatory cytokines, such as IL-10 are likely related to the development of oral tolerance in FPIES.  Additionally, levels of antibodies specific to casein, a key component of milk, were low in children with CM-FPIES.    There remain a lot of unanswered questions about FPIES, but this study helps to shine some light on this mysterious type of food allergy.

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.