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Monday, July 11, 2016

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation

You are more than just one human being.  That may sound like an inspirational quote, but it’s actually a scientific fact: there are literally millions of bacteria living on, in, and around you that play crucial roles in the ways that your body and your mind work.  And now, thanks to newer technology, we have the ability to see how these ‘old friends’ – bacteria have likely been around since the emergence of humans – interact with our own cells to change how our immune system works.
In this month’s issue of the Journal of Allergy and Clinical Immunology, Garn and colleagues provide an overview of how these microbes influence our metabolism and can lead to inflammation, based on the insights from the International von-Behring-Röntgen-Symposium (J Allergy Clin Immunol 2016; 138(1): 47-56).  While our knowledge of the microbiome keeps on growing, the fact is that there remains so much to be researched.  For example, how does our modern age of hygiene, where we have eliminated so many of the old infectious agents with which we have co-evolved, impact chronic inflammation?  How do resident microbes interact with food to cause inflammation, or resolve it?  What role does biodiversity (which plummets while on antibiotics) play in maintaining the balance between promotion and resolution of inflammation?  And how do these microbes educate our immune systems during infancy and childhood?  Unfortunately, these questions remain mostly unanswered but there are some promising leads.  For example, a study involving 560 babies of families from Baltimore, New York City, and St. Louis demonstrated that exposure to allergens in the first few months of life may be associated with a reduced risk of recurrent wheeze, while exposure to microbes may reduce both the risk of atopy and atopy plus wheeze.

Extracellular RNA, DNA, and proteins that may come from microbes have been shown to mediate inflammation.  These molecules alter the cytokines released by our own cells, and can lead to upregulation of inflammatory responses.  While research is extremely preliminary, the influence of the microbiome on allergic, autoimmune, gastrointestinal, and neuropsychiatric disease is becoming more and more appreciated, possibly opening doors to new management strategies.  So embrace your inner germs and realize that you’re more than just one, sole human being.

Friday, July 8, 2016

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

C-O-P-D (chronic obstructive pulmonary disease) is a series of four letters that strikes terror in the hearts (and lungs) of millions throughout the world.  It’s a condition in which there is chronic inflammation within the lungs that leads to their destruction, causing problems in breathing.While the consequences of COPD have been long known, the immunology behind it is still largely unknown.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Dr. Barnes reviews the inflammatory mechanisms behind COPD (J Allergy Clin Immunol 2016; 138(1): 16-27).
As he mentions, one of the difficulties behind figuring out how immune dysfunction causes COPD is that COPD doesn’t seem to be a single disease.  Different types of immune cells and mediators seem to be involved in different ways in different patients, and our knowledge continues to grow about how we can tease apart all these endotypes and phenotypes.

However, some common themes are emerging.  Patients with COPD have lower levels of anti-oxidants, leading to excess reactive oxygen species (ROS), which, in turn, trigger the inflammatory response.   These ROS may also promote lung cancer by activating growth factors and damaging DNA directly.  The other major common theme is that there is systemic inflammation that “spills over” to cause an increased risk of heart disease, diabetes, lung cancer, and pneumonia.

Currently, we don’t have treatments to help reverse the damage from COPD, and most of our efforts remain in prevention and control of symptoms.  But with greater knowledge on the roles immune system, we may be able to help people, who have been diagnosed with COPD to regain control of their lungs, and their lives.

Thursday, July 7, 2016

Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes

It’s not surprising that expecting mothers carry a lot of weight in their bellies.  But they also carry a lot of weight on their shoulders.  What to do, and what not to do, complicates nearly every decision when there’s a second person to think about, even the relatively minor act of using a nasal steroid spray to treat allergic rhinitis.  Fortunately for them, Dr. Berard and colleagues conducted a study to help address these concerns (J Allergy Clin Immunol 2016; 138(1): 97-104).
They looked at nearly 300,000 pregnancies in Montreal between 1998 and 2008 to find pregnant women who took intranasal triamcinolone as well as other intranasal steroids.  They then looked at the number of major abnormalities at birth, spontaneous loss of pregnancies, and underweight newborns, and compared the rates to those who did not use intranasal triamcinolone. 
For the most part, the results are comforting.  They suggest that there is no link between using intranasal triamcinolone (and, by extension, all nasal steroid sprays) and major birth abnormalities or spontaneous fetal loss.  However, out of 296 pregnancies, there were 5 cases of respiratory defects in babies born to mothers who used triamcinolone during the first trimester.  This was a statistically significant finding.  Of note, no link between respiratory defects and other nasal steroid sprays could be found.
The implications of this study are also covered in an accompanying editorial by Drs. Namazy and Schatz, who praise the importance of the study, the first of its kind trying to determine the safety of nasal steroids during pregnancy (J Allergy Clin Immunol 2016; 138(1): 105-106).  They also mention that controlling allergic rhinitis during pregnancy may be helpful in preventing snoring, which is linked to hypertension during pregnancy.Namazy and Schatz try to make sense of why triamcinolone may be correlated with respiratory defects.  It may be due to unmeasured confounders, but that is unlikely since these confounders were present in both the triamcinolone and non-exposed groups.  Or perhaps it’s a biologic effect of triamcinolone, since animal studies of intramuscular triamcinolone have shown similar defects.  Or, it may just be due to pure chance.

Regardless, the authors suggest that, to be on safe side, intranasal steroids like fluticasone or mometasone should be used instead of triamcinolone during the first trimester.  

Thursday, June 9, 2016

Allergen Immunotherapy: No Evidence of Infectious Risk

Nearly three million Americans this year will be administered subcutaneous allergen immunotherapy for a variety of different reasons, including allergic rhinitis, asthma, allergic conjunctivitis, and venom allergy.  Altogether, these are over 16 million allergy shots.  Despite low risks of a large local reaction (0.7-4%) or systematic allergic reaction (0.2%), it has been shown to be relatively safe, cost-effective disease-modifying treatment.  However, recent proposed changes by the United States Pharmacopoeia requiring that vials of allergens be mixed in a strictly sterile fashion threaten the availability of allergen immunotherapy.

To investigate whether this is a real concern, Balekian and colleagues looked through the records of over 3000 patients who collectively received more than 130,000 injections over the preceding 10 years from Massachusetts General Hospital and Brigham and Women’s Hospital (J Allergy Clin Immunol 2016; 137(6): 1887-1888).  They could not find evidence of any local or systemic bacterial infection due to allergen immunotherapy.

Their research supports the community of allergists who maintain that current practices to guarantee sterility and safety are enough to prevent bacterial infection.  They conclude that the proposed changes won’t make a difference in infection rates, but will prevent people who need allergen immunotherapy from receiving them.

Identification of Immunoglobulin E

The year is 1966: Lyndon B. Johnson is the president squaring off against the Soviet Union, the Beatles are at the height of their popularity, and Neil Armstrong is training to one day become the first man on the moon.  And, tucked away in a laboratory at the Children’s Asthma Research Institute and Hospital in Denver, Colorado, Kimishige Ishizaka and his team are busy at work isolating the antibody that mediates allergic reactions, now called immunoglobulin E.

In this month’s issue of the Journal of Allergy and Clinical Immunology, Dr. Ishizaka recounts the way in which he and his team members eventually discovered reagin, later to be called Immunoglobulin E (J Allergy Clin Immunol 2016; 137(6): 1646-1650).  Through complex purification techniques and shrewd application of scientific principles on patients with plasma cell myeloma, he was able to identify the protein that led to a local reaction to ragweed, and figured out that the binding of allergens, like ragweed, dust mites and egg, to IgE on basophils and mast cells leads to histamine release.  Even though technology has advanced considerably and certain practices, like Dr. Ishizaka’s use of himself as a test subject, have changed, the role of Immunoglobulin E remains central to the field of allergy.

Omalizumab for the treatment of chronic spontaneous urticaria: a meta-analysis of randomized clinical trials

Imagine having an itch that you just couldn’t get rid of.  Worse yet, imagine that itch was accompanied by hives and localized swelling that can’t help but consume your attention.  That’s the reality for up to 1% of the world’s population, who have a disease called chronic spontaneous urticaria (CSU, also called chronic idiopathic urticaria).  The good news is that 70% resolve within 5 years. The bad news is that the standard treatment, non-sedating anti-histamines, only works in 50% of CSU patients.  That’s where Zhao and colleagues step in, with their article in this month’s issue of the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 137(6): 1742-1750).

They examine the role of omalizumab, a medication that targets IgE, the human antibody which is central to the disease process of urticaria.  Omalizumab has been on the market for the treatment of urticaria since 2014.  Zhao and colleagues looked at 7 randomized controlled trials, with 1230 antihistamine- refractory CSU.  By metaanalysis, they assessed how effective and safe omalizumab is in the treatment of CSU. 

Their conclusion is that omalizumab has a safety profile comparable to placebo.  73% had an adverse effect with omalizumab, compared to 69% with placebo.  They also state that, at the dose of 300mg, omalizumab led to a complete response in 36% of patients.  Altogether, this suggests that omalizumab is a safe and effective treatment option for hard to treat chronic spontaneous urticaria.

Wednesday, May 11, 2016

Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers

Not all stuffy noses are alike.  That’s the conclusion of a research study by Tomassen and colleagues published this month in the Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol 2016; 137(5): 1449-1456).  Despite affecting one out of eight Americans, little is really known about chronic rhinosinusitis and treatment is often really frustrating.  To figure out more personalized approaches to tackling chronic rhinosinusitis, Tomassen’s group collected tissue samples from patients with chronic rhinosinusitis, as well as people who had no history of chronic rhinosinusitis.  They then analyzed 14 bio-markers to see if they could find groups of patients who had particular patterns of inflammation.

Ten distinct endotypes, or subgroups linked to biological pathways, that correlated to different features were identified.  The biggest differentiator was the level of IL-5.  Patients with higher levels were more likely to have polyps (outgrowths of the mucous membranes associated with more severe disease) and/or concomitant asthma.  Combined with the other markers, these findings can help identify people who would be expected to respond to different types of medications.  Since there are new medications that target individual inflammatory markers, such as IL-5, this information can provide valuable insight into personalizing an approach to reduce the frustration in treating chronic rhinosinusitis.