Brave new world of immunotherapy - Twitter summary from 2014 #ACAAI meeting

Dr Hal Nelson discussed whether to "retire" traditional SCIT in favor of SLIT drops, rush and cluster SCIT. Dr Hal Nelson offered his insights about the future of immunotherapy now that SLIT tablets are here.

Rush IT works but adverse reactions still remain in the double digits even with pre-medication.

Cluster IT
involves multiple injections in one day. It gets patients to maintenance and symptom relief quicker and is generally safe. Cluster immunotherapy - 15 injections over 6 wks vs. 13 injections over 13 weeks, the rates of systemic reactions were similar (3% and 4%). Systemic reaction rates to Rush IT protocols are still in double digits even with aggressive pretreatment with H1 and H2 antagonists and steroids.

Ways to improve safety and convenience: omalizumab, SLIT, Intralymphatic, Epicutaneous or Intradermal IT.


Mechanisms of allergen-specific immunotherapy (click to enlarge the image). The diagram is based on: Mechanisms of allergen-specific immunotherapy. Akdis CA, Akdis M. J Allergy Clin Immunol. 2011 Jan;127(1):18-27.

Ragweed liquid sublingual SLIT data. JACI 133:751. Creticos et al. JACI 2014; 133:751-8 - First US report of the Ragweed SLIT drops, made by Greer - 429 subjects, 90% tolerated 50 Amb a 1. Total combined score was 20% lower in Ragweed SLIT drop group compared to placebo group. Dr Nelson commented that rates of local oral reactions appears lower with drops than with tablets. Relative cost of SCIT 12.5 Amb a 1 units/mo = $7.80/yr vs. SLIT 50 Amb a 1 u/d for 6 mo/y = $488/yr.

Amar et al studied multiple allergen SLIT - also drops - Timothy monotherapy was better than when mixed with other allergens.

- Epicutaneous allergen-specific IT - Sentri et al JACI 2011.

In epicutaneous IT, local reactions are common and 8% even experienced mild systemic reactions.

Intralymphatic immunotherapy - 3 injections at time 0, 4 wk and 8 wk were equivalent to 52-week, weekly SCIT for Timothy grass. The promise of intralymphatic immunotherapy was discussed in PNAS 2008 105: 17908. Dr Nelson showed the intralymphatic immunotherapy study again - 3 IL injections were better than standard SCIT with many more injections.  Benefits of intralymphatic immunotherapy persist 3 years post discontinuation. However, a follow up study giving IL injections q2wk failed to replicate the results of the initial study.

Dr Stephen Durham presented on why allergists should embrace SLIT.

Durham et al JACI 2006; 117: 802-09 - one of the first studies of the Grass SLIT product initially developed by ALK, now Merck's tab. The 5 grass pollen (300IR) product developed by @StallergenesCom is also effective with reduction in symptoms and medication use.

Both the @Merck grass SLIT and the @StallergenesCom grass SLIT tablets have shown safety and efficacy in children older than 5. Local side effects from these SLIT tablets common - 40% will experience oral itch, it usually goes away with 2 to 4 weeks of treatment.

Now on to ragweed SLIT-tablet, Dr Creticos was again the lead author, a tablet with 12 Amb a 1 was effective and tolerated. Use of ragweed SLIT was associated with lower rates of loratadine, mometasone and olopatadine, also lower symptom scores compared with placebo.

Reviewing recent history of SLIT literature shows efficacy. Dr Durham said ragweed SLIT probably works as well as intranasal steroids and better than antihistamines for symptom relief.

A recent JACI Phase II study of HDM SLIT tablet showed ability to reduce ICS while maintaining asthma control in DM allergic asthmatics. There was a reduction in daily dose of ICS by 100 mcg with HDM SLIT, according to this preliminary pilot study.

There is an exciting bold study ongoing in Europe - GAP-Grass SLIT given for 3 years to 800 children, the primary outcome is the time to first asthma episode. The GAP study will thus evaluate primary prevention - treating children with Grass Induced Allergic rhinitis, but no asthma, with SLIT.

Dr Durham believes the treatment effects between SCIT and SLIT are similar when you look at the well-designed 'big' trials. Immune tolerance network funded study of Durham's is comparing SCIT to SLIT in a head to head trial using NAC as outcome measure. SLIT tablet use is associated with increased IL-10 and TGF-B production, reflecting likely engagement of regulatory T cells. SLIT tablets also show persistent immunologic effects with increases in specific IgG4 even 2 years after stopping a 3 yr course of treatment.

Dr Durham: At this time, equipoise suggests that decision about SLIT vs SCIT should come down to patient preference.

Dr. David Bernstein discussed "Emerging Immunotherapies - Will we 'cure' allergies?" Dr Bernstein is already giving take home message - to say we will cure allergies is premature.

Limitations of SCIT include long duration of treatment, several allergens are non-standardized and not well studied, risk of anaphylaxis.

He discussed allergoids, fusion molecules, peptide immunotherapy, and recombinant vaccines.

Allergoids are modified allergens complexed to aldehydes. They are used via SCIT to reduce adverse reactions and preserve allergenicity.

Allergoids are allergens chemically modified with gluteraldehyde or formaldehyde - thye have reduced IgE binding but maintained immunogenecity. Allergoids are then linked to adjuvants such as aluminum hydroxide or tyrosine. These are used as "pre-seasonal" injections. Studies conducted had small numbers of patients but rates of systemic reactions were low.

Non-adjuvant virus-like particles coupled to Der p1 were shown to stimulate B cells to induce strong IgG responses (no clinical trials though). Other experimental approaches include fusion protein of Fel d1 with FcGamma - this inhibits mast-cell signaling (no clinical trials yet).

Phase III trials are underway for synthetic immunoregulatory epitopes "peptide immunotherapy" or SPIREs. Cat, Grass and HDM thus far. 

Recombinant Bet v 1 vaccine is also developed for treatment of birch allergy - 8 SC build up doses are followed by 10 monthly maintenance. The 2 higher doses of recombinant Bet V 1 were associated with Grade 2 and 3 systemic reactions, however. 

This is a Twitter summary from 2014 #ACAAI meeting. The post is a part of series. See the rest here: http://allergynotes.blogspot.com/search/label/ACAAI

The Twitter summary was made possible by @DrAnneEllis and @MatthewBowdish

Several allergists did a great job posting updates from the 2014 meeting of the #ACAAI. I used the website “All My Tweets” to review the tweets. For comparison, here are the tweets from previous #ACAAI meetings (scroll down the page for the past years): http://allergynotes.blogspot.com/search/label/ACAAI

What's New in Food Allergy? Twitter summary from 2014 #ACAAI meeting

Alessandro Fiocchi and Robert A Wood presented this workshop.

Egg allergy is the only food allergy that can present at birth, suggesting prenatal factors involved in sensitization.

There are limits of the 'prohibitionist approach' to food allergy care.

Supplemental probiotics don't substantially alter intestinal microbiota, which is why we haven't yet seen robust effects.



8 foods cause 90% of food allergies (click to enlarge the image). The likelihood of a negative oral food challenge is shown in relation to the respective values of skin prick test (SPT) and serum IgE (sIgE).

Potential approaches for therapy food allergy: Xolair, chinese herbs, oral immunotherapy, ingestion of extensively heated milk and egg, patch immunotherapy.

For oral immunotherapy (OIT), it's important whether the intervention is transient or long-lived.

There are two groups of milk and egg allergy patients based on severity. Mild patients can be exposed to heated milk or egg will helps treat food allergy. Dr Wood recommended all kids with milk or egg allergy to be considered for intro of heated egg/milk. Although Dr Wood has some cut-offs for IgEs (milk below 20, egg below 10), they will challenge kids with higher IgE (though success is low).

Can peanut proteins be engineered to block IgE binding sites that will allow for IT but be safer than normal peanut protein? Dr Wood developed a product called EMP-123 that worked best when delivered per rectum - Wood, Allergy, 2013.

Exercise is becoming a risk factor for OIT adverse effects, so no exercise within 2 hours of food OIT dosing is strongly recommended.

Dr Wood discussed the following study: Peanut SLIT in CoFAR - JACI 2013;131:119. There was some protection with slight increase by 68 weeks. But most benefit occurred within the first 44 weeks of therapy.

Dr Wood reviewed milk OIT vs SLIT - JACI 2012. SLIT less effective than OIT.

True tolerance with OIT is only accomplished in a minority of patients. Rates of adverse reactions to food IT are significant but likely acceptable.



Food allergy management in 4 steps (click to enlarge the image).

This is a Twitter summary from 2014 #ACAAI meeting. The post is a part of series. See the rest here: http://allergynotes.blogspot.com/search/label/ACAAI

The Twitter summary was made possible by @DrAnneEllis and @MatthewBowdish

Several allergists did a great job posting updates from the 2014 meeting of the #ACAAI. I used the website “All My Tweets” to review the tweets. For comparison, here are the tweets from previous #ACAAI meetings (scroll down the page for the past years): http://allergynotes.blogspot.com/search/label/ACAAI

Why is there an Allergy Epidemic? Twitter summary from 2014 #ACAAI meeting

This is a summary of the debate Hygiene Hypothesis/Microbiome vs Climate Change.

According to Dr Portnoy, CO2 on Mauna Loa went from 320 ppm to 400 ppm from 1960 to 2010, sunlight goes in, heats up the Earth and can't get out. Health effects of CO2: rodent and insect borne diseases, changes in seafood borne diseases, contamination of drinking H2O, etc. There's an association with CO2 and allergy epidemic. Increasing levels of CO2 production lead to increase of ragweed pollen production and potency. This also explains increased ragweed allergy in cities (where there is more CO2) than in rural areas. However, even he admits that association does not prove causation.

Dr Ownby is arguing for hygiene hypothesis and microbiome. His declaration is that he is happy that he was raised on a farm.

It should really be the Microbiota Hypothesis rather than the Hygiene Hypothesis.

Most people moved off farms in last century and access to clean water was not really universal until the 1970s, the start of epidemic.

90% of antibiotics given to livestock are for non-infectious reasons (ie to make them fatter). TV dinners started in 60s/70s. We also don't buy fresh foods that may have soil contamination but prepackaged sterile foods.



Allergic (atopic) march (click here to enlarge the image). Allergic (Atopic) March refers to the natural history or typical progression of allergic diseases that often begin early in life. These include atopic dermatitis (eczema), food allergy, allergic rhinitis (hay fever) and asthma.

There is an allergy gap between Russian and Finnish kids, with differences in cat exposure and ground H20 contamination as proof - Allergy 66:886. Here's the link to the Allergy Gap paper in Allergy http://t.co/gv1rJmdQNr

Dr Stan Szefler discussed acetaminophen as a suspected reason for allergy epidemic. “When we experienced Reye's Syndrome in the 1970s, we changed from ASA to acetaminophen, so the timing is right.”

Two hypothesis for acetaminophen making asthma worse 1) in utero exposure, 2) childhood exposure - #2 is stronger. You should be familiar with Beasley article - AJRCCM 2011 http://t.co/d53sOX5ZgZ

Dr Peden discussed smoking, air pollution and indoor triggers as root cause for allergy epidemic. Ozone and environmental smoke exposure enhance allergic airways disease. Ambient air pollution impairs T regs in humans - JACI 126:845. Exposure to tobacco promotes IgE, DNA methylation resulting in Th2 and genetic factors increase risk of response to irritants.

Dr Portnoy still claims it's still climate change at the root - driving people indoors and thus winning Dr Peden's arguments indirectly. Dr Peden continued to argue convincingly that tobacco smoke and pollution contributes to microbiome, climate change and all others.

Dr Tom Platts-Mills said there were multiple allergy epidemics, not just one. Hay fever started around 1905, peanut food allergy around 1995 and pediatric asthma epidemic 1970s. Dr Platts-Mills: Allergy Epidemic actually followed 3 phases - SAR 1st, then pediatric asthma, and finally food allergy, decades apart.

What happened in 1954, the origins of the pediatric asthma epidemic?... Introduction of TV. Most children are not exposed to pollen these days. Inactivity due to indoor living leads to asthmatic changes.

This is a Twitter summary from 2014 #ACAAI meeting. The post is a part of series. See the rest here: http://allergynotes.blogspot.com/search/label/ACAAI

The Twitter summary was made possible by @DrAnneEllis and @MatthewBowdish

Several allergists did a great job posting updates from the 2014 meeting of the #ACAAI. I used the website “All My Tweets” to review the tweets. For comparison, here are the tweets from previous #ACAAI meetings (scroll down the page for the past years): http://allergynotes.blogspot.com/search/label/ACAAI

Turbinates to Bronchioles: the one airway concept in asthma treatment - Twitter summary from 2014 #ACAAI


Allergies and asthma

Dr. Tim Craig discussed adult asthma: Defining allergies in asthma can allow to develop plans for avoidance, determine if immunotherapy, or monoclonals are indicated.

@DrAnneEllis: In one of Craig's studies, 95% of asthmatics had positive skin tests. Much higher than what I see in my practice.

The rates of positive skin tests are higher in those whose asthma onset was before the age of 30. In a cohort of NON-allergic asthmatics, there were more females and cough was the prominent symptom. Those asthmatics with cat allergy had lowest PC20 values on methacholine challenge, ie more severe disease. The article by Wu et al JACI 2014 133: 1280-8 defines 6 endotypes of asthma, based on allergic status, obesity, presence of polyps, and others. Dr Craig showed the meta-analysis by @AllergyNet demonstrating clear benefit of immunotherapy in the treatment of asthma. A @CochraneAirways meta-analysis of SLIT showed benefits for AR symptoms and medication use, but for asthma p value didn't quite make it.

Non-allergic rhinitis (NAR)

Dr. Jonathan Bernstein discussed Non-allergic rhinitis and asthma.

Non-allergic rhinitis (NAR) consists of neurogenic, vasomotor rhinitis, NARES (NAR with eosinophils) and idiopathic endotypes. Idiopathic/neurogenic/vasomotor rhinitis is what we see clinically most commonly and it is difficult to treat.

Consensus definition for NAR is underway - at least 6 sub-phenotypes will be identified, it is still a diagnosis by exclusion. If age over 35 at onset, no family history of allergy, absence of outdoor symptoms in spring and around furred pets, 95% will have NAR.

NAR and AR have equal rates of nasal congestion and post-nasal drip, but rhinorrhea is more common in AR. If you can actually measure nasal cytology on NAR patients you can identify the subtype of NARES, which tends to respond better to therapy. More about NARES here: Nonallergic rhinitis with eosinophilia syndrome and related disorders. http://t.co/aqpiOkAHND

Neuronal pathways possibly determine NAR phenotypes - tachykinins, CGRP and and TRP channels are all being studied. Ipratropium, anticholinergic agent is beneficial in NAR, as is capsaicin, supporting the role of neurogenic pathways in this disease. Azelastine and bepotastine also can engage TRPV1 channels and thus may have benefit in NAR, olopatadine did not, in Bernstein's study.

RADS and RUDS

Irritant-induced asthma is also referred to as reactive airways dysfunction syndrome or RADS, Non-allergic phenotype.

Irritant-induced rhinitis is also thus termed reactive upper airways dysfunction syndrome or "RUDS". Dr Bernstein presented the concept that RUDS and RADS are linked, similar to the one airway hypothesis of AR and allergic asthma.

Small Airways in Asthma

Dr. Kevin Murphy discussed the Importance of the Small Airways in Asthma. Dr Murphy has Chaired the FIT bowl committee for 23 years!

Asthma Insight and Management study (AIM) is a national survey of patients, MDS, RN, and asthma educators in the US. The AIM study showed that rate of assessment of lung function remains low - only 30% of patients had PFTs in the previous year. The AIM study also showed identical rates of hospitalization and ER visits to those reported in the Asthma in America study 10 yrs previously. Although NAEPP guidelines were updated in 2002 and 2007, very little changed over the last 10 yrs in terms of asthma outcomes.

There was a recently described Small Airways Asthma Phenotype: Day and night symptoms, frequent use of SABA/oral steroids and ICS failure.

Of note, it's failure to respond to coarse particle ICS that helps to define small airways asthma. Small airways asthma has a normal FEV1, but abnormalities noted in FEF25-75 and other small airway measurements. Small airway dysfunction is associated with poor asthma control, i.e. normal FEV1, reduced FEF25-75.

Impulse oscillometry measures airway resistance.

Smaller particles can enter smaller airways (common sense). Those with 1.5 micron diameter are termed "highly respirable". Ciclesonide, hFa-beclomethasone, and hFA-flunisolide are the 3 ICS on the market (in the US) in this 1.5 micron range. Of note, HFA-BDP (beclomethasone) is available in a large particle size as well as small particle size.

Great point being made about the extra-fine particle ICS debate - Delivery Device matters!!! Concerns were raised by audience members about the safety of these extra-fine particle ICS products - are they more systemically absorbed? Dr Murphy reiterates the importance of always giving lowest effective dose of ICS, titrate down once control achieved if possible. Here is the link to the "Price" study that generated so many comments at the #ACAAI discussion about extra-fine ICS therapy: http://t.co/vMQ8fFNbZX. The study was QVAR vs. Fostair/Clenil, sponsored by Research in Real-Life Ltd and TEVA Phamaceuticals http://t.co/hx1Pwldj42

This is a Twitter summary from 2014 #ACAAI meeting. The post is a part of series. See the rest here: http://allergynotes.blogspot.com/search/label/ACAAI

The Twitter summary was made possible by @DrAnneEllis

Several allergists did a great job posting updates from the 2014 meeting of the #ACAAI. I used the website “All My Tweets” to review the tweets. For comparison, here are the tweets from previous #ACAAI meetings (scroll down the page for the past years): http://allergynotes.blogspot.com/search/label/ACAAI

Atopic Dermatitis In-Depth - Twitter summary from 2014 #ACAAI meeting

"Atopic Dermatitis In-Depth" with Peter Lio and Mark Boguniewicz:

Dr Lio is a dermatologist from Chicago who is especially interested in AD. “Many allergists feel abandoned by the dermatologists in the care of severe atopic dermatitis”. Dr Lio says as a dermatologist, he is an 'externist' rather than an internist.

In darker skin types, it can be difficult to appreciate erythroderma. Comprehensive goal of AD care: Moisturization, Antibiotics, Antipruritics and anti-inflammatories.

Filaggrin

Dr Lio discussed the importance of filaggrin - barrier and moisturization roles. Keratinocytes differentiated in presence of IL4 and IL13 have significantly less filaggrin to the point it is a functional deficiency.

Dr Boguniewicz: NJ screens for 5 most common filaggrin mutations, mainly in European background, but over 30 mutations described. Insurance often doesn't want to cover filaggrin mutation testing. Exam for 'hyperlinear palms' is the poor man's test for filaggrin mutation. Hyperlinear palms via @Docallergy http://t.co/H5i78AV8LG

The typical filaggrin patient has early onset, severe, persistent AD with increase in allergic sensitization and increased risk of asthma.



Allergic (atopic) march (click here to enlarge the image). Allergic (Atopic) March refers to the natural history or typical progression of allergic diseases that often begin early in life. These include atopic dermatitis (eczema), food allergy, allergic rhinitis (hay fever) and asthma.

Moisturizer

More moisturizer = less eczema! Most of the very expensive moisturizers are really no better than cheaper products like petroleum jelly. During day, Dr Lio recommends creams (more cosmetically elegant and moisturizing) and then soak and seal at night (with petroleum jelly).

There is some concerns about shea butter with tree nut allergy but no data to show it cross-reacts. Dr Lio recommends virgin coconut oil and sunflower oil. The coconut oil also has antibacterial properties. But he recommends them with other medications. Sunflower oil first, then medications and then petroleum jelly on top for night regimen. Moisturizer tips: If the patients complains that cream is cold, then float in bath tub to warm it up. If cream feels too hot, then keep in fridge (not freezer).



Atopic Dermatitis Treatment - Illustrated (click to enlarge the image).

Bleach baths

Dr Lio likes bleach baths. Dr Lio uses 1/4-1/2 cup bleach in full bath tub for his patients. Here is Lio's slide on bleach bath recs #ACAAI http://t.co/FFk1J6vrut

Anti-inflammatory therapy

Anti-inflammatory component is probably the most important part of the treatment regimen. Dr Lio feels that steroid ointments are generally preferred. Pearl: If patient says the eczema "comes right back after we stop" then steroid potency is probably too low.

Dr Lio prefers steroid ointments over creams because there are less additives in ointments and it helps with barrier function. Dr Boguniewicz agrees steroid ointments are bettert creams but notes that patients who are "outdoorsy" can get in trouble with dirt and sweating.

Protopic/Elidel problems: cancer scare (Dr Lio discounts the risk) and costs (but they should be going generic soon). Once eczema is clear, then use tacrolimus twice weekly because the skin is NEVER normal even when it looks OK.

“Eczema Boot Camp”

Dr Lio does Eczema Boot Camp: QD - 10-min dilute bleach bath, topical therapy (TAC), emollient application and then wet wraps. Eczema boot camp lasts 3-5 days - if not better after one week then, Dr Lio has patients call him. Wet wraps on for 2 hours at least, Dr Lio recommends to sleep in it if they can tolerate it.

Eczema Action Plan

Dr Lio uses an "Eczema Action Plan" and feels this is the single most important education he does - empowers patients. Dr Lio's website has lots of resources http://t.co/kPB2NdtNsX -- Here is Lio's "Eczema Action Plan" http://t.co/WgFOc5aqpy

Dr Bowdish: This was perhaps the single most mind-blowing session that I attended at this #ACAAI. These recs will improve my practice.

Atopic Dermatitis (Eczema) Action Plan by National Jewish Health:



Phototherapy

60-70% of patients get improvement with phototherapy, but it's a hassle (three times weekly) and expensive (but generally well covered).

Severe cases

Dr Lio discourages prednisone bursts or tapers, instead he prefers cyclosporine for severe patients, it acts quickly and 80-90% clear in 1 month. Dr Lio does 5mg/kg/day of modified cyclosporine, generally taper off in 3 months - monitor BP, BUN/Cr, CBC, LFTs, Uric Acid. Dr Boguniewicz feels kids tolerate cyclosporine much better than adults - less HTN and other ADRs. Other immunosuppressants for SEVERE patients: Azathioprine (Imuran), Mycophenolate (CellCept).

Dr Lio uses full dose cyclosporine, and if doing great then adds full dose CellCept for 1mo, then weans cyclosporine over 1-2 mos, and then off. Dr Lio doesn't use methotrexate but Dr Boguniewicz has patients he works with that do.

Eczema mimickers

Eczema mimickers (ie Wiskott-Aldrich) are extremely rare but you have think about other causes too. Think about these rare zebras if you also have immunodeficiency (WAS) or autoimmunity (IPEX). DOCK8 are the tough ones. However, even they have severe viral infections.

PPV of SPT or sIgE to foods in eczema isn't great, it's more of a fishing expedition and probably more helpful if negative. Dr Boguniewicz: Food challenges in eczema patients are, umm, challenging. The majority of food allergy in eczema is an issue with patients aged 5 years or younger.

Handouts for this (W-23) and other workshops can be found here http://t.co/t144uPKdcT

This is a Twitter summary from 2014 #ACAAI meeting. The post is a part of series. See the rest here: http://allergynotes.blogspot.com/search/label/ACAAI

The Twitter summary was made possible by @MatthewBowdish and @DrAnneEllis

Several allergists did a great job posting updates from the 2014 meeting of the #ACAAI. I used the website “All My Tweets” to review the tweets. For comparison, here are the tweets from previous #ACAAI meetings (scroll down the page for the past years): http://allergynotes.blogspot.com/search/label/ACAAI
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