Step doses for drug provocation tests to NSAIDs (ingestion challenges)

Hypersensitivity to non‐steroidal anti‐inflammatory drugs (NSAIDs) are of great concern because they are frequently encountered in daily clinical practice. Drug provocation tests (DPT) are particularly needed for NSAIDs.

This retrospective study from the University Hospital of Montpellier (France) evaluated eliciting dose thresholds during NSAIDs DPT. 311 positive DPT were analyzed.

The following steps for future DPT were suggested:

1. for the rapid absorption group (Acetylsalicylic acid, ibuprofen, ketoprofen, tiaprofenic acid), every 30 min: 20%‐30%‐50% of daily therapeutic dose

2. for the moderate absorption group, every 30 min: for diclofenac 5%‐15%‐30%‐50% and for celecoxib, 20%‐80%

3. for the slow absorption group, piroxicam, 25%‐75% separated by a 3h interval.

A surveillance period of 3h after the last dose is mandatory for patients.

DPT protocols for NSAID are empirical, driven by the knowledge on patterns of DHR, cross‐reactivity between NSAID and pharmacological effects of these all drugs.

References:

Data‐driven step doses for drug provocation tests to non‐steroidal anti‐inflammatory drugs (NSAIDs), 2019.
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14075

Dupilumab is very effective in difficult‐to‐treat adult atopic dermatitis patients

Dupilumab was approved for the treatment of moderate to severe atopic dermatitis (AD) in 2018. This study evaluated the effect of 16 weeks treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate‐severe AD.

Effectiveness of dupilumab was expressed as number of patients achieving EASI‐50 (Eczema Area and Severity Index) or EASI‐75, as well as patient reported outcomes measures (Patient‐Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus).

138 patients were treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult‐to‐treat AD -- 60% of them patients did not improve on 2 or more immunosuppressive drugs.

After 4 months, at week 16, the mean percent change in EASI score was 73%.

The most reported side effect was conjunctivitis, occurring in 34% patients. This is way higher than the reported incidence of 11-13% in the drug brochure.

During dupilumab treatment, disease severity related serum biomarkers (TARC, PARC, periostin, and IL‐22), eotaxin‐1, and eotaxin‐3 significantly decreased.

References:

Dupilumab is very effective in a large cohort of difficult‐to‐treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry. Lieneke FM Ariëns et al.
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14080

Skin test for acyclovir drug allergy

Adverse drug reactions affect up to 10% of people. When drug reactions resembling allergy happen, they are called drug hypersensitivity reactions (DHRs). Drug hypersensitivity reactions may be allergic or nonallergic. Drug allergies are drug hypersensitivity reactions caused by the immune system.

Case scenario:

A 50-year-old male reported generalized pruritus and maculopapular rash after the second dose of acyclovir taken around 2014 for suspected shingles (no shingles developed). No LOC or SCARs.

He takes amlodipine and metoprolol XL for BP control.

SPT/ID test with acyclovir can be done using the following protocol:

-----

Acyclovir Skin Test Immediate Reaction

-----

Prick Test

Substance / Concentration / W/F (mm)

Saline
Histamine
Acyclovir 0.5 mg/ml

-----

Intradermal Test

Substance / Concentration / W/F (mm)

Saline
Histamine
Acyclovir 0.005 mg/ml
Acyclovir 0.05 mg/ml
Acyclovir 0.5 mg/ml
Acyclovir 5 mg/ml

Stock concentration: Acyclovir IV 50 mg/ml

-----

As a general precaution: Beta-blockers and ACE inhibitors should be stopped several days before any skin test or challenge with medications. The number of days depends of the half-life of each medication (5 half lives is the recommended period). The temporary stop in taking the medications has to be approved by the prescribing physician.



Drug allergy management in 5 steps (click to enlarge the image).



Classification of adverse drug reactions (ADR) (click to enlarge the image).

References:

Immediate allergy from valacyclovir. D. G. Ebo C. H. Bridts L. S. De Clerck W. J. Stevens. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1398-9995.2008.01700.x

Delayed allergy to acyclovir revealed by lymphocyte proliferation test. Marcello Albanesi et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232537

Dupilumab in real life: much higher frequency of conjunctivitis and eosinophilia reported

Dupilumab (Dupixent (R)) is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials.

This real-life French multicenter retrospective cohort study included 241 patients treated during March 2017-April 2018.

The median follow-up time was 4 months (still a very short time, considering that most patients are expected to be on the therapy for longer than 6 months).

Conjunctivitis

Conjunctivitis was reported in 40% patients vs 8-13% in trials, a 4-fold increase. Conjunctivitis was treated with artificial tears and cyclosporine eye drops.

Eosinophilia

The proportion with eosinophilia (greater than 500 cells/mm3) during follow-up was higher than that at baseline. The previous clinical trials showed transient eosinophilia in less than 2% of patients, the incidence was 5-fold higher in this trial (9.5%).

27 of 241 patients stopped dupilumab because of adverse events (AEs).

This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a much higher frequency of conjunctivitis and eosinophilia.



Atopic dermatitis maintenance (click to enlarge the image).

References:

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. J Am Acad Dermatol. 2019 Jul;81(1):143-151. doi: 10.1016/j.jaad.2019.02.053. Epub 2019 Feb 27.
https://www.ncbi.nlm.nih.gov/pubmed/30825533

Dupilumab in the Real World: Beware Adverse Effects. Medscape.
https://www.medscape.com/viewarticle/916710

Toothpaste instead of allergy shots? Oral mucosal immunotherapy (OMIT) for allergic rhinitis

Oral mucosal immunotherapy (OMIT) via a toothpaste has been in the works since 2012 but it is still not FDA-approved as of 2019. The toothpaste base is called Allerdent (R). Most insurances do not pay for oral mucosal immunotherapy (OMIT) as of 2019 (see below). The cost is approximately $400 for 3 months. The recommended duration of treatment is 3 years. Several allergens can be mixed together.

Dr. William Reisacher, ENT, an associate professor of otolaryngology at Weill Cornell, is a co-founder and chief medical officer of Allovate, the company takes makes the Allerdent (R) oral mucosal immunotherapy (OMIT) toothpaste. In the video below he shows how to mix the allergens in the toothpaste base and load the dispenser:



In 2016, Dr. Reisacher published a review of alternative routes to allow IT: intralymphatic immunotherapy (ILIT), epicutaneous immunotherapy (EPIT), local nasal immunotherapy (LNIT), oral immunotherapy (OIT), and oral mucosal immunotherapy (OMIT) (http://vivo.med.cornell.edu/display/pubid84995912076).

From BC/BS website info:

The following allergy treatments are not covered because they are considered investigational including, but not limited to:

1) Provocative and neutralization therapy for food allergies, by sublingual, intradermal, and subcutaneous routes. Provocative and neutralization therapy involves administering neutralizing doses rather than standard doses of allergens either under the tongue or into the skin;
2) Sublingual immunotherapy (SLIT) except for the following FDA approved products: Oralair®, Grastek®, Ragwitek®, and Odactra.
3) Urine autoinjections (autogenous urine immunization) - (a substance from the urine is injected into the skin);
4) Repository emulsion therapy;
5) Low dose immunotherapy also known as the "Rinkel" technique;
6) Enzyme-Potentiated Desensitization;
7) Acupuncture for allergies;
8) Homeopathy for allergies;
9) Rhinophototherapy.
10). Oral mucosal immunotherapy, including Allerdent® compounded toothpaste.

Subcutaneous immunotherapy performed in the home setting is considered investigational.

https://www.bluecrossnc.com/sites/default/files/document/attachment/services/public/pdfs/medicalpolicy/allergy_immunotherapy_desensitization.pdf

Allergy sufferers find relief in immunotherapy toothpaste - Fox News:



Related reading:

https://allovate.com/how-allerdent-works
https://news.weill.cornell.edu/news/2014/10/reisacher-allerdent-immunotherapy/
https://www.foxnews.com/health/allergy-sufferers-find-relief-in-immunotherapy-toothpaste
https://www.popsci.com/allergy-immunotherapy-toothpaste

In 2017, Pediatric Allergy Solutions (“PAS”) and Allovate Therapeutics (“Allovate®”) announced that they have signed an exclusive agreement to combine PAS’s fingerstick allergy test and Allovate’s Allerdent®, a patented toothpaste-based system for the delivery of allergy immunotherapy to enable primary care physicians to offer personalized allergy care: https://vimeo.com/269966553

PPD-free hair dyes: Alternative hair dyes for patients allergic to para-phenylenediamine (PPD)

Para-phenylenediamine is an azo dye, most commonly used in permanent hair dyes as a black dye. It is also used in black rubbers, photographic developers, fabric dyes, epoxy resin curing agents, oils and greases, and gasoline. Potential cross-reactions include preservatives of the paraben family, para-aminobenzoic acid, sulfonamides (including diuretics and diabetes agents), and benzoic acid ester group anesthetics. Even if the hair product is "PPD free", other phenylenediamine variants may cause reactions.

Pure, uncontaminated Lawsonia inermis (henna tree) should not cause reactions in PPD-allergic patients and may be a reasonable alternative as a hair dye. Pure henna is an extremely rare cause of allergic contact dermatitis (ACD).

The vast majority of reactions to hair-dye products are caused by para-phenylenediamine (PPD). As of 2019, PPD has been used in most permanent, demipermanent, and semipermanent hair-dye products. PPD was the contact allergen of the year in 2006.

Some manufacturers produce permanent and demipermanent dyes using para-toluenediamine sulfate (PTDS) instead of PPD (see below), 57% of patients allergic to PPD will tolerate hair dyes based on PTDS.

Practical recommendations for 3 patch tests:

1. TRUE patch test. Test for PPD with TRUE patch test.

2. Hair dye series patch test. If contact allergy to PPD is confirmed: test with a complete hair dye series. If that series is unavailable, at least do a patch test for PTDS. Patients who are allergic to PPD but test negative for allergy to PTDS will very likely tolerate the PPD-free hair-dyes based on PTDS.

3. Specific hair dye patch test. Although patients who are patch test negative to PTDS will likely tolerate the PTDS-based hair-dyes, the recommendation is to do a patch-test for any proposed PTDS-based hair dye. If the test is negative, then use the product.

In patients allergic to hair dye: do not use a hair dye without a patch test.  

Alternative to PPD-hair dyes

PPD-Free Hair Dyes Based on PTDS:

- Wella Koleston Perfect (permanent), Wella Color Charm (demipermanent) - The Wella Corporation, Richimond, VA

- Schwarzkopf Igora Royal (permanent) - Schwarzkopf & Dep, Rancho Dominguez, CA

- Goldwell Color Chic (permanent), Goldwell ReShade for Men (demipermanent)

- Sanotint Light (demipermanent) - Sanotint, Cosval Arese, Italy, PSS, Iinthicum Heights, MD

- L'Oréal Paris Excellence To-Go 10-Minute Cre`me Colorant (demipermanent) - IL'Oreal USA Inc, Clark, NJ

Pure henna is an alternative hair dye. Uncontaminated Lawsonia inermis (henna tree) is an extremely rare cause of allergic contact dermatitis (ACD).

PPD cross-reactions

In PPD-allergic patients, cross-reactions may occur with other chemicals such blue disperse clothing dyes. Cross-reactions have also been reported to para-aminobenzoic acid-containing sunscreens and topical sulfonamides.



Hair dye-induced allergic contact dermatitis (click here to enlarge the image).

References:

https://www.medscape.com/viewarticle/747496
https://www.medscape.com/viewarticle/546029_2
https://www.consultant360.com/articles/allergic-contact-dermatitis-hair-dye
UpToDate, 2019.

Xylitol nasal spray (XLEAR) and irrigation for treatment of chronic rhinitis and sinusitis

Xylitol nasal spray (XLEAR) is commercially available OTC for treatment of rhinitis: http://www.xlear.com/xlear-sinus-care/

However, most of the published studies focused on xylitol nasal irrigation rather than nasal spray. The studies with small with 20 to 50 patients each and the results were mixed. The references are below.

As of year 2019, xylitol nasal spray (XLEAR) and irrigation are not the standard of treatment for chronic rhinitis and sinusitis.

References:

PubMed search: https://www.ncbi.nlm.nih.gov/pubmed/?term=xylitol+nasal
https://www.ncbi.nlm.nih.gov/pubmed/28390807
https://www.ncbi.nlm.nih.gov/pubmed/30274540
https://www.ncbi.nlm.nih.gov/pubmed/24574278
https://www.ncbi.nlm.nih.gov/pubmed/24999540
https://www.ncbi.nlm.nih.gov/pubmed/21994147

Can Microbes Protect from Asthma? Twitter summary from the 2019 WSAAI meeting

Donata Vercelli spoke on "Can Microbes Protect from Asthma? Studies with Amish & Hutterite Gut Microbiota".

Asthma & allergy are to a large extent environmental diseases that can be treated but not cured.

Erika von Mitius showed a "farm effect" in Alpine Europe, where exposure to cows, hay and unpasteurized milk lead to protection from allergies and asthma. Since then we have been asking and answering why this occurs with relations to genetics, specific farm exposures, and what other components of the farm environments are responsible for protection.

Recent NEJM article addressed two genetic similar populations from a specific region in Europe who settled in different areas of the US - the Amish and Hutterites. Their origins are only 800 km apart in Europe. But while they are very similar in origins (genetics), diet, religion, etc., their farming is very different. Amish non-mechanized single-family farms. Hutterites: large, industrial farming. So for asthma and allergic sensitization Amish are 3-4x lower than Hutterites. While there are differences in cell types (eosinophils, neutrophils, etc) there are no major difference in T regulatory cells.

Asthma protection requires innate immunity. Inflammation appears to generate a neutrophilic response as opposed to eosinophilic responses. This appears to depend on type of exposures and suggests that microbiome plays a strong relationship with risk of childhood asthma.

Gene expression patterns in PBLs of Amish and Hutterite children differ especially in innate immune pathways. Endotoxin much higher in Amish homes, a proxy for microbial load in these homes: https://twitter.com/MatthewBowdish/status/1087398982991503360

Dust collectors suggested inhalation of Amish, but not Hutterite, dust extract is sufficient to block allergen-induced airway hyperreactivity and eosinophilia in mice- important because even this dust was enough to create this phenotype. Found asthma protection in “Amish mice” requires innate immunity, most notably in MyD88-TRif.

Farm effect involved environmental microbiome: https://twitter.com/MatthewBowdish/status/1087401056202452992

This relationship of the risk of asthma and the gut microbiome happens very early: https://twitter.com/MatthewBowdish/status/1087401767636066304

Amish but not Hutterite fecal microbiota are sufficient to suppress allergen-induced AHR and OVA-specific IgE. Profiles of BAL eosinophilia in germ-free mice associated with Amish fecal microbiota showed regulatory eosinophils with regulatory transcription signatures (Prg3) in Amish mice (inflammatory eos in Hutterites).

What is happening between gut and environment? May be "pioneer taxa" are transferred from mother to infant, then the pioneers create a micro-environment for beneficial microbiota to come from the environment (dust) during the 1st year of life.

Dr. Lozupone talked on gut microbiome and how it affects health and inflammation:

Gut microbes affect your health by competitively excluding pathogens, metabolically transforming your diet and drugs, and modulating your immune system. Excellent summary!

Factors that influence microbiome: age, diet, location. Early microbe exposures influence allergy and asthma likely from epigenetic changes. Different approaches using microbiome therapeutics - transplant ecosystem, prebiotics, probiotics.

Dr. Laidlaw mentioned that they have good success with single day protocols.

Commensal micro-derived butyrate induces differentiation of colonic regulatory T Cells, driving the colon away from inflammation.

Age is associated with the most pronounced differences in the gut microbiome.

This is a Twitter summary from the 2019 WSAAI meeting. This summary was compiled from the tweets posted by Matthew Bowdish @MatthewBowdish and Ray Firszt @RayFirszt, who attended the 2019 Western Society of Allergy, Asthma and Immunology (WSAAI) meeting. The tweets were labeled #WSAAI. The text was edited by me.

What have we learned from aspirin desensitization in AERD? Twitter summary from the 2019 WSAAI meeting

Katherine Woessner presented on "What have we learned from aspirin desensitization in AERD: How can the methods be improved."

AERD is chronic eosinophilic (Type 2) inflammation of sinuses +/- the lungs with sensitivity to all COX-1 inhibiting NSAIDS with age of onset in 3rd or 4th decade. No obvious genetic signature that is associated with AERD.

AERD always has chronic sinus disease but not always with asthma, although it usually develops 1-5 years after onset of rhinitis. Asthma is not necessary to make dx of AERD. It needs CRS and NSAID sensitivity.

Known baseline abnormalities in AERD - decreased PGE2 is main one: https://twitter.com/MatthewBowdish/status/1087452002102083585

“All you need to know about AERD” in one slide: https://twitter.com/MatthewBowdish/status/1087452732892491776

Diagnosing AERD is difficult. History can be problematic. Small amounts of aspirin can often be tolerated, sometimes small amounts of alcohol can augment symptoms. Only way to diagnose AERD is with ASA/NSAID challenge.

83% of AERD patients will react to alcohol (nasal congestion, even wheeze). Patients with AERD appear to be sensitive to all alcohol. Mechanism is unclear.

Reactions to oral Aspirin Challenge: https://twitter.com/MatthewBowdish/status/1087454672925876224

Addition of a Leukotriene Receptor Antagonist (LTRA) does not change the outcome of oral aspirin desensitizations.

Treatment of AERD:

1. Avoid COX-1 inhibitor NSAIDs
2. Highly-selective COX-2 inhibitors and Acetaminophen are generally well-tolerated
3. ASA Desens if needed

Q: Who should get ASA Desens?

A: Pts with recurrent chronic sinusitis/polyps, all AERD pts except those well-controlled on ICS, ICS/LABA & LTMDs, those who require antiplatelet therapy w/ASA or other COX-1 inhibitors.

Optimization of ASA Desensitization: FEV1 over 60% (or 1.5 L). https://twitter.com/MatthewBowdish/status/1087458466195595264

Try to increase FEV1 at baseline. If unable, it may be OK to start since patients might have irreversible airway obstruction.

ASA Desensitization Protocol: https://twitter.com/MatthewBowdish/status/1087458962318880768

Safety of ASA Desensitization:

- Scripps have done more than 1400 challenges with only 3 systemic reactions (all responded to 1 Epi)
-Average time to reaction is 102 minutes
-Typical provoking dose is 45-100 mg ASA

Safety of asa desensitization: note expedited protocols don’t seem to be safe. Reactions can be severe. Need another blocking drug before single day desensitizations: https://twitter.com/RayFirszt/status/1087458667589296128

Cross desensitization to other NSAIDS occurs. However, you can only use ASA for desensitization purposes.

Nasal congestion improves immediately during asa desensitization. However, airway irritability remains unchanged.

Aspirin Dosing after ASA Desensitization:

-81mg ok for cardiovascular diz prevention
-325mg ok to be cross-desensitized to any doses of all NSAIDs
-650mg BID initial starting dose for AERD; about 50% can decrease to 325 mg BID after 1-6 months

https://twitter.com/RayFirszt/status/1087459807592939520

Biologics targeting TH2 inflammation seem to be effective in AERD. Biologics like omalizumab and others (anti-IL5, anti-IL4/13) may have a role in AERD but there have not been big enough studies to show that it works or helps in polyps or ASA challenges, some studies are ongoing as we speak.

“In an ideal world, it would be great to have a clinical test to confirm AERD other than desensitization.”

Salicylates are not COX inhibitors and have no effect in AERD. There is some evidence that low salicylate diet might be helpful.

Bits of Wisdom from the front lines of ASA Desensitization: https://twitter.com/MatthewBowdish/status/1087462072860893184

This is a Twitter summary from the 2019 WSAAI meeting. This summary was compiled from the tweets posted by Matthew Bowdish @MatthewBowdish and Ray Firszt @RayFirszt, who attended the 2019 Western Society of Allergy, Asthma and Immunology (WSAAI) meeting. The tweets were labeled #WSAAI. The text was edited by me.



Drug allergy management in 5 steps (click to enlarge the image).

Bacteriotherapy of eczema: host microbe interactions in pathogenesis of atopic dermatitis - Twitter summary from the 2019 WSAAI meeting

Richard Gallo presented on "Host Microbe Interactions in the pathogenesis of atopic dermatitis."

The size of the skin surface area for microbiota interface is 25 square meters when your take into account the hair follicles. Not only the general size of the hair follicle surface area, but there are also nerve fibers and blood vessels in the hair follicle: https://twitter.com/MatthewBowdish/status/1087466779423662082

The immune system exerts pressure for beneficial interactions but driving microbiota towards commensalism and mutualism and away from competition, amensalism and predation/parasitism. Skin produces antimicrobial peptides (AMPs) that are essential for defense of the skin. AMPS in host control of microbial growth: https://twitter.com/MatthewBowdish/status/1087470294636290049

Another way the skin protects is Reactive Adipogenesis, where AMPs produced by fat cells causes expansion of adipose layer in response to local infections with S aureus. Evidently GI surgeons have used this phenom to find areas of colitis for a century. When they open patients up, they look for the area of the bowel wrapped in more fat..

Pathophysiology of Atopic Dermatitis involves deficiency of AMP. Patients with AD have deficiencies in AMP that lead to susceptibility to Staph aureus. S. aureus seems to trigger AD also. They are both interdependent on each other. Moisturizers improve barrier repair which leads to a decrease in IL4, while increasing AMP. Blocking IL4 reduces Staph. aureus colonization and correlates with improved disease.

Atopic dermatitis promotes Staph aureus but does Staph aureus cause Atopic Dermatitis? In a couple of recent studies, it's been shown that S aureus preceded development of atopic dermatitis - JACI 2017 139(1):166 and J Invest Dermatol 2017 137(12):2497.

Topical and systemic antibiotics are not effective in atopic dermatitis. Antibiotics did not kill Staph. aureus. Antibiotics only worked if impetigo was present clinically. Bleach baths don’t seem to be more effective than regular baths. Bacteria do not seem to be changed by adding bleach.

Plausible molecular explanations for causal association between S aureus and atopic dermatitis: https://twitter.com/MatthewBowdish/status/1087473587575873536

How can we treat atopic dermatitis related to Staph. aureus without use of antibiotics which seem to be ineffective?

Applying topical bacteriotherapy in a small trial completely eliminated Staph. aureus - this is an exciting application of skin microbiome. There were no adverse events from topical application of microbiome therapy. Effective anti Staph. aureus agent. Microbiome transcriptome diversity improved with the application. Skin inflammation improved only after 1 week of application.

This is a Twitter summary from the 2019 WSAAI meeting. This summary was compiled from the tweets posted by Matthew Bowdish @MatthewBowdish and Ray Firszt @RayFirszt, who attended the 2019 Western Society of Allergy, Asthma and Immunology (WSAAI) meeting. The tweets were labeled #WSAAI. The text was edited by me.



Atopic dermatitis maintenance (click to enlarge the image).