Allergy Notes: 10/2011

Fragrances and asthma - summary from 2011 CSACI meeting

Decreased expression of leptin/leptin receptor linked to severe asthma and airway remodeling

The adipokine leptin is a potential new mediator for bronchial epithelial homeostasis. TGF-beta is a tissue growth factor the dysregulation of which is associated with airway remodeling.

TGF-beta decreased leptin receptor expression (inhaled steroid fluticasone reverses that). Leptin decreased the spontaneous release of TGF-beta and increased cell proliferation.

Severe asthma was associated with a reduced expression of leptin and its receptor and an increased RBM thickness with unaltered TGF-beta expression.

The authors concluded that decreased expression of leptin/leptin receptor characterizes severe asthma and is associated with airway remodeling.

Severe asthma - differential diagnosis and management (click to enlarge the image).

References:
Leptin and leptin receptor expression in asthma. Bruno A, Pace E, Chanez P, Gras D, Vachier I, Chiappara G, La Guardia M, Gerbino S, Profita M, Gjomarkaj M. J Allergy Clin Immunol. 2009 Jun 17.

Metabolomics in pediatric asthma - summary from 2011 CSACI meeting

Metabolomics is the scientific study of chemical processes involving metabolites. Inflammometry is a hot topic.

Inducing sputum in kids is difficult. FeNO is promising but highly variable. Exhaled breath condensates are not well established.

There is a unique metabolic profile in atopic patient urine by NMR. The test is accessible in kids and could be practical. The computer assessment was able to very accurately predict the diagnosis of pediatric asthma based on urinary profiles in a blinded fashion.

A similar computer model was able to clearly differentiate adults with asthma from COPD in ER population. We need data on other atopic conditions (AR, AD, etc.) to see if the urine test shows asthma or simply atopy.

Disclaimer: The text was edited, modified, and added to by me. I was invited to speak on the topic of social media use by the allergists during the 2011 CSACI meeting.

Recombinant allergens - summary from 2011 CSACI meeting

Phototherapy for Allergic Rhinitis

Phototherapy has immunosuppressive effect. Both ultraviolet (UV) and visible light are widely used for the therapy of various inflammatory skin diseases. Phototherapy, using a combination of UV-A (25%), UV-B (5%) and visible light (70%), may represent a therapeutic alternative in patients with allergic rhinitis.

79 patients were randomly assigned to receive:

- a combination of UV-A (25%), UV-B (5%) and visible light (70%), in the phototherapy group

- low-intensity visible light, in the control group

The efficacy of treatment was assessed by symptom score before treatment and 1 month after the end of treatment.

Nasal scores decreased in both groups but the decrease was highly significant in the phototherapy group.

The study authors concluded that phototherapy may be an effective modality in the treatment of allergic rhinitis.

In the meantime, before the beneficial effects of phototherapy are confirmed by other studies, you can consider some of the more conventional treatment options for allergic rhinitis shown in the diagram below:

Treatment Options for Allergic Rhinitis (click to enlarge the image).

References:

Phototherapy for Allergic Rhinitis: A Prospective, Randomized, Single-blind, Placebo-controlled Study. Cemal Cingi, MD; Hamdi Cakli, MD; Aytekin Yaz, MD; Murat Songu, MD; Cengiz Bal, MD. Ther Adv Resp Dis. 2010;4(4):209-213 and Medscape.

Rhinophototherapy: gimmick or an emerging treatment option for allergic rhinitis? Rhinology. 2011 15 1;49(5):499-506.

Image source: Wikipedia, a Creative Commons license.

IgE- and non-IgE-mediated food allergies - summary from 2011 CSACI meeting

This summary was compiled from tweets posted by Dr. Stuart Carr @allergydoc4kidz, the president of the Canadian Society of Allergy and Clinical Immunology (CSACI). The tweets were labeled #CSACI and they reached more than 10,000 people. I would strongly encourage you to post updates on Twitter from the CME conferences that you are planning to attend in the future.

Zave Chad spoke on IgE- and non-IgE-mediated food allergies:

FPIES

FPIES presents with vomiting and diarrhea, and may progress to shock. It starts early in infancy. There is 50% resolution per year for milk-induced FPIES.

Adult non-IgE reactions to shellfish may be the same process as pediatric FPIES. Milk protein enteropathy looks similar to celiac disease, but it usually self-limiting.

Deficit in TGF-beta (and its receptors) may be important in development of FPIES. Increased TNF-alpha also seems to be important for FPIES.

Tests for food allergy

Pre-test probability is still the most important factor in assessing the value of SPT or sIgE for food allergy. Component-resolved diagnostics are becoming increasingly useful in determining the appropriateness of an oral food challenge.

Atopy patch testing (APT)

Atopy patch testing (APT) is not routinely advocated. There is a lot of work to be done before it can be used in clinical practice. A 2-year clinical experience with APT in Halifax suggests poor PPV and NPV, and clinicians are not enthusiastic.

Time of food introduction

There is growing evidence that optimal timing of food introduction for development of tolerance is between 4-6 months.

The introduction of eggs at 4 months (4/12) is associated with less allergy than the introduction of egg at 12 months (12/12). There are similar data for gluten and celiac disease.

"Screening" tests for food allergy

Tim Vander Leek (@TedNorton) is speaking about the role of SPT and the lack of utility of "screening" tests for food allergy.

There is a lot discussion around role of "screening" tests for food allergy. Some allergists think that is should be avoided at all costs because it is “hard to to unring the bell.”

In atopic dermatitis, it is better to focus on good aggressive skin care rather than testing for (unlikely) causative/contributing foods.

The article by Campbell (J Paediatr Child Health 2011, June 17) is a good review of the limited causative role of food allergy in atopic dermatitis.

Wade Watson spoke on controversies around food allergy.

For example, in infant with confirmed cow’s milk allergy (CMA), what do you say/do about egg, peanut (PN), etc.?

According to Bill Moote, "skin testing for foods they have not eaten is probably not rational.” If the parents are anxious to introduce the food at home, consider “open feed” in the allergy clinic rather than test.

Children with food allergy have poorer perceived general health and quality of life (QOL).

There are few data and published recommendations on the subsequent food introduction in children with established food allergy.

Disclaimer: The text was edited, modified, and added to by me. I was invited to speak on the topic of social media use by the allergists during the 2011 CSACI meeting.

Identification of asthmatic patients who respond to Singulair (montelukast) is important as response is variable

Leukotrienes (LTs) include cysteinyl LTs (CysLTs) and LTB(4). They are potent lipid mediators that have a role in the pathophysiology of asthma.

Receptors

2 receptor subtypes for CysLTs have been identified: CysLT(1) and CysLT(2). The activation of the CysLT(1) receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including:

- increased airway smooth muscle activity

- microvascular permeability

- airway mucus secretion

LTB(4) might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness.

Eicosanoids are signaling molecules made by oxygenation of 20-carbon essential fatty acids. There are 4 families of eicosanoids (PP-LT): prostaglandins (PG), prostacyclins (PGI), leukotrienes (LT) and thromboxanes (TX).

Medications

CysLT(1) receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids (ICS).

Combination of CysLT(1) receptor antagonists (LTRA) and inhaled glucocorticoids (ICS) in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy.

The identification of subgroups of asthmatic patients who respond to CysLT(1) receptor antagonists is relevant for asthma management as the response to these drugs is variable.

CysLT(1) receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma.

The LTRA Singulair will be available as a significantly less expensive generic medication in August 2012.

References:

Leukotriene modifiers for asthma treatment. Montuschi P, Peters-Golden ML. Clin Exp Allergy. 2010 Dec;40(12):1732-41. doi: 10.1111/j.1365-2222.2010.03630.x.

Montelukast failure index that may be helpful in predicting response in patients with asthma http://goo.gl/AzRPF

Image source: Montelukast, from Wikipedia, the free encyclopedia, public domain.

Adverse reactions to biological modifiers - summary from 2011 CSACI meeting

Biomarkers for autoimmunity in CVID - summary from 2011 CSACI meeting

Eosinophilic esophagitis as the main cause of dysphagia in adults

Eosinophilic oesophagitis (EoE) was first described in the early 1990s, and was considered rare in adults. Since then, it has rapidly evolved as a distinctive chronic inflammatory oesophageal disease with increasing incidence and prevalence in the westernized countries.

Currently, EoE represents the main cause of dysphagia in adult patients (according to the review authors). This disease is more prevalent in males and is frequently associated with allergies.

Diagnosis

The diagnosis is established based on:

- esophageal symptoms
- dense eosinophilic oesophageal infiltration
- exclusions of other conditions leading to oesophageal eosinophilia

Eosinophilic Esophagitis (click here to enlarge the image).

Treatment

Topical corticosteroids lead to a rapid improvement of active EoE clinically and histologically.

Especially in children, elimination diets can have similar efficacy as topical corticosteroids.

Esophageal dilation of EoE-induced esophageal strictures can also be effective in improving symptoms, but this therapy has no effect on the underlying inflammation.

In any case, neither the diagnostic nor the long-term therapeutic strategies are as yet defined.

References:

Eosinophilic oesophagitis: latest intelligence. Schoepfer AM, Simon D, Straumann A. Clin Exp Allergy. 2011 Mar 24. doi: 10.1111/j.1365-2222.2011.03739.x.

Comments from Twitter:

@RyanMadanickMD: Disagree, NOT "main" cause in adults, though certainly EoE is increasing in both prevalence and incidence -- MT @DrVes: Eos esophagitis as the main cause of dysphagia in adults goo.gl/wKxI1

New approaches to gene therapy for primary immunodeficiencies

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies (PIDD). However, many patients lack an HLA-identical donor. For that group, gene therapy may be a therapeutic option.

Gene insertion by viral vectors has provided proof of concept for PIDD cure. However, leukemic transformation due to insertional mutagenesis has tampered the initial optimism.

Primary immunodeficiency disorders (PIDD) (click to enlarge the image)

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

DNA double-strand breaks

New approaches are based on introduction of DNA double-strand breaks into:

- the endogenous locus to achieve gene correction
- a safe genomic location ("safe harbor")

Target-specific endonucleases that induce site-specific DNA double-strand breaks are:

- homing endonucleases
- zinc finger nucleases

Transposons

An alternative approach to achieve gene insertion is based on transposons. Transposons are DNA elements that spontaneously translocate from one chromosomal location to another.

References:

Gene therapy for primary immunodeficiencies: Looking ahead, toward gene correction. Pessach IM, Notarangelo LD. J Allergy Clin Immunol. 2011 Mar 24.
Primary immunodeficiencies (PIDD)

Does Breathing Training Work for Asthma Management?

For years, there has been public interest in breathing modification techniques as an adjunct treatment of asthma. Surveys suggest that 30% of people with asthma use them, often without the knowledge of their physicians.

Many clinicians remain sceptical regarding breathing training in asthma, which may be due to some exaggerated claims linked to training 'packages' including the Buteyko method.

Recent trials have investigated a variety of breathing training programmes. Most of them focused on slow, regular, nasal, abdominal breathing and reduced ventilation.

Current evidence suggests that breathing training programmes can be effective in improving patient-reported outcomes such as symptoms, quality of life and psychological impact. It may also reduce the use of rescue bronchodilator medication (e.g. albuterol). However, there is little evidence that airways physiology, hyper-responsiveness or inflammation is affected by such training.

References:

The Role of Breathing Training in Asthma Management. Anne Bruton; Mike Thomas. Curr Opin Allergy Clin Immunol. 2011;11(1):53-57, Medscape, 2011.

Image source: "Lung Plush from I Love Guts: I Lung You!" available from Amazon.com Toys & Games.

Transcription errors from allergy and immunology clinic notes

Here are some examples of transcription errors noted in allergy and immunology clinic dictations:

- "he had 67 pneumonias". It was supposed to be "6-7 pneumonias".

- "he needs to use the inhaler every 4-6 years". It was supposed to be "every 4-6 hours".

- "he is allergic to pot". It was supposed to be "he is allergic to weed", according to his allergist.

- "subtle light lesions". It was supposed to be "satellite lesions".

Always double check for errors.

Comments from Twitter:

@AllergieVoeding: pot is the often used pseudonym. Daily used here in Holland.

@DrVes: The thing is the patient from that transcription was allergic to ragweed and weeds, not to "pot" (marijuana, "weed").

Poison Ivy Allergy - ACAAI Video

Dr. Luz Fonacier discusses poison ivy allergy including treatments and home remedies. Information from the American College of Allergy, Asthma and Immunology (ACAAI).

Legume Allergy: lentils, chickpeas, peas, beans, and peanuts

This Spanish study included 54 children with allergic reactions after exposure to legumes. Legumes were defined as lentils, chickpeas, peas, white beans, and peanuts.

The diagnosis of legume allergy was confirmed by positive skin prick test with legume extracts and food challenges, or a recent convincing history of severe reactions.

The onset of allergic reactions was at 2 years.

Allergy to lentil was the most frequently diagnosed legume allergy (80%), followed by allergy to chickpea (59%).

In conclusion:

- lentils and chickpeas are the legumes that cause most allergic reactions
- allergy to more than 1 legume is common
- boiled legume extracts provided the best results

Oral Food Challenges (click to enlarge the diagram).

References:

Clinical features of legume allergy in children from a Mediterranean area. Martínez San Ireneo M, Ibáñez MD, Sánchez JJ, Carnés J, Fernández-Caldas E. Ann Allergy Asthma Immunol. 2008 Aug;101(2):179-84.

Pea Allergy

Image source: Frozen green peas. Wikipedia, Jina Lee, GNU Free Documentation License.

Seafood allergy in children linked to high rate of anaphylaxis (20%), shrimp is the most common cause

Both food allergy and seafood (fish, mollusk, and crustacean) consumption have increased over the past 40 years.

Seafood allergy is now one of the leading cause of food-related anaphylaxis in both the United States and Australia.

This Australian study included a retrospective chart review of 167 children presenting to tertiary Allergy Service with an allergic reaction to seafood. 94% had evidence of co-existent atopic disease.

Crustacean allergy

Prawn/shrimp was the most common seafood implicated. 20% presented with a history of anaphylaxis to seafood.

Over 50% of crustacean-allergic children could tolerate non-crustacean fish.

Fish allergy

Sensitization to other fish species was very common in fish-allergic children, with 30% reporting reactions to at least two species. 16% developed symptoms to fish vapours.

In children with allergy to tuna and/or salmon, at least 21% were able to tolerate the fish in a tinned form.

Seafood is a relatively common and important cause of food allergy, presenting with a high rate of anaphylaxis (20%).

References:

Seafood allergy in children: a descriptive study. Turner, Ian Ng, Andrew Kemp, Dianne Campbell, Volume 106, Issue 6, Pages 494-501 (June 2011).

Image source: A steamed tail-on shrimp, Wikipedia, public domain.

FEF25%-75% cutoff value of less than 58% predicts bronchial involvement in patients with allergic rhinitis

Allergic rhinitis (AR) may be considered a risk factor for the onset of asthma. Recently, it has been reported that forced expiratory flow between 25% and 75% of vital capacity (FEF25%−75%) may predict a positive response to bronchodilation test in asthmatic children. Bronchial hyperreactivity (BHR) is frequently detected in AR patients.

360 patients with allergic rhinitis (AR) were evaluated in this Italian study:

- 66% had ”positive” results for bronchodilation test
- FEF25%−75% was abnormal in 21%
- 21% had severe BHR

An FEF25%−75% cutoff value of less than 58% of predicted may discriminate patients with both severe BHR and reversibility.

This study suggests a role of FEF25%−75% as a marker of early bronchial involvement in patients with persistent allergic rhinitis. FEF25%−75% value of less than 58% of predicted may suggest the co-existence of severe BHR and reversibility.

References:

Relationship between bronchial hyperreactivity and bronchodilation in patients with allergic rhinitis. Giorgio Ciprandi, Alessio Signori, Ignazio Cirillo, Volume 106, Issue 6, Pages 460-466 (June 2011).

Image source: Spirometry, from Wikipedia, the free encyclopedia, GNU Free Documentation License.

Introduction of cooked egg at 4 to 6 months of age might protect against egg allergy

Until recently, infant feeding guidelines have long recommended delaying introduction of solids and allergenic foods to prevent allergy in high-risk infants, despite a paucity of evidence.

In a population-based cross-sectional study of 2,600 infants, parents reported on infant feeding before skin prick testing for egg white. Egg-sensitized infants were then offered an egg oral food challenge (OFC).

Compared with introduction at 4 to 6 months, introducing egg into the diet later was associated with higher risks of egg allergy:

- odds ratio [OR] 1.6 for introduction at 10-12 months
- OR 3.4 for introduction after 12 months

At age 4 to 6 months, first exposure as cooked egg reduced the risk of egg allergy compared with first exposure as egg in baked goods (OR, 0.2).

Duration of breast-feeding and age at introduction of solids were not associated with egg allergy.

Introduction of cooked egg at 4 to 6 months of age might protect against egg allergy.

Oral Food Challenges (click to enlarge the diagram).

References:

Can early introduction of egg prevent egg allergy in infants? A population-based study. J Allergy Clin Immunol. 2010 Oct;126(4):807-13.

No evidence to recommend routine food allergy testing before introducing highly allergenic foods. Restricting maternal diet during pregnancy or lactation is not recommended for preventing food allergy. Medscape, 2011.

Ovomucoid- and ovalbumin-specific IgE/IgG(4) ratios predict reactivity to baked egg. JACI, 2012.

Image source: Wikipedia, public domain.

Spirometry: FEF 25-75% may predict reversible airflow obstruction in children

This new study challenges the assumption that the assessment of forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) does not provide additional information in asthmatic children with normal FEV(1) percent predicted.

Among 400 children with normal FEV(1), FEF 25-75%, and FEV(1)/FVC were correlated with:

- methacholine challenge

- peak expiratory flow

- fraction of exhaled nitric oxide (FeNO)
- bronchodilator responsiveness

FEF(25-75) at 65% of predicted value had a 90% sensitivity and a 67% specificity for detecting a 20% increase in FEV(1) after albuterol inhalation.

The study authors concluded that FEF 25-75% was well correlated with bronchodilator responsiveness in asthmatic children with normal FEV(1). FEF 25-75% might be of use in predicting the presence of reversible airflow obstruction.

What is spirometry? A simple breathing test (video). From The Lung Association YouTube channel: Dr. Roger Goldstein explains what spirometry is (a simple breathing test), who should get tested and what spirometry tells health-care professionals. Visit www.lung.ca for more information.

References:

Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol. 2010 Sep;126(3):527-34.e1-8. Epub 2010 Jul 16.

Resurrection men and the FEF25-75. JACI, 2010.

Image source: Spirometry, from Wikipedia, the free encyclopedia, GNU Free Documentation License.

Asthma resolves in 65% of children in a 40-year cohort study

A Tasmanian population-based cohort study enrolled 9,000 7-year-old schoolchildren in 1968. The outcome measure was asthma remission, defined as no asthma attack for 2 years and no current asthma medication use, or no self-reported asthma in adult life but with parent-reported childhood asthma.

Asthma had remitted in 65% of children.

Factors negatively associated with asthma remission:

- childhood onset (OR 0.38) and later-onset allergic rhinitis (0.42)
- childhood onset (0.66) and later-onset eczema (0.66)
- maternal asthma (0.66)
- childhood chronic bronchitis (0.56)

- passive smoking (0.75) and lower socio-economic status (less convincing evidence)

Some of the risk factors discussed in the study are part of the allergic (atopic) march shown below:

Allergic (atopic) march (click here to enlarge the image).

Childhood-onset asthma (3.76) was more likely to remit than adult-onset asthma. Gender did not influence remission.

While inherited factors cannot be changed, the effect of allergic rhinitis or eczema on asthma remission might be altered by early, aggressive treatment. Every effort should be made to lessen passive exposure to tobacco smoke.

References:

Factors influencing asthma remission: a longitudinal study from childhood to middle age. Thorax 2011;66:508-513 doi:10.1136/thx.2010.146845

Back to Basics: The art of physical examination and physician-patient communication

Back to Basics: The art of physical examination and the physician-patient encounter. A video by the orthopedic surgeon Howard J. Luks, MD @hjluks

Factors predicting long-term outcomes in pediatric-onset eosinophilic esophagitis (EoE)

Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis (CE).

This study from Cincinnati Children's Hospital, one of the leading centers for EoE research, included histologic review of 4,000 pediatric esophageal biopsy specimens.

At an average of 15 years after initial endoscopy, quality of life was decreased among patients with retrospectively identified histologic eosinophilic esophagitis (rEoE) and chronic esophagitis (CE).

"Multi-ring esophagus" in eosinophilic esophagitis (left), infiltration of eosinophils (right). Source: Wikipedia.

Rates of dysphagia were 49% in patients with rEoE and 37% in CE.

Food impaction was reported in 40% of patients with rEoE and 14% in CE.

Increased esophageal eosinophil counts (odds ratio [OR], 1.6) during childhood were predictive of dysphagia during early adulthood.

Food allergy (OR, 2.7), allergic rhinitis (OR, 3.5), and asthma (OR, 2.1) were associated with dysphagia. Food impaction was more common among patients with reported food allergy (OR, 3.1).

Eosinophilic esophagitis (EoE) is associated with reduced quality of life and persistent symptoms 15 years after presentation. Increased esophageal eosinophil counts and the occurrence of food allergy and atopy in childhood increase the rate of dysphagia in young adulthood.

The risk factors discussed in the study are part of the allergic (atopic) march shown below:

Allergic (atopic) march (click here to enlarge the image).

References:

Long-term outcomes in pediatric-onset esophageal eosinophilia. Debrosse CW, Franciosi JP, King EC, Buckmeier Butz BK, Greenberg AB, Collins MH, Abonia JP, Assa'ad A, Putnam PE, Rothenberg ME. J Allergy Clin Immunol. 2011 May 31.

Use of inhaled steroid and montelukast may be related to behavioral problems, including hyperactivity

An increased prevalence of behavioral problems has been described among children with asthma.

This Turkish study included 400 children with asthma. They were assessed for the following behavioral problems:

- attention deficit-hyperactivity disorder (ADHD)
- attention deficit (AD)
- hyperactivity and impulsivity (HI)
- oppositional defiant disorder (ODD)

Prevalences of AD, hyperactivity, ADHD, and ODD were not significantly different between the study and control groups.

Among those patients receiving leukotriene antagonist (LTRA) drugs adjunctive to inhaled corticosteroids (ICS), duration of treatment was correlated with hyperactivity (P = 0.03), AD (P = 0.04), ADHD (P = 0.042), and ODD (P = 0.03).

Patients with asthma receiving LTRA abd ICS treatment had a higher risk for oppositional behavior (4 times compared with the control group (P = 0.04) and 8 times compared with patients with asthma not using any drug (P = 0.02).

The authors concluded that tather than asthma itself, adjunctive use of ICS+LTRA therapy appears to be related with symptoms of common behavioral problems, including hyperactivity, AD, ADHD, and ODD and to increase the risk of ODD.

However, most of the p values in this study were marginally significant, with large confidence intervals, and I would not put too much emphasis on the results until I see more convincing evidence of causation, rather than association.

Asthma Inhalers (click to enlarge the image).

References:

Common behavioral problems among children wıth asthma: Is there a role of asthma treatment? Hulya Ercan Saricoban et al. Ann of Allergy, Asthma and Immunology, Volume 106, Issue 3, Pages 200-204 (March 2011).
Montelukast failure index that may be helpful in predicting response in patients with asthma http://goo.gl/AzRPF
Asthma
Image source: Openclipart.org, public domain.

Nobel Prize in Medicine for 2011 goes to discoverers of dendritic cells and toll-like receptors (TLR)

This @DrSilge's tweet says it all: "All your Nobels are belong to us." -Immunology. (Immunology's been busy in the lab, not so up to date on its memes.)

Chicagoan Bruce A. Beutler, MD, a 1981 graduate of The University of Chicago Pritzker School of Medicine, is one of three winners of the Nobel Prize in Physiology or Medicine for 2011. He shares the honor with Jules A. Hoffmann for their discoveries concerning the activation of innate immunity, and with Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity. Unfortunately, Professor Steinman died over the weekend.

The summaries of the research provided below are taken from the Nobel Prize website.

The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3. Image source: Wikipedia.

Jules Hoffmann made his pioneering discovery in 1996, when he and his co-workers investigated how fruit flies combat infections. They had access to flies with mutations in several different genes including Toll, a gene previously found to be involved in embryonal development. When Hoffmann infected his fruit flies with bacteria or fungi, he discovered that Toll mutants died because they could not mount an effective defense. He was also able to conclude that the product of the Toll gene was involved in sensing pathogenic microorganisms and Toll activation was needed for successful defense against them.

Bruce Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock, a life threatening condition that involves overstimulation of the immune system. In 1998, Beutler and his colleagues discovered that mice resistant to LPS had a mutation in a gene that was quite similar to the Toll gene of the fruit fly. This Toll-like receptor (TLR) turned out to be the elusive LPS receptor. When it binds LPS, signals are activated that cause inflammation and, when LPS doses are excessive, septic shock. These findings showed that mammals and fruit flies use similar molecules to activate innate immunity when encountering pathogenic microorganisms. The sensors of innate immunity had finally been discovered.

The discoveries of Hoffmann and Beutler triggered an explosion of research in innate immunity. A dozen different TLRs have now been identified in humans and mice. Each one of them recognizes certain types of molecules common in microorganisms. Individuals with certain mutations in these receptors carry an increased risk of infections while other genetic variants of TLR are associated with an increased risk for chronic inflammatory diseases.

Dendritic Cell Subsets (click to enlarge the image).

Ralph Steinman discovered, in 1973, a new cell type that he called the dendritic cell. He speculated that it could be important in the immune system and went on to test whether dendritic cells could activate T cells, a cell type that has a key role in adaptive immunity and develops an immunologic memory against many different substances. In cell culture experiments, he showed that the presence of dendritic cells resulted in vivid responses of T cells to such substances. These findings were initially met with skepticism but subsequent work by Steinman demonstrated that dendritic cells have a unique capacity to activate T cells.

References:

Dendritic Cells
Toll-like receptors (TLRs)
Nobel laureate: “I was a little bit disbelieving, so I went to Google News and saw my name there, so I knew it was real” http://goo.gl/mdv0n

Disclaimer: I am an Allergist/Immunologist and Assistant Professor of Medicine and Pediatrics at the University of Chicago.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children

This study included 55 pediatric patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) admitted between 2000 and 2007 to 2 hospitals in Boston.

Skin reactions to drugs (click to enlarge the image).

Etiology

Drugs were identified as the most likely etiologic agent in 53% of children:

- antiepileptic drugs were the most common agents
- sulfonamide antibiotics
- chemotherapy drugs

Acute Mycoplasma pneumoniae infection was confirmed in 22% children, and herpes simplex virus was confirmed in 9% of children (9%).

Treatment

Treatment included:

- systemic antimicrobial agents (67%)
- systemic corticosteroids (40%)
- antiviral drugs (31%)

Intravenous immunoglobulin was administered to 38% of children.

Recurrence

18 of children had recurrence of SJS up to 7 years after the index episode.

Half of affected children suffered long-term complications - 47% of children suffered long-term sequelae that mostly involved the skin and eyes.

References:

Recurrence and Outcomes of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children. PEDIATRICS Vol. 128 No. 4 October 1, 2011, pp. 723 -728, (doi: 10.1542/peds.2010-3322).

The Current Understanding of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Medscape, 2011.

How to administer influenza vaccine in egg-allergic patients

Both TIV (trivalent inactivated influenza vaccine) and LAIV (live-attenuated influenza vaccine) are produced in eggs. However, influenza vaccine can be administered in a single dose and it is well tolerated by nearly all recipients who have egg allergy. More conservative approaches, such as skin testing or a 2-step graded challenge, are no longer recommended for patients with mild reactions.

Mild reaction or severe reaction?

As a precaution, clinicians should determine if the presumed egg allergy is based on a mild or severe reaction.

Mild reactions are defined as hives alone.

Severe reactions involve cardiovascular changes, respiratory and/or gastrointestinal (GI) tract symptoms, or reactions that require the use of epinephrine.

Recommendations regarding influenza vaccination for persons who report allergy to eggs - Advisory Committee on Immunization Practices (ACIP), 2011--12 influenza season. CDC.

When to consult an allergist?

Clinicians should consult with an allergist for children with a history of severe reaction. Severe allergic reactions to eggs involve cardiovascular changes, respiratory and/or gastrointestinal (GI) tract symptoms, or reactions that require the use of epinephrine.

Most vaccine administration to people with egg allergy can happen without the need for referral. Only 1% of children have IgE–mediated sensitivity to egg, and of those, a very small minority have a severe allergy.

Standard preconditions

Standard immunization practice should include the ability to respond to acute hypersensitivity reactions. Therefore, influenza vaccine should be given to people with egg allergy with the following preconditions:

- Appropriate resuscitative equipment must be readily available

- Ovalbumin content up to 0.7 micrograms/0.5 mL per vaccine dose has been well tolerated. Click here for ovalbumin content of TIV. LAIV vaccine is not recommended for egg allergic individuals.

- After immunization, the vaccine recipient should be observed in the office for 30 minutes, the standard observation time after receiving immunotherapy.

- For children who need a second dose, the same product brand is preferred, if possible, but it does not need to be from the same lot as the first dose.

References:

Recommendations for Prevention and Control of Influenza in Children, 2011–2012. PEDIATRICS Vol. 128 No. 4 October 1, 2011, pp. 813 -825, (doi: 10.1542/peds.2011-2295)

Diagram: Precautions for administering influenza vaccine to presumed egg-allergic recipients.

Ovalbumin content of TIV

Allergy Notes