Asthma Treatment with Inhaled Steroids: Daily or On Demand (PRN)?

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Please note that the discussion below applies only to mild asthma.

For mild persistent asthma:

Although the IMPACT and BEST studies suggest that on-demand therapy in some patients with mild persistent asthma achieves a similar degree of asthma control based on symptoms and functional outcomes, the IMPACT study indicates that regular and on-demand therapy is not equivalent for controlling airway inflammation.

For mild intermittent asthma:

On-demand treatment with SABAs as suggested by the international guidelines is a reasonable option. Alternatively, courses of anti-inflammatory drugs for asthma (e.g. low-dose ICS, LTRAs) can be prescribed to subgroups of patients with intermittent asthma including those with seasonal allergic asthma or perennial allergic asthma exposed to triggering factors (e.g. cold, upper respiratory tract infections) also considering the good tolerability of these drugs.

Asthma classification and treatment for each stage (click to enlarge the image).

References:
Pharmacotherapy of Asthma: Regular Treatment or On Demand? Medscape.
http://www.medscape.com/viewarticle/714427

Should patients with mild asthma use inhaled steroids? CCJM, 2010.

Image source: Symbicort Turbuhalers, Wikipedia, public domain.

Next Generation of Flu Vaccines: Cell-based Technology May Replace Eggs

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From Medscape:

The half-century-old egg-based method of producing flu vaccine has major limitations: a lengthy 6 to 9-month manufacturing process and the need to forecast and select the virus strains to be used in the vaccine at least six months ahead of the flu season, not to mention the annual demand for hundreds of millions of fertilized chicken eggs.

In place of eggs, the nearly $1 billion Novartis plant is using laboratory-grown mammalian cells that are capable of hosting a growing virus. Cell culture-based vaccines are already approved for use in some European countries.

References:

Next Generation of Flu Vaccines Coming of Age: Cell-based Technology May Replace Egg-based Flu Vaccines

Influenza Vaccines for the Future - NEJM, 2010 http://goo.gl/cPIgz

Image source: Medium white eggs in carton, Wikipedia, M. Chambers, Creative Commons Attribution-ShareAlike 3.0 License.

Elderly people more prone to insect sting anaphylaxis, probably due to elevated tryptase

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This study included 274 patients who were diagnosed with honeybee or wasp venom allergy.

Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively).

There was not only a general increment in tryptase levels in elderly people but also a continuous increase in tryptase concentrations even below the cut-off (11.4 mug/l) with increasing age.


A yellow jacket wasp with a typical narrow waist (left) and a honey bee with a fat hairy "fuzzy" body (right). Image source: Wikipedia 1, 2, GNU Free Documentation License.

Serum tryptase is a risk factor for severe anaphylactic reaction to hymenoptera stings. This is the first evidence that basal serum tryptase levels increase continuously with age. Tryptase is an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people.

As those patients are at increased risk for life-threatening anaphylactic reactions, it should be considered to adjust VIT in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life-long continuation.

References:
Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly. Guenova E, Volz T, Eichner M, Hoetzenecker W, Caroli U, Griesinger G, Burow G, Mitev V, Biedermann T. Allergy. 2010 Feb 1. [Epub ahead of print]

Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. NEJM, 1987.

"First Peanuts, Now Pets" - Pets in Airline Cabins Can Pose Allergy Risk

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From the NYTimes and the CMAJ:

1 in 10 people have allergies to animals, and for some, exposure to dogs and cats can set off an asthma attack or a life-threatening reaction like anaphylaxis.

“The thing about allergies is they’re unpredictable,” Dr. Stanbrook said. “You can have mild reactions for a long time and then have a severe one — it’s hard to predict.”

References:

Pets in Airline Cabins Pose Allergy Risk, Doctors Say

ACAAI President Says Peanut Bans Are An Overreaction To Food Allergies - NPR http://goo.gl/IH4jC - 122 comments and counting.

Pretreatment with omalizumab improves tolerability of immunotherapy in allergic asthma

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Although specific immunotherapy is a valuable treatment option for patients with allergic asthma, the potential for systemic allergic reactions has limited its use, especially for patients with symptomatic disease.

Use of omalizumab in patients whose asthma was symptomatic despite use of inhaled corticosteroids was associated with fewer systemic allergic reactions to specific immunotherapy and enabled more patients to achieve the target immunotherapy maintenance dose.

References:

Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. Massanari M, Nelson H, Casale T, Busse W, Kianifard F, Geba GP, Zeldin RK. J Allergy Clin Immunol. 2010 Feb;125(2):383-9.

http://www.ncbi.nlm.nih.gov/pubmed/20159249

Oral corticosteroids were withdrawn in 74% of severe asthma patients treated with omalizumab- Current Medical Research and Opinion, 2010.

Response to omalizumab after 16 weeks is a predictor of continuing persistent response to omalizumab in asthmatics. Allergy 2011.

Image source: Wikipedia, public domain.

Pollen.com adds new features for allergy season

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The AAAAI offers a mobile "app" for pollen status updates as of December 2011. Go to pollen.aaaai.org on your mobile to see it, otherwise the regular PC browser redirects to the old page.

- A customizable dashboard – MyPollen – offers allergy information to registered users based on their geographic location

- Pollen Diary keeps track of symptoms

Pollen.com reportedly garners visitor traffic around 3 million per month during peak allergy season.


Pollen-producing plants (weeds and trees) in Omaha, Nebraska. V. Dimov, M.D.

References:

Pollen.com adds new features for allergy season
Pollen.com - National Allergy Forecast for Today

Somebody "edited" the box of a "Sinus and Allergy" medication on Flickr

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Image source: Amanda P. DeBusk. Flickr.

Ambient fine particles and ozone exacerbate respiratory conditions including asthma

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In New York City, age was a significant effect modifier for hospitalizations, and children age 6 to 18 years consistently had the highest risk.

Among children age 6 to 18 years, there was a 26% increased rate of ICU admissions and a 19% increased rate of general hospitalizations for each 12-mug/m(3) increase in PM(2.5). For each 22-ppb increase in ozone, there was a 19% increased risk for ICU admissions and a 20% increased risk for general hospitalizations.

Warm weather patterns of ozone and PM(2.5) disproportionately affect children with asthma and appear responsible for severe attacks that could have been avoided.

References:

Age-related association of fine particles and ozone with severe acute asthma in New York City. Silverman RA, Ito K. J Allergy Clin Immunol. 2010 Feb;125(2):367-373.e5.

http://www.ncbi.nlm.nih.gov/pubmed/20159246
Association of ozone exposure with asthma, allergic rhinitis, and allergic sensitization http://goo.gl/6v6zI

heavy traffic, Wikipedia, GNU Free Documentation License.

Intravenous montelukast may be effective as treatment for acute asthma

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583 adults with acute asthma were treated with standard care during a 60-minute screening period.

Patients with FEV(1) lower than 50% predicted were randomly allocated to intravenous montelukast 7 mg or placebo.

Montelukast increased FEV(1) at 60 minutes postdose by 0.32 L (0.10 L more than placebo). However, treatment failure did not differ between groups.

Intravenous montelukast added to standard care in adults with acute asthma produced relief of airway obstruction throughout the 2 hours after administration, with an onset of action as early as 10 minutes.

However, a follow-up study in children did not show a significant difference from placebo (the results and the link to the PubMed abstract will be posted on this website in the near future).

References:

A randomized placebo-controlled study of intravenous montelukast for the treatment of acute asthma. Camargo CA Jr, Gurner DM, Smithline HA, Chapela R, Fabbri LM, Green SA, Malice MP, Legrand C, Dass SB, Knorr BA, Reiss TF. J Allergy Clin Immunol. 2010 Feb;125(2):374-80.
http://www.ncbi.nlm.nih.gov/pubmed/20159247?dopt=Abstract

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

Updated: 03/28/2010

Beyond Advair: Relovair (fluticasone/vilanterol) is a new ICS/LABA combination currently in trials with a new inhaler

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GlaxoSmithKline (GSK) announced on March 19, 2010 that the first asthma patient has started treatment with Relovair™ (fluticasone furoate/vilanterol trifenatate) in an asthma exacerbation study, marking the start of the Phase III clinical development programme with this once daily therapy.

The asthma programme for Relovair (previously referred to as ‘Horizon’) will assess the potential benefit of the combination of inhaled corticosteroid, fluticasone furoate, and long-acting beta agonist, vilanterol trifenatate versus the component products and existing treatments for asthma.

The programme will consist of a range of 8 studies to determine the efficacy and safety of Relovair in asthma patients who remained uncontrolled on current treatment. The initiation of the exacerbation study complements a 12-month safety study that is already underway in support of the COPD programme. An additional 6 efficacy studies are scheduled to start within the next quarter.

This study will evaluate Relovair 100/25mcg against fluticasone furoate 100mcg in patients whose asthma remains uncontrolled on current therapy. The primary endpoint - time to first severe asthma exacerbation - will inform on both safety and efficacy.

The ongoing 12 month safety study, will evaluate the overall safety profile of Relovair and has been designed to support both the asthma and COPD indications.

Patients across all of the Relovair programs will be dosed using a unique single step activation inhaler.

Relovair is being developed under the long-acting beta2 agonist (LABA) collaboration entered into in November 2002 with Theravance, Inc. a biopharmaceutical company with a pipeline of internally discovered product candidates.

References:

GlaxoSmithKline commences Relovair Phase III asthma programme

Risk of asthma exacerbations: Relative to SABA-only therapy, LABA use is associated with a lower risk of ED visit http://goo.gl/4sDc9

Image sources: Wikipedia, public domain, Advair Diskus.

FDA: 46 new cancer cases in children with eczema treated with pimecrolimus and tacrolimus in the post-market period

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The FDA said 46 cancer cases and 71 infection cases have been reported in patients aged 16 and younger from 2004 to 2008 with Novartis' Elidel and Astellas' Protopic.

Both drugs -- also known as pimecrolimus and tacrolimus respectively -- already carry strong warnings about cancer and infection, but officials should consider expanding them to include the new post-marketing reports.

Pimecrolimus. Image source: Wikipedia, public domain.

Patients with atopic dermatitis were at 1.5 times greater risk of getting cancer in a large UK study of 4.5 million people. The cancers included lymphoma, melanoma, and non-melanoma skin cancer. http://bit.ly/bGjdpO

What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?

(A) NFkB

(B) calcium

(C) ipraimmunophilin

(D) NFAT

(E) calcineurin

(F) calmodulin

(G) AP-1

Answer: E.

References:
May need wider eczema caution for kids: FDA | Reuters

Drugs acting on immunophilins: Cyclosporine, Tacrolimus, Sirolimus

French drug review journal is sued for calling for the tacrolimus based ointment Protopic to be banned - BMJ http://goo.gl/dqRHK

Diagnostic guidelines for hyper-IgE syndrome (HIES)

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The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.

Phagocyte immunodeficiencies (click to enlarge the image).

A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy.

Diagnostic guidelines for STAT3-deficient HIES:

- Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate.

- Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES.

- Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.

The level of IgE increases during childhood until about 10 years of age. At age 10, the total IgE reaches a value that is typically maintained throughout adult life.

References:

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010 Feb;125(2):424-432.e8.
Hyper IgE Syndrome (HIES)

Allergy and Immunology News of the Day

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Partial improvement of solar urticaria after omalizumab.

http://www.ncbi.nlm.nih.gov/pubmed/20159260?dopt=Abstract

Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions.

http://www.ncbi.nlm.nih.gov/pubmed/20159266?dopt=Abstract

Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.

http://www.ncbi.nlm.nih.gov/pubmed/20159245?dopt=Abstract

Role of pharmacogenomics in improving the management of asthma. There is a large amount of interindividual variability in both therapeutic and adverse responses to asthma therapies. Genetic variability can account for 50% to 60% of this variability.

http://www.ncbi.nlm.nih.gov/pubmed/20159237?dopt=Abstract

Infants with eczema are at increased risk for mental health problems at age 10 years." Even if cleared afterward, eczema at age 1 to 2 years may cause persistent emotional and behavioral difficulties. http://www.ncbi.nlm.nih.gov/pubmed/20159252?dopt=Abstract

Infant eczema with concurrent sleeping problems appears to be a risk factor for the development of mental health problems. http://goo.gl/5AVv

Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Steroids: LABA Add-on Worked Best

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182 children who had uncontrolled asthma while receiving 100 µg of fluticasone bid were randomly assigned to receive each of three blinded step-up therapies for 16 weeks (4 months):

- 250 µg of fluticasone twice daily (ICS step-up)
- 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily (LABA step-up)
- 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up)

A differential response occurred in 161 of 165 patients who were evaluated.

The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up and ICS step-up.

White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up.

The drugs with the best chance of success -- 45% -- were long-acting beta-agonists (LABAs), the study suggested. But safety concerns limit the use of these agents, the best known of which are Serevent and Foradil and the combination products Advair and Symbicort.

30% of the children did best either with a leukotriene-receptor antagonist (LTRA, brands include Accolate, Singulair, and Zyflo) or by doubling the dose of the child's current inhaled steroid medication.

References:

Step-up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids. NEJM.
Choosing Asthma Step-up Care. NEJM.
How to Treat Kids' Hard-to-Control Asthma. WebMD.

Off label use of inhaled corticosteroid/long-acting bronchodilator (LABA) in a 2-year-old child - AAAAI Ask the Expert.

Image source: Wikipedia, public domain.

Basophil expression levels of CD203c might be used to monitor asthma

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CD203c is a basophil cell surface marker used to diagnose and monitor various allergic diseases.

Expression levels of CD203c were significantly higher on basophils from patients with asthma exacerbation than patients with stable asthma or healthy subjects.

In contrast, no differences in spontaneous expression levels of CD63 or CD69 were observed. The basophil activation test (BAT) relies on CD63 (tetraspanin) - a marker for flow cytometric quantification of in vitro activated basophils. CD69 - An early activation marker on T cells and NK cells.

Basophil granulocyte. Image source: Wikipedia.

Asthma exacerbation was accompanied by increased expression of CD203c on basophils that decreased significantly during remission. Basophil expression levels of CD203c might therefore be used to monitor asthma in patients.

References:
CD203c expression on human basophils is associated with asthma exacerbation. Ono E, Taniguchi M et al. J Allergy Clin Immunol. 2010 Feb;125(2):483-489.e3.
http://www.ncbi.nlm.nih.gov/pubmed/20159259?dopt=Abstract

A variety of diseases may be associated with IL-33: the new kid in the IL-1 family

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Interleukin-33 (IL-33) is a newly described member of the IL-1 family that is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis.

The IL-33 receptor, consisting of ST2 and IL-1 receptor accessory protein, is also widely expressed, particularly by T helper 2 (TH2) cells and mast cells.


Video: Interleukin-1 binding to its receptor on a cell surface, created from structural data.

The Good:

IL-33 is host-protective against helminth infection and reduces atherosclerosis by promoting TH2-type immune responses.

The Bad:

IL-33 can promote the pathogenesis of asthma by expanding TH2 cells and mediate joint inflammation, atopic dermatitis and anaphylaxis by mast cell activation.

IL-33 could be a new target for therapeutic intervention across a range of diseases. In particular, IL-33/ST2 pathway may provide new therapeutic targets for allergic rhinitis and asthma (http://goo.gl/3utyB).

References:
Disease-associated functions of IL-33: the new kid in the IL-1 family. Foo Y. Liew1, Nick I. Pitman1 & Iain B. McInnes. Nature Reviews Immunology 10, 103-110 (February 2010) | doi:10.1038/nri2692

IL-33 and its receptor ST2 play important roles in allergic rhinitis http://goo.gl/xYCga

Teamwork helps fire ants - National Geographic video

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Since South American fire ants arrived in Mobile, Alabama, in the 1940s, they have spread to become one of the most reviled pests in the Sunbelt. There have been several failed, and heavily politically influenced, eradication campaigns. The fire ants (red or black) are very aggressive and build nests in mounds of fresh soil.


Video: Teamwork helps fire ants reproduce, take down prey, and strip bones clean.

There is no venom extract for fire ant hypersensitivity but a whole-body extract is available.

Skin testing with fire ant whole-body extract is indicative of specific IgE antibodies if a positive response occurs at a concentration of 1:100 wt/vol or less by prick method, or 1:1000 wt/vol or less by intradermal method.

The dosage schedule for fire ant immunotherapy is less well defined. A maintenance dose is 0.5 mL of a 1:100 wt/vol concentration.

References:
Insect Venom Allergy: A Short Review

Related:
Fire Ant Bites. eMedicine Specialties > Emergency Medicine > Environmental, 2009.

Updated: 05/02/2010

CD8 thymocyte differentiation: T cell two-step

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A new study demonstrates that commitment to the CD8 lineage in the thymus requires sequential T cell antigen receptor (TCR) and interleukin 7 (IL-7) signaling.

The TCR signal first induces IL-7 responsiveness, then recognition of IL-7 induces the nuclear factor Runx3, which specifies the CD8 lineage.

Runt-related transcription factor 3 (Runx3) encodes a member of the runt domain-containing family of transcription factors. It functions as a tumor suppressor, and the gene is frequently deleted or transcriptionally silenced in cancer.

This video describes the cellular signaling that takes place with the T cell receptor. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

References:

CD8+ thymocyte differentiation: T cell two-step. Nature, 2010.
http://www.nature.com/ni/journal/v11/n3/abs/ni0310-189.html
Genomics and the Multifactorial Nature of Human Autoimmune Disease. NEJM, 2011.

Chronic psychosocial stress may cause asthma exacerbations

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Stress activates the hypothalamic-pituitary-adrenal axis. Release of endogenous glucocorticoids may play a role in airway homeostasis.

Chronic psychosocial stress evokes asthma exacerbations.

Animal studies suggest that social stress induces corticosteroid insensitivity. Such mechanisms amplify airway inflammation in response to infections, allergen, or irritant exposure.

References:

Social stress and asthma: The role of corticosteroid insensitivity. Haczku A, Panettieri RA Jr. J Allergy Clin Immunol. 2010 Feb 10. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/20153032?dopt=Abstract

Stress and asthma. JACI Journal Club.

Image source: openclipart.org, public domain.

Endothelium-derived prostaglandin I PGI(2) decreases migration of eosinophils and may be a therapeutic target

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Enhanced eosinophil migration from the blood into the tissue is a hallmark of allergic diseases. Prostaglandin (PG) I(2) is the major prostanoid released by endothelial cells.

PGI(2) attenuated the migration of eosinophils through cell-free filters.

The inhibitory effect of PGI(2) on eosinophils was prevented by the IP antagonist Cay10441 and the adenylyl cyclase inhibitor SQ22536.

Similarly, PGI(2) prevented the adhesion of eosinophils to fibronectin and the upregulation and activation of the adhesion molecule CD11b.

Endothelium-derived PGI(2) might be fundamental for the maintenance of the endothelial barrier function against infiltrating cells. Selective IP agonists might have beneficial effects in allergic inflammation.

Mast cells quickly generate different mediators from the metabolism of arachidonic acid: leukotrienes and prostaglandins (LTC4, LTB4, PGD2). These substances are produced within minutes of IgE-receptor crosslinking on the surface of mast cells.

Eicosanoid synthesis. Image source: Wikipedia.

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).

Arachidonic acid. Image source: Wikipedia.


LTC4 is a cysteinyl leukotriene, as are D4 and E4. Image source: Wikipedia.

LTB4. Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4. Image source: Wikipedia.

Prostaglandin D2. Image source: Wikipedia.

What is the most potent bronchoconstrictor?

(A) LTB4

(B) LTC4

(C) acetylcholine

(D) histamine

(E) thromboxane A2 (TXA2)

(F) methacholine

Answer: B

CysLTs are the most potent bronchoconstrictor agents yet discovered, about 100-1000 times more potent than histamine. The second most potent bronchoconstrictor is thromboxane A2 (TXA2).

Cysteinyl‐LTs and LTB4 are, respectively, the most potent bronchoconstrictor agents and one of the most effective leukocyte chemotaxins yet.

References:
http://www.ncbi.nlm.nih.gov/pubmed/20153037?dopt=Abstract

Mast Cells and Basophils

Colleges make efforts to accommodate students with food allergies

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From USA Today:

The allergic student of even a few years ago might have had to take chances or just skip eating anything made in a public kitchen altogether.

Nowadays, many college and university dining halls have adopted signs that point out common allergens, while others offer frozen meals and special items like gluten-free bread.

A few others, including Brown University, College of the Holy Cross, and Franklin and Marshall College, have gone even further, opening allergy-free kitchens and offering made-to-order meals prepared by specially-trained cooks.

The University of Wisconsin at Madison has begun cataloging all its ingredients and the allergens in them. Students will be able to search a database to see if specific items or meals include allergens.

Eight top allergens account for 90 percent of all food allergies (click to enlarge the figure).

Matthew Greenhawt, an allergist and clinical lecturer at the University of Michigan, says he anticipates "an explosion of kids about to arrive on college campuses who have food allergies." But their attitudes toward those allergies are often apathetic or risky. Many who knew they had allergies intentionally ate those foods, often because they had yet to experience a severe reaction. "Our data suggest that there are students out there taking risks."

References:
http://www.usatoday.com/news/education/2010-02-16-IHEdormfoodallergies16_ST_N.htm

Image source: Wikipedia, public domain.

Hormone replacement therapy (particularly estrogen) may increase asthma risk

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Women who used hormone replacement therapy (HRT) were 21% more likely to be diagnosed with asthma than those women who never used HRT.

Women who used estrogen-only HRT were 54% more likely to develop asthma compared to their “natural” menopause counterparts.

Estrogen and asthma pathogenesis have been studied, but the findings are equivocal. Estrogen is known to have both inflammatory and anti-inflammatory effects.

References:
http://jaci-nbop.blogspot.com/2010/02/estrogen-replacement-and-asthma-risk.html

Women are more likely to be diagnosed with asthma and suffer greater morbidity than men. Medscape, 2011.

Image source: Estriol. Wikipedia, public domain.

Comments:

Arin Basu - Interesting findings. I could not access the full text, but a few facts need to be taken into consideration:
* The effects are small; would be interesting to see what the risk differences are. Think for instance,
* Overall incidence was around 12.8 per 10, 000 person-years, over a period of 12 years, so roughly about 1 in 1000 women using HRT might develop asthma annually?
* There are subgroups of women who appear to be more susceptible than others:
[ Excerpt: The increase in risk of asthma onset was only significant among women reporting the use of oestrogen alone (HR=1.54, 95% CI 1.13 to 2.09) particularly in never smokers (HR=1.80, 95% CI 1.15 to 2.80) and women reporting allergic disease prior to asthma onset (HR=1.86, 95% CI 1.18 to 2.93). A small increase in the risk of asthma onset associated with the use of oestrogen/progestagen was also observed in these subgroups.]

? So, smoking reduces the risk?
Anyway, very interesting study and thanks for pointing it out.

Th2 Immune Pathway Modulation in the Treatment of Severe Asthma

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New therapeutic approaches are needed for patients with severe asthma who are refractory to standard therapy with high doses of inhaled corticosteroids plus long-acting β2-agonists (ICS and LABA).

Current guidelines for patients with severe asthma recommend the addition of oral corticosteroids, which are associated with substantial morbidity, and, for those with allergic asthma, anti-IgE (omalizumab, Xolair).

In a subgroup of patients, the severe asthma is mediated by T-helper 2 (Th2)–type CD4+ T cells which produce a characteristic repertoire of interleukins (ILs), including IL-4, IL-5, and IL-13.

Biological modifiers of Th2-type ILs, such as monoclonal antibodies, soluble receptors, and receptor antagonists may be a rational strategy in this subgroup.

References:
Role of Th2 Immune Pathway Modulation in the Treatment of Severe Asthma and Its Phenotypes.
http://www.annals.org/content/152/4/232.short?rss=1

Image source: Crystal structure of human IL-4. Wikipedia, public domain.

Increased airway vascularity and angiogenesis may contribute to airway inflammation in asthma

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Asthma is a chronic inflammatory disease of the airways characterized by the following structural changes:

- subepithelial fibrosis
- smooth muscle cells hypertrophy/hyperplasia
- epithelial cell metaplasia
- angiogenesis

These structural changes are thought to correlate with asthma severity and to account for the development of progressive lung function deterioration.


Chronic Asthma, animation video by Focus Medica Pte. Ltd.

References:
Angiogenesis in asthma. Ribatti D, Puxeddu I, Crivellato E, Nico B, Vacca A, Levi-Schaffer F. Clin Exp Allergy. 2009 Dec;39(12):1815-21.

IgE to specific peanut allergens (Ara h) may identify peanut-sensitized individuals at risk of severe symptoms

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Allergen-specific IgE testing is often performed with crude peanut extract, but the results may be difficult to interpret because of cross-reactions between peanut and other plant allergens.

From a birth cohort, IgE antibody levels to peanut and birch pollen were measured.

Peanut symptoms were reported in 87% of the children with IgE reactivity to any of the peanut allergens Ara h 1, 2 or 3 but not to Ara h 8 vs 17% of children with IgE reactivity to Ara h 8 but not to Ara h 1, 2 or 3.

Symptoms were more severe in children with Ara h 1, 2 or 3 reactivity.

IgE analysis to peanut allergen components may be used to distinguish between peanut-sensitized individuals at risk of severe symptoms and those likely to have milder or no symptoms to peanut.


8 top allergens account for 90 percent of food allergies. Specific IgE levels (sIgE) that predict the likelihood of passing an oral food challenge are shown in the figure. (click to enlarge the image). Sensitivity of blood allergy testing is 25-30% lower than that of skin testing, based on comparative studies (CCJM 2011).

References:
IgE to peanut allergen components: relation to peanut symptoms and pollen sensitization in 8-year-olds. A. Asarnoj et al. Allergy, 2010.
http://www3.interscience.wiley.com/journal/123276060/abstract

Food Allergy: A Short Review

Food Allergen Avoidance

Food Challenges

Mind Maps: Food Allergy

Mnemonics: Food Allergy

Pearls and Pitfalls of Allergen Testing - JCAAI http://goo.gl/6ThcC and http://goo.gl/Bfnhn

Comparison of diagnostic methods for peanut, egg, and milk allergy - skin prick test (SPT) vs. specific IgE (sIgE) (click to see the spreadsheet).

Overdiagnosis of Food Allergy: IgE and skin-prick testing should be confined to the realm of experts (allergists). Medscape, 2011.

Living on a farm and parental allergen sensitization reflected in utero at gene expression level

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Environmental factors, including the intrauterine environment, can influence the risk of allergy development.

mRNA expression of 17 genes was determined by PCR in term placenta of 36 families participating in the ALADDIN study (Assessment of Lifestyle and Allergic Disease During Infancy).

CD14 was expressed at higher levels in fetal side of placentas from families living on a farm compared to not living on a farm.

At the maternal side of the placenta, higher expression of STAT4 and lower expression of GATA3 were detected in families with sensitized compared to nonsensitized mothers. IL-12 was lower expressed when the families were living on a farm compared to not living on a farm.

Living on a farm and parental allergen sensitization are reflected in the intrauterine environment at the gene expression level.

CD14 is a component of the innate immune system and exists in 2 forms:

- anchored into the membrane by a glycosylphosphatidylinositol (GPI anchor) tail (mCD14)
- soluble form (sCD14)

Our innate immune system recognizes LPS via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. CD14 was the first described pattern recognition receptor (PAMP receptor).

TLR4 (for LPS)

CD14

In the initial stages of an immune response, the innate immune system recognizes the presence of pathogens and provides the first line of defense. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

References:

Joerink M, Oortveld MAW, Stenius F, Rindsjö E, Alm J, Scheynius A. Lifestyle and parental allergen sensitization are reflected in the intrauterine environment at gene expression level. Allergy 2010; DOI: 10.1111/j.1398-9995.2010.02328.x.
http://www3.interscience.wiley.com/journal/123276059/abstract

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Children living on farms exposed to a wider range of microbes leading to lower asthma risk. NEJM, 2011.
Protective role of contact with livestock and farming lifestyle on asthma, in particular during childhood. ERJ January 1, 2012 vol. 39 no. 1 67-75.

Image source: OpenClipArt.org, public domain.