Allergy Notes: 10/2010

FOXP2 (speech and language gene) allows you to tell others about FOXP3

What is FOXP2?

Forkhead box protein P2, also known as FOXP2, is a protein that in humans is encoded by the FOXP2 gene, located on human chromosome 7. FOXP2 orthologs have also been identified in all mammals for which complete genome data are available.

The FOXP2 protein contains a forkhead-box DNA-binding domain, making it a member of the FOX group of transcription factors, involved in regulation of gene expression. In addition to this characteristic forkhead-box domain, the protein contains a polyglutamine tract, a zinc finger and a leucine zipper.

In humans, mutations of FOXP2 cause a severe speech and language disorder. Because of this, FOXP2 has been dubbed the "speech and language gene."

What is FOXP3?

FOXP3 (forkhead box P3) functions as the master regulator in the development and function of regulatory T cells. FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. The fork head domain is a type of protein domain which is often found in transcription factors and whose purpose is to bind DNA.

Regulatory T cells (Tregs) with transcription factor Foxp3 are the 'master regulator' population with many levels of complexity. Foxp3 is a key regulator but insufficient and unnecessary to specify all aspects of the T regs lineage. There is Treg cell diversity - distinct subphenotypes of Foxp3+ Treg cells are found in different anatomical locations http://bit.ly/3kAVQJ

References:
FOXP2. Wikipedia.
T Lymphocytes

IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked) syndrome

Regulatory T cells become autoaggressive when Foxp3 is extinguished

Rural children have more asthma morbidity compared with urban children

Asthma disproportionately affects minority and low-income children.

The researchers administered a survey to parents of children enrolled in urban and rural school districts in Arkansas, USA.

Provider-diagnosed asthma was similar in the rural vs urban groups (19% vs 20%).

However, rural children were more commonly diagnosed as having chronic bronchitis (7% vs. 2%). Rural children had more asthma morbidity compared with urban children, including recurrent trouble breathing, recurrent cough, recurrent chest tightness, and repeated episodes of bronchitis.

There were no differences in health care utilization between groups.

Asthma prevalence was similar between rural and urban groups in Arkansas, but asthma morbidity was higher in the rural group.

References:
A comparison of asthma prevalence and morbidity between rural and urban schoolchildren in Arkansas. Pesek RD, Vargas PA, Halterman JS, Jones SM, McCracken A, Perry TT. Ann Allergy Asthma Immunol. 2010 Feb;104(2):125-31.

Asthma is a major problem for inner city children - it may be an even bigger one for poor rural children. Annals and Reuters, 2011.

Image source: OpenClipArt.org, public domain.

IgE levels frequently elevated in chronic urticaria, associated with disease severity and duration

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.

Elevated IgE levels in patients with chronic urticaria have been noted previously. This Israeli study measured the IgE levels in patients with chronic urticaria and examine the relationship between these levels and:

- urticarial severity
- urticarial duration
- autologous serum skin test
- anti-thyroid antibodies

Serum total IgE levels from 203 patients with chronic urticaria were measured and compared with nonatopic individuals. 23% of the chronic urticaria patients were classified as mild, 33% were classified as having moderate and 43.8% as having severe chronic urticaria.

Total IgE levels were elevated, above 175 U/ml, in 34% of patients, compared with 8.6% of healthy controls.

Diagnosis of Chronic Urticaria (click to enlarge the image).

There was an association between increased total IgE and chronic urticaria severity - 93% of patients with increased IgE suffered from moderate-to-severe chronic urticaria, this was observed in only 69% of patients with normal IgE.

Autologous serum skin test and anti-thyroid antibodies were positive in 36% and 15% patients, respectively. There was an association between increased IgE and the presence of autologous serum skin test, anti-thyroid antibodies and urticarial duration lasting more than 25 months.

Total serum IgE levels are frequently elevated in patients with chronic urticaria and these are associated with disease severity and duration.

Anti-FceR1 autoantibodies in chronic autoimmune urticaria: IgG against FceRI (receptor for IgE) (click to enlarge the image).

References:
Elevated Serum Total IgE - A Potential Marker for Severe Chronic Urticaria. Kessel A, Helou W, Bamberger E, Sabo E, Nusem D, Panassof J, Toubi E. Int Arch Allergy Immunol. 2010 May 20;153(3):288-293.
Urticaria: A Short Review
Chronic Urticaria Due to Thyroid Antibodies
Chronic Idiopathic Urticaria

Anti-FceR1 Autoantibodies in Chronic Urticaria
Autologous serum skin test in chronic idiopathic urticaria

Video: "Attack of the Dust Mites"

Video: "Attack of the Dust Mites" via @MatthewBowdish.

The average bed could be home to up to 1.5 million house dust mites.

The bugs, which are less than a millimetre long, feed on scales of human skin and produce allergens which are easily inhaled during sleep.

Dust mite allergen avoidance. The main allergen is in the dust mite feces. Use 3 control measures for 3-6 months to see an effect on the allergy symptoms (click to enlarge the image).

Fatal consequence of allergic rhinitis - case report

A 43-year-old woman with allergic rhinitis had a sneezing episode with closing of her eyes while driving at 40 miles per hour and crashed into another vehicle, killing the other driver. She sustained leg fractures.

An insurance industry–sponsored study from the United Kingdom claims that more than 2 million UK drivers have had an accident or momentarily lost control of their car as a result of sneezing while driving.

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

References:
Fatal consequence of allergic rhinitis. Spector SL, Tan RA. J Allergy Clin Immunol. 2010 Aug 30 (a paid access is required to read the full text).

Image source: OpenClipArt.org, public domain.

Allergic rhinitis could begin as early as 18 months of life

Early onset of allergic rhinitis (AR) is poorly described, and rhinitis symptoms are often attributed to infections.

In this French study, data on AR-like symptoms (runny nose, blocked nose, sneezing apart from a cold) were collected using a questionnaire administered during the health examination at age 18 months included in the follow-up of the PARIS birth cohort.

Prevalence of AR-like symptoms in the past year was 9.1% of the 1850 toddlers of the study cohort. AR-like symptoms and dry cough apart from a cold were frequent comorbid conditions.

Parental history of AR in both parents increased the risk of suffering from AR-like symptoms with an odds ratio (OR) 2.09.

Significant associations were found with the presence of biological markers of atopy, especially blood eosinophilia and sensitization to house dust mite (OR 1.54 and OR 2.91). There was no relation with sensitization to food.

These results support the hypothesis that AR could begin as early as 18 months of life.

Suspicion of AR should be reinforced in infants with:

- parental history of AR

- biological evidence of atopy - blood eosinophilia and sensitization to inhalant allergens

References:

Does allergic rhinitis exist in infancy? Findings from the PARIS birth cohort. Herr M, Clarisse B, Nikasinovic L, Foucault C, Le Marec AM, Giordanella JP, Just J, Momas I. Allergy. 2010 Aug 30.

http://www.ncbi.nlm.nih.gov/pubmed/20804465?dopt=Abstract

Allergies May Start in Baby's First Month http://goo.gl/5e6Gg and http://goo.gl/tg039
Doctors are to expose babies to dust mites in an attempt to halt the rising allergy epidemic http://goo.gl/kr2E7 - Not likely to work.

Image source: Wikipedia, GNU Free Documentation License.

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

Dog in the home means dog allergen in the home, the dog breed does not matter

Dust samples were collected from the floor of infants' bedrooms and processed for the main dog allergen Canis familiaris 1 (Can f 1). The characterization of the dog was based on coat type, dander level, and shedding.

The number of dogs in the home was not related to dog allergen levels. Homes with exclusively outdoor dogs had lower levels of dog allergen than homes with indoor dogs. Homes where the dog was allowed in the infant's bedroom had significantly higher Can f 1 levels on the child's bedroom floor.

Dogs in the home corresponded to dog allergen in the home. No dog characteristic, other than altered status, was associated with allergen levels in the home.

References:
Dog characteristics and allergen levels in the home. Nicholas C, Wegienka G, Havstad S, Zoratti E, Ownby D, Johnson CC. Ann Allergy Asthma Immunol. 2010 Sep;105(3):228-233.

Indoor Allergen Avoidance

From the Blogosphere: Barrack Obama's Daughter Has Asthma, Gets a "Hypoallergenic" Dog

How a Doctor Almost Killed Her Dog - ibuprofen, the key ingredient in Motrin, poisons dogs. NYTimes.

Hypoallergenic dogs won't help allergy sufferers much, says study http://goo.gl/KBr6W

Dog allergen levels in homes with hypoallergenic compared with nonhypoallergenic dogs: no difference http://goo.gl/Ijevw
Image source: Yellow Labrador Retriever, Wikipedia, GNU Free Documentation License.

Top Ten Fall Allergy Myths - NBC Video

Source: NBC, Washington, DC.

Menopausal asthma: new phenotype characterized by neutrophilic airway inflammation

Female hormones play a role in women's lung health, especially in asthma pathophysiology. Growing interest has recently been aroused in asthma related to short-term reproductive states (menstruation and pregnancy). However, menopausal asthma has been little studied.

This Italian study included 40 women with menopausal asthma, 35 women with premenopausal asthma and 30 age-matched healthy controls.

Urinary LTE-4, induced sputum inflammatory cells, and exhaled LTE-4, IL-6, pH, and NO levels were measured.

Women with menopausal asthma showed decreased estradiol concentrations, high sputum neutrophils, and exhaled IL-6.

Women with premenopausal asthma presented instead an essentially eosinophilic inflammatory pattern.

The researchers postulate the existence of a new biological phenotype of menopausal asthma that is mainly characterized by neutrophilic airway inflammation and shares several characteristics of the severe asthma phenotype.

References:
Foschino Barbaro MP, Costa VR, Resta O, Prato R, Spanevello A, Palladino GP, Martinelli D, Carpagnano GE. Menopausal asthma: a new biological phenotype? Allergy 2010; DOI: 10.1111/j.1398-9995.2009.02314.x.
Hormone replacement therapy (particularly estrogen) may increase asthma risk

Women are more likely to be diagnosed with asthma and suffer greater morbidity than men. Medscape, 2011.
Asthma in pregnancy - under-diagnosed and under-treated http://goo.gl/xDK6

Most patients with eosinophilic esophagitis are highly atopic individuals: 80% have food and inhalant sensitization

This study compared the results of serum IgE testing, patch testing, and epicutaneous skin testing to measure allergic sensitization in 53 pediatric patients with eosinophilic esophagitis (EE). Food and inhalant sensitivities were assessed using skin prick testing and serum specific IgE measurement.

The overall prevalence of food and inhalant sensitization was 80%, with higher total IgE levels in sensitized vs nonsensitized patients (median, 150 vs 13 IU/mL).

For foods, serum IgE measurement detected more positive results than did skin prick testing. Specific IgE to milk was most common (43%). Inhalants were implicated as frequently as were foods.

32% of patients had a cluster of multiple sensitivities that included pollens, soy, grains, peanut, and tree nuts and had higher total IgE levels.

Most, but not all, patients with EE are highly atopic individuals with frequent allergic sensitivities. Thus, serum IgE measurement or skin prick testing may be useful in identifying relevant food sensitivities and in distinguishing subgroups of patients with EE, making a more directed approach to food avoidance possible.

The presence of allergic rhinitis, sensitization to aeroallergens, or both ranges from 42% to 93% in children with eosinophilic esophagitis. In addition, dietary therapy has a role in EoE treatment. According to the most recent consensus document, children with eosinophilic esophagitis should be evaluated for food and aeroallergen sensitization (Liacouras CC, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol 2011 (July); 128(1):3-20.)

References:

Serum IgE measurement and detection of food allergy in pediatric patients with eosinophilic esophagitis. Erwin EA, James HR, Gutekunst HM, Russo JM, Kelleher KJ, Platts-Mills TA. Ann Allergy Asthma Immunol. 2010 Jun;104(6):496-502.

Eosinophilic esophagitis after specific oral tolerance induction for egg protein http://goo.gl/fzmip

Repeating allergy testing in children with eosinophilic esophagitis whose original tests were negative. Ask the Expert, AAAAI, 2011.

Subcutaneous immunoglobulin (SCIG) replacement for primary antibody deficiency

Intravenous immunoglobulin (IVIG) therapy has been a staple of replacement therapy for primary antibody deficiency for years.

More recently, subcutaneous immunoglobulin (SCIG) replacement has been shown to be an effective and safe alternative to IVIG.

Risk of systemic reactions during SCIG infusion is less than 1%. Many patients prefer SCIG over conventional IVIG.

SCIG therapy has been widely used in European countries for years. The U.S. Food and Drug Administration approved the first SCIG product in 2006.

CSL Behring, the maker of Vivaglobin (Immune Globulin Subcutaneous [Human]) announced that Hizentra is now commercially available. Hizentra is the first and currently only subcutaneous 20% liquid immunoglobulin (Ig) therapy indicated for the treatment of patients with primary immunodeficiency disease (PIDD).

References:
Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Moore ML, Quinn JM. Ann Allergy Asthma Immunol. 2008 Aug;101(2):114-21; quiz 122-3, 178.

Risk factors for death of asthma

This prospective cohort study included 865 adults with severe asthma. Patients were followed up until death or the end of the study (mean, 2 years).

Risk factors for death in asthma included:

- higher severity-of-asthma scores
- lower perceived asthma control scores

The highest risk patients seem to have severe asthma but they "do not feel it" until it is too late.

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

References:
Risk factors for death in adults with severe asthma. Omachi TA, Iribarren C, Sarkar U, Tolstykh I, Yelin EH, Katz PP, Blanc PD, Eisner MD. Ann Allergy Asthma Immunol. 2008 Aug;101(2):130-6.

An approach to recalcitrant, severe asthma - AAAAI Ask the Expert, 2011.

Poorly controlled maternal asthma increases risk of pre-term delivery

Concerns regarding harmful effect of asthma medications during pregnancy often result in inadequate treatment of asthma in pregnancy. However, risks caused by poorly controlled maternal asthma may be greater than the potential adverse effects by the asthma medications.

In this study from Mexico, the incidence of preterm delivery was higher among patients with inadequate asthma control during the first part of pregnancy (11.4%) compared with patients with adequate asthma control (6.3%).

Patients who were hospitalized for asthma during pregnancy had a higher incidence of preterm delivery (16.4%) compared with asthmatic women without a history of hospitalization (7.6%).

The authors concluded that there is a substantial risk for preterm delivery caused by poorly controlled maternal asthma.

References:
Asthma control during pregnancy and the risk of preterm delivery or impaired fetal growth. Bakhireva LN, Schatz M, Jones KL, Chambers CD. Ann Allergy Asthma Immunol. 2008 Aug;101(2):137-43.
First-trimester asthma exacerbations may lead to birth defects
Asthma exacerbations during pregnancy can be reduced with a FENO-based treatment algorithm - number needed to treat was 6 (Lancet, 2011).
Image source: Wikipedia, GNU Free Documentation License.

The most common allergic disorder which requires hospitalization: Angioedema

Angioedema is a well-recognized side effect that may occur in patients taking angiotensin-converting enzyme inhibitors (ACEi).

Researchers analyzed angioedema hospitalizations (1998-2005). The angioedema hospitalization rate was 3.3 in 100,000 in 1998 and rose to 4.0 in 100,000 in 2005.

The total number of hospitalizations for non-angioedema allergic disorders declined during the same period and was surpassed by angioedema hospitalization rates after 2000.

ACE-inhibitor-induced angioedema affecting the upper lip (click to enlarge the images).

African American patients had double rate of angioedema hospitalizations compared to non-African American patients.

The authors concluded that angioedema has become the dominant allergic disorder that results in hospitalization in the United States.

References:

Increasing hospitalizations due to angioedema in the United States. Lin RY, Shah SN. Ann Allergy Asthma Immunol. 2008 Aug;101(2):185-92.
Angioedema Due to Angiotensin Converting Enzyme Inhibitors
Angioedema due to the renin inhibitor aliskiren. CCJM, 2011.

Asthma in pregnancy - under-diagnosed and under-treated

Asthma is among the most common serious medical problems in pregnancy, and its prevalence may be increasing. Management is problematic because asthma may harm the fetus, yet little is known about fetal risks of asthma medications.

This study participants were a random sample of 3,609 mothers of nonmalformed infants born in Massachusetts between 1998 and 2006.

Physician-diagnosed asthma was present in 13.9% and possible asthma in an additional 16.0%.

Higher rates of asthma were observed among women who were younger, white, obese, and less well educated, had lower income, and smoked during pregnancy.

Medications:

- Leukotriene modifiers were used by only 3.4% of asthmatic women

- Inhaled steroid use increased from 19.0% during 1997-1999 to 23.3% in 2003-2005

- Use of inhaled beta(2)-agonists exceeded 50% in both periods

Less than 40% of women with poorly controlled asthma symptoms reported use of a controller medication.

High rates of asthma and asthma symptoms, together with the low rates of use of controller medications, underscore the need to better understand the risks and safety of asthma medications during pregnancy.

References:

Asthma in pregnancy and its pharmacologic treatment. Louik C, Schatz M, Hernández-Díaz S, Werler MM, Mitchell AA. Ann Allergy Asthma Immunol. 2010 Aug;105(2):110-7.

Women are more likely to be diagnosed with asthma and suffer greater morbidity than men. Medscape, 2011.
Asthma and pregnancy. JACI, 2011.
Asthma exacerbations during pregnancy can be reduced with a FENO-based treatment algorithm - number needed to treat was 6 (Lancet, 2011).

Image source: Wikipedia, GNU Free Documentation License.

Atopic march (allergic march) - the progression from atopic dermatitis to asthma - mediated by filaggrin defect?

PubMed databases from 1950 to the present were searched for relevant articles pertaining to epidemiologic and genetic evidence of the progression of the atopic march.

The data suggest that a sequence of atopic manifestations occurs, typically atopic dermatitis in infancy followed by allergic rhinitis and/or asthma in later stages. Reduced filaggrin expression is implicated as a major predisposing factor for atopy.

Longitudinal studies of individuals carrying loss-of-function filaggrin gene mutations are needed to define the risks associated with epidermal barrier dysfunction and identify targets for barrier repair and prevention of atopic dermatitis and other atopic disease.

Image source: Skin layers. Wikipedia, public domain.

The link between eczema/food allergy/allergic rhinitis/asthma ("allergic march") is under-appreciated. I discuss it, when relevant, with all patients and during lectures with students, residents and staff.

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

References:

From atopic dermatitis to asthma: the atopic march. Spergel JM. Ann Allergy Asthma Immunol. 2010 Aug;105(2):99-106; quiz 107-9, 117.
Early food sensitization and presence of FLG mutation in infants with eczema increase the risk for later asthma. JACI, 2011.

Loss-of-function mutations in filaggrin gene are associated with atopic dermatitis, and now with peanut allergy too. JACI, 2011.

Gene defect can triple risk of peanut allergy - filaggrin has already been shown to be a factor in eczema and asthma. BBC, 2011.

Filaggrin gene mutations are associated with atopic asthma http://goo.gl/5mQlj

Asthma in the elderly - differences in diagnosis and management

Asthma prevalence increases with age, as does the risk of dying from asthma.

The National Guidelines for the Diagnosis and Management of Asthma (U.S.) apply to all ages.

However, the elderly patients are very heterogeneous. Their asthma can begin at any time and can vary in severity. It is frequently associated with comorbid lung diseases. Many patients have irreversible airway obstruction, which is due to severe airway remodeling, chronic obstructive pulmonary disease (COPD), or bronchiectasis.

Diagnosis should include chest radiography (CXR) and computed tomographic scanning (CT of the chest) to diagnose other lung diseases if FEV(1) remains low after treatment.

Asthma pathogenesis includes not only IgE-mediated allergy but also innate immune inflammation from endotoxin and trypsin-like proteases, and therefore evaluation and control of environmental exposures is an important part of management.

Elderly patients have reduced response to bronchodilators and increased side effects from beta adrenergic agonists and glucocorticoids.

In addition, many elderly patients have difficulty inhaling aerosols, and therefore nebulizers might be a better delivery system.

Oral medications have the benefit of greater ease of administration and greater efficacy on the peripheral airways. Leukotriene antagonists and low-dose theophylline are often helpful additives to aerosol glucocorticoids.

References:
Asthma in the elderly: Diagnosis and management. Reed CE. J Allergy Clin Immunol. 2010 Jul 29.

Allergy and Asthma in the Elderly, Seminars in Respiratory and Critical Care Medicine and Medscape, 2010. http://goo.gl/UHiq6

Asthma prevalence increases with age, as does the risk of dying from asthma. Clin Exp Allergy 2011.

Image source: OpenClipart.org, public domain.

Allergy Notes