Monoclonal antibody (AMG 157) against a new target in asthma, thymic stromal lymphopoietin (TSLP)

What is TSLP?

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that may be important in allergic inflammation. TSLP, which was discovered as a growth factor for lymphocyte progenitors, is a protein released from epithelial cells in response to irritating stimuli. It initiates signaling pathways leading to inflammation driven by type 2 helper T (Th2) cells.

What is the immunology basis for TSLP effects?

Cytokine receptors include the following types:

- Type I (hematopoietin receptors - IL-3 and Epo)
- Type II
- IL-1 family receptors - they share Toll-like/IL-1 receptor (TIR) domain
- TNF receptors
- Seven-transmembrane α-helical receptors


(click to enlarge the image)

Interleukin-7 receptor (IL7R)

Interleukin 7 receptor (IL7R) is also known as CD127 (Cluster of Differentiation 127) is a type I cytokine receptor. Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands.

Type I cytokine receptors are mediated through JAK/STAT and bind: IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, GM-CSF.


Key steps of the JAK-STAT pathway. Image source: Wikpedia, public domain.

IL7R plays a critical role in the V(D)J recombination during lymphocyte development. A defect in IL-7RA leads to SCID (T-/B+/NK+).

Thymic stromal lymphopoietin (TSLP)

Thymic stromal lymphopoietin (TSLP) signals through a heterodimeric receptor complex composed of the TSLP receptor and the IL-7R alpha chain. Some researchers have classified TSLP as a "master regulator" of the Th2 response due to overexpression of the cytokine in pulmonary tissue and skin cells result in Th2-induced asthma and dermatitis.

TSLP is produced mainly by non-hematopoietic cells as fibroblasts, epithelial cells and different types of stromal cells.

Anti-TSLP is a potential new therapeutic target in asthma.

TSLP could be a master switch in the signaling between airway epithelium and other inflammatory cascades or it could be a part of a concerted action by several parallel pathways (e.g., those involving interleukin-33, interleukin-25, and interleukin-17).

Anti-TSLP (AMG 157) as asthma treatment

AMG 157 is a humanized anti-TSLP monoclonal immunoglobulin G2delta that binds human TSLP and prevents receptor interaction.

A small double-blind, placebo-controlled study included 31 patients with mild allergic asthma who received three monthly doses of AMG 157 (700 mg) or placebo IV. AMG 157 decreased measures of allergen-induced early and late asthmatic responses (FEV1, blood and sputum eosinophils before and after the allergen challenge, FeNO).

TSLP could play a key role in allergen-induced airway responses and persistent airway inflammation in allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined yet from these data. The study was funded by the AMG manufacturer, Amgen, and published in the NEJM.

References:

Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses — NEJM http://buff.ly/1kntbHZ

TSLP in Asthma — A New Kid on the Block? — NEJM http://buff.ly/1knte6T

Vitamin D 50,000 IU per week together with ICS or ICS/LABA improved FEV1 in asthma after 6 months

This randomized trial included 130 patients with asthma aged 10 to 50 years from Iran during a 6-month period. Vitamin D was measured before, and 4 and 6 months after the intervention. Patients were divided in 2 groups randomly. Both groups received asthma controllers (budesonide or budesonide plus formoterol) according to their stage. The intervention group received vitamin D supplementation (100,000-U bolus intramuscularly plus 50,000 U orally weekly).

FEV1 was significantly better in the intervention group after 6 months. The authors concluded that vitamin D supplementation associated with asthma controllers could significantly improve FEV1 in mild to moderate persistent asthma. It takes time to work and the effect tooks months to emerge.

References:

The effects of vitamin D supplementation on airway functions in mild to moderate persistent asthma. Saba Arshi et al. Annals of Allergy, Asthma & Immunology, Volume 113, Issue 4, Pages 404–409, October 2014.
http://www.annallergy.org/article/S1081-1206(14)00463-3/abstract

Image source: Wikipedia, public domain.

Only 15% of YouTube videos for asthma education discussed all steps of correct inhaler use

How to Use a Metered Dose Inhaler (MDI) (albuterol, Xopenex, Flovent, Symbicort, Dulera, Alvesco, Qvar) - CDC video:



Only 15% of YouTube videos for asthma education discussed all steps of correct inhaler use http://buff.ly/1CrFusv - Our #WISC14 abstract. Are you going to the WAO International Scientific Conference 2014 (WISC) 2014? Share your abstract below in the comments section.

http://www.worldallergy.org/wisc2014/

The full WISC program is available online. It would be great to see you during any of the sessions I will participate in - see the list here: http://buff.ly/1CrGCMH

Also, I will be filming the next edition of the WAO TV videos.

The full text of the abstract is below. Dr Joshi from Cornell did a great job:

Quality of YouTube videos for patient education on how to use asthma inhalers

Sunday, 7 December 2014: 17:50 - 18:10
Exhibition Hall-Poster Area (Sul America). Smita Joshi, MD , Department of Medicine, Weill Cornell Medical College, New York, NY; Ves Dimov, MD , University of Chicago, IL

Background: Inhalers are crucial to the delivery of asthma medications, however their effectiveness is dependent on proper inhaler technique. This study evaluates YouTube videos on their content and ability to inform viewers on how to effectively use an asthma inhaler.

Methods: The website YouTube.com was queried for the search phrase “how to use asthma inhaler”. The resulting videos were assessed for duration, number of views, number of likes and dislikes, source of video, and content. Content was analyzed for proper inhaler usage. Specifically, videos were assessed whether they discussed the following 9 important steps of inhaler use: removing the cap, priming the inhaler, shaking the inhaler, breathing out before inhaler use, dispensing the medication, taking a deep/slow breath (or several breaths in the pediatric patient using a spacer), holding one’s breath (unless patient took several breaths with a spacer), waiting before taking a repeat dose, and rinsing the mouth after inhaler use.

Results: The search phrase returned 12,400 videos that were sorted by the default filter of “relevance”. The 20 videos on the first page of the results were analyzed since these are the videos patients are most likely to view by visitor statistics. On average, the videos were 2 minutes and 33 seconds long, with 31,589 views, 47 likes and 5 dislikes. Eight videos were from health care organizations, 5 from a professional society, 2 from health care professionals, and 5 from nonprofessional educational groups. Only 15% of YouTube videos (3 videos) discussed all 9 steps of correct asthma inhaler use. The 3 videos were from health care organizations. The most steps were discussed by videos from health care organizations (average 7.25 steps) and professional societies (average 7 steps). Videos from nonprofessional educational groups (average 4.6 steps) and health care professionals (average 4.5 steps) discussed the least number of steps. Only 50% of videos (10 videos) discussed the use of a spacer.

Conclusions: The quality of YouTube videos on asthma inhaler use varies considerably. In our analysis, only 15% of videos discussed all steps of correct asthma inhaler use. Videos from health care organizations and medical societies were more comprehensive than those from nonprofessional educational groups and health care professionals not posting on behalf of a medical organization. There is a need for more reliable and accurate patient education videos on YouTube.

Should all patients with asthma get the pneumococcal vaccine?

Should all patients with asthma get the pneumococcal vaccine?

The simple answer is yes, unless there are contraindications. The explanation is below.

The CDC considers asthmatics at increased risk of pneumococcal disease and therefore have suggested that all asthmatics ages 19 to 64 receive pneumococcal vaccine (Pneumovax 23). The Pneumovax 23 package insert states that anyone who is at “increased risk” receive the vaccine. CDC recommendation is based upon a study that showed that asthmatics are at increased risk. CDC website states that asthmatics ages 19 to 64 receive the vaccine.

What is the recommended age range for patients with asthma get the pneumococcal vaccine?

Ages 19-64.

Which pneumococcal vaccine should patients with asthma get?

Pneumovax 23.

Should patients with asthma receive Prevnar 13?

As of 2014, the answer is no. Patients should receive Pneumovax 23.

Can you please explain when and why the recommendations for vaccination were changed for people with asthma and for cigarette smokers?

The 1997 CDC recommendations for the use of PPSV exclude asthma in the chronic pulmonary disease category because no data on increased risk of pneumococcal disease among people with asthma were available when the recommendation was issued. In 2008, the Advisory Committee on Immunization Practices (ACIP) reviewed new information that suggests that asthma is an independent risk factor for pneumococcal disease among adults. ACIP also reviewed new information that demonstrates an increased risk of pneumococcal disease among smokers. Consequently, ACIP recommends to include both asthma and cigarette smoking as risk factors for pneumococcal disease among adults age 19 through 64 years and as indications for PPSV23.

In its September 2010 publication of updated recommendations for prevention of invasive pneumococcal disease among adults, ACIP recommends vaccinating adult asthmatics with PPSV23. Should I give PPSV23 to people with mild, intermittent asthma or exercise-induced asthma? Why isn't PPSV23 recommended for asthmatic children?

PPSV23 is recommended for adults 19 years and older with all types of asthma. Available data do not indicate that asthma alone increases the risk of invasive pneumococcal disease among people younger than 19 years, so PPSV23 is not currently recommended for people younger than 19 years with asthma. For more information, go to www.cdc.gov/mmwr/preview/mmwrhtml/mm5934a3.htm.

For whom is the 23-valent pneumococcal polysaccharide vaccine (PPSV23) recommended?

PPSV23 vaccine is recommended for all people who meet any of the criteria below:

1. All adults age 65 yrs and older

2. Age 2 through 64 yrs with any of the following conditions:
a. cigarette smokers age 19 yrs and older
b. chronic cardiovascular disease (e.g., congestive heart failure, cardiomyopathies; excluding hypertension)
c. chronic pulmonary disease (including COPD and emphysema, and for adults ages 19 years and older, asthma)
d. diabetes mellitus
e. alcoholism
f. chronic liver disease, cirrhosis
g. candidate for or recipient of cochlear implant
h. cerebrospinal fluid (CSF) leak
i. functional or anatomic asplenia (e.g., sickle cell disease, splenectomy)
j. immunocompromising conditions (e.g., HIV infection, leukemia, congenital immunodeficiency, Hodgkin's disease, lymphoma, multiple myeloma, generalized malignancy) or on immunosuppressive therapy
k. solid organ transplantation; for bone marrow transplantation, see www.cdc.gov/vaccines/pubs/hemato-cell-transplts.htm.
l. chronic renal failure or nephrotic syndrome

Is pneumococcal polysaccharide vaccine (PPSV23) contraindicated in pregnancy? Our patient has asthma and is pregnant.

No. According to the 2014 adult immunization schedule, PPSV23 is recommended in pregnancy if some other risk factor is present (e.g., on the basis of medical, occupational, lifestyle, or other indications).

References:

Indications for pneumococcal vaccine (Pneumovax 23) in asthma. AAAAI http://buff.ly/1tzByqE
Ask the Experts: Pneumococcal Vaccines (PCV13 and PPSV23) http://buff.ly/1ugxl5I
Adult vaccine schedule - CDC (PDF)
http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-schedule-easy-read.pdf
Image source: Streptococcus pneumoniae from Wikipedia, the free encyclopedia, public domain.

Top Asthma Articles for October 2014

Here are my suggestions for some of the top articles about asthma published recently:

What is the best spacer? AeroChamber, toilet paper roll (?!), paper towel roll, rolled paper, plastic bottle spacer, bottle-holding chamber, nebulizer reservoir tubing? Paper towel roll was the best in this study: http://buff.ly/1jtRHCp

Infant wheeze: Among children with 3-4 risk factors, 38% had asthma at school age http://buff.ly/1eHUs2q

Study: job strain is probably not an important risk factor for severe asthma exacerbations http://buff.ly/1eHVafV

Severe refractory asthma: 2013 update in ERS (free full text) http://buff.ly/1hDrhCi

Yoga for asthma: a systematic review and meta-analysis http://buff.ly/1mcHr60 - Yoga was not helpful as asthma therapy.

Free but basic app: Spirometry Android medical app review http://buff.ly/1f26fhE

Refractory asthma: mechanisms, targets, and therapy - 2014 free full text review in EAACI journal Allergy http://buff.ly/1rDvXcr

Neutrophils from allergic asthmatic patients release metalloproteinase-9 upon direct exposure to allergens http://buff.ly/1rDwhrA

Weight reduction in obese patients with asthma improves outcomes by mechanisms not related to airway inflammation http://buff.ly/1kpBuzh

Outdoor air pollution and asthma: In-vehicle exposure during commuting with open windows can be very high. http://buff.ly/1fD7DYh

Air pollution decreases children's lung function by 1-3% (FEV1) http://buff.ly/1k1L3Id

Smoke-free legislation is associated with substantial reductions in preterm births and admissions for asthma http://buff.ly/1i3D6lp

Almost half of all children have at least one episode of wheeze before 6 years of age. Daily inhaled corticosteroids are associated with a small but statistically significant effect on growth http://buff.ly/1ncOxrP

Asthma Impact on the Nation - CDC Infographic http://buff.ly/1j9Xn9D

New test determines Free IgE Levels in Serum from Patients Treated with Omalizumab http://buff.ly/1olLYGH

The articles were selected from Twitter @Allergy and RSS subscriptions. Some of the top allergy accounts on Twitter contributed links. I appreciate the curation provided by @Aller_MD @IgECPD @DrAnneEllis @mrathkopf.

Please feel free to send suggestions for articles to AllergyGoAway AT gmail DOT com and you will receive an acknowledgement in the next edition of this publication.


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