Exhaled breath analysis could create "molecular fingerprints" or "breath prints"

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Exhaled breath constitutes more than 3,500 components, the bulk of which are volatile organic compounds in miniature quantities:

- systemic biomarkers
- lung biomarkers

Assessment of lung biomarkers may be useful in airway inflammatory diseases:

- nitric oxide and inflammatory indicators in exhaled breath condensate such as oxidative stress markers (eg, hydrogen peroxide and isoprostanes)
- nitric oxide derivatives (eg, nitrates)
- arachidonic acid metabolites (eg, prostanoids, leukotrienes, and epoxides)
- adenosine

Exhaled breath temperature measurement and devices of the “electronic nose” type have been explored.

Exhaled breath temperature measurement and other techniques could create "molecular fingerprints" or "breath prints".

Inflammation in asthma (mind map). FeNO is a marker of oxidative stress. See more Allergy and Immunology mind maps here.

References:
Human exhaled breath analysis. Todor A. Popov, Annals of Allergy and Imm, Volume 106, Issue 6, Pages 451-456 (June 2011).

Image source: NioxMino.

IL-37 is inhibitor of innate immunity

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The function of interleukin 37 (IL-37; formerly IL-1 family member 7) has remained elusive. Expression of IL-37 in macrophages or epithelial cells almost completely suppressed production of pro-inflammatory cytokines, whereas the abundance of these cytokines increased with silencing of endogenous IL-37 in human blood cells.

IL-37 emerges as a natural suppressor of innate inflammatory and immune responses.



Cytokine receptors (click to enlarge the image).


Overview of the innate immune system (a mind map diagram) (click to enlarge the image).

References:
IL-37 is a fundamental inhibitor of innate immunity. Nature Immunology 11, 1014 - 1022 (2010).

Selective serotonin reuptake inhibitors (SSRIs) do not affect the results of skin prick tests

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Some drugs may cause false negative results by suppressing the reactivity of the skin prick tests (SPTs). This Turkish study aimed to show whether escitalopram, fluoxetine and sertraline had any effect on the reactivity of SPT.

24 patients who were seen at the outpatient clinic of a Psychiatry Department were included in the study.

SPTs with positive control (histamine), negative control and 3 common aeroallergens were performed in the beginning, at the first and fourth weeks.

There were no significant differences between the 3 mean diameters measured at 3 time points in addition to the mean diameters of the wheals between groups using escitalopram, sertraline and fluoxetine.

Escitalopram, fluoxetine and sertraline do not seem to affect the reactivity of SPTs.

References:

The Effects of Antidepressants on the Results of Skin Prick Tests Used in the Diagnosis of Allergic Diseases. Isik SR, Celikel S, Karakaya G, Ulug B, Kalyoncu AF. Int Arch Allergy Immunol. 2010 Jul 27;154(1):63-68.

Effect of intranasal antihistamines on allergy skin testing http://goo.gl/j6O26 - Perform a histamine skin test prior to full SPT battery.

The rise and rise of allergies, but why?

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There is little doubt that the number of reported allergies is increasing in the U.S. and the UK. Research published in 2007 showed the number of hospital admissions in the UK for food allergies had increased by 500% since 1990. Number of Americans with allergies two to five times higher now than 30 years ago.

Here are some of the reasons why:

- Hygiene theory - Living cleaner lifestyles means the immune system has fewer germs to deal with and may overreact when it comes into contact with harmless substances. Exposure to microbes explains some of the inverse relation between asthma and growing up on a farm, according to a 2011 NEJM study. However, promoting the hygiene theory for allergy prevention as "eat dirt hypothesis" does little to convince the parents.

- Mother's diet - Pregnancy and breastfeeding could offer protection against allergies. However, the studies regarding avoidance of food allergens are contradicting, for example, early introduction of puffed corn covered with peanut butter may protect Israeli infants from development of peanut allergy.

- Allergen exposure - Higher exposure to substances which provoke an immune reaction. It is clear that high exposure to dust mite increases the risk of dust mite allergy. Spring allergies now start sooner and fall allergies end later, thanks to global warming.

- Atmospheric pollution - Chemicals in the air provoking an immune response, for example, diesel particles serve as a vehicle that carries pollen in deeper in the lungs.

References:

The rise and rise of allergies. BBC.
Why your allergies are bugging you. CNN, 2011.
Nothing to sneeze at - There are many hypotheses as to why allergy rates are soaring worldwide. CMAJ, 2011.
Shorter duration and nonexclusivity of breastfeeding are associated with increased risk of asthma symptoms in children. ERJ January 1, 2012 vol. 39 no. 1 81-89.

Image source: OpenClipArt.org, public domain.

Venom immunotherapy for insect allergy

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Indications for venom immunotherapy

Venom immunotherapy is requires careful selection of patients: only those with a history of systemic allergic reaction to a sting and evidence of venom-specific IgE antibodies with a positive venom skin test or elevated specific IgE level.

Large local reactions are not usually a predictor of systemic reactions. The risk of anaphylaxis in patients with large local reactions is 5–10%, and venom immunotherapy is not typically recommended. Adults with cutaneous systemic reactions are still advised to undergo venom immunotherapy. There is no test for either large local or cutaneous reactors that predicts which patients will progress to anaphylaxis.


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.

Safety of venom immunotherapy

Adverse reactions to venom immunotherapy are no more common than reactions during inhalant allergen immunotherapy (SCIT). Systemic symptoms occur in 5–15% of patients during the initial weeks of treatment, regardless of the regimen used.

Fewer than 5% of patients receiving venom immunotherapy ever require epinephrine treatment for a reaction to an injection.

Large local reactions to venom injections occur in up to 50% of patients, especially with the dose 20–50 mcg.

Efficacy of venom immunotherapy

Venom immunotherapy is 75–98% effective in preventing sting anaphylaxis (95–100% for the 300 mcg dose of mixed vespid venoms). Most patients can discontinue treatment after 5 years.

Studies of immunotherapy with a 100 mcg dose of individual venoms (honeybee, yellow jacket or wasp) have been associated with 75–95% efficacy.

Insect species and immunotherapy dose

The selection of venom extracts dependens on the positive venom skin test reaction, or venom-specific IgE antibody levels. The immunotherapy prescription should include all that are positive.

The standard recommended dose of 100 mcg of each venom. This is considered equivalent to the venom protein content of 2-4 insect stings. The amount of venom protein injected by a honeybee sting is 50 mcg. However, the amount of venom injected by the vespids is much lower, in the range of 2–20 mcg per sting.

Schedule for venom immunotherapy

The schedule for venom immunotherapy depends on the recommendations of the source laboratory which prepared the allergen extract.

Some of the products available in the USA include:

- "modified rush" regimen (ALK-Abello Labs, Round Rock, TX) achieves maintenance dose in 8 weekly injections

- "traditional" regimen (Hollister-Stier Labs, Spokane, WA) achieves maintenance dose in 4–6 months

In one study, both regimens were equally effective. The frequency of systemic reactions was also similar.

When the full maintenance dose is achieved, it is repeated in:

- 1 week
- 2 weeks (after the 1st dose of maintenance injection)
- 3 weeks (after the 2nd dose of maintenance injection)

"Traditional" regimen schedule based on the package insert for Hollister-Stier venom extracts (Spokane, WA) (always verify with the manufacturer)

Week 1, concentration 1 mcg/ml, volume 0.05 ml
Week 2, concentration 1 mcg/ml, volume 0.1 ml
Week 3, concentration 1 mcg/ml, volume 0.2 ml
Week 4, concentration 1 mcg/ml, volume 0.4 ml
Week 5, concentration 10 mcg/ml, volume 0.05 ml
Week 6, concentration 10 mcg/ml, volume 0.1 ml
Week 7, concentration 10 mcg/ml, volume 0.2 ml
Week 8, concentration 10 mcg/ml, volume 0.4 ml
Week 9, concentration 100 mcg/ml, volume 0.05 ml
Week 10, concentration 100 mcg/ml, volume 0.1 ml
Week 11, concentration 100 mcg/ml, volume 0.2 ml
Week 12, concentration 100 mcg/ml, volume 0.4 ml
Week 13, concentration 100 mcg/ml, volume 0.6 ml
Week 14, concentration 100 mcg/ml, volume 0.8 ml
Week 15, concentration 100 mcg/ml, volume 1 ml
Week 16, concentration 100 mcg/ml, volume 1 ml
Week 18, concentration 100 mcg/ml, volume 1 ml (2 weeks later after the 1st dose of maintenance injection, 1 ml)
Week 21, concentration 100 mcg/ml, volume 1 ml (3 weeks later after the 2nd dose of maintenance injection, 1 ml)
Monthly injection, concentration 100 mcg/ml, volume 1 ml, for 3 years

References

Chapter 57 – Insect Allergy, David B.K. Golden, Adkinson: Middleton's Allergy: Principles and Practice, 7th ed., 2008.

3-Day Rush Venom Immunotherapy in Bee Allergy: Safe, Inexpensive and Instantaneously Effective (http://goo.gl/afeso)

Stinging Insect Guidelines - 2001 Update by AAAAI and ACAAI. Medscape, 2011.
Bee Aware Allergy - Insect allergy educational website by Hollister-Stier Laboratories.

Related reading

Honeybee immunotherapy is less safe and less effective than for other flying Hymenoptera http://goo.gl/RgAjj

Component-based allergen microarray for kiwi fruit allergy (Act d 1) has diagnostic sensitivity of 66%, specificity of 56%

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Allergy to kiwi fruit is increasingly reported. Currently, the reliability of diagnosis by measurement of allergen-specific IgE with extracts or by skin testing with fresh fruit is unsatisfying.

With an allergen microarray, the researchers measured specific IgE (Act d 1, 9 and 7-specific IgE) to a panel of 9 kiwifruit allergens in 237 individuals with kiwifruit allergy. The extent of sensitization to latex was also determined.

The panel of kiwifruit allergens showed a diagnostic sensitivity of 66%, and a specificity of 56%.

Kiwifruit- and latex-allergic patients contained Hev b 11-specific IgE significantly more frequently than latex-allergic patients without kiwifruit allergy.


Cross-reactivity in Pollen-Food Allergy Syndrome (PFAS) or Oral Allergy Syndrome (OAS) (click to enlarge the image).

Act d 1 can be considered a marker allergen for genuine sensitization to kiwifruit. A component-based kiwifruit allergen microarray would improve the prognostic value of in vitro diagnostic tests.



Molecular Allergy Component Testing, a video by the manufacturer of ImmunoCAP testing system.

References:
The performance of a component-based allergen microarray for the diagnosis of kiwifruit allergy. Bublin M, Dennstedt S, Buchegger M, Antonietta Ciardiello M, Bernardi ML, Tuppo L, Harwanegg C, Hafner C, Ebner C, Ballmer-Weber BK, Knulst A, Hoffmann-Sommergruber K, Radauer C, Mari A, Breiteneder H. Clin Exp Allergy. 2010 Nov 17. doi: 10.1111/j.1365-2222.2010.03619.x.

Exhaled nitric oxide (FeNO) greater than 42 ppb discriminates between eosinophilic and non-eosinophilic asthma

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It has been claimed that exhaled nitric oxide (FeNO) could be regarded as a surrogate marker for sputum eosinophil count in patients with asthma. However, the FeNO threshold value that identifies a sputum eosinophil count ≥3% in patients with asthma has been poorly studied.

This retrospective study included 295 patients with asthma aged 15–84 years.

FeNO ≥41 ppb gave 65% sensitivity and 79% specificity for identifying a sputum eosinophil count ≥3%.

A threshold of 42 ppb was found to discriminate between eosinophilic and non-eosinophilic asthma.

Patients receiving high doses of ICS (≥1000 μg beclometasone) had a significantly lower FeNO threshold (27 ppb) than the rest of the group (48 ppb).

Atopy also significantly altered the threshold (49 ppb for atopic vs 30 ppb for non-atopic patients) and there was a trend for a lower threshold in smokers (27 ppb) compared with non-smokers (46 ppb).

High-dose ICS and smoking were independent predictors of sputum eosinophilia.

FeNO is able to identify a sputum eosinophil count ≥3%. Thresholds vary according to dose of ICS, smoking and atopy.

Inflammation in asthma (mind map). FeNO is a marker of oxidative stress. See more Allergy and Immunology mind maps here.

NIOX MINO display. The device needs to be plugged in at all times.

References:
Exhaled nitric oxide thresholds associated with a sputum eosinophil count ≥3% in a cohort of unselected patients with asthma. Thorax 2010;65:1039-1044 doi:10.1136/thx.2009.124925

Practical points on using NIOX MINO fractional exhaled nitric oxide (FENO) measuring device

Image source: Wikipedia.

Chronic urticaria may induce a hypercoagulable state (risk for blood clots)

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The pathogenesis of chronic spontaneous urticaria (CU) may be associated with thrombin generation through the extrinsic coagulation pathway. Little is known about the components of the intrinsic coagulation pathway potentially involved.

This Japanese study included 36 patients with CU.

Classical coagulation assays revealed elevated levels in patients with CU: fibrinogen, D-dimer, and fibrin and fibrinogen degradation products (FDP).

All parameters of a global coagulation test, APTT clot waveform analysis, showed a hypercoagulable pattern and were significantly correlated to disease severity of CU.


The coagulation cascade. Legend: Black arrow = conversion/activation of factor. Red arrows = action of inhibitors. Blue arrows = reactions catalysed by activated factor. Grey arrow = various functions of thrombin. Image source: Wikipedia, public domain.

CU is characterized by elevated blood coagulation potential with involvement of the intrinsic coagulation factors, which may contribute in vivo to the generation of fibrin even by small amounts of thrombin. Asthma is also associated with a procoagulant state in the bronchoalveolar space (Blood, 01/2012).


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


Chronic Urticaria Treatment (click to enlarge the image).

References:

Increase of coagulation potential in chronic spontaneous urticaria. Takeda T, Sakurai Y, Takahagi S, Kato J, Yoshida K, Yoshioka A, Hide M, Shima M. Allergy. 2010 Nov 17. doi: 10.1111/j.1398-9995.2010.02506.x.

16% of children with a history of penicillin allergy may be missed if amoxicillin skin test not done

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Penicillin skin testing is an effective tool for determining penicillin allergy. The standard skin test panel at Mayo Clinic included benzylpenicillin polylysine, penicillin G, and benzylpenicilloate.

Amoxicillin should be considered part of the penicillin skin test panel when testing children, according to a new study.

The majority of the children (90%) had a negative penicillin skin test, 9% had a positive penicillin skin test, and 1% had an equivocal result.

Of children who had a positive skin test:

- 47% were positive to benzylpenicillin polylysine

- 29% were positive to penicillin G

- 35% were positive to benzylpenicilloate

Penicillin skin testing is still very useful and is the most important component in the evaluation of penicillin allergy. However, 16% of children with a history of penicillin allergy, especially to amoxicillin, may be missed if an amoxicillin skin test is not included with the other components of the penicillin skin test.

If the children have a reaction to amoxicillin specifically and the penicillin skin test and amoxicillin skin test are negative, an amoxicillin challenge should be under medical supervision.

If someone is not allergic to the penicillin, but is responding to amoxicillin, it would indicate that the beta lactam "backbone" is not what they're allergic to - they are allergic to the side chain of one of the penicillin derivatives. In this case many other cephalosporins or beta lactams may be used.


Manifestations of beta-lactams hypersensitivity: MAUS (click to enlarge the image).

References:

Kids More Likely to Show Allergy to Amoxicillin Than Adults. Medscape.

Diagnosis of Immediate Hypersensitivity to β-Lactam Antibiotics Can Be Made Safely with Current Approaches. Int Arch Allergy Immunol. 2011 Nov 1;157(3):311-317.

Testing for penicillin allergy can be done at any age. Consider testing with PrePen, Penicillin G and ampicillin. AAAAI Ask the Expert, 2012.

Image source: Penicillin nucleus, Wikipedia, GNU Free Documentation License.

Moisture and mold problems in kitchen and main living area increase risk for wheezing

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Building inspection was performed by building engineers in the homes of 400 children who were followed up with questionnaires from birth to the age of 18 months. Specific immunoglobulin E levels were measured at the age of 1 year.

Various fungi including Penicillium and Aspergillus spp. growing in culture. Image source: Wikipedia, University of Sydney, Australia, Creative Commons Attribution ShareAlike 2.5 License.

Doctor-diagnosed wheezing was associated with the severity of moisture damage in the kitchen and with visible mold in the main living area and especially in the bedroom of the child.

The risk for parent-reported wheezing apart from cold increased with the severity of moisture damage in the kitchen.

Moisture damage in the bathrooms or other interior spaces had no significant association with wheezing.

This birth-cohort study supports previous observations that moisture mold problems in the kitchen and in the main living area increase the risk for wheezing in early childhood.

References:

Confirmed Moisture Damage at Home, Respiratory Symptoms and Atopy in Early Life: A Birth-Cohort Study. PEDIATRICS Vol. 124 No. 2 August 2009, pp. e329-e338 (doi:10.1542/peds.2008-1590).
Exposure to visible mold and/or dampness during first 2 years of life associated with asthma risk - but odds ration (OR) was very close to 1.0. Allergy, 2011.

Sublingual immunotherapy (SLIT) for Alternaria-induced allergic rhinitis

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27 patients with rhinitis with or without intermittent asthma and allergy to Alternaria were enrolled in this study.


Alternaria sp. Image source: Wikipedia, CDC, public domain. Alternaria is a genus of ascomycete fungi that are major plant pathogens. They are also common allergens in humans.

After a baseline season, SLIT or matched placebo was given for 10 months.

After treatment, patients receiving SLIT had an improvement in symptoms and a reduction in medication intake.

Skin prick test reactivity decreased only in the SLIT group. No change was seen in specific IgG4 levels in the 2 groups, whereas Alt a 1 specific IgE levels increased in the active group.

One patient in the active group reported oral itching and conjunctivitis at the beginning of treatment.

SLIT seems effective and safe and may represent a valuable therapeutic option in respiratory allergy due to Alternaria.

Mechanisms of allergen-specific immunotherapy (click to enlarge the image).

References:
Sublingual immunotherapy for Alternaria-induced allergic rhinitis: a randomized placebo-controlled trial. Cortellini G, Spadolini I, Patella V, Fabbri E, Santucci A, Severino M, Corvetta A, Canonica GW, Passalacqua G. Ann Allergy Asthma Immunol. 2010 Nov;105(5):382-6. Epub 2010 Sep 26.

Subcutaneous Immunotherapy (SCIT)

Flagellin works through TLR5 as a potential vaccine adjuvant

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Flagellin is a potent activator of many cell types.

Flagellin has the following properties

- adjuvant
- promoter of cytokine production
- trigger of a recruitment of T and B lymphocytes
- activates TLR5(+)CD11c(+) cells and T lymphocytes

The plasticity of flagellin has allowed for the generation of flagellin-Ag fusion proteins that are effective vaccines in animal models. The adjuvant effect of flagellin brings a lot of human research interest.


Pathogen Recognition Receptors, TLRs. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

References:
Flagellin as an adjuvant: cellular mechanisms and potential. Mizel SB, Bates JT. J Immunol. 2010 Nov 15;185(10):5677-82.

Toll-like receptors (TLRs)

Most asthma is not optimally controlled despite availability of effective medications. Why?

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Unlike in other chronic diseases such as coronary artery disease and diabetes, comorbidities tend to be overlooked in asthma, possibly because the asthma population is younger and is assumed to be relatively free of comorbidities.

Some commonly overlooked comorbidities linked with asthma include:

- related allergic disorders - food allergy, allergic rhinitis, etc.
- obesity
- depression
- sleep disturbances - OSA, etc.
- adverse events associated with some asthma treatments, particularly long-term corticosteroid use

Poor compliance is a major reason for loss of asthma control. Poor adherence to asthma medications (less than 80%) was seen in 75% of children (JACI, 2011).



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

If asthma treatment is not working, check DAT:

Diagnosis - not asthma at all (VCD, CF, FBA), asthma plus AR, GERD

Adherence - compliance with medication - 24% of asthma exacerbations are attributable to ICS medication nonadherence (http://goo.gl/1i8ET)

Technique - NEB, HFA with spacer, DPI, etc.

3 C's of care - communication, continuity, concordance (finding common ground) are critical for asthma management (http://goo.gl/8gJM6).

Asthma Inhalers (click to enlarge the image).

References:

Asthma and High Healthcare Use. Gershon AS, Wang C, Guan J. Thorax. 2010;65:612-618, and Medscape.
Severe asthma in children - differential diagnosis and management
24% of asthma exacerbations are attributable to ICS medication nonadherence (http://goo.gl/1i8ET)