Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Santa Claus’ reindeers and nasal popyposis
2. Winter hay fever : a Christmas gift for Swiss school children
3. Severe allergic reactions to exposure to Methylisothiazolinone (MIT)
4. Respiratory symptomatology and menstrual cycle (MC)
5.Smelly biomarker of ‘neutrophilic’ asthma

Dear colleagues and readers,

As we begin this New Year with a new series of Updates, we would like to thank you for your loyalty and the friendly interest many of you have expressed.

During this past year, we have produced 50 one-page Updates on a wide range of practical allergology subjects, 9 on asthma (3 on inhaled corticosteroids), 7 on food allergy, 6 on environmental factors, 5 on nutritional factors, 6 on organ allergy (digestive tube, eye, skin, and so on).

We have tried to stick to practical information, often original, sometimes anecdotal, while doing our best to avoid general overviews and suggesting that those who wished to go further on the subject refer to the paper in question.

We intended to turn these BUAs into training tools, trying with our colleague and friend Luis Taborda to prepare MCQs on the topics treated. But it soon became obvious that the authors’ opinions were often too specialised or personal to be considered as generally applicable.

However, consulting the UEMS/EAACI questionnaires showed us how accurate, varied and high quality the answers were supposed to be, and also how necessary it was for new allergists trying to qualify or for those looking to update their knowledge, to have a clear idea of the latest findings in Immunology and more generally in biology or even genetics.

That is why we will try from time to time to propose such subjects in our BUAs, in the style of: “All you wanted to know about… without ever daring to ask”.

A final, but often repeated desire for more interactivity, not only amongst ourselves but also with the whole allergist community, will be realised with the creation of a real Forum in the, we hope, very near future.

Such are our plans. We are now looking forward your suggestions.

1. Father Christmas’s reindeer and nasal popyposis

Theme: ENT Allergology
Key words: Reindeer nose – Human nose – Nasal microcirculation – Nasal polyposis

In a surprising publication entitled “Why Rudolph’s nose is red”, a group of Dutch and Norwegian researchers, alluding to Santa Claus and his legendary sleigh pulled by Rudolph and several other reindeer through Northern Europe’s frozen plains, wanted to understand why in the legend as well as in reality the reindeers’ noses were red (A.M.Van Kuyjen et al BMJ 2012 17 December  e8/311).

They thus compared, in vivo, using a high technology video-microscopic system, the nasal microcirculation of 2 reindeers to that of the nasal septal mucosa of 5 healthy volunteers and a patient with grade 3 nasal polyposis. In this way they managed to evaluate vascular density and flow index, as well as reactivity to some local drugs (vasoconstrictor or anaesthetic), and perform an accurate statistical analysis.

The researchers found many similarities between healthy humans and reindeer. Analyses, confirmed by the first-ever biopsic studies, show hairpin-like capillaries rich in red blood cells with a perfused vessel density, as well as crypt or gland-like structures.

But what comes out of this research is that the vascular density of the reindeer’s nasal mucosa is 25% higher that the healthy human being’s, which explains the reindeer’s legendary luminous red nose (and also antler ends). This enables these animals’ nasal mucosa to protect, under extreme polar conditions, their brain temperature.

The authors remind us on this occasion of all the other nasal functions, i.e. humidification, filtration, inflammation control, oxygen dispensation to cells, and response to allergens. On top of that, this delicate technique reveals the functional aspect of nasal microcirculation which even makes it a hemodynamic marker usable in intensive care.

Finally, nasal polyposis (one case only, but an advanced one) reveals the microvasculature irregularity with total absence of hairpin-like capillaries and gland-like structure.

2. Winter hay fever: a Christmas gift for Swiss school children

Theme: ENT Allergology
Key words: Winter hay fever – Alder pollen – Global warming

A Swiss doctor from Grabs (a small village in Eastern Switzerland), with the help of Zurich allergist colleagues, reported the unusual observation in school children of the area of a rhinitis close to hay fever but occurring in winter (M.Gassner et al NEJM 2012 December 21 on line).

They consequently gathered all data on allergic manifestations of the past 25 years among 15-year-old school children in the small village of Grabs, as well as the specific IgE antibodies to 103 molecular allergens (using ImmunoCAP ISAC), that is from 54 students in 1986 and 46 in 2006. In 2010, they retested 12 of them (then +/-39 years old) for various common inhalant allergens. At the same time atmospheric pollen levels were measured with the use of Hirst-type pollen traps.

Already in 2006 they had observed IgE antibodies to the main allergen of alder trees (Aln gl) in 10.9% of healthy subjects, but these were not seen with pollen of other trees. Besides, among the 12 former students retested, three of them had become sensitized to alder. Similarly, although none of the children reported having had allergic symptoms between 1983 and 1986, 6 students had such symptoms in 2006 and their rhinitis was attributed to a common cold.

The explanation came from the observation around Christmas of 2011 of large amounts of alder pollen in the trap. Indeed, just over a decade ago, 96 hybrid trees of the Alder family, with high winter resistance, had been planted along a main boulevard in Grabs, where children walk or ride the bus on their way to school. Changing temperatures and street lighting may have influenced the release of pollens from these trees in winter (Alnus x spaethi, A. japonica x et A.subcordata).

That is why the authors entitled their study “Hay fever as a Christmas gift".

3. Severe allergic reactions to exposure to Methylisothiazolinone (MIT)

Theme: Allergen – Skin allergyRespiratory allergy
Key words: Methylisothiazolinone – Contact eczema – Asthma – Cosmetics - Paints

Chemicals such as cosmetics or preservatives usually cause allergic manifestations through direct contact: the result is allergic contact dermatitis, a type IV immune reaction. The inhalation of other industrial chemical allergens such as isocyanates may cause severe reactions, but only rare skin ones.

Now, it appears that a preservative, MIT, recently introduced in marketed cosmetics and paints in Europe, and hitherto mostly responsible for dermatitis, is also causing respiratory allergic reactions, sometimes severe, when inhaled (M.Dirgaard Ludov et al BMJ 2012 December 4). Hence, in Denmark, allergic reaction to this compound in patients with eczema rose from 1.4% in 2009 to 3.1% in 2011 (55 positive reactions out of 2470 patch tests). Half these cases had been exposed to MIT via cosmetics, and over one third via paints. Among the latter, eczema, sometimes accompanied by asthma, had occurred at home after use of paint or after working or staying in a recently painted place. Dermatitis was located on uncovered skin (face and neck) or in the popliteal fossa. Some cases required hospitalisation.

The authors then inventoried 17 paint brands whose MIT concentration ranged from 10 to 300 ppm, and in an experimental study observed that emissions from painted glass plates were measurable for nearly 26 days.

In the 80’s, MIT was marketed in proportions of 1/3 with its chlorate derived product (even more responsible for sensitization) and the combination of both was considered as the main cause of preservative contact dermatitis.

MIT on its own has been regulated since 2000 in paints and lacquers for professional use and the first observations of this type of allergy were issued in 2004. For cosmetics, concentration was limited to 15 ppm, but since 2005 in Europe and the USA a maximum of 100 ppm has been tolerated. And yet, MIT is not regulated for domestic cleaners, which means that it is difficult for the consumer to detect MIT presence or concentration.

Knowing the health hazards of this exposure to airborne allergens in many environments, the authors ring alarm bells for European authorities to reduce authorised concentrations, or even ban some products.

4. Respiratory symptomatology and menstrual cycle (MC)

Theme: Asthma
Key words: Menstrual cycle – Asthma – Tobacco - Overweight

Variations in respiratory symptomatology (RS) as a function of the menstrual cycle are the object of an important paper by Northern authors (F.Macsali et al AJRCCM 2012  29 November ahead of print) concerning 3926 women aged 20-44 from Sweden, Norway, Denmark and Estonia, whose questionnaire answers were analysed by chronobiology methods, along with stratification by BMI, smoking and asthma status.

These were women with a regular MC of 28 days on average, taking neither contraceptive nor hormones, with whom RS was recorded daily between the 1st day of the last menstruation and the 3 last days of the MC. The originality of this study comes from the use of the ‘cosinor’ methodology to describe the RS rhythm. We know that the MC comprises a 1st oestrogenic phase of 10-14 day follicular maturation followed by ovulation with a 0.5° central temperature increase, then the 2nd luteal phase with progesterone secretion and decrease in FSH and LH ending with menstruation at the dip of the hormonal secretion.

Since hormonal factors are linked to metabolic, and smoking has an anti-oestrogenic effect, it was important to take these factors into account and above all to know whether some patients had been diagnosed as asthmatic.

The following was observed, with significant rhythmic oscillations for each symptom and each subgroup:
• Wheezing was at its highest from day 10 to 22 of the MC, with a drop in frequency at the time of ovulation and in almost all subgroups.
• Shortness of breath was highest from day 7 to 21 with a drop at mid MC in several subgroups.
• Coughing peaked just following putative ovulation for asthmatics, smokers and those who are overweight (BMI ≥23kg/m²).

While these variations were observed in all groups, it is among asthmatics that therapy should be considered most carefully, as this would imply adjusting the treatment on an individual basis, taking into account chronobiological variations of each patient’s MC, to be monitored over several months.

5. Smelly biomarker for ‘Neutrophilic’ asthma

Theme: Asthma
Key words: Hydrogen sulphide – FEV1 – Neutrophils - FeNO

Sulfide hydrogen (H2S), well known terrible smelly gas, produced by many cell types in the lungs, has been recently discovered as capable of inducing vascular smooth muscle relaxation and being an anti-inflammatory and anti-oxidant agent.

J.Saito of London Brompton Hospital (et al JACI 2013 131 1 p.232-4), in search of new bio markers, attempted to measure its levels in the serum and supernatants from induced sputum in asthmatic patients. The very sensitive technique used required several adjustments before being considered as reliable because levels (between 10 and 100µmol/L) evaporate rapidly after sampling.

40 asthmatics and 15 healthy controls were the object of the preliminary study:
- 23 asthmatics of an average age of 47 years: severe asthma (SA) requiring per os and inhaled corticosteroids, in association with long-term agonist β2.
- 17 asthmatics of an average age of 36 years, suffering from moderate asthma (MA) controlled by inhaled corticosteroids.
- controls had an average age of 40 years.

Results were as follows:
• There was no significant difference in healthy subjects’ and asthmatics’ saliva. But provoked sputum and serum revealed significantly higher levels in SA and MA than in controls.
• Besides, there was an inverse correlation between sputum H2S and FEV1, and also a negative one with reversibility to albuterol, two signs of persistent airway obstruction.
• There was a positive correlation between sputum H2S and the percentage of sputum neutrophils, but not with macrophages and eosinophils.
• Finally, an inverse correlation was observed between sputum H2S and FE NO, the latter usually considered as an expression of eosinophilic asthma.

Overall, after multiple linear regression, it appears that sputum H2S levels (but not the serum ones) are associated to sputum neutrophilia, decrease in FEV1, bronchospasm irreversibility to agonist β2 and increase in BMI, all signs pointing to the neutrophilic asthma of an aging and overweight subject; contrary to eosinophilic asthma, moderate and reversible to albuterol.

Thus, H2S could be considered as a bio marker for the neutrophilic asthma phenotype. An assumption to be confirmed on larger cohorts, as well as the necessity of specifying the possible origin of sputum H2S (bacterial flora of deeper airways?).

Comments and questions welcome:

*Pr. Claude Molina

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**Dr Jacques Gayraud

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Last updated 29 October 2014