Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Allergic reactions of medical personnel to allergen extracts
2. Cold Urticaria (CU) : immuno-genetic and molecular data
3. Allergic consequences of climate changes
4. Risks of childhood allergy and asthma under phthalate exposure
5. Sputum eosinophilia and asthma (A)

1.  Allergic reactions of medical personnel to allergen extracts

Theme: allergens
Key words: medical staff – allergen extracts – beta blocking agent – timothy grass – pollens – pets

A rare case of occupational anaphylaxis, is reported by two US authors in a 32-year-old female compounding technician  while preparing an immunotherapy vial of timothy grass allergen extracts, who accidentally stuck herself on the hand with a needle (M.L Bandino et M.S.Tankersley JACI  2012 129 1 250-251). Within minutes, a local wheal-and -flare response appeared at the needle-stick site followed by rhino-conjunctivitis, diffuse urticaria, then a facial peri-orbital and tongue angio-oedema, requiring several adrenaline injections before stabilising. Admittedly, this woman was atopic, suffering from allergic rhinitis, which included sensitization to timothy grass, but usually treated by Loratadine®, and also from a regular hypertension by a β-blocking agent (Atenolol®), regarded as risk- factor of resistance to treatment.

Commenting on this observation, the Danish author S.Dreborg (JACI 2012 129 in press) reminds us that this type of risk can concern all medical staff. He quotes the case of a nurse, assigned to work on allergenic provocative tests in a Paediatrics hospital unit, with no allergy history, who started coughing the following winter, then as soon as she resumed work and undertook a 1st provocative test, had an asthma attack followed, despite having stopped working,  by a  rhino-conjunctivitis,.

In 1970 in Sweden, 18 out of 20 paediatric allergy nurses showed signs of sensitization, despite installation of an air extraction system. A nurses’ Union sent a web- questionnaire to 570 participants on the subject of allergic risks at work, and received 418 (71%) answers. Conducting skin tests (prick-tests, scarification or ID) was judged as responsible, but fingers were also pointed at immunotherapy and inhaled provocative tests. Allergens most frequently implicated were pollens and pets.

The authors set forth a series of recommendations on the training and careful handling of allergenic extracts, which they intend to submit to ad hoc Committees. A similar initiative in France and French-speaking countries, in the form of a Forum aimed at gathering similar observations would be welcome.

2.  Cold Urticaria (CU) : immuno-genetic and molecular data

Theme: skin allergy
Key words: cold urticaria – Ig deficiency – repeated infections – auto immunity – gene PLCG2 – phospholipase

CU is a diagnosis that allergists may be confronted by, atopy being not excluded from its pathogenesis. It is also due to mast cell degranulation by cold temperatures, and can culminate in anaphylaxis.

In an article dedicated to an inherited CU associated with antibody deficiency and auto-immunity (M.J.Ombrello et al NEJM 2012 January 12 330-338) a group of US researchers undertook a large number of immunologic and genetic investigations with 27 subjects belonging to three families  of European ancestry.

From a clinical point of view, every subject’s CU began in childhood and continued throughout their life. But it is not the contact with cold that triggers CU (ice-cube tests were negative as well as cold water immersion) but essentially cold air or wind. 15 subjects out of 26 also showed allergic manifestations.

26 out of 27 suffered from immunologic disorders: in 75% of cases a deficiency in immunoglobulins, associated  in 56% with susceptibility to sinus and lung infections. Signs of auto-immunity were also observed (auto-antibodies or associated auto-immune disease : granulomatous rash, vitiligo, inflammatory arthritis, thyroiditis, granulomatous lesion of larynx and soft palate).

Common lab tests showed reduced IgA and IgM serum levels, circulating natural killer cells and B lymphocytes, but higher IgE levels. In 13 of 21 treated subjects (62%) antinuclear antibodies were found.

From the genetic point of view, DNA sequencing, particularly through the Sanger enzymatic technique and identification of single nucleotide polymorphisms (SNP) showed some deletions in gene PLCG2 encoding phospholipase-active proteins, particularly PLCγ2 , signaling molecule expressed in many cells such as mast cells, B lymphocytes and natural killer.

This genetic research highlights the importance of molecular mechanisms contributing to the defence of the organism and immune tolerance.

The possible treatment of CU clinical manifestations by phospholipase inhibitors is a current subject of research and a possible example of targeted molecular pharmacology. The administration of immunoglobulins IV may be useful in some cases, but prescribing them in France is currently regulated.

3.  Allergic consequences of climate changes

Theme: allergy and environment
Key words: global warming – CO2 – tree pollens – grass – Ambrosia - Alternaria

A series of publications on the health impact of climate changes and global warming in the years to come ( L.Ziska et al: Proc.Natl.Acad.Sci.USA and JACI 2012  1 29 27-32) reveals that atmospheric gas accumulation, particularly CO2, influences photosynthesis and plant growth. This slogan sums up the consequences: “More sneezing in a warmer world”. Three types of plants are concerned: trees in spring, grass in summer and Ambrosias (ragweed) in autumn.

Tree flowering is now 2 to 4 weeks earlier, whether it be oaks or birches in the USA but also in Europe (Swiss and Denmark), and 1-3 weeks earlier for olive trees in Spain.

The same can be said of grass, whose pollen counts have increased as well as their allergenic protein contents, particularly for the US Artemisia and the European species Pellitory (Parietaria Officinalis). However, there is not always a direct relationship between atmospheric concentrations of CO2 and increased allergenic effect of these pollens.

However for Ambrosia (ragweed) there is a clinical and experimental impact of CO2 and T° on pollen allergenicity, proved by the authors,. They also remind us of importance of latitude, after having observed a 27-day lengthening in the pollen season over 15 years in some parts of northern USA, ending on a humoristic note when they recommend that Canadians should stock up on handkerchiefs for the years to come.

Finally, even molds are concerned by these climate changes. Such is the case of Alternaria whose sporulation has increased.

Thus, climate changes induce a higher exposition to allergens, in theory more so in the countryside than in towns. However, the role of gas (NO2 and Ozone) and particle pollutants (PM2,5) on respiratory mucous as well as pollen biology is, in large cities of the Western world, an exacerbation factor to allergy symptoms. Finally, let us recall that this anthropogenic accumulation of atmospheric gases also account for extreme climate events such as heavy rainfalls and thunderstorms; the latter were the cause of acute and spectacular episodes of rhinitis and asthma in Europe.
These notions should be kept in mind, if only for setting up the sequencing of preventive treatments (immunotherapy) of our allergic patients.

4.  Risks of childhood allergy and asthma under phthalate exposure

Theme: asthma - allergens
Key words: asthma – phtalates – benzyl-butyl-phtalate

Phtalates (Pht) are indoor pollutants emitted by everyday consumer goods, such as food packaging, plastic components, medical equipment (tubes and perfusion bags), toys, and cosmetics. They are often considered as endocrine disruptors impacting reproductive functions, and carcinogenic. A group of Chinese authors from Taiwan, having assumed the allergenic effect of these Pht, the degree of exposure to which can be measured by their metabolites in blood and urine, conducted a case control study of 101 pre-school children (2-6 years of age) selected between 2007 and 2009 in a population of several thousand.

A considerable amount of data was collected from parental questionnaires, daily monitoring of clinical symptoms, specific and total IgE levels, concentration of various indoor pollutants in patients’ homes, including 5 Phts in dust samples, and concomitant analysis of urine metabolites as well as creatinine concentration. The data were then subjected to statistical analysis.

Apart from the higher percentage of boys in the test group than in the control one, demographic, family, and environmental characteristics were almost identical in both groups, albeit with a higher percentage of atopic subjects in the 1st group.

Essentially, it appeared that high levels of benzyl-butyl-phtalate (BBzP) in home dust are significantly associated with cases of allergic manifestations (rhino-conjunctivitis, asthma or dermatitis) whereas its urine metabolite, mono-benzyl-phtalate (MBzP), was higher in asthmatics than in controls.
Overall, high levels of DBP (dibutyl-phtalate) and its metabolites MBP (mono-n-butyl-phtalate) and MEHP (mono-2-ethylhexyl-phtalate) may be regarded as risk factors for clinical manifestations concerning lung, skin or eyes.
Admittedly Phts, whose concentrations in urine were lower than in dust, are not the only culprits for poor quality indoor air (an important role is also played by exposure to fungus) but their contribution remains notable and for the first time quantitatively assessed, and particularly for BBzP

5.  Sputum eosinophilia and asthma (A)

Theme: asthma
Key words: sputum eosinophilia – asthma – blood eosinophilia - FENO

Having observed that a subgroup of asthmatics did not have airway eosinophilia, which it is regarded as asthma-typical, the NIH Californian authors ( K.W.Mc Grath  AJRCCM 2012 20 January  in press) wanted to determine the size and characteristics of this group, through repeatedly analysing the cytology data from these patients’ sputum.

995 asthmatics, aged 12-70, suffering from mild-to-moderate asthma and belonging to 9 different national cohorts, underwent repeated sputum induction, with the usual technique (2 to 4 times) followed by cytology examination in search of eosinophils (EO). The positivity threshold was fixed at 2% or more of the number of cells.

Three groups of subjects were discriminated : Asthmatics (A) with persistent EO, those with intermittent EO (at least once) and those who were consistently negative. Comparing cytological tests to blood eosinophilia or to FENO did not show any reliable sensitivity or specificity.

645 A. followed standard inhaled corticosteroids (ICS), 350 did not. The first statistical analyses reveal that 83% ICS have no sputum EO and 36% of the non ICs. Which constitutes a large group of non-eosinophilic asthmatics. This absence of EO was observed even in A whose disease was well-controlled.

From a therapeutic point of view, eosinophilic A. reacted favourably to 2 weeks of anti-inflammatory treatment (IC + anti-leukotriene Zafirlukast) with an improvement in airflow obstruction. This was not the case for non-eosinophilic A in whom only albuterol (β2 agonist) induced bronchodilation.

On the whole, more than half the patients with mild-to-moderate asthma showed a persistent absence of sputum eosinophils.

Among the different clinical forms of A., this group definitely represents a particular phenotype which responds only poorly to anti-inflammatory therapy.
Practically, this research should incite us to look more frequently for EO in our asthmatic patients’ sputum.

NB : As part of a general bibliography, our readers are encouraged to look at the special issue of Nature (Outlook 24 Nov 2011 479 7374) which presents a 27 page exclusive paper on Allergies.

Comments and questions welcome:

Pr. Claude Molina    and/or    Dr Jacques Gayraud
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Last updated 15 October 2014