December World Medical Journal Review
Shyam S. Mohapatra, Ph.D., WAO Guest Editor, University of South
Florida College of Medicine, Tampa, FL, USA, reviewed premier December
medical journal articles for practicing allergists. WAOのWeb編集担当、南フロリダ大学Shyam
1. Abnormalities of the bronchial arteries in asthma.
This study compares the structure of the bronchial arteries, which
supply systemic blood to the airways, tracheobronchial lymph nodes and
nerves, in post-mortem lungs of three groups of subjects (n=12): one
group with fatal asthma and death due to asthma, one group with fatal
asthma and death not due to asthma, and one non-asthmatic group. In
the two asthmatic groups, the intimal area was significantly larger
than in the control group. Gender, age, smoking and duration of asthma
were found to have significant effects on the intimal area in
asthmatics. The increase in intimal area was associated with smooth
muscle proliferation and reduplication and calcification of elastica
but not with inflammatory cell infiltration.
Editorís Comments: This paper is interesting because quantitative
analysis of bronchial arteries has not been done before. However,
although the differences are statistically significant, the number of
subjects in each group is small and the clinical significance of these
findings in the context of severe or fatal asthma is unclear.
Green F.H.Y et al.
Chest 2006;130 1025.
2. Safety of trivalent inactivated influenza vaccine in children 6
to 23 months old.
This paper reports on the screening for medically attended events in the
clinic, emergency department or hospital after administration of
trivalent inactivated influenza vaccine to children 6-23 months old
between 1991 and 2003 (45,356 children with 69,359 vaccinations). This
is a retrospective cohort study using self-control analysis with chart
review of vaccine data from significant medically attended events at
eight managed care organizations in the United States. The primary
endpoint was any medically attended event associated with administration
of trivalent vaccine within the risk windows of 0-3 days and 1-14 days.
All individual ICD-9 codes and predefined aggregate codes were examined.
The results showed that 13 of 14 medical conditions including acute
upper respiratory tract infection, asthma, bronchiolitis and otitis
media were less likely to occur after vaccination. Only one condition,
gastritis/duodenitis was more likely to occur after 14 days of
vaccination; however, it was not significant after chart review. Editorís
Comments: This report is the largest study of the safety of vaccines in
infants with a variety of medical conditions suspected of reacting
adversely to vaccination. It clearly establishes that flu vaccination of
infants in the presence of certain diseases, including upper respiratory
tract infections, allergies and asthma, is safe. It should be pointed
out, however, that this is a retrospective study based on medical
records and not an actual trial. In addition, the results showed that
the vaccine may cause gastritis, the reason for which is unclear.
Hambidge SJ et al.
JAMA 2006; 296:16: 1990-7.
3. Role of small airways in asthma: Investigation using
high-resolution computed tomography.
Small airways may have an important role in asthma but their
pathophysiological relevance remains unclear. Their condition is assumed
to reflect air trapping and may be a useful noninvasive indicator of
airway disease. The objective of this study was to use high-resolution
computed tomography for evaluating lung density and to determine
correlations with clinical and physiologic variables in 29 patients with
stable asthma. Both lungs were scanned at full-inspiration and
full-expiration to measure the percentage of lung occupied by low
attenuation areas (LAA%;<-960 Hounsfield units) and the mean lung
density. Asthma severity, pulmonary function, methacholine airway
sensitivity and reactivity, and sputum eosinophil counts were also
evaluated. The results showed that the mean lung density increased and
LAA% decreased in all patients during the expiratory phase compared to
the inspiratory phase. In conclusion, expiratory/inspiratory
high-resolution computed tomography is useful for assessing small airway
involvement in airflow obstruction, airway hypersensitivity and more
severe diseases such as asthma. Editorís Comments: HRCT can be very
useful in diagnosing small airway disease. Tetsuya Ueda, MD
J Allergy Clin Immounol 2006; 118:1019-25.
4. Successful management of mite-allergic asthma with modified
extracts of Dermatophagoides pteronyssinus and
The objective of this prospective, double-blind, placebo-controlled
study of 64 subjects was to evaluate the clinical efficacy and safety
of a vaccine containing depigmented, polymerized allergens of
Dermatophagoides pteronyssinus and D. farinae (equal
amounts) in individuals diagnosed with mild to moderate asthma and
rhinoconjunctivitis. The bronchial provocation test (BPT) was used to
determine clinical efficacy. Among 54 patients who completed the
study, the allergen-treated group experienced a significant
improvement in BPT (p < 0.001), while the placebo group did not (p =
0.648). At the end of the study, allergen (n=20) vs. placebo (n=9)
group (p=.013; odds ratio, 5.71[1.76, 18.51]) needed more than twice
the amount of allergen to obtain a positive BPT. The active group
showed median improvement of 53.76% in total symptom and 58.09% in
medication scores over placebo. Thus, immunotherapy with a mixture of
modified allergen extracts of D. pteronyssinus and D.
farinae is safe and efficacious to treat mite-allergic asthma.
Editorís Comments: Although polymerized allergens have been tested in
other allergies, there have been few reports on their use in dust mite
therapy in mild/moderate asthmatics. This study demonstrates that
polymerized allergen immunotherapy is safe and effective.
Jose-Carlos Garcia-Robaina, MD, PhD
J Allergy Clin Immounol 2006;118:1026-32
provocation test (BPT)
5. FceRI-mediated signal strength plays a key role in regulating
basophil signaling and deactivation.
This study characterized the mechanisms for the control of FceRI-triggered
basophil activation, which is a critical mediator of the symptoms of
allergic disease and its underlying TH2-type response. Human basophils
were purified by Ficoll density centrifugation and negative selection
with immunomagnetic beads. Levels of various intracellular signal
proteins were measured by Western blotting, and mediator release was
analyzed either spectrofluorometrically (histamine) or by ELISA (IL-4
and IL-13). Supraoptimal anti-IgE concentrations led to lower mediator
release than optimal concentrations but simultaneously to greater
histamine release. In parallel, basophil signaling proteins (syk, p38
mitogen-activated protein kinase, and extracellular signal-regulated
kinases 1 and 2) were more rapidly phosphorylated at higher anti-IgE
concentrations but more transiently activated in the supraoptimal range.
This regulation involved the inositol 5í phosphatase, SHIP, which was
phosphorylated with supraoptimal anti-IgE but not with lower
concentrations. Basophils stimulated with N-formyl-methionylleucyl-phenylalanine
failed to phosphorylate SHIP in the supraoptimal concentration range.
Editorís Comments: It appears that the kinetics of IgE-mediated
signaling and mediator release in primary human FceRI+ cells varies
substantially. This paper shows that the magnitude of stimulation and
the phosphatase SHIP play an important role in terminating these events. Bernhard
F. Gibbs, PhD.
J Allergy Clin Immounol 2006; 118:1060-7.
6. Sequence, haplotype, and association analysis of ADRB2 in
This study identified ADRB2 polymorphisms and haplotypes in White and
African American subjects and correlated them with asthma phenotypes. A
5.3 kb region of ADRB2 was sequenced in 669 individuals --429 Whites and
240 African Americans. Twelve polymorphisms, representing an optimal
haplotype tagging set, were genotyped in Whites (338 patients and 326
control subjects) and African Americans (222 patients and 299 control
subjects). The study identified 49 polymorphisms, 21 of which were
novel. Thirty-one polymorphisms (frequency > 0.03) were used to identify
24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. An
association of genotype with the ratio FEV1/FVC was observed in African
Americans. This report demonstrates that additional genetic variants
besides +46 (Gly16Arg) are important in determining asthma phenotypes.
For example, the length of a poly-C repeat (+1269) in the 3í
untranslated region of ADRb2 may influence lung function and may account
for variation in b-agonist responses, especially in African Americans.
Editorís Comments: A comprehensive evaluation of gene variation,
haplotype structure, and linkage disequilibrium is important in
understanding the influence of the b2-adrenergic receptor gene ADRB2 on
disease susceptibility, pulmonary function, and therapeutic response in
different ethnic groups with asthma. This study demonstrates that there
are additional ADRB2 genetic variants besides +46 (Gly 16 Arg) and +79 (Gln
27 Glu) that are important in determining asthma phenotype. Gregory
A Hawkins AM
J Respir Crit Care Med Vol 174 20061101-1109, 2006.
7. Polymorphisms in the muscarinic receptor 1 gene confer
susceptibility to asthma.
Here the authors investigated the role in asthma of the human
cholinergic receptor muscarinic-1 (CHRM1) gene located on chromosome
11q13. The receptor is widely distributed in the lungs and may be
involved in airway constriction, epithelial cell proliferation and
inflammation. In a case-controlled study using 326 Japanese patients
with asthma and 333 healthy control subjects, 9 single-nucleotide
polymorphisms in the CHRM1 gene were examined. The functional
consequences of the -9697C > T and -4953A > G polymorphisms at the
regulatory region were also determined using an mRNA reporter assay,
which suggested associations with asthma. Haplotype analysis showed that
the -9697T/9695T/-4953A haplotype was associated with a lower risk of
asthma (p= 0.00055) and the 9697C/-6965T/-4953G haplotype was associated
with an increased risk of asthma (p=0.020). The -9697T/-4953A haplotype
was also associated with lower luciferase activity in vitro compared
with the 9697C/-4953G haplotype. Taken together, these results suggest
that the CHRM1 gene on chromosome 11q13 is an important determinant for
susceptibility to asthma. Editorís Comments: Since the beginning of
asthma genetic studies, several candidate genes linked to asthma
phenotypes have been found at the 11q13 locus. This study demonstrates
that CHRM1, which is also at 11q13, is an important susceptibility gene
for asthma. Yukiko Maeda
Am J Respir Crit Care Med Vol 174 2006 1119-1124.
8. A3 adenosine receptor signaling contributes to airway mucin
secretion after allergen challenge.
Mucus hypersecretion is characteristic of asthma, but the cellular
and molecular mechanisms that regulate mucin production and secretion
are poorly understood. This study uses genetics to investigate the
contribution of the A3 adenosine receptor, A3AR, to mucus production and
secretion in a mouse model of allergen-induced pulmonary disease. A3AR
is part of a signaling pathway that is upregulated in the
mucin-producing goblet cells of the airway, but mucin production in
response to allergen is similar in wild-type and A3AR-deficient mice.
Overexpression of this receptor in Clara cells neither induces mucin
production itself nor enhances mucin production in response to allergen
challenge, and A3AR is not required for mucus cell metaplasia. In
contrast to the lack of effect on mucin production,
agonist-induced mucin secretion was reduced in A3AR-deficent
mice. Thus, mucin secretion induced by allergen treatment is stimulated
via A3AR. In pulmonary disorders in which adenosine levels are elevated,
signaling through this receptor may contribute to airway obstruction by
mucus. Editorís Comments: Mucus production and secretion in the
airway is a complex phenomenon, and this study shows that the two
processes are distinct. A3AR signaling does not affect mucus production
but does promote mucus secretion. This is important since adenosine
levels in the lung are increased as a result of inflammation and damage.
Hays W. J. Young
Am J Respir Cell Mol Biol Vol 35 2006 549-558.
9. Respiratory syncytial virus infection reduces B2-adrenergic
responses in human airway smooth muscle.
This study addresses the hypothesis that respiratory syncytial virus
(RSV) has direct effects on cAMP formation and B2-adrenergic receptor
(ADRβ2) density and that the ADRβ2 haplotype influences this response. A
recombinant RSV expressing green-fluorescent protein (rgRSV) was first
used to determine whether RSV could infect cultured human airway smooth
muscle cells (HASM). Then, the influence of RSV infection on
β2-adrenergic responsiveness was determined by measuring differences in
isoproterenol (ISO)-induced cyclic AMP (cAMP) formation, ADRβ2 density
and Gi expression in HASM cells infected with RSV, with
ultraviolet-inactivated RSV, or with vehicle. The cultured HASM cells
were efficiently infected by RSV, and ISO-induced cAMP formation was
significantly reduced in RSV-infected cells, compared to cells infected
with ultraviolet-inactivated RSV or mock-infected, in a time- and
concentration-dependent manner. Forskolin-induced cAMP formation and Gi
expression were not altered in cells infected with RSV, suggesting that
the influence of RSV on β2-adrenergic relaxation was upstream of cAMP
formation. ADRβ2 density was reduced in cells infected with RSV and the
Arg16Gln27 ADRβ2 haplotype was associated with decreased ISO-induced
cAMP formation (p<0.05) and with decreased ADRβ2 density at baseline
(p<0.05). Editorís Comments: The use of b2-agonists in the treatment
of airway obstruction associated with RSV infection has been
controversial. The results of this study show that β2-agonist effects
may be related to direct effects of RSV on HASM, and that the ADRβ2
genotype may predict bβ-adrenergic responses. Paul E. Moore Am
J Respir Cell Mol Biol Vol 35 2006 559-564.
10. Airway hyperreactivity in exacerbation of chronic asthma is
independent of eosinophilic inflammation.
The authors of this report have developed an animal model to
investigate the mechanisms underlying an acute exacerbation of chronic
asthma. Ovalbumin (OVA)-sensitized BALB/c mice were exposed to
aerosolized OVA, either as a chronic low-level challenge for four weeks,
a single moderate-level challenge, or chronic low-level followed by
single moderate-level challenge (the acute exacerbation group). Compared
with animals receiving chronic challenge alone, mice in the acute
exacerbation group exhibited more marked inflammation, with involvement
of intrapulmonary airways and lung parenchyma, and increased numbers of
lymphocytes and eosinophils in bronchoalveolar lavage fluid. They also
developed airway hyperreactivity (AHR) to methacholine, demonstrable as
increased transpulmonary resistance and decreased compliance. This
pattern of AHR was absent in chronically challenged animals but was
present in animals given a single moderate-level challenge. However,
compared with animals receiving a single moderate-level challenge,
inflammation and AHR were induced more rapidly in the acute exacerbation
group. Eosinophil-deficient GATA1 dbl mice exhibited undiminished AHR in
the acute exacerbation model. Thus, mice with pre-existing airway
lesions resembling mild chronic asthma, when exposed to a moderately
high concentration of inhaled antigen, experience the symptoms of an
acute exacerbation. The inflammatory response involves distal airways
and is associated with a distinct pattern of AHR, which develops
independently of the enhanced eosinophilia. Editorís Comments:
Eosinophilia has been considered the hallmark of allergic asthma. This
study shows that the extent of airway hyperreactivity and eosinophilia
actually depends upon the magnitude of antigen exposure in a specific
state of the disease. Thus, chronic asthma can be devoid of eosinophilia.
Jessica S. Siegle
Am J Respir Cell Mol Biol Vol 35 2006 565-570.
11. Role of epithelial damage and angiogenesis in childhood
Airway remodeling and inflammation are characteristic features of
adult asthma that have been little studied in childhood asthma. This
study examines epithelial and vascular changes as well as the
inflammatory response in airways of asthmatic children. The study
analyzed bronchial biopsies obtained from 44 children undergoing
bronchoscopy for clinical indications other than asthma: 17 had mild to
moderate asthma (aged 2-25 yr), 12 had atopy without asthma (1-11 yr),
and 15 were controls without atopy or asthma (1-14 yr). Epithelial cell
loss, basement membrane thickness, number of vessels and inflammatory
cells were quantified in sub epithelium by histochemisty and
immunohisto-chemisty. The results showed increased epithelial loss and
basement membrane thickening in children with asthma compared to
controls (p = 0.005 and 0.0002, respectively) and atopic children (p =
0.002 and 0.005, respectively). The number of vessels and eosinophils
was increased in asthmatic children (p = 0.03 and p = 0.0002,
respectively) and in atopic children without asthma (p = 0.03 and p =
0.008, respectively) compared to controls. When the results were
stratified according to age, the children younger than six years with
asthma had increased epithelial loss, basement membrane thickening, and
eosinophilia compared to controls of the same age. In conclusion,
epithelial damage and basement membrane thickening, which are
characteristic pathologic features of adult asthma, are present even in
childhood asthma. Other changes, such as airway eosinophilia and
angiogenesis were also observed in atopic subjects suggesting that they
may represent early events in the natural history of asthma. Editorís
Comments: This is an excellent study essentially showing that childhood
asthma is not significantly different from adult asthma. Angelo
Am J Respir Crit Care Med Vol 174 2006 975 -981.
WAO Now: What's New in the World of WAO
February GLORIA Placements
The 5th International Congress of the
Egyptian Society of Pediatric Allergy & Immunology
February 8-9, 2007
International GLORIA Faculty:
Michael A. Kaliner
Module 8: Anaphylaxis
San Diego Allergy Society
February 12, 2007
San Diego, California
US GLORIA Faculty:
Allen P. Kaplan
Module 7: Angioedema
GLORIA is supported through unrestricted
educational grants from:
2007 Seminars & Conferences Placement
Regional Asthma Congress - Egyptian Society of
Allergy and Clinical Immunology
January 31 Ė February 2, 2007
WAO Invited Lecturer:
Michael A. Kaliner
"A Global Perspective on Genetics, the Environment and Allergy"
2007 AAAAI Annual Meeting
Monday, February 26, 2007, 4:45 pm - 6:00 pm
San Diego Convention Center
Upper Level, Room 32 AB
Thomas A. E Platts-Mills, USA
Michael A. Kaliner, USA
Is Early Exposure to Allergen Protective?
Adnan Custovic, United Kingdom
How Does the Environment Influence Genetic Responses?
Robert F. Lemanske Jr., USA
Environmental Intervention in the Management of Allergic Diseases
Erika Von Mutius, Germany
We have the pleasure of announcing four new interviews with
well-respected allergists. Take a moment to
listen to them share their extensive knowledge.
- Prof. Jean Bousquet -- WHO-GARD: The global alliance against
chronic respiratory diseases
- Prof. Paul Van Cauwenberge -- Allergic Rhinitis: A disease
remodeling the upper airways?
- Prof. G. Walter Canonica -- Real life classification of allergic
- Dr. Ronald Dahl - Allergenic Cross Reactivity
WAO Committees and Councils 2007: A Year in Review and plans for the
The year 2006 saw the selection and successful completion of the
first three WAO Short-Term Research Fellowships and the selection of the
first WAO Long-Term Research Fellow. As we move into 2007 WAO will
consider major epidemiological surveys of allergic disease, look
in-depth at the management of anaphylaxis worldwide, and publish the
Allergy Prevalence Survey responses of our member societies.
We have surveyed our membership to ascertain the educational needs
of our constituents and placed GLORIAô and Seminars and Conferences
programs in every region of the World. World Allergy Forum symposia were
presented at EAACI, AAAAI and ACAAI. This high level of activity will
continue worldwide with three Seminars and Conferences programs, 28
GLORIA programs, and two World Allergy Forum symposia in 2007.
Specialty and Training
In 2006, the WAO Specialty and Training Council published its report
"ďAllergy Practice Worldwide" and also "Requirements for Physician
Training in Allergy: Key Clinical Competencies Appropriate for the Care
of Patients with Allergic or Immunologic Diseases - A Provisional
Position Statement of the World Allergy Organization." The third
document in this series, "What is an Allergist?," will be published
early in 2007. These documents already are providing an important
reference source for our member societies and helping them to promote
our specialty on a global level.
Web site initiatives saw the launching of WAO Conversations and
Interactive Case Reviews and the monthly e-letter being translated into
seven languages. On the horizon for the Web site in 2007 will be a
series of Web-based seminars (in conjunction with AAAAI), Ask the Expert
and an online Membership Directory.
In 2006, we achieved significant progress in the Emerging Societies
Program. We placed pollen traps in the CIS Region and are developing a
WAO Aeroallergen Sampling Manual to support this program. The Emerging
Societies Meeting in Buenos Aires produced valuable insight into allergy
practice in the underserved areas of Latin and Central America; we are
moving forwards with the assistance of our member societies in the
region and in collaboration with ACAAI, AAAAI and the National
Institutes of Health in the USA, to help our fellow allergists in these
countries. 2007 will see an ESM in Bangkok for our colleagues in the
Asia Pacific region, in association with a new ESM partner, the Western
Pacific Allergy Organization.
Sign up for On-Line Journal Subscription Ė
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And In Other News
Allergy Book Reviews
Concise Clinical Immunology for Healthcare Professionals
Mary T Keogan, Eleanor M. Wallace, and Paula OíLeary
List Price: £25.99 (about $50.00 USD)
Taylor and Francis Books
Thomas Chacko, MD, 2nd year Fellow
University of South Florida College of Medicine, Tampa, FL
This text is a concise and easy to access manual about the complex field
of clinical immunology.
The purpose of this book is to provide the physician and other
healthcare professionals with an introductory book on clinical
immunology. It also covers basic immunology, laboratory investigations
and the treatment of various immunological disorders.
This book is geared toward the novice student, the first year
sub‑specialty resident in allergy and immunology, and other physicians
who want to learn basic immunology as it impacts clinical immunology. It
provides the key features without getting lost in details.
The book's 426 pages are divided into four chapters: basic immunology,
clinical immunology, immunotechniques and diagnostic testing, and
treatment of immunological disorders. Each chapter has multiple,
2-4-page sections on various subjects within a chapter. At the end of
some sections, there are references for further reading. There are also
various diagrams and a self‑assessment test at the end of each chapter.
Case presentations (14 total) are dispersed within some chapters.
This is an excellent book on the basics of clinical immunology. The
sections are arranged to allow for quick retrieval of key facts. The
self‑assessment exams keep the reader actively thinking to emphasize
salient information. Other sources are necessary for a more in-depth
review of this complex subject, but this is a great start, even for
those with considerable skills in these areas.
In summary, this book will be particularly helpful for the novice
student or physician who wants to learn about clinical immunology.
Cystic Fibrosis in the 21st Century
Bush, A., Alton, EWFW., Davies, JC., Griesenbach, U. & Jaffe, A.
List price: $180.00 USD
Dr RG Stirling BSc(Hons), MBBCh(Hons), MRCPI, FRACP
Department of Allergy Immunology & Respiratory Medicine; Alfred Hospital
& Monash University; Melbourne, Australia
Recent decades have seen an explosion of knowledge in Cystic Fibrosis
(CF), surrounding CFTR structure, function and the mechanism by which
this gene defect causes human disease. This book addresses these
developments in some detail, yet also broadly scopes a range of current
CF-related research activity. Further in-depth consideration is given to
the challenge of clinical care in relation to airway infection,
inflammation and the management of the extrapulmonary manifestations of
A state of the art overview of recent advances in Cystic Fibrosis.
This volume is largely aimed at researchers and clinicians established
in CF, needing to update and broaden their understanding of CF.
This book acknowledges the multidisciplinary approach necessary for
advancing CF care by blending a strong scientific base to the broad
clinical needs of the CF population. Edited and written by leading
figures in CF research, this volume highlights developments in
understanding of CFTR structure and function, yet provides useful
updates in the key management and therapeutic questions for pediatric
and to a lesser degree adult CF care.
This volume places substantial emphasis in the description of current
knowledge of CFTR structure, function and their interrelationships. The
interactions and significance of genotype, modifier genes, infection and
inflammation provide many complex challenges to our understanding of CF,
and this book also provides a broad yet succinct research update in a
number of these areas. For the practicing clinician, however, CF in the
21st century is evolving as a disease of adulthood and many emerging
adult medical issues including bone disease, GORD, non-invasive
ventilation and the complex management challenges of airway clearance,
psychosocial counselling, ethics, transition, palliation and
transplantation, require further attention. Nevertheless, this volume
provides a valuable supplement and addition for those seeking to update
and broaden their understanding of Cystic Fibrosis.
Find more allergy book reviews on the WAO Website