266 CORRESPONDENCE
JANUARY 2009
REFERENCES
1. J Allergy Clin Immunol 2008;121:1071-298.
2. Letts CFC. The eruption of Vesuvius adapted from the Letters of Pliny. Cambridge:
Cambridge University Press; 1937. p. 167-9.
3. Radice B, trans. The letters of Pliny the Younger. Baltimore: Penguin; 1967. p. 16.
4. Bigelow J. Nature in disease; illustrated in various-discourses and essays. Boston:
Phillips, Sampson; 1858. p. 208.
doi:10.1016/j.jaci.2008.07.038
Reply
To the Editor:
In recounting the unfortunate volcanic pollution–related res-
piratory death of the great but obese historian and naturalist Pliny
the Elder, Dr Cohen1 has introduced 2 topics that merit further in-
vestigation and that were not covered in our review.2 The acute
and chronic respiratory effects of volcanic air pollution at levels
lower than those of Mount Vesuvius are not well understood.3
In addition, it is not known whether the inflammatory or physio-
logic pulmonary impairment associated with obesity makes chil-
dren or adults more vulnerable to the respiratory effects of air
pollution.
Diane R. Gold, MD, MPH
Augusto A. Litonjua, MD, MPH
From the Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Mass. E-mail: diane.gold@channing.harvard.edu.
Disclosure of potential conflict of interest: D. R. Gold has received research support from
the National Institutes of Health and the US Environmental Protection Agency. A. A.
Litonjua has received research support from the National Institutes of Health.
REFERENCES
1. Cohen SG. Asthma and obesity: an archival addendum. J Allergy Clin Immunol
2009;123:265-6.
2. Litonjua AA, Gold DR. Asthma and obesity: common early-life influences in the
inception of disease. J Allergy Clin Immunol 2008;121:1075-84.
3. Mannino DM, Ruben S, Holschuh FC, Holschuh TC, Wilson MD, Holschuh T.
Emergency department visits and hospitalizations for respiratory disease on the
island of Hawaii, 1981-1991. Hawaii Med J 1996;55:48-54.
doi:10.1016/j.jaci.2008.07.039
Probiotics for the treatment or prevention of
eczema
To the Editor:
Lee et al1 provide a timely review of the effects of probiotic
supplementation for the prevention or treatment of eczema. How-
ever, their review fails to meet published standards for the quality
of systematic reviews on several criteria, and this has led to inap-
propriate conclusions.2
First, their literature search was not sufficiently comprehensive
and failed to identify important trials relevant to their review. At
the time of their literature search in July 2007, there were 3
randomized controlled trials of probiotics for treating eczema that
had been published in peer-reviewed journals but were not
included in their review.3-5
A second issue is the clarity of their reporting. The methods of
trial selection and data extraction were not adequately described,
and it is unclear what the inclusion and exclusion criteria were for
this review or whether 2 independent investigators undertook this
process in parallel, as recommended by many authorities.
Third, there is no evidence of an a priori design in their report.
This means that they have used the outcome measures of the
clinical trial publications rather than defining the most important
J ALLERGY CLIN IMMUNOL
outcome measures themselves. The result is a mix of investigator-
assessed outcome measurement (SCORAD score) and mechanis-
tic data without any outcome measure assessed by the study
participants or their parents.
Fourth, the methods used in their meta-analyses are inappro-
priate. For prevention studies, they included data from the same
subjects 3 times over (Kalliomaki 2001, Kalliomaki 2003, and
Rautava 2002), which led to an exaggeration of the clinical benefit
of probiotics for eczema prevention. In the meta-analyses of
probiotic treatment studies, the data from crossover and parallel-
group trials are combined without consideration for the difference
in study design, and for the study of Viljanen, data from one third
of study participants have been excluded from meta-analysis (see
their Fig 2, comparisons 3 and 4).
These defects in methodologic rigor have led to an exaggeration
of the clinical benefits of probiotics for eczema prevention. They
have also led to an overestimation of the likelihood that probiotics
are effective for treating established eczema, which is in contrast
to our more rigorous systematic review of probiotics for treating
eczema.6 Finally, the authors state that prenatal and postnatal pro-
biotic treatments are safe, without making any formal assessment
of adverse events reported in the clinical trials that they reviewed.
In view of a recent report of fatal bowel ischemia and previous re-
ports of probiotic sepsis, this form of treatment cannot be consid-
ered free from risk in all patient groups.7
We recognize the value of systematic reviews to inform clinical
practice and policy-making decisions. The methodologic quality
of such reviews is, however, of fundamental importance, and
poor-quality reviews can be misleading. The review of Lee et al1
does not do justice to the published literature regarding the effects
of probiotics for the treatment or prevention of eczema.
Robert J. Boyle, BSc, MBChBa,b
Jo Leonardi-Bee, PhDd
Fiona J. Bath-Hextall, BSc, PhDc,d
Mimi L. K. Tang, MBBS, PhDb,e
From athe Department of Paediatric Allergy, Imperial College, London, United King-
dom; bAllergy and Immune Disorders, Murdoch Children’s Research Institute, Uni-
versity of Melbourne, Melbourne, Australia; cthe School of Nursing, Faculty of
Medicine and Health Science, and dthe Division of Epidemiology and Public Health,
University of Nottingham, Nottingham, United Kingdom; and ethe Department of
Paediatrics, University of Melbourne, Melbourne, Australia. E-mail: r.boyle@nhs.net.
Mimi Tang is supported by a Murdoch Children’s Research Institute Salary Grant. Robert
Boyle is supported by a National Institute for Health Research Clinical Lectureship.
Disclosure of potential conflict of interest: R. J. Boyle has received research support from
the Ilhan Food Allergy Foundation, the Murdoch Children’s Research Institute, and the
Jack Brockhoff Foundation and has served as a member of the Cochrane Skin Group. J.
Leonardi-Bee has received research support from Health Technology Assessment. M.
L. K. Tang is on the advisory board for the Nestle Nutrition Institute and has received
research support from the Jack Brockhoff Foundation, the Ilhan Food Allergy
Foundation, the Foundation for Children, the National Health and Medical Research
Council, and the Food Allergy and Anaphylaxis Network. F. J. Bath-Hextall has
declared that she has no conflict of interest.
REFERENCES
1. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of probiotics for prevention
and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol 2008;121:
116-21.
2. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Devel-
opment of AMSTAR: a measurement tool to assess the methodological quality of
systematic reviews. BMC Med Res Methodol 2007;7:10.
3. Folster-Holst R, Muller F, Schnopp N, Abeck D, Kreiselmaier I, Lenz T, et al. Pro-
spective, randomized controlled trial on Lactobacillus rhamnosus in infants with
moderate to severe atopic dermatitis. Br J Dermatol 2006;155:1256-61.
4. Hattori K, Yamamoto A, Sasai M, Taniuchi S, Kojima T, Kobayashi Y, et al. [Effects
of administration of bifidobacteria on fecal microflora and clinical symptoms in
infants with atopic dermatitis]. Arerugi 2003;52:20-30.
J ALLERGY CLIN IMMUNOL
VOLUME 123, NUMBER 1
5. Passeron T, Lacour JP, Fontas E, Ortonne JP. Prebiotics and synbiotics: two prom-
ising approaches for the treatment of atopic dermatitis in children above 2 years.
Allergy 2006;61:431-7.
6. Boyle RJ, Bath-Hexall F, Murrell D, Leonardi-Bee J, Tang ML-K. Probiotics for
treating eczema. Cochrane Database Syst Rev 2008. In press.
7. Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are
the risks? Am J Clin Nutr 2006;83:1256-64.
Available online September 22, 2008.
doi:10.1016/j.jaci.2008.07.042
Reply
To the Editor:
We would like to address Boyle et al’s evaluation1 of our 2007
meta-analysis on probiotics for the prevention and treatment of
pediatric atopic dermatitis.2
With regard to the clarity of our reporting, we failed to
explicitly state that our search was limited to English-language
publications. Given the potential probiotic-enhancing effects of
prebiotics, we decided it was reasonable to examine probiotic-
only regimens.
Kalliomaki et al’s 4-year follow-up data were included
because they provided an extended look at the outcome of
interest. However, we acknowledge the potential problem of
their inclusion. The stark differences in the participant pool size
and interventional approaches, as described in the summary
table in our article’s Online Repository at www.jacionline.org
(Table E2),2 led us to the reasonable assumption that the Rau-
tava and Kalliomaki studies enrolled independent groups of par-
ticipants. Was there a common pool of atopic women shared by
these 2 groups? If so, reporting of these trials did not make this
apparent. Taking your point into consideration, however, the ef-
fect is 0.61 (95% CI, 0.48-0.78) and 0.64 (95% CI, 0.50-0.82)
when recomputed excluding the follow-up study and then addi-
tionally excluding the Rautava data, respectively. Comparing
this with the published pooled relative risk ratio of 0.69 (95%
CI, 0.57-0.83), it seems that having included the 2 studies in
question actually yielded a more conservative summary effect
size.
In terms of the treatment trials, Boyle et al1 make a valid argu-
ment for including subjective measures of response in addition to
the objective physician-driven SCORAD point system. But again,
we focused on accepted objective measurements as the primary
outcome.
The omission of the Folster-Holst et al study3 might have been
due to a delay in PubMed indexing. With these additional trial
data identified, the weighted mean difference in final SCORAD
score decreased to 25.26 from the published effect size of
28.56, whereas the 95% CI narrowed from 218.39 to 1.28 to
28.19 to 22.34. However, our conclusion remains unchanged
regarding the (lack of) effectiveness of probiotics for pediatric
atopic dermatitis treatment.
The difference in study design between a crossover trial and a
parallel-group trial does not preclude statistical pooling. We
extracted data from the first half of the crossover design, one of 3
approaches described in the Cochrane Handbook for Systematic
Reviews of Interventions.4 Unlike the other treatment trials, the
Viljanen study examined 3 groups: placebo, Lactobacillus GG,
and a mixture of 4 different probiotics.5 We chose to exclude
the third group (accounting for the absence of one third of the par-
ticipants). A preferable approach might have been to calculate a
CORRESPONDENCE 267
weighted mean of the data from the 2 arms. It is highly unlikely,
however, that this would have affected our summary data, but
your point is well taken. Please understand that limitations to in-
clude these details in the Methods section were due to size and
thus caused the large generation of electronic files to complement
the publication.
In regard to safety, there are always cases of extreme
adverse findings. Among the trials we evaluated for meta-
analysis, only 1 reported significant gastrointestinal effects
associated with heat-inactivated Lactobacillus GG, which con-
sequently terminated further enrollment of participants.6 None
of the meta-analyzed trials used heat-inactivated probiotics. In
addition, any mild adverse effects reported were never re-
ported to be significantly greater in the treatment than placebo
arms.
Joohee Lee, MD
Leonard Bielory, MD
From the University of Medicine and Dentistry of New Jersey (UMDNJ), Newark, NJ.
E-mail: bielory@umdnj.edu.
Disclosure of potential conflict of interest: The authors have declared that they have no
conflict of interest.
REFERENCES
1. Boyle RJ, Leonardi-Bee J, Bath-Hextall FJ, Tang MLK. Probiotics for the treatment
or prevention of eczema. J Allergy Clin Immunol 2009;123:266-7.
2. Lee J, Seto D, Bielory L. Meta-analysis of clinical trials of probiotics for prevention
and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol 2008;121:116-21.
3. Folster-Holst R, Muller F, Schnopp N, Abeck D, Kreiselmaier I, Lenz T, et al. Pro-
spective, randomized controlled trial on Lactobacillus rhamnosus in infants with
moderate to severe atopic dermatitis. Br J Dermatol 2006;155:1256-61.
4. Deeks JJ, Higgins JPT, Altman DG, editors. Analysing and presenting results. In:
Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of inter-
ventions 4.2.6 [updated September 2006]; section 8. Available at: http://www.
cochrane.org/resources/handbook/hbook.htm. Accessed October 6, 2006.
5. Viljanen M, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T,
et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants:
a double-blind placebo-controlled trial. Allergy 2005;60:494-500.
6. Kirjavainen PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of
atopic disease: underscoring the importance of viability. J Pediatr Gastroenterol
Nutr 2003;36:223-7.
Available online September 22, 2008.
doi:10.1016/j.jaci.2008.07.043
Automatic epinephrine device use in children
with food allergies
To the Editor:
Järvinen et al1 recently reported that of 413 children surveyed
from a private practice–based pediatric food allergy referral clinic
in New York, 78 (19%) required epinephrine administration for
95 allergy reactions, 12 (13%) required 2 doses, and 6 (6%) re-
quired 3 doses. Between 2004 and 2008, data on 298 children
aged 1 to 16 years who had been prescribed epinephrine devices
and were attending our National Health Service specialist pediat-
ric allergy outpatient clinic in Manchester, United Kingdom, were
collected onto standardized forms (summarized in Table I).2 All
but 16 (5%) patients had more than 1 device. The survey was ap-
proved by the local regional ethics committee. Eighteen (6%)
children had used epinephrine devices for 22 reactions before ar-
rival in the hospital, but none used a second device for the same
allergic reaction.
The administration of epinephrine in the community by
nonphysicians was just over twice as high (14% of patients) in