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LETTERS TO THE EDITOR 833

J ALLERGY CLIN IMMUNOL


VOLUME 135, NUMBER 3

emerged regarding other day-to-day issues. Physicians were


overall misinformed about the availability of epinephrine in
both restaurants and ambulances. When questioned regarding
quality of life, only 10% of family practitioners and 31% of
pediatricians believed that severe allergies have a major impact
on quality of life. This differs markedly from results of previous
studies about patients perceptions regarding the effects of food
allergy on quality of life.10 More pediatric A/I specialists (78%)
than others (P 5 .03) believed that life-threatening
allergic reactions today are more common than 10 years
ago, consistent with published data,11 and most physicians in
all groups recognized that asthma is a risk factor for severe
reactions.
Similar to our surveys of patients and the general public, this
study clearly demonstrates the need for ongoing education
regarding anaphylaxis. As with previous studies, knowledge
gaps are especially apparent for primary care and emergency
physicians, who are most often the physicians on the front line in
the treatment of this common and life-threatening condition.
Ashley M. Altman, DOa
Carlos A. Camargo, Jr, MD, DrPHb
F. Estelle R. Simons, MDc
Philip Lieberman, MDd
Hugh A. Sampson, MDe
Lawrence B. Schwartz, MD, PhDf
F. Myron Zitt, MDg
Charlotte Collins, JDh
Michael Tringale, MSMh
Marilyn Wilkinson, ScDi
Robert A. Wood, MDa
From athe Department of Pediatrics, Division of Allergy and Immunology, Johns
Hopkins University School of Medicine, Baltimore, Md; bthe Departments of
Medicine and Epidemiology, Massachusetts General Hospital, Boston, Mass; cthe
Department of Pediatrics and Child Health, Section of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; dthe Departments of
Internal Medicine and Pediatrics, University of Tennessee College of Medicine, Germantown, Tenn; ethe Department of Pediatrics, Division of Allergy and Immunology,
Icahn School of Medicine at Mount Sinai, New York, NY; fthe Department of
Medicine, Division of Rheumatology, Allergy & Immunology, Virginia Commonwealth University, Richmond, Va; gthe Department of Medicine, State University of
NY Stony Brook, Stony Brook, NY; hAsthma and Allergy Foundation of America,
Landover, Md; and iAbt SRBI, Inc, Silver Spring, Md. E-mail: rwood@jhmi.edu.
The Asthma and Allergy Foundation of America supported this study.
Disclosure of potential conflict of interest: A. M. Altman has received research support
from the National Institutes of Health (NIH) and is employed by the Johns Hopkins
University School of Medicine. C. A. Camargo has received consultancy fees from
the Asthma and Allergy Foundation of America, Dey/Mylan, and Sanofi-Aventis and
has received research support from Sanofi-Aventis. F. E. R. Simons is a board member for the Sanofi Canada Medical Advisory Board. P. Lieberman has received
research support from Meda, Sanofi, Mylan, AstraZeneca, Genentech, and Novartis.
H. A. Sampson has received research support from the National Institute of Allergy
and Infectious Diseases/NIH and the Food Allergy Research and Education; is Chair
of the PhARF Award review committee; has received consultancy fees from Allertein Therapeutics, Regeneron, and Danone Research Institute; and has received lecture fees from ThermoFisher Scientific, UCB, and Pfizer. L. B. Schwartz has
received consultancy fees from Sanofi, Viropharma, and Genentech; has received
research support from GlaxoSmithKline, NeilMed, Merck, CSL Behring, and
Dyax; and has received royalties from ThermoFisher, Hycult & BioLegend, Millipore & Santa Cruz, Elsevier, and UpToDate. F. M. Zitt has received lecture fees
from Integrity/Mylan and Sanofi and has received payment for the development
of educational presentations from Integrity. C. Collins has received research support
from Sanofi-Aventis and Pfizer and has received travel support from Mylan Specialty, LLP. M. Tringale has received research support from Sanofi-Aventis. R. A.
Wood has received consultancy fees from the Asthma and Allergy Foundation of
America, is employed by Johns Hopkins University, has received research support
from the NIH, and has received royalties from UpToDate. M. Wilkinson declares
that she has no relevant conflicts of interest.

REFERENCES
1. Russell W, Farrar J. Evaluating the management of anaphylaxis in US emergency
departments: guidelines vs. practice. World J Emerg Med 2013;4:98-106.
2. Simons FER, Ardusso LR, Bilo MB, Cardona V, Ebisawa M, El-Gamal YM,
et al. International consensus on (ICON) anaphylaxis. World Allergy Organ J
2014;7:9.
3. Wood RA, Camargo CA, Lieberman P, Sampson HA, Schwartz LB, Zitt M, et al.
Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the
United States. J Allergy Clin Immunol 2013;133:461-7.
4. Fineman S, Dowling P, ORourke D. Allergists self-reported adherence to anaphylaxis practice parameters and perceived barriers to care: an American College of
Allergy, Asthma and Immunology member survey. Ann Allergy Asthma Immunol
2013;111:529-36.
5. Krugman SD, Chiaramonte DR, Matsui EC. Diagnosis and management of foodinduced anaphylaxis: a national survey of pediatricians. Pediatrics 2006;118:
e554-60.
6. Wang J, Sicherer SH, Nowak-Wegrzyn A. Primary care physicians approach
to food-induced anaphylaxis: a survey. J Allergy Clin Immunol 2004;114:689-91.
7. Grossman SL, Baumann BM, Garica Pena BM, Linares MYR, Greenberg B,
Hernandez-Trujillo VP. Anaphylaxis knowledge and practice preferences of
pediatric emergency medicine physicians: a national survey. J Pediatr 2013;163:841-6.
8. Aun MV, Blanca M, Garro LS, Ribeiro MR, Kalil J, Motta AA, et al. Nonsteroidal
anti-inflammatory drugs are major causes of drug-induced anaphylaxis. J Allergy
Clin Immunol Pract 2014;2:414-20.
9. Rudders SA, Banerji A, Corel B, Clark S, Camargo CA Jr. Multicenter study of
repeat epinephrine treatments for food-related anaphylaxis. Pediatrics 2010;125:
e711-8.
10. Sicherer SH, Noone SA, Munoz-Furlong A. The impact of childhood food allergy
on quality of life. J Allergy Clin Immunol 2001;81:461-4.
11. Simons FER. Anaphylaxis. J Allergy Clin Immunol 2010;125:S161-81.
Available online January 7, 2015.
http://dx.doi.org/10.1016/j.jaci.2014.10.049

Increasing rate of hospitalizations for foodinduced anaphylaxis in Italian children: An


analysis of the Italian Ministry of Health
database
To the Editor:
The clinical pattern of food allergy (FA) in childhood is
changing in many Western countries. The most severe clinical
manifestation of FA is anaphylaxis. The number of food-induced
anaphylaxis (FIA) cases seems to be increasing in the United
States and Australia.1,2 Few studies of FIA in European children

FIG 1. Increasing trend of the number of hospital admissions for FIA


among Italian children from 2006 to 2011. The increased incidence of
hospital admissions for FIA was more pronounced in children aged 5 to 14
years than in those younger than 4 years (1128% and 144.2%, respectively;
P < .05).

834 LETTERS TO THE EDITOR

J ALLERGY CLIN IMMUNOL


MARCH 2015

FIG 2. Main foods responsible for anaphylaxis requiring hospitalization among Italian children as reported
by the specific ICD-9-CM code.

have been conducted in recent years, and most were limited by


small populations or a regional focus.3-5
We previously reported an alarming increasing trend in hospital
admissions for FIA among Italian children during the 2001 to
2005 period.6 To explore whether this trend has continued during
more recent years, we investigated with a retrospective, casebased study the number of FIA-related hospital admissions and
the food responsible for the episode in children 14 years or
younger living in Italy by querying the statistics system database
of the Italian Ministry of Health (http://www.salute.gov.it) in all
Italian hospitals between January 1, 2006, and December 31,
2011, using the International Classification of Diseases,
9th Revision, Clinical Modification (ICD-9-CM) discharge diagnostic codes for FIA. The number of fatal cases of FIA was also
recorded. Data regarding the Italian pediatric population living
in those years were from the Italian National Institute of Statistics
database (http://www.istat.it). See this articles Online Repository
at www.jacionline.org for a description of data collection.
A total of 3121 FIA-related hospital admissions of 2552
subjects (mean age, 15.5 years; minimum, 0 year; maximum,
92 years; 56.5% males) were identified with the ICD-9-CM codes
during the 6-year study period. Hospital admissions for FIA
occurred mainly in the North of Italy (2253, 72.2%; P < .01).
During the same period, there were 2252 FIA-related admissions
(72.1%) of 1785 patients 14 years or younger (mean age, 5.18
years; 60.9% boys). In these patients also, FIA-related hospital
admissions occurred mainly in the North of Italy (1724, 76.5%;
P < .01).
When examining FIA hospitalization rates by age, we observed
that the increased incidence of hospital admissions for FIA was
more pronounced in children aged 5 to 14 years than in those
younger than 4 years (1128% and 144.2%, respectively; P <.05)
(Fig 1). An increasing trend of the number of hospital admissions
for FIA for patients older than 14 years was also found (163.8%;
P < .05), with a rise in all age groups. Four fatal cases of FIA
were identified in patients older than 14 years, and the foods
responsible were peanuts, crustaceans, fruits, and vegetables; in
1 case, the food responsible was not reported.

Fig 2 shows the rate of FIA episodes according to the ICD-9_4 years and 5-14 years). A total of
CM code and age group (<
17.2% of the subjects 14 years or younger required multiple
hospital admissions for FIA (from 2 to 10 times per year) in the
same year. In most cases, children were younger than 4 years
(67.8%) (see Fig E1 in this articles Online Repository at www.
jacionline.org).
Considering the pediatric population aged 14 years or younger
living in Italy during the 6-year study period (ranging from
8,337,511 in 2006 to 8,380,158 in 2011), we estimate an incidence
of hospital admission for FIA of about 4.4 episodes per 100,000
children/year. Given our previous results related to the 2001 to 2006
period,6 and the Italian pediatric population 14 years or younger
between 2001 and 2011, we estimate that the rate of hospital
admissions for FIA among the Italian pediatric population increased
from about 0.001% in 2001 to 0.005% in 2011 (P <.05) (see Fig E2
in this articles Online Repository at www.jacionline.org).
Our results demonstrate a continuous increasing trend in the
hospital admission rate for FIA in Italian children. It appears that
every 23 hours a child in Italy requires hospital admission because
of FIA.
This increase could be related to several factors. One could be
the general increase in FA prevalence among children and the
increased susceptibility to many allergens. The North-South
gradient observed in our study, which is in line with results
obtained in Australia and the United States,7,8 suggests a potential
role for vitamin D insufficiency. It has been reported that
decreased sunlight/ultraviolet B exposure contributes to immune
system defects, abnormal gut microbiota, gastrointestinal infections, and compromised mucosal barrier integrity, leading to
sensitization and FA.7,8 According to this view, a high prevalence
of vitamin D deficiency was identified in Italian children (>50%
of the subjects), most of whom lived in Northern Italy (average
latitude of 45 degrees).9
A strength of our study is that we queried a nationwide
hospital and vital statistics database. This study design is
particularly useful in time trends because clinical practice and
principal discharge diagnosis coding are unlikely to change

J ALLERGY CLIN IMMUNOL


VOLUME 135, NUMBER 3

significantly during a relatively short period. The main limitation of our study is related to the possibility of inaccurate
coding and that individual anaphylaxis cases are not validated
by medical record review. Unexpectedly, a relatively high
percentage of children 4 years or younger (17.2%) required
multiple hospital admissions for FIA in the same year (from 2 to
10 times per year). In most cases, the children were younger
than 4 years (67.8%).
In conclusion, FIA-related hospital admissions in Italian
children increased year on year from 2001 to 2011. This finding
suggests that the trend is also increasing in the European pediatric
population as well as in the United States and Australia. This
alarming finding should prompt (1) studies aimed at identifying
the causative factor(s), (2) policies to ensure safe environments
for children affected by FA, and (3) more effective health care
strategies to limit the burden of FA and to prevent FIA
hospitalizations.
We thank Jean Ann Gilder (Scientific Communication srl., Naples, Italy) for
editing the article.
Rita Nocerino, RNa
Ludovica Leone, LDNa
Linda Cosenza, MDa
Roberto Berni Canani, MD, PhDa,b
From athe Department of Translational Medical Science, bEuropean Laboratory
for the Investigation of Food Induced Diseases, University of Naples, Naples, Italy.
E-mail: berni@unina.it.

LETTERS TO THE EDITOR 835

This study received no grant from any funding agency in the public, commercial, or notfor-profit sectors. All authors had full access to all the data in the study and take
responsibility for the integrity of the data and the accuracy of the data analysis.
Disclosure of potential conflict of interest: The authors declare that they have no relevant
conflicts of interest.
REFERENCES
1. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis,
and treatment. J Allergy Clin Immunol 2013;133:291-307.e5.
2. Burks AW, Tang M, Sicherer S, Muraro A, Eigenmann PA, Ebisawa M, et al.
ICON: food allergy. J Allergy Clin Immunol 2012;129:906-20.
3. Gupta R, Sheikh A, Strachan DP, Anderson HR. Time trends in allergic disorders
in the UK. Thorax 2007;62:91-6.
4. Tejedor Alonso MA, Moro Moro M, Mugica Garca MV, Esteban Hernandez J,
Rosado Ingelmo A, Vila Albelda C, et al. Incidence of anaphylaxis in the
city of Alcorcon (Spain): a population-based study. Clin Exp Allergy 2012;42:
578-89.
5. Cetinkaya F, Incioglu A, Birinci S, Karaman BE, Dokucu AI, Sheikh A. Hospital
admissions for anaphylaxis in Istanbul, Turkey. Allergy 2013;68:128-30.
6. Berni Canani R, Nocerino R, Terrin G, Leone L, Troncone R. Hospital admissions
for food-induced anaphylaxis in Italian children. Clin Exp Allergy 2012;42:
1813-4.
7. Mullins RJ, Clark S, Camargo CA Jr. Regional variation in epinephrine autoinjector prescriptions in Australia: more evidence for the vitamin D-anaphylaxis hypothesis. Ann Allergy Asthma Immunol 2009;103:488-9.
8. Camargo CA Jr, Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin
D. J Allergy Clin Immunol 2007;120:131-6.
9. Marrone G, Rosso I, Moretti R, Valent F, Romanello C. Is vitamin D status known
among children living in Northern Italy? Eur J Nutr 2012;51:143-9.
Available online January 25, 2015.
http://dx.doi.org/10.1016/j.jaci.2014.12.1912

835.e1 LETTERS TO THE EDITOR

DESCRIPTION OF DATA COLLECTION


Through a specific application we queried the episode statistics
system database of the Italian Ministry of Health for FIA-related
hospital admissions in all subjects presenting to all public
hospitals in Italy between January 1, 2006, and December 31,
2011 (the last year for which data were available in the database at
the time of the analysis) using the ICD-9-CM discharge
diagnostic codes for FIA: 995.60, anaphylactic shock caused by
unspecified food; 995.61, anaphylactic shock caused by peanuts;
995.62, anaphylactic shock caused by crustaceans; 995.63,
anaphylactic shock caused by fruits and vegetables; 995.64,
anaphylactic shock caused by tree nuts and seeds; 995.65,
anaphylactic shock caused by fish; 995.66, anaphylactic shock
caused by food additives; 995.67, anaphylactic shock caused by
milk product; 995.68, anaphylactic shock caused by eggs; and
995.69, anaphylactic shock caused by other specified food.
This is the only data set on hospital use, outcomes, and charges
designed to study childrens use of hospital services in Italy.

J ALLERGY CLIN IMMUNOL


MARCH 2015

Database contains discharge-level records, not patient-level


records. The target in our population includes pediatric and adult
discharges from community, and the discharges are sorted by
patients age, sex, year and location of the admitting hospital, and
the number of fatal cases. Although the hospital database has
changed during the study period (ie, the number of Italian
hospitals), the changes would not appear to have significantly
affected the findings of increased FIA-related hospital admissions
observed.
Access to database is limited to a specific request. Uses are
limited to research and statistical reporting.
For more information on the database, visit the Italian Ministry
of Health Web site at http://www.salute.gov.it.
REFERENCE
E1. Berni Canani R, Nocerino R, Terrin G, Leone L, Troncone R. Hospital admissions for food-induced anaphylaxis in Italian children. Clin Exp Allergy 2012;
42:1813-4.

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VOLUME 135, NUMBER 3

FIG E1. Recurrence of hospitalization in the same patient for FIA in a single
year.

LETTERS TO THE EDITOR 835.e2

835.e3 LETTERS TO THE EDITOR

FIG E2. Trend in admission rate for FIA in Italian pediatric population
_14 years) between 2001 and 2011. The data from 2001 to
(subjects aged <
2005 are from Berni Canani et al.E1

J ALLERGY CLIN IMMUNOL


MARCH 2015