To the Editor
At present, strict food avoidance is the only standard treatment for
food anaphylaxis. Incidental exposure, cross-contamination, incomplete
adherence, nutrient and psychological deprivations in parallel to
significant quality of life impairment of the patient and his/her family
led to many attempts to find alternative therapies, including oral
immunotherapy (OIT) that showed promising clinical implications
[1]. During OIT, gradually increasing
doses from very small amounts are given to the patient at specified
intervals until a predetermined final dose is reached (build-up phase).
If the patient reaches this final dose, he/she has to take this
maintenance continuously in a regular daily schedule (maintenance
phase). An allergic reaction as mild as local pruritus of the lips or as
severe as anaphylaxis is the main limitation of both phases. The primary
consequence during OIT is the reduction of anaphylaxis risk in
accidental exposures and the second consequence is the achievement of
permanent tolerance (PT)[2].
During desensitization, unresponsiveness is accessible as long as the
patient adheres to the instructions, while during PT, unresponsiveness
is independent of adherence to the schedule. Natural tolerance (NT) is
seen in infants with food allergy and develops with increasing the age
but inducible permanent tolerance (IPT) is seen in some patients doing
OIT [2,
3]. Currently, not only the immunologic
mechanisms or prognostic factors in success or failure of OIT and the
achievement of PT are not fully understood but also it is not clear that
inducible permanent tolerance really works like natural tolerance? How
can we say to a patient with food anaphylaxis that he/she is definitely
cured? Therefore, we designed this study to assess the possible
reactions of patients with anaphylaxis after the achievement of PT.
This prospective cohort study was conducted on patients with cow’s milk
anaphylaxis who underwent OIT in the Allergy and Clinical Immunology
Department of Rasoul-e-Akram Hospital, Tehran, Iran
[4]. All of the participants or their
parents signed written informed consent form and the Ethics Committee of
Iran University of Medical Sciences approved this study
(IR.IUMS.FMD.REC.1397.333). Twenty-one patients who met the inclusion
criteria, including cow’s milk anaphylaxis, successful OIT with more
than 48 months of the maintenance phase, complete adherence to
maintenance phase protocol were allocated to this study. After 4 weeks
of complete dairy avoidance, they underwent a standard oral food
challenge (OFC) [5]. Eight out of 21
individuals who could pass the OFC were diagnosed as PT and approved for
this study.
In the first week, they were asked to take a double and triple amount of
the maintenance dose in the hospital. All of them consumed this amount
of milk without any reaction and then they were asked to take any amount
of cow’s milk or dairy products regardless of timing similar to
non-allergic individuals. They were given a 24-hour contact number to
report any symptoms immediately, and we followed them weekly by phone
for 6 months. Any kind of reactions, the severity of symptoms, type of
relieving drug, the interval of usage, amount of milk consumption, and
the existence of aggravating factors such as exercise, fever, and
infection was monitored. All of them showed a significant decrease in
specific IgE and IgG4 to cow’s milk before and after the OIT. Seven of
eight participants showed some reactions after cow’s milk consumption.
Reactions were mild and only oral antihistamines were used for treating
the reactions. All of the symptoms were appeared along with exacerbating
factors. Cow’s milk consumption without aggravating factors was safe
independent of the amount and interval of the consumption. Exercise in
the first hour after drinking milk was the most common trigger in our
participants. Data are shown in table 1.
We conducted a prospective cohort study in cow’s milk anaphylactic
patients with successful OIT. Out of 21 patients, only 8 cases passed
the OFC after 4 weeks of cessation of dairy consumption and were
diagnosed as PT state [2]. There are
two different definitions in OIT. Desensitization refers to a temporary
state of unresponsiveness of the adaptive immune system to a specific
antigen, which is dependent on continuous use of the predetermined
amount of that food, while permanent tolerance is defined as persistent
unresponsiveness of the adaptive immune system to that antigen,
irrespective of amount and consumption continuity
[2, 3].
It is estimated that about 30 to 90% of individual who undergo OIT are
able to achieve desensitization state
[2, 6]
but the rate of PT is unknown and is reported between 28 to 36 % in
limited trials [3,
6], it is suggested longer maintenance
phase and higher amount of daily use may have some role in PT
development [2].
In this study, 8 of 21 (38%) patients developed PT. The success rate of
PT induction was not our aim. We wanted to provide more information
about possible reactions related to milk ingestion after PT achievement.
The main question was: Can we really give assurance to patients with
anaphylaxis that they are completely safe in the exposure to the culprit
food, regardless of the dose and continuity of consumption? To the best
of our knowledge, it is the first time to follow these individuals after
PT development; however, Nowak-Wegrzyn A and Deborah M
[2, 7]
also asked this question without a clear response. Allergic reactions
are the main side effects during OIT in both escalation and maintenance
phases. It is important to consider that in the maintenance phase of
desensitization, patients may show severe reactions to previously
tolerated doses in association with exercise, viral infection, dosing on
an empty stomach, menses, and asthma exacerbation. It is hypothesized
that these factors may increase intestinal permeability, thereby leading
to loss of protection to the previously tolerated dose, even when the
maintenance dose has been achieved regularly
[2]. Interestingly, our study showed
these factors could affect the unresponsiveness state even when PT has
developed; however, none of our patients showed severe reactions. The
present study showed the dose and continuous consumption of food
allergen were not involved in the reaction after PT development but
aggravating factors are still important.
Signature
1-Saba Arshi, MD, associate professor of allergy & clinical immunology,
Allergy department, Rasoul e Akram hospital, Iran University of Medical
Sciences, Tehran, Iran,
2- Fatemeh Alizadeh, MD, pediatrician, pediatric department, Rasoul e
Akram hospital, Iran University of Medical Sciences, Tehran, Iran,
3-Mohammad Nabavi, MD, associate professor of allergy & clinical
immunology, Allergy department, Rasoul e Akram hospital, Iran University
of Medical Sciences, Tehran, Iran,
4- Mohammad Hasan Bemanian, MD, associate professor of allergy &
clinical immunology, Allergy department, Rasoul e Akram hospital, Iran
University of Medical Sciences, Tehran, Iran,
5-Sima Shokri, MD, assistant professor of allergy & clinical
immunology, Allergy department, Rasoul e Akram hospital, Iran University
of Medical Sciences, Tehran, Iran,
6-Majid KhoshMirsafa, Phd, assistant professor of immunology, Immunolgy
department, medical school, Iran University of Medical Sciences, Tehran,
Iran
7-Farhad Seif, Phd, assistant professor of immunology, department of
allergy & immunology, Academic Center for Education, Culture, and
Research, Tehran, Iran
8- Morteza Fallahpour, MD, assistant professor of allergy & clinical
immunology, Allergy department, Rasoul e Akram hospital, Iran University
of Medical Sciences, Tehran, Iran,