Discussion
In this study, 10.04% of our patients with cystic fibrosis underwent
diagnostic work up due to symptoms suggesting any drug related
hypersensitivity reaction and we confirmed drug allergy in 0.9% of the
study population. Unlike previous studies, none of the children
exhibited beta-lactam hypersensitivity, instead a non-beta lactam
antibiotic, TMP/SMX was the culprit agent responsible for DHRs.
There is limited data concerning prevalence of confirmed DHRs in general
population. Rebelo et al demonstrated parentally-reported drug allergy
prevalence as 4.6% in children and diagnostic work up revealed
confirmed drug allergy in 0.2% of the study population (19). In a
population based study concerning school aged children, the true
frequency of immediate type drug hypersensitivity was shown as 0.11%
(20). In the present study, the prevalence of DHRs was similar to
general population, however, lower than the prevalence of DHRs compared
to some previous studies (28.8-61.9%) (7-9, 21).
Since there is contradictory results about the frequency of DHRs in the
literature, we summarized these studies in Table 3 to make a comparison.
In earlier studies, the prevalence of DHRs in patients with CF ranged
between 28.8-61.9% (7-9, 21, 22). There might be a number of comments
for this. The majority of patients with cystic fibrosis included were
only adults or adults and children. Burrows et al demonstrated that the
age of the patients with CF who experienced a DHR was older and a higher
proportion of patients older than 25 years had DHRs compared with
younger patients. Further, higher number of antibiotics courses were not
associated only with higher risk of antibiotic allergy but also with
allergy to more than one antibiotic (22). However, Roehmel et al showed
that DHRs were drug-specific and dependent on cumulative annual dose
(7). The definitions of DHRs might not fit all criteria for DHRs defined
in guidelines. Pleasant et al described the DHRs as rash and drug
induced fever in their study (8). Besides, the clinical presentations of
DHRs were not detailed in most of these studies. Probably the most
important problem in these studies was that the guidelines defined
allergy assessment steps were not followed, and most studies were
retrospective and based on questionnaires and / or medical records.
Nevertheless, skin tests and DPTs were not performed for confirmation of
true drug allergy (7-9, 21, 22). It is well-known that, minority of
suspected DHRs were proved to be accurate drug allergy (19).
It is encouraging that our results are consistent with that found by
Matar (11), Braun (12) and Caimmi (10) et al ranging between 0.71-2.3%.
Caimmi et al. conducted skin tests and DPTs on 14% of 171 patients with
suggestive DHR due to beta-lactam antibiotics and 2.3% of the study
cohort was diagnosed as immediate type beta-lactam allergy (10). The
reason for higher frequency of DHRs in cystic fibrosis has been argued
that repetitive antibiotic administrations may result in increased risk
of sensitization (7, 21, 22). Rather, recurrent exposure to drugs,
especially by courses longer than applied to everyone might contribute
to development of tolerance. Unfortunately, our patients also used
antibiotics frequently. One fourth of our patients were hospitalized due
to pneumonia which were treated by parenteral antibiotics within last
year. Although we did not have the data related to the total number of
antibiotic courses up to child’s age; in the last year, nearly all
consumed antibiotics at least once and half of the cases used
antibiotics more than twice.
One unanticipated finding was that there were no cases with beta-lactam
allergy, besides two patients were diagnosed as TMP/SMX allergy (0.9%).
Recently, in a population of 601 patients with cystic fibrosis, the
prevalence of TMP/SMX hypersensitivity was indicated as 0.49% and found
as the second class of antibiotics responsible for DHRs (12).
Self-reported sulfa allergy ranged between 0.07-2.7% in different
populations (23-25). Increased antigenicity to sulfamethoxazole in
sulfamethoxazole-hypersensitive patients with cystic fibrosis was
demonstrated. T cells from sulfamethoxazole-hypersensitive patients with
cystic fibrosis were stimulated with oxidative metabolites of
sulfamethoxazole more than sulfamethoxazole-hypersensitive patients
without cystic fibrosis in terms of higher secretion of IFN-g, IL-6, and
IL-10. Additionally, recurrent infections might enhance sulfamethoxazole
metabolite formation, therefore increased protein adduct formation
associated with the stimulation of sulfamethoxazole-responsive T cells
(26). In view of the results of these studies, physicians dealing with
cystic fibrosis should be more vigilant about DHRs due to TMP/SMX HRs
which was an understudied area.
As far as we know, this is the first study which focused on prevalence
of any drug hypersensitivity reaction in patients with cystic fibrosis.
In the present work, we extensively inquired patients and reviewed
medical records for DHRs related to drugs other than beta-lactam and
non-beta lactam antibiotics. Due to chronic nature of cystic fibrosis,
the patients frequently exposed not only to antibiotics but also NSAIDs,
proton pump inhibitors and others (6). Use of the offending drug or
cross-reactive ones in chronic or repetitive treatment schedules enhance
the risk for DHRs. Actual drug allergy was shown to be more frequent in
patients with chronic diseases (27, 28). However, we were unable to
demonstrate hypersensitivity to drugs other than antibiotics.
There are some limitations of this study. We did not have detailed
information about the classes of antibiotics and NSAIDs and duration of
treatment courses used during lifetime. The study had both retrospective
and prospective aspects that some of diagnostic tests might not have
been done with optimum timing.
As adverse drug reactions accumulate over time, the physicians will try
to manage their patients with CF with limited number of treatment
options. Therefore, it is crucial to assess cases according to
established diagnostic protocols. Numerous and long-term use of multiple
drugs during management of cystic fibrosis may contribute to tolerance
development and protect patients from actual drug allergy.