Drug hypersensitivity: questionnaire Special article

Alergol Inmunol Clin 2001;16: 48-53
ENDA (European
Network on Drug
Allergy)
Initially translated into Spanish
by the Drug Allergy
Committee of the Spanish
Society of Allergology and
Clinical Immunology
48
Special article
Drug hypersensitivity: questionnaire
En daily clinical practise the assessment of drug hypersensitivity reactions
is, with exceptions few and far between, both difficult and complex.
There is however an almost unanimous agreement in that far less
such reactions are detected and diagnosed than the number that actually occurs.
A number of factors may help explain this phenomenon: (1) The clinical entities
involved are themselves quite heterogeneous and are usually grouped into
disease contexts as disparate as urticaria, hepatitis, diverse nephropathies, blood
dyscrasias, and other; (2) Even though important progress has been made in the
realms of immunology and pharmacology, the pathophysiology of adverse drug
reactions is still imperfectly known; (3) The classical Gell and Coombs classification
appears insufficient for explaining all the cases, and there is no updated
and useful classification for drug reactions; finally, (4) There is a lack of standardisation
and, even worse, of validation of the in vitro and in vivo methods
available for establishing a correct diagnosis.
Because of all these limitations and of the evident need to provide solutions,
be they provisory or definitive, in the daily Allergy practise it is usual to
record a detailed anamnesis that sometimes is complemented with the performance
of skin tests and/or laboratory tests and analyses. Drug tolerance tests
are also often carried out in order to complement the clinical assessment. However,
there are still a large number of cases in which alternative medication is
prescribed without a definitive diagnosis having been established, and even occasionally
selecting drugs that may not be adequate because of toxicity or that
are altogether ineffective or inefficient. It should be stressed that establishing a
correct diagnosis is the adequate way and requisite for being able to recommend,
in each particular case, future preventive measures and a correct and appropriate
therapy.
Two clearly differentiated phases may be considered in the diagnosis of
drug hypersensitivity reactions: the assessment of the patient when he/she is
first referred for study of his/her problem, when the symptoms have usually already
remitted, and the assessment of the patient in the acute phase. In the latter
case, establishing a differential diagnosis is essential, as the supposedly involved
drug may have to be withdrawn and alternative therapy offered while
the reaction abates. This sometimes implies that drugs may have to be withdrawn
that were actually required for the therapy of the process for which they
had initially been prescribed. In the acute cases, a very detailed anamnesis is of
utmost importance, together with laboratory tests for assessment of routine haematological
parameters and of the hepatic and renal function. This acute phase
is unique and it is highly improbable for it to repeat itself, so it represents a similarly
unique opportunity for carrying out all the determinations that are deemed
pertinent. Once the acute phase has ended, the Allergologist shall apply
the diagnostic procedures that are possible in each case; these will usually in-

volve skin tests, laboratory tests and a study of drug challenge
tolerance in an attempt to establish the relation between
the intake of the suspect drug or drugs and the debut
of the reaction.
With the double aim of facilitating the Allergologists’
work and of unifying criteria, the drug allergy
group of the European Academy of Allergy and Clinical
Immunology (ENDA, European Network on Drug
Allergy) considered it adequate to prepare a questionnaire
that might represent a reference for all those who occasionally
demand an organised approach to the problem.
This questionnaire was published in Allergy in September
19991. The ENDA also considered that, for it to have
adequate diffusion, the questionnaire should be translated
into the various languages and published in the
Journals of the National Scientific Societies, and entrusted
this task to the ENDA members in each particular
country. In our own case, in Spain, this task was taken
over by Dr. M. J. Torres and Dr. C. Mayorga, from the
Immunotoxicology group of the "Carlos Haya" Hospital
in Málaga, and by Dr. M. Blanca, Head of the Allergology
Service of the "La Paz" University Hospital in Madrid.
Two of them are also members of the Drug Allergy
Committee of the Spanish Society of Allergology and
Clinical Immunology.
Even though, in a first perusal, the questionnaire
may seem to be rather complex, it usually requires but little
time for completion and is equally useful for the assessment
of reactions in the acute phase and in remission.
Although it might have some limitations in the space available
for completing it, the user is free to modify those
spaces he/she deems necessary. The questionnaire does
stress the clinical features, but it also includes common laboratory
parameters and even those used at research centres,
which, even though they may not be fully standardised,
may in the future help us achieve a better
understanding of drug hypersensitivity reactions.
In our country, a number of working groups from
Drug hypersensitivity: questionnaire
various centres with Allergology Units have since a long
time ago put forward similar proposals for the generation
of protocolised questionnaires for the assessment of these
conditions. Moreover, there are publications available
from some of these groups in which the questionnaires are
much more specific and are aimed at the assessment of
definite problems, such as adverse reactions to β-lactams
or to NSAIDs, among other drug groups. Even so, it is our
hope that this questionnaire, which aims at being a single
one valid for any type of reaction, may be valid if not for
all at least for a number of Allergologists who have to assess
immunologically based adverse drug reactions. The
ideal outcome would be that, as a consequence of its use
and its development, other authors might put forward further
new ideas that might improve the assessment of drug
hypersensitivity reactions.
REFERENCE
1.- Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity:
questionnaire. Allergy 1999; 54: 999-10003.
DRUG REACTIONS COMMITTEE OF THE
SEAIC
M. Blanca (Madrid)
J. M. Cortada Macías (Palma de Mallorca)
P. García Robaina (Tenerife)
T. Lobera Labayru (Logroño)
E. Martí Guadaño (Barcelona)
J. Quiralte Enríquez (Jaén)
M. Sánchez Cano (Madrid)
M. J. Torres (Málaga)
J. Vigaray Conde (Madrid)
M. G. Canto (Coordinator) (Madrid)
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ENDA
ANEXO. Drug hypersensitivity
Protocolo Nº: ..........................
INVESTIGATOR: Date of protocol:................
Name:.......................................................................................................Center:...............................................................................
Address:....................................................................................................Tel/Fax/E-mail:......................................................................
PATIENT:
Name:....................................................................................... Date of birth:......................................................Age:.....................years
Weight:..............kg Height:.................cm
Profession:........................................................................................................City:..........................................................Sex: M F
Risk groups: Medical staff Pharmaceutical industries Farmers Others / specify........................................................
CURRENT COMPLAINTS:.......................................................................................................................................................................
.............................................................................................................................................................................................................
.............................................................................................................................................................................................................
DRUG REACTION: DATE OF REACTION:.....................................
(Multiple boxes can be ticked; underline the choice if necessary; chronology can be characterized with numbers)
CUTANEOUS SYMPTOMS:
Maculopapular exanthema
DIFFERENTIAL DIAGNOSIS:
Macular exanthema
Urticarious exanthema
............................................................................................
AGEP (Acute generalized exanthemous pustulosis)
Eczematoid exanthema
............................................................................................
Erythema exudativum multiforme
Bullous exanthema
Stevens Johnson syndrome /NET (M. Lyell)
...........................................................................................
Fixed drug exanthema CONTRIBUTING FACTORS:
Purpura -> Thrombocyte count:............................ Viral infections: Flu-like infection Other:...................
palpable hemorrágica-necrotizante Fever
Visceral organ involvement:...................................................... Suspicion of photosensitivity No Yes Unknown
Contact dermatitis Topic cause Haematogenous cause ........... Stress
Urticaria Vasculitis Exercise
ONLY pruritus Other/Specification: ...............................................................
Urticaria ...............................................................................................
Angioedema/Location/s: ...............................................................
Conjunctivitis EVOLUTION:
Other/Specification:............................................................................... Intensity
50
Morphology/Location/s:..........................................................
..................................................................................................
EFFLORESCENCES: Distribution / Dynamics (⇑⇓) h / days
generalized
GASTROINTESTINAL AND RESPIRATORY SYMPTOMS: ASSOCIATED SYMPTOMS:
Nauseas/Emesis Involvement of: Liver Kidney Other / Specification: .........
Diarrhea Fever...........°C
Gastrointestinal cramps Malaise
Pair/Burning Locations/s:.....................................................

ANEXO. Drug hypersensitivity (cont.)
Drug hypersensitivity: questionnaire
GASTROINTESTINAL AND RESPIRATORY SYMPTOMS: ASSOCIATED SYMPTOMS:
Cough Edema Location/s:............................................
Dysphonia Pain/Burning Location/s:............................................
Dyspnea PEFR or FEV1:...................................... Arthralgia/Myalgias Location/s:............................................
Wheezing/Bronchospasm Lymphadenopathy
Other/Specification:...............................................................
Rhinitis CARDIOVASCULAR SYMPTOMS:
Rhinorrhea Tachycardia Pulse: ............./min.
Sneezing Hypotension Blood pressure: ............................mmHg
Nasal obstruction Collapse
Other/Specification:........................................................................
PSYCHIC SYMPTOMS:
Arrhythmia
Other/Specification: ...............................................................
Fear/Panic reaction Vertigo INVOLVEMENT OF OTHER ORGANS:
Fainting (e.g. periphearal neuropathy, lung involvement, cytopenia, etc.)
Paraesthesia/Hyperventilation .......................................................................................
Sweating ..........................................................................................
Other/Specification:........................................................................ ..........................................................................................
CLINICAL OUTCOME:............................................................................................................................................................................
List all drugs including Over The Counter substances, natural remedies and additive-containing food taken at the time of the reaction:
.............................................................................................................................................................................................................
.............................................................................................................................................................................................................
.............................................................................................................................................................................................................
SUSPICIOUS DRUGS:
Drug’s generic name ± additives / Daily dose / Route of application Interval between dose and reaction: Previous therapy with this drug:
Indication: / Duration of therapy:
1. .........mg/d; ............; .....d No Unknowm
Yes -> Symptoms:...........................
2. .........mg/d; ............; .....d No Unknowm
Yes -> Síntomas:.............................
3. ........mg/d; ............; ......d No Unknowm
Yes -> Síntomas:.............................
4. ........mg/d; ............; ......d No Unknowm
Yes -> Síntomas:.............................
5. ........mg/d; ............; ......d No Unknowm
Yes -> Síntomas:.............................
6. ........mg/d; ............; ......d No Unknowm
Yes -> Síntomas:.............................
............................................................................................................................................................................................................
CURRENT DRUGS: .......................................................................................................
MANAGEMENT FOLLOWING ACUTE DRUG REACTION: No therapy
Antihistamines .......................................
Blockers ................................................
Stopping suspicious drugs No.# ...............................................................................................
Antihistamines local systemic
Corticosteroids local systemic
Bronchodilatators local systemic
Shock treatment
Change to substitute/s:
Epinephrine Plasma expanders Other: .....................................
Type/Name: ......................................................................................................................................
Tolerance: ........................................................................................................................................
Other / Specification:..........................................................................................................................
Dosis reduction (Drug................................)..................................................................................................
Other / specify:............................................................................................................................................
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ENDA
ANEXO. Drug hypersensitivity (cont.)
PERSONAL HISTORY:
1) Have similiar symptoms been observed without the intake of the suspicious drugs?
2) MEDICAL HISTORY:
Yes No Unknown
Asthma Autoinmune (Sjögren, Lupus, etc) Urticaria pigmentosa / syst. mastocytosis
Nasal polyposis Lymphoprolific (ALL, CLL, Hodgkin, etc.) Chronic urticaria
Cystic fibrosis Intervertebral disk surgery HIV positivity
Diabetes Liver:............................................................... Kidney: ..........................................................
Other / Specification:.......................................................................................................................................................................
3) ALLERGIC DISEASES: ............................................................................................................................................................
(e.g. pollinosis, atopic dermatitis, food allergy, Hymenoptera venom allergy, latex alergy, etc.)
4) DRUG REACTIONS DURING PREVIOUS SURGERY: ............................................. Dentist Local anaesthesia Anestesia general
5) REACTIONS DURING PREVIOUS VACCINATIONS: ........................................ Polio Tetanus Rubella Measles Hepatitis B
Diphteria Other................................ Unknown
FAMILY HISTORY: Allergies / Drug allergies:
.............................................................................................................................................................................................................
REMARKS:
.............................................................................................................................................................................................................
.............................................................................................................................................................................................................
.............................................................................................................................................................................................................
DIAGNOSTIC PROCEDURES: RESULS
ACUTE DIAGNOSTICS: (already performed) ................. DATE NORMAL ABNORMAL QUESTIONABLE
Blood: Full blood count: Eosinophils............................ Value:..........rel.; ............abs.
Other:................................... Value:..........rel.; ............abs.
ECP (Eosinophil cationic protein) .......................... Value:........
C-reactive protein / Erythrocyte sedimentation rate Value:........
Flowcytometry (Specify: ....................................) .............................................
Tryptase ............................................................. Value:........
Liver parameters: GOT................................................................... Value:........
GPT................................................................... Value:........
γGT.................................................................... Value:........
alk. Phosphatase ............................................... Value:........
Kidney: Creatinine .......................................................... Value:........
Methylhistamine ................................................. Value:........
Others:............................................................... .............................................
Special: Mediators and metabolites (IL-4, IL-5, IL-10, IFNγ). Value:.....................................
Immune complex analysis.................................... .............................................
Complement analysis........................................... .............................................
Skin biopsy ..............................................................................................................................................
DIAGNOSTICS: NEGATIVE POSITIVE QUESTIONABLE
Skin tests: Prick: ............................................................... Inmmediate-R. Late-R
............................................................................ Inmmediate-R. Late-R
............................................................................ Inmmediate-R. Late-R
Intradermal: ....................................................... Inmmediate-R. Late-R
............................................................................. Inmmediate-R. Late-R
Scratch-Patch: .................................................... Inmmediate-R. Late-R
............................................................................. Inmmediate-R. Late-R
............................................................................. Inmmediate-R. Late-R
Other: ................................................................ Inmmediate-R. Late-R
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ANEXO. Drug hypersensitivity (cont.)
Drug hypersensitivity: questionnaire
Blood analysis: Total IgE Value:.........................
Specific IgE for drugs: CAP RAST Value:.........................
............................................................................ Value:.........................
............................................................................ Value:.........................
............................................................................ Value:.........................
Specific IgG / Coombs Test dir:........................................................................................................................
Coombs test indir...........................................................................................................................................
Other............................................................................................................................................................
Cellular tests: Lymphocyte transformation test (TTL):...................................... YES:.................
.............................................................................................. YES:.................
.............................................................................................. YES:.................
Basophil activation test (Specify:: ..........................................) .....................
CAST assay........................................................................... .....................
Other:.................................................................................. .....................
CONCLUDING INTERPRETATION:
Type I reaction (IgE mediated) a: A.........................................................................................
Type II reaction (antibody mediated) a: B.........................................................................................
Type III reaction (inmune complete mediated) a: C.........................................................................................
Type IV reaction (cell-mediated, late-type reaction) a: D.........................................................................................
Cytotoxic reaction, cell-mediated a: E.........................................................................................
Pseudoallergic reaction a: F..........................................................................................
Pharmacological reaction a: G.........................................................................................
Psychophysiological reaction a: H.........................................................................................
Other:............................................................... a: I..........................................................................................
Test de provocación: Local anesthetics:...............................................
NSAID:..............................................................
..............................................................................
..............................................................................
Aspirin:..............................................................
Paracetamol:.......................................................
Nimesulid:..........................................................
β-lactam:............................................................
.............................................................................
Other:.................................................................
PROBABILITY SCALE CONCERNING THE CAUSAL RELATIONSHIP BETWEEN DRUG & REACTION: (Please mark the drug’s letter on the scale)
Certain Probable Possible Doubtful Unrelated/Not assessible
Please specify:........................................................................................................................................................................................
DECLARATION TO REGULATORY AGENCY: No Yes To whom?: ................................................................................Date: .........
REMARKS:............................................................................................................................................................................................
.............................................................................................................................................................................................................
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