Stevenson et al . 2019 Retrospective – multivariable ( AUS ) 24 logistic regression |
|
Testing * 80.6 % ( NPV 97.1 %) |
60.8 % - - |
Trubiano et al . 2020 Prospective data – ( AUS / USA ) 25 multivariable logistic regression |
Clinicians ( n = 622 primary validation ; 945 external validation ) |
3 point clinical criteria ( max score 5 ) Low / Moderate / High Low risk criteria : PEN-FAST score < 3 |
Testing * 70.7 % ( NPV 96.3 %) |
78.5 % Europe 26 - |
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PAGE 16
frequently reported in the
community , with antibiotic sulfonamides ( for example , sulfamethoxazole , dapsone ) the most common .
Patients often refer to these by the misnomers ‘ sulfur ’ or ‘ sulfa ’ allergies . Avoid these terms as patients incorrectly assume they are also allergic to non-antibiotic sulfonamides ( for example , celecoxib or diuretics ), other sulfur-containing medicines or sulfite preservatives . 40
Australian sulfonamide antibiotics include sulfamethoxazole , sulfadiazine , sulfadoxine , sulfacetamide and the combination drug sulfasalazine , which contains sulfapyridine .
Allergy to sulfonamides may be lost over time and not reproducible on rechallenge . 21 , 30 Caution is required because , while rare , sulfonamides are implicated in SCAR , such as SJS and DRESS . 41 Genetic screening for HLA-B * 13:01 in patients of Southeast Asian descent may potentially prevent dapsone hypersensitivity . 42
In patients with a reported sulfamethoxazole allergy , cross-reactivity with dapsone is reported in fewer than 20 % of cases and is a safe alternative , especially in those with a history of low-moderate risk sulfamethoxazole allergy .
33 , 43 , 44
Low-risk sulfonamide allergies may be amenable to either direct delabelling or direct oral challenge . Dapsone can be used in low-moderate risk allergies . Non-antibiotic sulfonamides can be used in certain settings and in all cases of reported sulfonamide antibiotic allergy .
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SEVERE CUTANEOUS ADVERSE REACTIONS
SCARs are T-cell-mediated reactions
with a skin predisposition ; however , they may have a systemic impact leading to increased morbidity and mortality . 45 SCARs are rare , affecting 1-3 % of the population in developed countries and 2-5 % in developing countries . 46 Traditionally , three phenotypes ( in order of decreasing frequency ) are described : SJS / TEN ( see figures 5 , 6 and 7 ), DRESS and AGEP ( see table 4 ). 46
A detailed clinical history , including the drug timeline , is crucial in diagnosing drug-associated reactions . In this context , drugs started in the previous 6-8 weeks are more likely to be causal . 45 The Naranjo Adverse Drug Reaction ( ADR ) Probability Scale score is a validated causality score that can help clinicians identify the culprit agents . It is used to assess whether there could be a causal relationship between a drug and clinical event . While this tool was not developed in the context of drug allergy , the simplified clinical questions and the possibility to determine if a reaction is definite , probable , possible or doubtful leads to interesting conclusions following drug allergic reactions . 47
Depending on the reported reaction and the phenotype , other scores are available to assist in clinical assessment .
In AGEP cases , the EuroSCAR group criteria validation score can be used to confirm the clinical diagnosis . 48 This score considers specific
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Table 3 . Examples of beta-lactams with side-chain similarity
Beta-lactam antibiotic
Amoxicillin , ampicillin
Cefalexin
Cefazolin
clinical criteria such as typical skin lesions ( for example , pustules , erythema , distribution ), presence of fever , clinical course , and certain typical laboratory and pathology findings . The scoring system allows the clinician to determine if AGEP is excluded , possible , probable or definite . AGEP presents with non-follicular sterile pustules on an erythematous skin surface , mostly on the folds area . 49 Fever and neutrophilia may be present and biopsy will identify spongiform subcorneal and / or intraepidermal pustules .
The European Registry of Severe Cutaneous Adverse Reactions ( RegiS- CAR ) focuses on DRESS . Clinical parameters ( for example , typical skin manifestations , fever , enlarged lymph nodes ), laboratory values ( such as eosinophilia , atypical lymphocytes ),
Beta-lactam antibiotic with a similar sidechain
Cefalexin , cefaclor
Amoxicillin , ampicillin , cefaclor
n / a
Cefuroxime Cefepime ,† ceftriaxone ,† cefotaxime ,† ceftazidime †
Cefepime
Ceftriaxone
Cefotaxime
Ceftazidime
Cefuroxime ,† ceftriaxone
Cefuroxime ,† cefepime , cefotaxime
Cefuroxime ,† cefepime , ceftriaxone
Cefuroxime ,† aztreonam
† Non-identical R1 sidechain with some clinical cross-reactivity
clinical evolution and biopsy findings are part of the specific criteria . The scoring system allows an estimate of the probability of this condition ( definite , probable , possible or no case ). 50 DRESS is a severe adverse drug reaction characterised by an extensive skin rash ( more than 50 %) and associated with visceral organ involvement , lymphadenopathy , eosinophilia and atypical lymphocytosis . 51
Among the SCARs , SJS / TEN is associated with higher morbidity and mortality , up to 50 %. 52 The typical cutaneous manifestations are skin necrosis , skin detachment ( positive Nikolsky sign ) and blistering of the mucous membranes . 49 Serious systemic manifestations are present , and the 7-point clinical score ( SCORTEN ) can be calculated to indicate a prognostic value . 53 The acute prognostic
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factors are age , presence of malignancy and clinical and laboratory elements such as heart rate , serum glucose , bicarbonate , and urea ; their presence allows an estimate of the patient ’ s mortality risk . 53 Considering the severity of this condition , the ALDEN ( algorithm of drug causality for epidermal necrolysis ) was developed , particularly for patients exposed to multiple medications . This tool is based on criteria such as type of drug , previous exposure , timing and possible alternative causes
54 , 55
.
Diagnostic tools in SCAR
The drug ingestion challenge remains
the gold standard for determining tolerance . 56 This involves administering one or multiple doses of the medication to a patient , with a monitoring period post-dose . In the context of SCAR , this carries possible risks , and the benefit must be weighed against the risk of possible disease re-activation . A South African study on antituberculosis drugs ( drug re-challenge was with empirically initiated IV corticosteroids ) reported mainly mild to
57 , 58 moderate reactions .
There is a lack of international validation for in vivo ( skin testing , such as patch testing [ PT ] and delayed intradermal testing [ IDT ]) and ex vivo ( assays , such as the lymphocyte transformation test [ LTT ] and enzymelinked ImmunoSpot [ ELISpot ]) tools to help the clinician determine if structurally non-related drugs can be recommended .
In vivo testing is usually performed
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