Journal of Immunology Research

Review Article

In Vitro Assays for Diagnosis of Drug-Induced Nonsevere Exanthemas: A Systematic Review and Meta-Analysis

Table 2

In vitro tests for the diagnosis of delayed drug allergies (other than SCARs).


Study	Test	Drugs tested	Hypersensitivity reactions	Subgroup	TP	TN	FP	FN	Sensitivity	Specificity	PPV	NPV	Test threshold for positive value

LTT
Ban et al. [20]	LTT	First-line antituberculosis medication	MPE	Isoniazid	0			6	0.0%
				Ethambutol	0			6	0.0%
				Rifampin	3			3	50.0%
				Pyrazinamide	0			6	0.0%
				All drugs	3			21	12.5%

Caubet et al. [17]	LTT	Beta-lactams (amoxicillin, cefuroxime)	Benign skin rashes	—	0	14	2	9	0.0%	87.5%	0.0%	60.9%

Chopra et al. [18]	LTT	Amoxicillin	Urticaria, angioedema, maculopapular rash, and erythema multiforme	—	2			9	18.2%

Fu et al. [21]	LTT	Multiple drugs¹	MPE	—	6			0	100.0%				n/a

Hari et al. [34]	LTT	Multiple drugs²	Bullous exanthema, MPE, and urticaria	—	14	15	1	7	66.7%	93.8%	93.3%	68.2%

Kalish et al. [35]	LTT	Multiple drugs³	Various types of rash	Sulfamethoxazole	4			12	25.0%
				Sulfisoxazole	3			8	27.3%
				Furosemide	6			7	46.2%
				Hydrochlorothiazide	1			3	25.0%
				All drugs	14			30	31.8%

Karami et al. [22]	LTT	anticonvulsant⁴	MPE	—	2	23	1	2	50.0%	95.8%	66.7%	92.0%

Lopez et al. [36]	LTT	Heparins	MPE, local reaction	All drugs	6	9	0	1	85.7%	100.0%	100.0%	90.0%

Luque et al. [37]	LTT	Beta-lactams (amoxicillin, penicillin G)	Exanthema, urticaria	All drugs	11	26	2	8	57.9%	92,9%	84,6%	76,5%
				Benzyl-penicilloyl poly-L-lysine	6	27	1	13	31.6%	96.4%	85.7%	67.5%
				Amoxicillin	10	27	1	9	52.6%	96.4%	90.9%	75.0%

Nyfeler et al. [25]	LTT	Multiple drugs⁵	n/a	All drugs	78	87	15	22	78.0%	85.3%	83.9%	79.8%
				Penicillin	58	2	1	19	75.3%	66.7%	98.3%	9.5%
				NSAIDs		68	9			88.3%
				Beta-lactams					74.4%

Ónodi-Nagy et al. [38]	LTT	Antibiotics/penicillins⁶	Maculopapular rash	All	1			9	10.0%
				Cefixime	1			0	100.0%
				Amoxicillin/clavulanic acid	0			9	0.0%

Orasch et al. [23]	LTT	Local anaesthetics	Angioedema, urticaria	—	6	6	0	4	60.0%	100.0%	100.0%	60.0%

Polak et al. [24]	LTT	Multiple drugs⁷	Drug-induced exanthems, eczema, and fixed drug eruption	DIE					33.3%
				Eczema					50.0%
				FDE					100.0%
				All reactions					36.6%	95.1%

Porebski et al. [42]	LTT	Antiepileptic drugs⁸	MPE	All drugs	7	24	0	16	30.4%	100.0%	100.0%	60.0%
				Carbamazepine	4			8	33.3%
				Oxcarbazepine	0			2	0.0%
				Lamotrigine	3			5	37.5%
				Phenytoin	0			1	0.0%

Porebski et al. [41]	LTT	Antiepileptic drugs⁹	MPE	—	6			10	37.5%

Rodriguez-Pena et al. [43]	LTT	Amoxicillin	MPE	LTT	2	8	0	7	22.2%	100.0%	100.0%	53.3%
Rodriguez-Pena et al. [43]	LTT	Amoxicillin	MPE	LTT+DC	8	8	0	1	88.9%	100.0%	100.0%	88.9%

Rozieres et al. [26]	LTT	Beta-lactams¹⁰	MPE	—	15	11	0	7	68.2%	100.0%	100.0%	61.1%

Sachs et al. [29]	LTT	Multiple drugs¹¹	Macular-erythrodermic exanthem, MPE	All drugs	9			3	75.0%	100.0%
				Aminopenicillins	5			1	83.3%
				Various drugs	4			2	66.7%

Sachs et al. [27]	LTT	Aminopenicillins	Cytopenia, maculopapular exanthem, and skin eruption	—	10			1	90.9%

Schmid et al. [45]	LTT	Quinolones¹²	Exanthema, MPE	—	6			0	100.0%				n/a

Schnyder and Pichler [46]	LTT	Amoxicillin, penicillin G	Exanthema	—	10	6	0	2	83.3%	100.0%	100.0%	75.0%

Srinoulprasert and Pichler [48]	LTT	Multiple drugs¹³	Anaphylaxis, late urticaria, and MPE	—	3			2	60.0%

Trautmann et al. [47]	LTT	Beta-lactams (ampicillin)	Macular or maculopapular exanthem	LTT	6	24	2	5	54.5%	92.3%	75.0%	82.8%
Trautmann et al. [47]	LTT	Beta-lactams (ampicillin)	Macular or maculopapular exanthem	Modified LTT	8	20	6	3	72.7%	76.9%	57.1%	87.0%

Warrington and Tse [28]	LTT	Penicillin	Maculopapular rashes	—	3			9	25.0%				n/a

Haw et al. [40]	Lymphocyte proliferation assay	Groups of drugs	MPE	Acute phase	5			1	83.3%

Whitaker et al. [39]	LTT	Piperacillin, tazocin	Mainly: MPE, fevers, urticarial eruptions, and flu-like symptoms	Postrecovery phase	1			2	33.3%
				MPE	10			5	66.7%
				Piperacillin	4			5	44.4%
				Tazocin	14			5	73.7%

ELISpot
Ben-Said et al. [31]	ELISpot (IFN-γ)	Beta-lactams	Exanthema	All drugs	6			6	50.0%				n/a
				Amoxicillin	6			4	60.0%
				Cefazolin	0			1	0.0%
				Imipenem	0			1	0.0%

Haw et al. [40]	ELISpot (IFN-γ, IL-4)	Groups of drugs	MPE	IFN-γ, acute phase	5			1	83.3%				Responses greater than the mean of all the background samples plus 2 SD of the background
				IL-4, acute phase	4			0	100.0%
				IFN-γ, postrecovery phase	3			0	100.0%
				IL-4, postrecovery phase	3			0	100.0%

Polak et al. [24]	ELISpot (IFN-γ, IL-4)	Multiple drugs⁷	Drug-induced exanthems, eczema, and fixed drug eruption	DIE, IFN-γ					51.9%				Responses greater than the mean of all the background samples plus 2 SD of the background
				Eczema, IFN-γ					100.0%
				FDE, IFN-γ					100.0%
				All IFN-γ					56.5%	82.9%
				DIE, IL-4					59.1%
				Eczema, IL-4					0.0%
				FDE, IL-4					100.0%
				All IL-4					56.6%	92.0%

Porebski and Czarnobilska [42]	ELISpot (GrB)	Antiepileptic drugs⁸	MPE	All drugs	12	23	1	11	52.2%	95.8%	92.3%	67.6%	values greater than the mean value plus 2 SD measured in control subjects
				Carbamazepine	8			3	72.7%
				Oxcarbazepine	1			1	50.0%
				Lamotrigine	3			5	37.5%
				Phenytoin	0			1	0.0%

Porebski et al. [41]	ELISpot (IFN-γ)	Antiepileptic drugs⁹	MPE	—	6	16	0	10	37.5%	100.0%	100.0%	61.5%	A mean result plus 2 SD

Rozieres et al. [26]	ELISpot (IFN-γ)	penicillin¹⁰	MPE	IFN-γ ELISpot	20	11	0	2	90.9%	95.0%	100.0%	84.6%	Result above 30 IFN-c SFC/106 PBMC (mean plus 2 SD)

Tanvarasethee et al. [49]	ELISpot (IFN-γ, IL-5)	Ceftazidime, ceftriaxone	MPE	Both IFN-γ and IL-5	10			15	40.0%				The values greater than the means plus 2 SD of IFN-γ and IL-5 SFC/106 PBMCs
				IFN-γ	6			19	24.0%
				IL-5	6			19	24.0%

ELISA
Porebski and Czarnobilska [42]	ELISA	Antiepileptic drugs⁸	MPE	All drugs	4	24	0	19	17.4%	100.0%	100.0%	55.8%	values greater than the mean value plus 2 SD measured in control subjects
				Carbamazepine	3			9	25.0%
				Oxcarbazepine	0			2	0.0%
				Lamotrigine	1			7	12.5%
				Phenytoin	0			1	0.0%

Porebski et al. [41]	ELISA (IFN-γ)	Antiepileptic drugs⁹	MPE	—	9	16	0	7	56.3%	100.0%	100.0%	69.6%	A mean

Halevy and Grossman [32]	IFN-γ release	Multiple drugs	CADR	High drug suspicion	23			3	88.5%
				Possible suspicion	2			0	100.0%
				Low suspicion	7			7	50.0%
				All drugs	32			10	76.2%

Sachs et al. [29]	ELISA (IL-5, IL-10, IFN-γ)	Multiple drugs¹¹	Macular-erythrodermic exanthem, MPE	18 challenge test (gold standard)					80.0%	62.0%	44.0%	89.0%	n/a
Sachs et al. [29]	ELISA (IL-5, IL-10, IFN-γ)	Multiple drugs¹¹	Macular-erythrodermic exanthem, MPE	All drugs	32			10	76.2%				n/a

BAT
Abuaf et al. [30]	BAT	Amoxicillin	Erythema, exfoliative dermatitis, and maculopapular rash	CD203c⁺	0	14	0	6	0.0%	100.0%	n/a	70.0%	2 SD (6%) exceeding the value of the nonstimulated control tube
				CD63⁺	2	11	3	4	33.3%	78.6%	40.0%	73.3%
				CD203c⁺ or CD63⁺	2	11	3	4	33.3%	78.6%	40.0%	73.3%

Caubet et al. [17]	BAT	Beta-lactams	Benign skin rashes	—	0	16	0	14	0.0%	100.0%	—	53.3%	SI (% of BL stimulation divided by % of negative control) >2 and the cut-off values for BL >7%

Other
Harenberg et al. [33]	Heparin-induced IgG assay	Low-molecular-weight heparin	Red plaques, skin necrosis	—	2			7	22.2%				n/a

Romano [44]	RAST	Aminopenicillins	Maculopapular eruption	—	0			24	0.0%				n/a

Tsuge et al. [19]	CD4+ cell proliferation, IFN-γ secretion	Phenytoin	MPE	CD4+ cell proliferation	7	10	1	0	100.0%	90.9%	87.5%	100.0%	n/a
Tsuge et al. [19]	CD4+ cell proliferation, IFN-γ secretion	Phenytoin	MPE	IFN-γ secretion	5	11	0	2	71.4%	100.0%	100.0%	84.6%	n/a

¹Multiple drugs: acetaminophen, amoxicillin, carbamazepine, cephazolin, and penicillin; ²multiple drugs: acetazolamide, allopurinol, amoxicillin, carbamazepine, cefazolin, ceftriaxone, dorzolamide, indapamide, losartan, metolazone, penicillin G, prednisolone, simvastatin, sulfamethoxazole, ticlopidine, torasemide, trimethoprim, verapamil, and vit. B-complex; ³multiple drugs: furosemide, hydrochlorothiazide, sulfamethoxazole, and sulfisoxazole; ⁴anticonvulsant: phenobarbital and lamotrigine; ⁵multiple drugs: carbamazepine, ciprofloxacin, cotrimoxazole, diphenylhydantoin, erythromycin, lysozyme, methylephedrine-HCl, minocycline, penicillin, sulfadoxine-pyrimethamine, sulfamethoxazole, theophylline, and trimethoprim; ⁶antibiotics/penicillins: amoxicillin, clavulanic acid, and cefixime; ⁷multiple drugs: amoxicillin, aztreonam, bisoprolol fumarate, candesartan, carbamazepine, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, clarithromycin, clindamycin, co-amoxiclav, codeine, doxycycline, erythromycin, flucloxacillin, fluconazole, gentamicin, hydroxychloroquine, itraconazole, levetiracetam, mercury, meropenem, omeprazole, oseltamivir, paracetamol, penicillin G, penicillin V, phenobarbital, phenytoin, Premarin, ramipril, senna, sodium valproate, tazocin, teicoplanin, tolterodine tartrate, trimethoprim, and vancomycin; ⁸antiepileptic drugs: carbamazepine, oxcarbazepine, lamotrigine, and phenytoin; ⁹antiepileptic drugs: carbamazepine, lamotrigine, and oxcarbazepine; ¹⁰beta-lactams: amoxicillin and ticarcillin; ¹¹multiple drugs: amoxicillin, ampicillin, carbamazepine, clorazepate, fenoterol, phenobarbital, and phenytoin; ¹²quinolones: ciprofloxacin, moxifloxacin, and norfloxacin; ¹³multiple drugs: amoxicillin, sulfamethoxazole, clavulanic acid, trimethoprim, and iomeron; groups of drugs: antibiotics, anticonvulsants, and antifungals. BAT: basophil activation test; CADR: cutaneous adverse drug reactions. CAP: commercially available kit to penicilloyl G and penicilloyl V; DIE: drug-induced exanthems; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; ELISpot: enzyme-linked immunospot assay; FACS: flow cytometric analysis; FDE: fixed drug eruption; FN: false negative; FP: false positive; LTT: lymphocyte transformation test; MPE: maculopapular exanthema; PBMC: peripheral blood mononuclear cells; RAST: radioallergosorbent test; SD: standard deviation; SI: stimulation index; TN: true negative; TP: true positive.