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Pharmacogenetics ofCutaneous Adverse Drug Reactions

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=0.0005 (CBZ-

=0.005 (PHT-SJS

P=0.001 (overall)

NS for drug exanthem

1×LTG and 1xPHT

(HLA-B*15:02 positive)

242.61), P

SJS group)

OR 18.5 (95% CI: 1.82–

188.40), P

group)

CBZ-drug exanthem and

PHT-drug exanthem NS

Controls

(n) Signicant associations Statistical analyses

=0.02

OR 19.22 (95% CI: 1.01–

365), P=0.012

OR 14.59 (95% CI: 0.74–

289), P=0.037

OR 8.5 (95% CI: 0.79–423),

HLA-B*58:01

P=0.045

HLA-DRB1*13:01

(continued)

AED-tolerant 48 HLA-B*15:02 OR 17.6 (95% CI: 2.9–105.2),

2 TEN

4 SJS

2 DRESS

Culprit

drugs Case phenotype Cases (n) Control phenotype

PHT

LTG

Study Location

Table 3 Studies that have reported genetic variants associated with hypersensitivity to aromatic antiepileptic drugs

Man etal. (2007) China CBZ

AED-tolerant 50 HLA-B*15:02 OR 25.5 (95% CI: 2.68–

6 CBZ-SJS

4 PHT-SJS

16 drug exanthem

5 CBZ-drug

PHT

LTG

Thailand CBZ

Locherernkul

etal. (2008)

exanthem

9 PHT-drug

exanthem

OXC

CLoB

3 CBZ/PHT-drug

exanthem

3 CBZ/LVT

1 LTG-drug

exanthem

1 OXC-drug

exanthem

LTG-tolerant 43 HLA-A*68:01

1 CLB-drug

exanthem

Europe LT G SJS/TEN 17 Healthy controls 1822 HLA-B*38 OR 6.8 (95% CI: 2.2–21),

Lonjou etal.

12 DRESS

UK LT G 10 SJS/TEN

Kazeem etal.

(2009)

(2008)

https://t.me/medicina_free

(OXC)

−4

V. L. M. Yip and M. Pirmohamed

OR 5.1 (95% CI: 1.8–15.1),

P=0.0041 (PHT)

NS (LTG-SJS)

OR 80.7 (95% CI: 3.8–

1714.4), P=8.4×10

HLA-B*13:01

HLA-Cw*08:01

HLA-DRB1*16:02

273 HLA-B*15:02

Controls

(n) Signicant associations Statistical analyses

67 LTG-tolerant, 93

healthy controls

35 113 PHT-tolerant,

OR 3.7 (95% CI: 1.4–10.0),

P=0.0154 (PHT)

OR 3.0 (95% CI: 1.1–7.8),

P=0.0281 (PHT)

OR 4.3 (95% CI: 1.4–12.8),

P=0.0128

NS against OXC-tolerant

controls

OR 8.8 (95% CI: 1.853–

81 HLA-B*15:02

9 OXC-tolerant

72 healthy controls

detected

41.790), P=0.011 (healthy)

292 HLA-B No signicant association

28 LTG-tolerant

264 healthy

detected

controls

OXC-tolerant 35 HLA-B No signicant association

86 Healthy controls 1296 NA No signicant association

detected

22.460), P=0.018 (healthy

controls)

1264 HLA-B*38:02 OR 6.239 (95% CI: 1.783–

28 OXC-tolerant

1236 population

controls

26 PHT-SJS/TEN

6 LTG-SJS

3 OXC-SJS

Culprit

drugs Case phenotype Cases (n) Control phenotype

LTG,

OXC

Taiwan PHT,

(continued)

Study Location

Hung etal.

Table 3

(2010)

42 LTG-drug

exanthem

3 LTG-DRESS

1 LTG-SJS

40 PHT-drug

exanthem

11 drug exanthem

PHT

UK (GWAS) LTG

McCormack

Hu etal. (2011) China OXC Drug exanthem 9

Shi etal. (2011) China LT G 2 SJS

He etal. (2012) China OXC Drug exanthem 14

etal. (2012)

4 PHT-DRESS

Lv etal. (2013) China OXC Drug exanthem 14

Pharmacogenetics ofCutaneous Adverse Drug Reactions

https://t.me/medicina_free

−17

(continued)

P=0.033

P=0.003

HLA-DRB1*14:05

Increased in CBZ-drug

exanthem vs. CBZ-tolerant

P=0.037

HLA-B*58:01

166 HLA-A*02:01

52 CBZ-tolerant

42 LTG-tolerant

72 healthy controls

P=0.024

HLA-DRB1*03:01

Reduced in CBZ-drug

exanthem vs. CBZ-tolerant

P=0.013

Increased in LTG-drug

HLA-A*30:01

HLA-B*13:02

exanthem vs. LTG-tolerant

HLA-A*33:03 P=0.048

exanthem vs. LTG-tolerant

P=1.1×10

Reduced in LTG-drug

3785 CYP2C9*3 OR 12 (95% CI: 6.6–20),

130 PHT-tolerant

3655 healthy

controls

183

=0.0048 (LTG-tolerant)

P<0.03 (PB)

Not signicant with PHT or

No association HLA-B*15:02

P<0.0001 (healthy)

B*35:01:01/C*04:01:01

40 CYP2C19*2 OR 4.5 (95% CI: 1.17–17.37),

CBZ-tolerant

controls

40 PB-, PHT- and

256 HLA-A*02:01:01/

31 AED-tolerant

225 healthy

=0.0179 (PHT-tolerant)

Increased in LTG-MPE vs.

tolerant and healthy controls

HLA-C*08:01 P

volunteers

<0.0001 (healthy)

Increased in PHT-MPE vs.

tolerant and healthy controls

40 CBZ-drug

exanthem

43 LTG-drug

exanthem

LTG

Li etal. (2013) China CBZ

44 DRESS

78 drug exanthem

PHT 61 SJS/TEN

Taiwan

Japan

Malaysia

(GWAS)

Chung etal.

(2014)

18PB-DRESS,

2PB-SJS/TEN

15 PHT-DRESS, 2

PHT

CBZ

Thailand PB

Manuyakorn

etal. (2013)

PHT-SJS/TEN

3 CBZ-SJS

4 CBZ-drug

Mexico CBZ

Fricke-Galindo

exanthem

1 PHT-drug

exanthem

PHT

LTG

etal. (2014)

10 LTG-drug

exanthem

4 LTG-SJS

1 CBZ/PHT-drug

exanthem

https://t.me/medicina_free

V. L. M. Yip and M. Pirmohamed

1.108), P=0.04

Controls

(n) Signicant associations Statistical analyses

AED-tolerant 50 HLA-A*24:02 OR 0.130 (95% CI: 0.015–

36.74), P=0.043 (tolerant

controls)

OR 4.86 (95% CI: 1.01–

23.47), P=0.049 (healthy

controls)

Above only for patients with

SJS

70 HLA-B*15:02 OR 6.25 (95% CI: 1.06–

32 AED-tolerant

38 healthy

volunteers

(paediatrics)

OR 14.52 (95% CI: 1.18–∞),

P=0.044 (tolerant controls)

OR 4.43 (95% CI 1.39–

13.97), P=0.016 (healthy

controls)

431 CYP2C9*3

16 PHT-tolerant

19 PB-tolerant

396 healthy

volunteers

(paediatric)

1 CBZ-TEN

3 CBZ-drug

exanthem

1 OXC--drug

exanthem

Culprit

drugs Case phenotype Cases (n) Control phenotype

OXC

PHT

LTG

China CBZ

(continued)

Study Location

Wang etal.

Table 3

(2014)

3 LTG-drug

exanthem

1 PHT-SJS

1 PHT-drug

exanthem

4 CBZ-SJS

Sun etal. (2014) China CBZ

2 CBZ-DRESS

5 CBZ-drug

OXC

exanthem

1 OXC-SJS

3 OXC-drug

exanthem

1 PB-SJS

1 PB-drug

exanthem

2 PHT-SJS/TEN

15 PHT-DRESS

2 PB-SJS/TEN

Thailand PHT

Suvichapanich

etal. (2015)

18 PB-DRESS

Pharmacogenetics ofCutaneous Adverse Drug Reactions

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96.31), P=0.0274 (SJS/TEN)

26.62), P=0.0077 (SJS/TEN)

17.54), P=0.0163 (SJS/TEN)

OR 5.18 (95% CI: 1.18–

22.74), P=0.0381 (DRESS)

11.51), P=0.0431 (SJS/TEN)

P=0.0431 (SJS/TEN)

P=0.0495 (SJS/TEN)

13.09), P=0.0133 (SJS/TEN)

23.36), P=0.0251 (SJS)

HLA-C*14:02 OR 6.49 (95% CI: 1.59–

HLA-B*51:01 OR 4.81 (95% CI: 1.32–

HLA-B*38:02 OR 3.70 (95% CI: 1.19–

HLA-B*58:01 OR 3.15 (95% CI: 1.11–8.91),

HLA-A*33:03 OR 2.70 (95% CI: 1.10–6.63),

CYP2C9*3 OR 4.30 (95% CI: 1.41–

(SJS)

−10

18.85), P=0.0003 (DRESS)

767.19), P=0.0046 (DRESS)

18.36), P=0.0478, (DRESS)

99.23), P=1.87×10

HLA-B*13:01 OR 6.76 (95% CI: 2.42–

HLA-B*56:02/04 OR 38.03 (95% CI: 1.88–

CYP2C19*3 OR 4.47 (95% CI: 1.09–

(continued)

60 PHT-tolerant 92 HLA-B*56:02 OR 10.40 (95% CI: 1.12–

21 DRESS

Thailand PHT 39 SJS/TEN

Tassaneeyakul

etal. (2016)

PHT-tolerant 100 CYP2C9*3 OR 5.70 (95% CI: 1.39–

21 DRESS

Thailand PHT 15 SJS

Yampayon etal.

(2017)

OXC-tolerant 101 HLA-B*15:02 OR 27.90 (95% CI: 7.84–

6 DRESS

22 drug exanthem

2 bullous

OXC 20 SJS/TEN

Taiwan/

Thailand

Chen etal.

(2017)

https://t.me/medicina_free

(CBZ

(pooled

−5

=0.009 (PHT-SJS/

=0.005 (CBZ-SJS/

V. L. M. Yip and M. Pirmohamed

=0.005 (LTG-

=0.033, (CBZ-

24.86), P=5.63 × 10

only)

HLA-A*24:02 OR 3.15 (95% CI: 1.86–5.32),

Controls

(n) Signicant associations Statistical analyses

81 AED-tolerant 322 HLA-B*15:02 OR 12.37 (95% CI 6.16–

analysis—CBZ, LTG and

PHT)

P=1.02×10

314 HLA-A*02:01/Cw15:02 OR 14.75 (95% CI: 1.54–

26 61 AED-tolerant

167.00), P

TEN vs. tolerant controls)

98.04), P=0.002 (PHT/

LTG-SJS/TEN vs. tolerant

controls)

OR 115.0.0 (95% CI:

HLA-B*38:01 OR 13.81 (95% CI: 2.18–

253 healthy

volunteers

4.68–81.09), <0.001

(LTG-SJS/TEN vs. tolerant

controls)

24.72), P

TEN vs. tolerant controls)

HLA-A*11:01 OR 36.33 (95% CI: 1.54–

HLA-A*24:02 OR 23.50 (95% CI: 2.49–

553.98), P=0.001 (PHT/

LTG-DRESS vs. tolerant

controls)

OR 27.77 (95% CI: 1.5–

17.33), P

DRESS vs. tolerant controls)

747.87), P

induced DRESS vs. tolerant

controls)

HLA-A*31:01 OR 29.50 (95% CI: 1.73–

56 CBZ-SJS/TEN

22 LTG-SJS/TEN

13 PHT-SJS/TEN

Culprit

drugs Case phenotype Cases (n) Control phenotype

LTG

PHT

(continued)

Study Location

Table 3

Shi etal. (2017) China CBZ

2 CBZ-SJS/TEN

4 CBZ-DRESS

3 LTG-SJS/TEN

3 LTG-DRESS

9 PHT-SJS/TEN

LTG

PHT

Spain CBZ

Ramírez etal.

(2017)

5 PHT-DRESS

Pharmacogenetics ofCutaneous Adverse Drug Reactions

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(PHT-MPE)

) (CBZ-SCAR)

−11

−9

56.60), P=0.003 (SJS/TEN

vs. tolerant controls)

OR 59.00 (95% CI: 2.49–

1395.74), P=0.003 (DRESS

vs. tolerant controls)

23.10), P=0.016 (SJS/TEN

vs. tolerant controls)

P=4.5×10

P=1.2×10

25.00), P=0.022 (DRESS)

29.35), P=0.039 (DRESS)

106.89), P=0.044 (SJS/TEN)

HLA-B*15:02 OR 5.71 (95% CI: 1.41–

332 HLA-B*15:13 OR 11.28 (95% CI: 2.25–

300 healthy

volunteers

16 32 PHT-tolerant

3 DRESS

HLA-A*31:01 OR 8.0 (95% CI: 4.10–15.80),

1321 CHFR4 (rs78239784) OR 7 (95% CI: 3.2–16),

844 LTG-tolerant

530 PHT-tolerant

323 1066 CBZ-tolerant

180 CBZ-drug

exanthem

134 LTG-drug

exanthem

CBZ

LTG

PHT

709 HLA-B*51:01 OR 5.83 (95% CI: 1.36–

649 healthy

22 60 PHT-tolerant

74 PHT-drug

exanthem

5 SJS/TEN

PHT 17 DRESS

HLA-C*14:02 OR 5.85 (95% CI: 1.16–

HLA-B*38:02 OR 12.67 (95% CI: 1.50–

volunteers

Malaysia PHT 13 SJS/TEN

Chang etal.

(2017)

Europe/

China

(GWAS)

Devi (2018) India PHT SJS/TEN 8 PHT-tolerant 11 HLA-B*15:02 Not signicant

McCormack

etal. (2018)

Thailand

(paediatric)

Manuyakorn

etal. (2020)

AED antiepileptic drug, CBZ carbamazepine, DRESS drug reaction with eosinophils and systemic symptoms, GWAS genome-wide association study, LTG lamotrigine, OXC

oxcarbazepine, OR odds ratio, PB phenobarbitone, PHT phenytoin, SCAR severe cutaneous adverse reaction, SJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis

https://t.me/medicina_free

V. L. M. Yip and M. Pirmohamed

In European patients, two studies have reported signicant association between HLA- B*38:01 and lamotrigine-induced SJS/TEN (Lonjou et al. 2008; Ramírez et al. 2017). However, the numbers of patients in both studies were relatively small with 17 (Lonjou etal. 2008) and 3 cases (Ramírez etal. 2017) of lamotrigineinduced SJS/TEN, respectively. A GWAS in Europeans was unable to detect any signicant associations in patients presenting mainly with lamotrigine-induced drug exanthem (McCormack etal. 2012). A study from the UK with 22 patients presenting with either lamotrigine-induced SJS/ TEN (n=10) or DRESS (n=12) did not detect any signicant HLA associations (Kazeem etal.

2009). Several studies in patients from Taiwan

(Hung et al. 2010) and China (Shi et al. 2011,

2017) were also unable to detect an association

between lamotrigine hypersensitivity and HLA- B*15:02. Given the small numbers studied, and the contradictory data, there is no good evidence to suggest that genetic screening should be carried out before the use of lamotrigine. The only factor that has been shown to reduce the incidence of lamotrigine cADRs is to start at a low dose and escalate slowly, especially in patients on concomitant sodium valproate.

The association between HLA-B*15:02 and susceptibility to phenytoin-induced SJS/TEN is unclear. One study in Thai patients and a second study from Taiwan detected a signicant association between HLA-B*15:02 and phenytoin-SJS/ TEN (Locharernkul et al. 2008; Hung et al.

2010). Subsequent studies in Thai (Tassaneeyakul

etal. 2016), Chinese (Shi etal. 2017) and Indian (Devi 2018) patients were unable to replicate the association. Phenytoin is primarily metabolised by CYP2C9, and loss-of-function mutations (e.g. CYP2C9*2/*3) reduce metabolism by 25–50% and have been associated with increased adverse events, since phenytoin has a narrow therapeutic range and a nonlinear pharmacokinetic prole (Silvado etal. 2018). A GWAS in 183 Taiwanese, Japanese and Malaysian patients with phenytoininduced SJS/TEN, DRESS and drug exanthem reported a signicant association with carriage of CYP2C9*3 (Chung etal. 2014). Interestingly, the

authors were able to detect delayed clearance of plasma phenytoin in patients with severe cADR providing a mechanistic link to the manifestation of hypersensitivity. The association between CYP2C9*3 and phenytoin hypersensitivity was replicated in a cohort of paediatric patients with phenytoin-SJS/TEN and two further cohorts of Thai patients with phenytoin-induced DRESS and SJS/TEN (Tassaneeyakul et al. 2016; Suvichapanich et al. 2015; Yampayon et al.

2017). The association was not detected in a

GWAS of 44 European patients presenting primarily with phenytoin-induced drug exanthem (n=40) (McCormack etal. 2012). A more recent GWAS in both European and Han Chinese patients reported that an intronic variant in the complement factor H-related 4 gene (CFHR4), rs78239784, was associated with phenytoininduced drug exanthem (McCormack et al.

2018). These results suggest that aberrant com-

plement activation may play a role as a potential causal mechanism in a subset of phenytoinsensitive patients. The genetic predisposition to phenytoin hypersensitivity thus presents a much more complex picture than carbamazepine, with a possibility of an association with HLA-B*15:02, CYP2C9*3 and CFH. Given the low use of phenytoin now, any further studies will have to combine forces worldwide to have adequate statistical power to detect genetic variants of low effect size.

The CPIC recommends consideration of genotyping for HLA-B*15:02 in patients considering phenytoin therapy regardless of ethnicity. If patients are positive for HLA-B*15:02, alternative AEDs should be considered. Where available, genotyping for CYP2C9 should also be considered for patients who are HLA-B*15:02 negative. The CPIC also make recommendations for dose adjustments depending on CYP2C9 genotype (Caudle etal. 2014). Screening for HLA- B*15:02 prior to phenytoin therapy was found to be cost-effective in a population from Singapore as part of screening for both phenytoin and carbamazepine (Dong etal. 2012). However, it was not cost-effective based on patient data from Hong Kong (Chen etal. 2016).

Pharmacogenetics ofCutaneous Adverse Drug Reactions

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5 Allopurinol Hypersensitivity

andHLA-B*58:01

The association between HLA-B*58:01 and allopurinol hypersensitivity was rst reported in a Taiwanese population (Hung et al. 2005).

Allopurinol is a xanthine oxidase inhibitor used in the treatment of gout (Ramasamy etal. 2013). Allopurinol hypersensitivity can manifest as severe cADRs including SJS/TEN and DRESS with an incidence of 0.69 per 1000 person years (Kim etal. 2013). The HLA-B*58:01 allele has been signicantly associated with susceptibility to multiple phenotypes of allopurinol hypersensitivity in populations globally (Table4).

Table 4 Studies that have reported genetic variants associated with allopurinol hypersensitivity

Study Location Hung etal.

Taiwan 3 TEN

(2005)

Lonjou etal.

Europe SJS/TEN 31 Healthy (2008) Kaniwa etal.

Japan SJS/TEN 10 Healthy (2008)

Tassaneeyakul

Thailand SJS/TEN 27 Allopurinol etal. (2009)

Kang etal.

Korea 20 DRESS (2011)

Cao etal.

China 13 SJS/TEN (2012)

Tohkin etal. (2013)

Niihara etal.

Japan

(GWAS)

Japan 3 SJS (2013)

Case phenotype

5 SJS/TEN 13 SJS 30 DRESS

5 SJS/TEN

3 DRESS 22 drug exanthem

SJS/TEN 14 Healthy

4 erythema multiforme

Cases

Control

(n)

phenotype

51 135

allopurinol tolerant 93 healthy subjects

controls

tolerant

25 Allopurinol

tolerant

38 63

allopurinol tolerant 572 healthy controls

controls

7 Allopurinol

tolerant

Patients with severe cutaneous adverse reactions (SJS/TEN and DRESS) were included in this cohort. Subsequent studies in Korean (Kang etal.

2011), Japanese (Niihara etal. 2013), Portuguese

(Gonçalo et al. 2013) and Chinese patients (Cheng et al. 2015) replicated the association between carriage of HLA-B*58:01 and susceptibility to severe cutaneous manifestations of allopurinol hypersensitivity. Several authors have

Controls (n)

228 HLA-B*58:01 OR 580.3 (95% CI:

1822 HLA-B*58:01 OR 61 (95% CI:

493 HLA-B*58:01 OR 40.8 (95% CI:

54 HLA-B*58:01 OR 348.3 (95% CI:

57 HLA-B*58:01 OR 97.8,

635 HLA-B*58:01 OR 580.07 (95% CI:

991 HLA-B*58:01 OR 66.8 (95% CI:

25 HLA-B*58:01 OR 65.6 (95% CI:

Signicant associations Statistical analyses

HLA-Cw*03:02 OR 82.1,

HLA-A*33:03 OR 20.5,

34.4–9780.9),

=4.7×10

−24

(tolerant) OR 393.51 (95% CI:

23.23–6665.26),

=8.1×10

−18

(healthy)

32–118), P<10

−8

10.5–158.9), P<0.0001

19.2–633.6),

P=1.6×10

=2.45×10

=9.39×10

=3.31×10

32.18–10,456.8), P=7.01 × 10

−13

−18

−11

−6

(tolerant) OR 471.09 (95% CI:

28.66–7744.39), P=3.15 × 10

−38

(healthy)

19.8–225.0), P=2.44×10

2.9–1497.0), P=9.733×10

−8

−4

(continued)

https://t.me/medicina_free

(continued)

Table 4

Study Location Gonçalo etal.

(2013)

Cheng etal. (2015)

Sukasem etal. (2016)

DRESS drug reaction with eosinophilia and systemic symptoms, GWA SJS Stevens–Johnson syndrome, TEN toxic epidermal necrolysis

Portugal 6 SJS

China 11 TEN

Thailand 13 SJS/TEN

Case phenotype

9 DRESS 6 drug exanthem

7 SJS/TEN 33 SJS 41 DRESS

10 DRESS 7 drug exanthem

Cases

Control

(n)

phenotype

31 Allopurinol

tolerant

92 75

allopurinol tolerant 99 healthy controls

30 100

allopurinol tolerant 1095 healthy controls

Controls (n)

23 HLA-B*58:01 OR 99.59 (95% CI

174 HLA-B*58:01 OR 127.6 (95% CI:

1195 HLA-B*58:01 OR 696.00 (95% CI:

V. L. M. Yip and M. Pirmohamed

Signicant associations Statistical analyses

17.91–553.72) (SJS) OR 85.36 (95% CI:

32.52–224.04) (HSS) Not signicant for drug exanthem

40.85–398.61), P=3.49×10 (tolerant) OR 154.86 (95% CI:

50.86–471.53). P=5.06×10 (healthy)

74.81–6475.01), P<0.001 (all phenotypes vs. tolerant) OR 579.00 (95% CI:

29.50–11362.67), P<0.001 (SJS/TEN vs. tolerant) OR 430.33 (95% CI:

22.64–8958.88), P<0.001 (HSS vs. tolerant) OR 144.00 (95% CI:

13.85–1497.03), P<0.001 (drug exanthem vs. tolerant)

genome-wide association study, OR odds ratio,

−30

−36

reported associations between allopurinolinduced SJS/TEN and presence of HLA-B*58:01 in European (Lonjou et al. 2008), Japanese (Kaniwa et al. 2008) and Thai patients (Tassaneeyakul et al. 2009). A GWAS in 14 Japanese patients with allopurinol-induced SJS/ TEN reported a signicant association with HLA- B*58:01 when compared with healthy volunteers (Tohkin etal. 2013).

A study in 38 Chinese patients with allopurinol hypersensitivity included 22 subjects presenting with allopurinol-induced drug exanthem and detected a signicant association between HLA- B*58:01 and all phenotypes of allopurinol hypersensitivity (Cao etal. 2012). The association with drug exanthem was replicated in a Thai cohort of 30 patients with 7 subjects in the study

presenting with allopurinol-induced drug exanthem (Sukasem etal. 2016). However, a separate study in Portuguese patients with 6 allopurinolinduced drug exanthem patients was unable to detect a signicant association with HLA- B*58:01 (Gonçalo et al. 2013). Taken together the association between allopurinol-induced drug exanthem and HLA-B*58:01 requires further investigation.

A large prospective study in 2926 Taiwanese patients screened patients for carriage of HLA- B*58:01 prior to treatment with allopurinol (Ko et al. 2015). Subjects who tested positive for HLA-B*58:01 were prescribed alternative treatment: no subjects in the study developed a serious cADR to allopurinol. A signicant difference was detected as 7 cases of serious cADRs would

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