Abstract
This cohort study examines patients with drug reaction with eosinophilia and systemic symptoms who also have pustules.
Manifestations of drug reaction with eosinophilia and systemic symptoms (DRESS) include diffuse rash, fever, lymphadenopathy, eosinophilia, and internal organ involvement.1,2,3,4,5 DRESS morphology is variable.1,2,4 A subset of patients with DRESS develop a pustular eruption that resembles acute generalized exanthematous pustulosis (AGEP) without meeting full AGEP criteria.1,2,3,4,6 The features and outcomes of patients with DRESS with pustules are not well described.
Methods
We retrospectively identified 67 patients with DRESS who met DRESS criteria (Registry of Severe Cutaneous Adverse Reactions [RegiSCAR]1 score ≥3) with concurrent pustules on examination and/or histology results who did not meet full AGEP criteria. The 13 patients (19.40%) with DRESS with pustulosis were compared with 54 patients (80.59%) with DRESS without pustulosis. Institutional review board approval was provided by Kristopher Fisher, MD, Ohio State University (2023H0077). Consent to obtain data was waived due to data security processes to protect patient confidentiality and a minimal associated risk.
Fisher exact and Wilcoxon rank sum tests (2-sided) were used for analysis (significance, P < .05), and the Benjamini-Hochberg procedure for multiple hypothesis testing was applied. Participants with missing data points were excluded from corresponding analyses.
Results
Of 13 patients with DRESS with pustulosis, 12 had clinical pustules while 1 had only histopathologic pustules. Hospitalizations lasted 10 days on average. Twelve patients (92.31%) had ongoing cutaneous symptoms at discharge, 5 (38.46%) were rehospitalized within 1 year, and 4 (30.77%) had DRESS recurrences. Recurrences were characterized by rash recrudescence or exacerbation (4 patients), eosinophilia (3 patients), and laboratory results that indicated potential liver and kidney dysfunction (1 and 2 patients, respectively).
RegiSCAR1 and European Study of Severe Cutaneous Adverse Reactions (EuroSCAR)3 scores for DRESS and AGEP were used to evaluate DRESS with pustulosis. RegiSCAR1 scores (mean, 4.46; range, 3-7) included possible (score, 3 [n = 2]), probable (score, 4-5 [n = 10]), and definite (score, ≥6 [n = 1]) DRESS. EuroSCAR3 scores (mean, 1.69; range, −10 to 7) included no (score, ≤0 [n = 3]), possible (score, 1-4 [n = 8]), and probable (score, 5-7 [n = 2]) AGEP. No patients met definite AGEP (score, 8-12). Although 2 patients (Table 1) received a EuroSCAR3 score of probable, their features favored DRESS, reflected in patient 5′s RegiSCAR1 score (definite) and patient 12’s extended latency period (approximately 25 days).
Table 1. Clinical Features of DRESS With Pustulosis.
| Patient No. | Suspected causal drug | Distribution and characteristics of pustules | Mucosal involvement | Intertriginous involvement | Acute kidney injury | Liver involvement | Eosinophilia | Neutrophilia | Leukocytosis | Lymphadenopathy | Fever | EuroSCAR score3 | RegiSCAR score1 | DRESS recurrence and/or flare |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Vancomycin | Diffuse | N | N | Y | N | Y | Y | Y | Y | Y | 2 | 4 | N |
| 2 | Cyproheptadine | Oral (tongue) | Y | N | N | Y | Y | Y | N | N | Y | 3 | 4 | N |
| 3 | Vancomycin | Extremities superficial | N | N | Y | N | N | Y | Y | N | Y | 4 | 5 | N |
| 4 | Lamotrigine | Diffuse; ear canals; nonfollicular | Y | Y | N | Y | Y | Y | Y | Y | Y | −3 | 4 | N |
| 5 | Vancomycin vs pip-tazo | Back, flank; subcorneal | N | N | Y | N | Y | Y | Y | N | Y | 7 | 7 | N |
| 6 | Vancomycin | Lateral arms | N | N | Y | Y | Y | Y | Y | N | Y | −10 | 5 | Y |
| 7 | Pantoprazole | Diffuse; facial patch | Y | Y | Y | Y | Y | Y | Y | N | N | 1 | 5 | Y |
| 8 | TMP-SMX vs allopurinol | Thighs | N | Y | Y | N | Y | N | Y | N | N | 4 | 4 | Y |
| 9 | Phenytoin | Diffuse; superficial | Y | Y | Y | Y | Y | Y | Y | N | N | 0 | 4 | N |
| 10 | Vancomycin | Back, trunk; thighs; subcorneal | Y | Y | Y | N | Y | Y | Y | N | Y | 4 | 5 | N |
| 11 | Doxycycline | Diffuse | N | Y | N | Y | Y | Y | Y | N | Y | 1 | 5 | N |
| 12 | Vancomycin vs pip-tazo | Generalized; nonfollicular | N | Y | N | N | Y | Y | Y | N | N | 5 | 3 | Y |
| 13 | Gabapentin | Unknown; intracorneal; subcorneal | N | Y | Y | N | Y | Y | Y | N | Y | 4 | 3 | N |
Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; EuroSCAR, European Study of Severe Cutaneous Adverse Reactions; N, no; pip-tazo, piperacillin-tazobactam; RegiSCAR, Registry of Severe Cutaneous Adverse Reactions; TMP-SMX, trimethoprim-sulfamethoxazole; Y, yes.
Patients with DRESS with pustulosis had less frequent liver involvement (46% vs 85%; P = .01), increased intertriginous involvement (62% vs 26%; P = .02), and more frequent recurrences (31% vs 2%; P = .004) and trended toward older age (57 vs 50.5 years; P = .30) and a higher body mass index (calculated as weight in kilograms divided by height in meters squared) (33 vs 27; P = .07) (Table 2). However, P values were not significant with Benjamini-Hochberg correction. No significant differences in vancomycin culpability rates (31% vs 33%; P = .35) or latency periods (24 vs 22 days; P = .82) were observed between groups.
Table 2. Comparison of DRESS With and Without Pustulosis.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| DRESS with pustulosis (n = 13) | DRESS without pustulosis (n = 54) | P value | Adjusted P valuea | |
| Age, median (IQR), y | 57 (16) | 50.5 (25.25) | .30 | .77 |
| Treatment | ||||
| Oral steroids | 13 (100) | 51 (94) | >.99 | >.99 |
| Intravenous steroids | 4 (31) | 19 (35) | >.99 | >.99 |
| Topical steroids | 13 (100) | 42 (78) | .10 | .38 |
| Antihistamines | 9 (69) | 43 (80) | .47 | .81 |
| BMI | 33 (16) | 27 (8.75) | .07 | .38 |
| RegiSCAR score, median (IQR) | 4 (1) | 5 (1.75) | .10 | .43 |
| Mucosal involvement | 5 (38) | 16 (30) | .53 | .86 |
| Intertriginous involvement | 8 (62) | 14 (26) | .02b | .19 |
| Head/neck involvement | 13 (100) | 52 (96) | >.99 | >.99 |
| Pruritus | 13 (100) | 52 (96) | >.99 | >.99 |
| Acute kidney injury | 9 (69) | 29 (54) | .37 | .79 |
| Liver involvement | 6 (46) | 46 (85) | .006b | .08 |
| Eosinophilia | 12 (92) | 44 (81) | .68 | .98 |
| Neutrophilia | 12 (92) | 40 (74) | .27 | .78 |
| Leukocytosis | 12 (92) | 39 (72) | .16 | .54 |
| Lymphadenopathy | 2 (15) | 26 (48) | .06 | .37 |
| Fever | 9 (69) | 38 (70) | >.99 | >.99 |
| Length of stay, median (IQR), d | 7 (8) | 6 (4) | .42 | .78 |
| Rehospitalization | 5 (38) | 21 (39) | >.99 | >.99 |
| DRESS recurrence and/or flare | 4 (31) | 1 (2) | .004b | .11 |
| Latency, dc | 25 (25) | 19 (16) | .41 | .83 |
| Latency, dd | 0-34 | 1-54 | NA | NA |
| Vancomycin latency, d,c,e | 24 (5.75) | 22 (11) | .82 | >.99 |
| Culprit drugf | ||||
| Antiepileptic | 3 (23) | 11 (20) | >.99 | >.99 |
| Antibiotic | 7 (54) | 34 (63) | .55 | .83 |
| Vancomycin | 4 (31) | 18 (33) | .35 | .82 |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DRESS, Drug reaction with eosinophilia and systemic symptoms; NA, not applicable; RegiSCAR, Registry of Severe Cutaneous Adverse Reactions.
Corrected P value using Benjamini-Hochberg procedure.
P < .05 indicates statistically significant result.
Indicates time from initial drug administration to onset of reaction.
Range of values.
Latency period for cases for which vancomycin was the single culprit.
Cases were only counted if a single culprit drug or class was identifiable.
Discussion
We observed known AGEP characteristics, including pustules, older age, higher body mass index, less frequent internal organ (liver) involvement, and increased intertriginous involvement, in patients with DRESS with pustulosis who did not meet AGEP criteria.1,2,3,4,6 Although not statistically significant, the data showed an association between the presence of a pustular eruption and frequency of DRESS recurrences, with some patients (n = 3) requiring reinitiation of immunosuppression or taper prolongation. Median latency period observations for both groups, including cases attributed to vancomycin, aligned with previously published literature.5
This study was limited by its retrospective, single-center, and underpowered nature (n = 67). Nevertheless, the results suggest that some patients with DRESS develop a pustular eruption and known AGEP features without receiving an AGEP diagnosis; these patients may represent a DRESS phenotype with an extended clinical course. Dermatologists should consider this prognostic implication when selecting treatments and follow-up intervals in DRESS with pustulosis. Future investigations should prospectively evaluate patients with DRESS with pustulosis through assessments of pustule distribution and character, histological analyses, and human leukocyte antigen allele typing.
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References
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