Fixing the concept of the neutrophilic fixed drug eruption

By Warren R. Heymann, MD, FAAD
Oct. 12, 2022
Vol. 4, No. 41

Can anyone other than your mother recognize you from your baby photograph? The concept that lesions have lives is nothing new — clinical and histopathological changes vary from lesional inception to involution. Despite this truism, confusion about nosology for many dermatoses, based on the timing of assessment, is replete in the medical literature. This commentary will focus on the neutrophilic fixed drug eruption (nFDE).

In 1987, Van Voorhees and Stenn detailed the case of a 79-year old man with a urinary tract infection who developed a trimethoprim/sulfamethoxazole-induced FDE. Histological studies were performed on days 1 and 5 after the drug exposure. The 1-day-old lesion showed a hypersensitivity response suggestive of Sweet’s syndrome: diffuse spongiosis, dermal edema and hemorrhage, eosinophils, and neutrophilic polymorphonuclear leukocyte abscess formations. At 5 days the histological changes were characteristic of a FDE. The authors underscored the dynamic changes that occur in the evolving FDE lesions, with neutrophilic infiltration appearing early. (1)

The term nFDE was coined by Agnew and Oliver when discussing the case of a 49-year-old Samoan man who developed a bullous FDE due to amoxicillin-clavulanic acid at the same site of a prior eruption 5 years earlier when antibiotics (presumably the same) were administered for furunculosis. A biopsy was performed on the new lesion 16 hours after the onset of the eruption. Histopathology revealed an intact epidermis with intraepidermal collections of neutrophils, serum and eosinophils. Within the dermis, a marked perivascular and interstitial mixed inflammatory infiltrate with a predominance of intact neutrophils was appreciated. Importantly, no interface changes were seen. The authors favored this lesion being a FDE rather than drug-induced Sweet’s syndrome because of its fixed location and the absence of systemic symptoms. (2)

Similar cases have been reported subsequently. A 51-year-old woman developed nFDE to naproxen. Histologically this case was similar to the original report in that there was no mention of interface changes. The timing of the biopsy relative to the onset of the rash was not reported. The authors questioned if nFDE is a distinct entity or just the earliest presentation of a FDE. (3) In other cases of nFDE, however, interface changes including necrotic keratinocytes have been reported with dermal neutrophilic infiltration (4,5) that may be accompanied by eosinophils. (5) Neither case reported systemic symptoms.

Acar et al reported the case of a 65-year-old woman who developed nFDE twice in response to gabapentin, with both episodes accompanied by fever and neutrophilic leukocytosis. A biopsy performed on day 7 of the initial eruption displayed a neutrophil-rich infiltrate without attendant vacuolar alteration or necrotic keratinocytes. The authors opined that their patient had nFDE rather than drug-induced Sweet’s syndrome because the lesions had the same distribution in both episodes and the neutrophilic infiltration was not as intense as usually observed in Sweet’s syndrome. (6)

Histologically, the hallmarks of FDE are vacuolar alteration at the epidermal-dermal junction, individually necrotic keratinocytes, and a perivascular infiltrate of lymphocytes and eosinophils. FDEs are mediated by CD8+ memory T cells in genetically predisposed patients. According to Anderson and Lee: “Within 24 hours of ingestion of a culprit medication, these CD8+ T cells migrate upward in the epidermis, produce cytokines such as interferon-gamma and TNF-alpha, and take on the phenotype of a natural killer cell, expressing the cell surface molecule CD56 as well as the cytotoxic molecules granzyme B and perforin… At the same time, CD4+ Foxp3+ regulatory T cells migrate into the epidermis, curbing the damage inflicted by the CD8+ T cells. The action of the CD4+ regulatory T cells, which includes the production of the anti-inflammatory cytokine IL-10, explains the self-limited nature of FDEs.” (7)

In a fascinating case report of a 56-year-old man with chronic myeloid leukemia, Bergman et al reported two episodes of a neutrophilic dermatosis, with attendant flu-like symptoms, due to the multiple tyrosine kinase inhibitor dasatinib. Lesions recurred at the same sites; intriguingly, these episodes occurred 5 years apart, while on dasatinib for the duration. The authors used the descriptive term “recurrent and fixed neutrophilic dermatosis” in this case. (8)

Li and Kazlouskaya sought to determine if nFDE is a distinct entity, a rare variant, or an early stage of FDE. They retrospectively analyzed 16 cases of FDE and demonstrated that neutrophils are relatively common (11/16, 68%) and that cases with abundant neutrophils have a significantly shorter onset-to-biopsy interval (3.7 versus 16.9 days). Their findings support the concept that nFDE is an early phase of FDE rather than a disorder sui generis. (9)

As trite as it is, clinical-pathologic correlation is of paramount importance in deciphering neutrophilic dermatoses. On a histologic basis alone, many of the features described could be observed in Sweet’s syndrome, adult-onset Still disease, autoinflammatory disorders, non-bullous bullous pemphigoid, or prurigo pigmentosa. A good clinical history and morphologic description will help guide your dermatopathologist. Conversely, if you get a report of neutrophilic involvement with or without classical features of FDE, it may be worthwhile determining if drugs are the culprit of the rash.

Point to Remember: In most circumstances, neutrophils may be observed early in fixed drug eruptions, rather than representing a distinct entity known as “neutrophilic fixed drug eruption”. For patients with systemic symptoms, however, further research is required to determine if neutrophilic fixed drug eruption, drug-induced Sweet’s syndrome, or recurrent and fixed neutrophilic dermatosis are part of a spectrum of disease.

Our expert’s viewpoint

Kiran Motaparthi, MD, FAAD
Associate Professor
Residency Program Director
Director of Dermatopathology
Department of Dermatology
University of Florida College of Medicine

The concept of a “neutrophilic FDE” is challenging to understand because: FDE is classically a lichenoid interface dermatitis, this term broadens the spectrum of histopathologic findings, and frankly because some prior descriptions of this entity actually represent a neutrophilic dermatosis, namely Sweet’s syndrome. At least two reports describe edematous plaques and variable systemic findings associated with classic histopathologic features of Sweet’s syndrome. (2, 6) Recurrence at prior sites of disease should not be used in isolation when distinguishing FDE from other dermatoses, and systemic symptoms are not always present in neutrophilic dermatoses. Other descriptions identify neutrophilic dermal infiltrates in examples of FDE with otherwise standard clinicopathologic features. (4, 5) In this scenario, this feature is noteworthy but should not prove ultimately distracting. Lastly, a few references do support the basis for considering a neutrophilic infiltrate as a manifestation of early FDE. However, prominent spongiosis and neutrophil exocytosis were described in these cases, and clinical features and distribution were more typical of FDE than Sweet’s syndrome. (1, 3) Of course, the best corroborating evidence is a later biopsy with standard features. (1) This idea is also easier to accept since I have observed cases of EM, Stevens-Johnson syndrome, and toxic epidermal necrolysis in which the first biopsy obtained at onset was primarily spongiotic with variable neutrophilic or eosinophilic spongiosis prior to the appearance of vacuolar change, keratinocyte apoptosis, and clinical evidence of necrosis. The following approach is suggested: classic histopathologic features of Sweet’s syndrome should be reported as such; otherwise standard cases of FDE with dermal neutrophils should be described as “FDE with neutrophilic infiltrate;” and a differential diagnosis should be provided for cases with clinical findings of FDE but with prominent spongiosis and neutrophil exocytosis instead of interface tissue reaction. In the last scenario, clinical follow-up and/or another biopsy should permit distinction between “the early stage of FDE” and “neutrophilic dermatosis.” Of note, this approach does not require the term “neutrophilic FDE,” which is likely to produce confusion.

1. Van Voorhees A, Stenn KS. Histological phases of Bactrim-induced fixed drug eruption. The report of one case. Am J Dermatopathol. 1987 Dec;9(6):528-32. doi: 10.1097/00000372-198712000-00010. PMID: 2965526.

2. Agnew KL, Oliver GF. Neutrophilic fixed drug eruption. Australas J Dermatol. 2001 Aug;42(3):200-2. doi: 10.1046/j.1440-0960.2001.00516.x. PMID: 11488716.

3. Ozkaya E, Büyükbabani N. Neutrophilic fixed drug eruption caused by naproxen: a real entity or a stage in the histopathologic evolution of the disease? J Am Acad Dermatol. 2005 Jul;53(1):178-9. doi: 10.1016/j.jaad.2005.01.095. PMID: 15965451.

4. Waldman L, Reddy SB, Kassim A, Dettloff J, Reddy VB. Neutrophilic Fixed Drug Eruption. Am J Dermatopathol. 2015 Jul;37(7):574-6. doi: 10.1097/DAD.0000000000000157. PMID: 25072682.

5. Suzuki S, Ho J, Rosenbaum M, Bhawan J. Neutrophilic fixed drug eruption: a mimic of neutrophilic dermatoses. Clin Exp Dermatol. 2019 Mar;44(2):236-238. doi: 10.1111/ced.13740. Epub 2018 Sep 9. PMID: 30198122.

6. Acar EM, Çorum Şirin S, Kilitci A, Elmas ÖF, Kemeriz F, Günay Ü. Generalized neutrophilic fixed drug eruption induced by gabapentin. Turk J Phys Med Rehabil. 2021 Mar 4;67(1):122-124. doi: 10.5606/tftrd.2021.5723. PMID: 33948555; PMCID: PMC8088806.

7. Anderson HJ, Lee JB. A Review of Fixed Drug Eruption with a Special Focus on Generalized Bullous Fixed Drug Eruption. Medicina (Kaunas). 2021 Sep 1;57(9):925. doi: 10.3390/medicina57090925. PMID: 34577848; PMCID: PMC8468217.

8. Bergman JC, Ly TY, Keating MM, Hull PR. Recurrent and Fixed Neutrophilic Dermatosis Associated With Dasatinib. J Cutan Med Surg. 2018 Nov/Dec;22(6):621-623. doi: 10.1177/1203475418775663. Epub 2018 May 13. PMID: 29754527.

9. Li A, Kazlouskaya V. Neutrophils in fixed drug eruptions: Corrections of a mistaken hypothesis. Am J Dermatopathol 2021: (in press).

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