A COMPREHENSIVE EXPLORATION OF FIXED DRUG ERUPTIONS WITH SPECIAL FOCUS ON BULLOUS FIXED DRUG ERUPTION AMONG PATIENTS ATTENDING TERTIARY CARE CENTER.

doi:DOI : 10.61336/ejcm/25-12-29

Abstract

Fixed drug eruptions are unique cutaneous drug reactions occurring at the same site after re-exposure to the offending drug. Clinically it present with diverse morphological patterns including macular, papular, bullous, pigmented, linear, generalised forms etc.. These varied presentations may mimic other dermatoses, making clinical recognition is essential. Most common drugs causing FDE are anti microbials, non-steroidal anti-inflammatory drugs, anti convulsants etc... This study aims to describe epidemiology, various morphological patterns and drugs causing fixed drug eruptions.MATERIALS AND METHODS: A prospective observational study was conducted over a period of two years in the department of DVL of tertiary care centre. Patients presenting with signs and symptoms of fixed drug reaction are enrolled in this study. Age, sex, morphological pattern, sites, drugs causing FDE are categorised. HPE was send wherever is necessary. RESULTS: The study had 40 cases of fixed drug eruptions in which adults aged between 25 to 49 years were commonly affected(82.5%) followed by old age 4 (10%) .Young adults aged between 19 to 24 involved 2 (5%) and children <12 years 1 (2.5%). Males were 22(55%) and females were 18(45%). Commonly affected sites were extremities, lips and genitalia. Most of the cases were localised bullous FDE 17(42.5%) followed by pigmented FDE 16(40%), generalised bullous FDE 4(10%) , erythema multiforme like FDE 1(2.5%), non-pigmented FDE 1(2.5%) ,and linear FDE 1(2.5%). Anti microbials 19(47.5%) and non-steroidal anti-inflammatory drugs16 (40%) were most common drugs implicated and other drugs were 5 (12.5%).Past history of FDE was positive in 11 (27.5%).

LIMITATIONS: This study has limited sample size. CONCLUSION: This study emphasizes different morphological patterns of fixed drug eruptions, most common type is localised bullous FDE with male predominance and highest prevalence in 25 to 49 age group. This study also shows that anti microbials are the most common drug implicated .It is important to know detailed drug history and previous history of drug allergies in rare forms of FDE.

Keywords

Fixed drug eruption

NSAIDS

INTRODUCTION

Fixed Drug Eruption (FDE) represents a distinctive form of cutaneous adverse drug reaction characterized by the recurrence of lesions at the same anatomical sites following re-exposure to the offending drug. First described by Burns in 1889, and the term coined by brocq in 1894[1, 2]. FDE typically manifests as well-demarcated, erythematous to violaceous macules or plaques that may evolve into bullous or erosive forms in severe cases. Upon healing, the lesions characteristically leave residual post-inflammatory hyperpigmentation, which serves as a hallmark for clinical diagnosis [3,4].

It can occur in different morphological patterns like pigmented FDE, localised and generalised bullous FDE, non-pigmented FDE ,linear FDE, psoriasiform FDE, erythema dyschromicum perstans like FDE, cellulitis like FDE, papular FDE, annular FDE, transitory giant FDE and ,erythema multiforme like FDE. Among the various morphologic subtypes of FDE, the generalisd bullous Fixed Drug Eruption (BFDE) represents a severe spectrum characterized by the development of generalised large flaccid blisters and erosions, with involvement of multiple mucosa. Clinically, BFDE can mimic life-threatening reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

A wide range of medications are known to trigger FDE and its variants, including antibiotics (especially co-trimoxazole, levofloxacin, and doxycycline), non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants (phenytoin), and antiretroviral or antiviral agents (entecavir) [5-8]. Despite being self-limited in most cases, the bullous forms can result in extensive epidermal detachment and systemic symptoms, underscoring the need for early recognition and differentiation from severe cutaneous adverse reactions.

AIMS AND OBJECTIVES

To describe the epidemiological trends, various morphological patterns, and common drugs causing Fixed Drug Eruption (FDE)..

MATERIAL AND METHODS

A prospective observational study was conducted over a period of two years in department of dermatology of Government medical college Ananthapuramu, Andrapradesh. All patients clinically diagnosed with Fixed Drug Eruption (FDE) attending the outpatient department or admitted in the dermatology ward during this period were included in the study after obtaining informed consent. Patients with uncertain drug history or multiple drug intake without clear temporal correlation and patients those who are not willing to participate in this study are excluded. Detailed clinical history was recorded in each case, including age and sex of the patient, temporal relationship between drug intake and lesion appearance, Number and sites of lesions involved, morphological pattern of lesions and causative drug(s) identified based on the history of recent medication use and recurrence on re-exposure. Lesions were categorized according to their morphological type (pigmented, bullous, erythema multiforme like, linear etc…). The sites of predilection (lips, extremities) were also documented. Skin biopsy was performed in selected cases, particularly in atypical or bullous lesions, to confirm the diagnosis and to exclude differential diagnosis such as erythema multiforme or Stevens–Johnson syndrome. Histopathological examination was carried out on formalin-fixed, paraffin-embedded tissue sections stained with haematoxylin and eosin. The diagnostic features of FDE, basal cell vacuolar degeneration, pigmentary incontinence, apoptotic keratinocytes, and dermal lymphocytic infiltrate with eosinophils and melanophages—were noted.

RESULTS

A total of 40 cases who presented to the department of DVL in a span of 2 years were included in this study.Majority of the patients belonged to the age group of 25–49 years followed by the elderly age group (>50 years). Only two patients were in the young adult group (19–24 years) and one patient was below 12 years of age. The male-to-female ratio was 1.2 : 1 (22 males and 18 females), showing a slight male predominance.

Fig.1 age wise distribution Fig.2 sex wise distribution

Localized bullous variant was the most frequent morphological type, observed in 17 (42.5%) cases, followed by pigmented FDE in 16 (40%) cases. Generalized bullous FDE accounted for 4 (10%) cases, while erythema multiforme–like, non-pigmented, and linear variants were seen in one case each (2.5%).

Table 1. Morphological patterns observed in study population

MORPHOLOGICAL PATTERN	NUMBER OF PATIENTS	PERCENTAGE
Localised bullous FDE	17	42.5%
Pigmented FDE	16	40%
Generalized bullous FDE	4	10%
EMF like FDE	1	2.5%
Non pigmented FDE	1	2.5%
Linear FDE	1	2.5%

Extremities, lips, and genitalia were most frequently affected sites. Other sites such as the trunk and face were involved less often. Lesions were localized in the majority of cases, whereas generalized involvement was observed in a few patients.

A positive past history of Fixed Drug Eruption was noted in 11 (27.5%) patients, indicating recurrence at the same sites following re-exposure to the offending drug.

Histopathological examination was performed in selected cases, particularly those with bullous lesions or atypical presentations. The consistent findings included basal cell vacuolar degeneration, melanin incontinence, scattered necrotic keratinocytes, and superficial perivascular lymphocytic infiltrate with eosinophils and melanophages,confirming the diagnosis of Fixed Drug Eruption.

Antimicrobial agents were identified as the most common causative group, implicated in 19 (47.5%) cases, followed by non-steroidal anti-inflammatory drugs (NSAIDs) in 16 (40%) cases. The remaining cases were attributed to miscellaneous medications

Table 2. Drugs implicated in the study population

SL.NO	DRUGS	NO.OF PATIENTS	PERCENTAGE1
1	ANTIMICROBIALS	19	47.5%
	Norfloxacin	5	12.5%
	Ciprofloxacin	3	7.5%
	Ofloxacin	3	7.5%
	Doxycycline	3	7.5%
	Cefixime	2	5%
	Amoxiclav	2	5%
	Metronidazole	1	2.5%
2	NSAIDS	16	40%
	Diclofenac	3	7.5%
	Aceclofenac	3	7.5%
	Etoricoxib	3	7.5%
	Ibuprofen	3	7.5%
	Paracetomol	2	5%
	Naproxen	2	5%
3.	ANTIEPILEPTICS	2	5%
	Phenytoin	1	2.5%
	carbamazepine	1	2.5%
4.	Gabapentin	1	2.5%
5	omeprazole	1	2.5%
6	Iodinated contrast	1	2.5%

Fig.3 localised bullous FDE presenting as flaccid bullae, erosions and crusts.

Fig.4 generalised bullous FDE:Histopathological examination shows necrotic keratinocytes at dermoepidermal junction and epidermis is separated from base and is necrotic.

Fig. 5 shows pigmented FDE presents as hyper pigmented plaque with erythematous boarder.HPE shows spongiosis,pigmentary incontinence in the upper dermis and inflammatory infiltrates in the dermis.

Fixed Drug Eruptions (FDE) are a distinctive type of cutaneous adverse drug reaction characterized by the recurrence of lesions at identical sites following re-exposure to the offending agent. In the present study, 40 clinically diagnosed cases of FDE were analyzed to evaluate their morphological patterns, demographic trends, site distribution, and drug associations.

In this study, the most common age group affected was 25–49 years, followed by individuals above 50 years. Only one case was reported in a child under 12 years. This predominance among adults is comparable to findings by sehgal et al(3) and patel et al(9), who also observed that FDE occurs most frequently in middle-aged individuals due to higher drug exposure. The male-to-female ratio of 1.2:1 indicates a slight male predominance, similar to studies by Sehgal et al. (3) and N’Diaye et al. (10).

With respect to morphological variants, the localized bullous type was the most frequent pattern (42.5%), followed by pigmented FDE (40%), generalized bullous FDE (10%). These findings are consistent with the studies of sehgal et al, who reported bullous and pigmenting forms as the most common morphological types. The presence of rare variants such as erythema multiforme–like and linear FDE emphasizes the wide morphological spectrum of this reaction pattern.

Extremities and mucosal sites were the most commonly affected areas in the current study, which correlates with the predilection reported in earlier research by Patel et al. (9). The recurrent involvement of these sites may be attributed to site-specific epidermal CD8⁺ memory T cells that persist after initial exposure.

In this study, antimicrobials were the most common causative group (47.5%), followed by NSAIDs (40%), and antiepileptics (5%). Among antimicrobials, norfloxacin was the most frequently implicated agent, followed by ciprofloxacin, ofloxacin, and doxycycline. The predominance of antimicrobials, especially fluoroquinolones, parallels the findings of Kumar et al. (11), who identified antibiotics and NSAIDs as the leading triggers for FDE in the Indian population. This is not concordance with the study of N’Diaye et al where the most common drug was antimalarials and the individual drug was chloroquine.

Post-inflammatory hyperpigmentation was a consistent feature in most cases, particularly in the pigmented and bullous variants. This aligns with the well-established observation that pigment incontinence and basal cell damage contribute to persistent discoloration even after lesion resolution.

Overall, the findings of this study reaffirm that FDE commonly affects adults, shows a slight male predominance, and demonstrates considerable morphological diversity. Recognition of these patterns is crucial, as atypical variants may mimic other bullous or pigmentary disorders. Identification of the offending drug and patient education regarding drug avoidance remain the cornerstone of management.

Parameter

Present Study (n=40)

Sehgal et al., 2016

N’Diaye et al., 2020

Patel et al., 2018

Kumar et al., 2019

Most Common Age Group

25–49 years

20–50 years

20–45 years

21–50 years

21–40 years

Sex Ratio (M:F)

1.2:1

1.4:1

1.1:1

1.2:1

1.3:1

Common Sites Involved

Extremities, lips, genitalia

Limbs, lips, genitalia

Face, limbs

Extremities, mucosa

Limbs, lips, genitalia

Predominant Morphological Type

Localized bullous (42.5%) and pigmented (40%)

Bullous, pigmented

Pigmented

Bullous and pigmented

Rare Variants Observed

Erythema multiforme–like, linear FDE (2.5% each)

Erythema multiforme–like

—

Non-pigmented

Most Common Causative Drug Class

Antimicrobials (47.5%), NSAIDs (40%)

Antibiotics

Antimalarials, antibiotics

Antimicrobials, NSAIDs

Antibiotics, NSAIDs

Most Common Individual Drug

Norfloxacin, ciprofloxacin

Cotrimoxazole

Chloroquine

Ciprofloxacin