Toxic epidermal necrolysis following a furosemide injection: a case report

Abstract

Background

Toxic epidermal necrolysis is a life threatening adverse cutaneous reaction mostly following drug administration. It is characterized by extensive detachment of skin and mucous membranes with a more than 30% total body surface area involvement. We document a rare occurrence of Toxic epidermal necrolysis following a furosemide injection.

Case presentation

A one-year-old female from Eastern Uganda was referred to our facility with history of a generalized skin eruption that started 2 days after a furosemide injection. On admission, she had extensive skin sloughing involving the face, trunk and limbs with 60% total body surface area involvement. A diagnosis of Toxic epidermal necrolysis was made, and she was started on supportive care. She showed initial improvement but later the parents left the hospital against medical advice and she died from home.

Conclusion

Furosemide a drug with structural similarities with Sulphonamide antibiotics, has been associated with the rare but life-threatening adverse reaction, Toxic epidermal necrolysis. This case report documents a possible case of Toxic epidermal necrolysis in a child following a furosemide injection to increase awareness amongst clinicians.

Introduction

Toxic Epidermal Necrolysis (TEN) is a severe adverse cutaneous reaction that predominantly involves the skin and mucous membranes, characterized by epidermal detachment > 30% of the patient’s total body surface area (TBSA) [1]. It’s a rare and life-threatening reaction that is commonly drug induced though other causes like infections or autoimmunity have also been documented [1, 2]. Mycoplasma pneumonia and Herpes simplex infections are some of the infectious causes while antibiotic Sulphonamides, anticonvulsants, Allopurinol and oxicam NSAIDs are drugs commonly associated with TEN cases. It is characterized by generalized erythema, bulla formation, and exfoliation of the epidermis that resembles scalding.

The Incidence of TEN in children is lower than in adults, 0.4% versus 1.9% in a study in USA [1] and has better outcomes [3].The female to male ratio is 1.5:1 and average mortality rate of TEN ranges from 14.8 to 48% with higher rates in elderly patients and those with a larger surface area of epidermal detachment [1, 4]. More than 50% of patients with TEN suffer from long term sequelae of the disease; including ocular lesions, cutaneous scaring, dyspigmentation, dental complications, genitourinary problems, and pulmonary problems [4, 5].

Management generally requires a multidisciplinary team with emphasis on withdrawal of the offending drug, supportive care with respiratory support, nutrition and wound care [3, 6] as well as prevention and treatment of superimposed infection.

This case report documents a rare occurrence of TEN following a furosemide injection in a child.

Case summary

A 1-year-old female from Eastern Uganda who was referred from a peripheral unit with a 4 day’s history of peeling skin. She had been hospitalized 8 days prior with an acute febrile illness managed as malaria on artemether/lumefantrine and paracetamol with initial improvement but later developed failure to pass urine with facial swelling. She was the later given “a drug to help her pass urine” (Furosemide) and 2 days later developed worsening fevers with generalized blisters all over her skin. She was started on steroids and IV antibiotics for 2 days at the peripheral unit without improvement and was then referred to our facility for further management (Fig. 2). This was her index admission and had no known chronic illnesses, drug or food allergies.

Fig. 2.

Timeline showing the chronology of events during patient’s illness

On admission, she was sick looking, afebrile with a temperature of 36.8 degrees Celsius, mild pallor and jaundice with no peripheral edema or signs of dehydration. She had periorbital swelling with corneal clouding and sloughing of the oral mucous membranes. She also had burn-like lesions involving the face, trunk and limbs with a positive Nikolsky sign but no discharge (Fig. 1). She had a total body surface area involvement of approximately 60%. She otherwise looked well-nourished with a weight of 11 kg, height of 86 cm with a z score of -1SD and Mid Upper arm circumference (MUAC) of 12.2 cm (normal for age).

Fig. 1.

A Shows the presentation at admission with skin desquamation and sloughing while B shows the progress after initiating management at our facility

The patient had mild signs of respiratory distress with tachypnoea at 43 breaths per minute, nasal flaring and oxygen saturations of 88–90% on room air. She otherwise had normal bronchovesicular breath sounds and normal examination findings of her other systems. Her Naranjo Adverse Drug Reaction probability score was five [5] indicating a probable connection between furosemide and the development of toxic epidermal necrolysis (TEN) (Table 1, Table 2).

Table 1.

Naranjo algorithm-ADR probability scale. causality assessment for the patient

Sn	Question		Yes	No	Do not know	Score
1	Are there previous conclusive reports of this reaction?		+ 1	0	0	+ 1
2	Did the adverse event appear after the drug was given?		+ 2	− 1	0	+ 2
3	Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?		+ 1	0	0	+ 1
4	Did the adverse reaction reappear upon re-administering the drug?		+ 2	− 1	0	0
5	Are there alternative causes (other than the drug) that could on their own have caused the reaction?		− 1	+ 2	0	0
6	Did the adverse reaction reappear upon administration of placebo?		− 1	+ 1	0	0
7	Was the drug detected in the blood or other fluids in toxic concentrations?		+ 1	0	0	0
8	Was the reaction worsened upon increasing the dose? Or, was the reaction lessened upon decreasing the dose?		+ 1	0	0	0
9	Did the patient have a similar reaction to the drug or a related agent in the past?		+ 1	0	0	0
10	Was the adverse event confirmed by any other objective evidence?		+ 1	0	0	+ 1
			Total score			+ 5
Score		Interpretation of the score
Total score ≥ 9		Definite. The reaction (1) followed a reasonable temporal sequence after a drug or in which a toxic drug level had been established in body fluids or tissues, (2) followed a recognized response to the suspected drug, and (3) was confirmed by improvement on withdrawing the drug and reappeared on re-exposure
Total score 5 to 8		Probable. The reaction (1) followed a reasonable temporal sequence after a drug, (2) followed a recognized response to the suspected drug, (3) was confirmed by withdrawal but not by exposure to the drug, and (4) could not be reasonably explained by the known characteristics of the patient’s clinical state
Total score 1 to 4		Possible. The reaction (1) followed a temporal sequence after a drug, (2) possibly followed a recognized pattern to the suspected drug, and (3) could be explained by characteristics of the patient’s disease
Total score ≤ 0		Doubtful. The reaction was likely related to factors other than a drug

Adapted from Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239‑245. https://doi.org/10.1038/clpt.1981.15

Table 2.

Rationale for the patient’s naranjo score of five

Question	Score	Rationale
1	+ 1	A review of literature confirms that furosemide, a sulfonamide-loop diuretic, is a documented, albeit rare, cause of toxic epidermal necrolysis (TEN)
2	+ 2	The adverse event manifested after the drug was administered
3	+ 1	The skin excoriations started reducing after furosemide was stopped
4	0	The suspected drug was not readministered
5	0	This could not be completely ruled out because alternative causes were not thoroughly investigated
6	0	No Placebo was administered in this case
7	0	Toxicology analysis wasn’t done due to unavailability of the service at the facility
8	0	A dose-response relationship could not be assessed because no dose reduction or escalation was carried out
9	0	A.J had no prior history of furosemide having been administered. It was her index hospitalization
10	+ 1	Although a skin biopsy which would confirm the diagnosis wasn’t taken off for analysis, the clinical presentation with epidermal detachment affecting over 60% of the Body surface area, mucosal involvement and the positive Nikolsky sign guided us to make the diagnosis

An admission diagnosis of partially treated malaria with likely acute kidney injury and Toxic Epidermal Necrolysis due to furosemide was made.

In her investigations however, the blood smear revealed no malaria parasites, the complete blood count showed hypochromic microcytic moderate anemia with hemoglobin of 6 g/dl and thrombocytopenia of 75 [10^{^}3/µL] (Table 3).

Table 3.

Complete blood count results for the patient at admission

Test	Result	Normal range	Unit
WBC	10.39	4–12	[10^6/µL]
NEUT	4.67	2–8	[10^6/µL]
LYMPH	5.06	0.8–7	[10^6/µL]
MONO	0.61	0.12–1.2	[10^6/µL]
EO	0.04	0.02–0.8	[10^6/µL]
BASO	0.01	0.0–0.1	[10^6/µL]
IG	0.06	0.0–999.9	[10^6/µL]
RBC	2.99	3.5–5.2	[10^6/µL]
HGB	6.0	12–16	g/dL
HCT	19.3	35–49	%
MCV	64.5	80–100	fL
MCH	20.1	27–34	pg
MCHC	31.1	31–37	g/dL
RDW-SD	43.9	35–56	fL
RDW-CV	18.7	11–16	%
PLT	75	100–300	[10^3/µL]

Her renal function test was normal with deranged serum electrolytes; mild hyponatremia, severe hypokalemia and hypochloremia (Table 4).

Table 4.

Chemistry results for the patient at admission

Renal function with serum electrolytes for A.J
Test	Result	Normal range	Unit
Creatinine	25	44–106	µmol/L
Urea	3.4	2.7–6.4	mmol/L
Na	133	135–150	mmol/L
K	1.75	3.5–5.0	mmol/L
Cl	90.0	98–110	mmol/L

Liver enzymes and liver function test for A.J
Test	Result	Normal range	Unit
ALT	72.1	0–41	U/L
ALP	181	40–129	U/L
AST	56.5	0–40	U/L
GGT	83	0–55	U/L
Albumin	1.78	3.5–5.0	g/dL
T bilirubin	24.1	0–17	µmol/L

Her liver enzymes were slightly elevated with hypoalbuminemia (Table 4). HIV serology was negative. We did not do any histology on skin lesions due to unavailability of the service at the facility.

The final diagnosis became Toxic Epidermal Necrolysis secondary to furosemide, Electrolyte imbalance and resolved malaria with moderate anemia.

She was managed as below:

1. Supportive care; Oxygen therapy by nasal prongs at 0.5L per minute, IV bolus of D10 at 55 ml stat and then nasogastric tube (NGT) for three hourly feeds

2. IV antibiotics; IV ampiclox 550 mg six hourly with IV gentamycin 55 mg once daily for 5 days

3. Skin care: Warm saltwater soaks with application of gentian violet ointment four hourly to prevent skin infection and Vaseline petroleum jelly was applied to keep the wound moist and prevent desiccation.

4. Pain management; Oral morphine 4 ml four hourly with bisacodyl tablets 2.5 mg once daily for 48 h

5. Blood products; transfused once with 110 ml of packed red blood cells over three hours

6. Nutrition: Stabilized on F75 (low calorie and low fat) for 48 h then transitioned back to normal feeds. Oral Potassium chloride (KCL) 300 mg twice daily was also given by the NGT to correct the hypokalemia (IV KCL was unavailable at the facility).

7. Without a Burns unit at the facility, the patient was managed in the paediatrics ward with consultation with surgeons. The Ophthalmology consult was pending.

By the fourth day after the above management was started, seven days after admission the patient was clinically better, stable off oxygen, able to feed orally (nasogastric tube was removed) and the skin lesions had started to dry and heal (Fig. 1B).

Despite this improvement, two days later the patient was taken from the hospital by her caregivers against medical advice (Fig. 2). Subsequent information obtained from the family indicated that the child died at home. Discussions with other caretakers identified several factors influencing their decision to leave the hospital prematurely. These included a prevailing belief that the child’s survival was unlikely despite treatment, concerns that survival might result in permanent disabilities such as blindness, and apprehensions regarding the long-term caregiving burden. Additionally, significant financial constraints related to extended hospitalization, including costs for food and loss of income, further contributed to their decision.

Discussion

Toxic Epidermal Necrolysis (TEN) is almost exclusively attributed to drugs and to a lesser extent infections or autoimmune disease [2, 7]. The drugs commonly implicated are Sulphonamide antibiotics [3], anticonvulsant agents, Allopurinol and rarely Oxicam non-steroidal anti-inflammatory drugs [5, 6, 8]. The aromatic amine moiety in their structure is implicated in the pathogenesis of TEN. Other reports have however, also implicated sulfonamide diuretics like furosemide as a rare cause of TEN [9, 10].These diuretics have structural similarities to Sulphonamide antibiotics with a non-aromatic amines have been documented to cause serious cutaneous adverse reactions such as TEN [11]. A systematic review done between 2004 and 2013 reported that 0.8% of the case reports showed TEN following use of furosemide [12].

For this patient who had just completed her three days course of artemether/lumefantrine and paracetamol, what raised our suspicion on the causal relationship was the onset of a blistering rash two days following the first-time administration of furosemide. The use of the Naranjo ADR probability scale gave us a score of five [5] which also indicated a probable relationship between TENS and furosemide in this patient [13]. The clinical signs, timing of the reaction, improvement following drug cessation, and prior case reports involving furosemide and related sulfonamide-loop diuretics were the basis for this. Due to limitation in resources, we were unable to do drug testing or histology to further confirm the diagnosis.

The differential diagnosis for this case included Stevens-Johnson-Syndrome (SJS), however the more than 30% epidermal detachment as opposed to 10% in SJS made it less likely. Bullous impetigo which causes skin blistering in children was another differential. However, its lesions are usually localized not widespread, with a purulent discharge (absent in this case). In addition, bullous impetigo usually has no mucosal involvement like what was seen in our patient (Fig. 1). A third differential in this case was staphylococcal scalded skin syndrome (SSSS) in view of generalized skin peeling with positive Nikolsky sign and its occurrence in infants and young children. The extensive oral mucosa involvement with corneal clouding and drug history made TEN the more likely diagnosis.

Other differential diagnoses included pemphigus vulgaris in view of the positive Nikolsky sign and mucosal involvement, however, it has a chronic course rather than acute and is not typically drug induced. Acute generalized exanthematous pustulosis would be another differential because of it being a drug related skin reaction however, it presents with minimal mucosal involvement and pustular eruptions not epidermal necrolysis.

The documented causal mechanism is of the immune adaptive type due to a class IV delayed hypersensitivity response and keratocyte apoptosis is caused by cytotoxic T cells (CD8) and natural killer (NK) cells (CD56) after being activated by the drug [14]. Drug metabolites like hydroxylamines from the Sulphonamides bind to keratocytes in the skin and render them antigenic with a resultant inappropriate immune activation. Severe cytotoxic proteins and cytokines including tumor necrotic factor (TNF) alpha are mediators of the extensive keratocyte apoptosis with resultant skin loss, systemic inflammation and mucosal involvement.

Our patient had extensive skin loss with a 60% total body surface area involvement which put her in the high-risk group for mortality. There has been reported direct correlation between mortality and percentage of body surface area involved that is, a higher percentage of total body surface area involvement has a higher risk of mortality [5]. This could have contributed to the fluid loss, electrolytes derangements and possible sepsis in our patient.

Conclusion

Furosemide is a drug commonly used in patients with renal or cardiac disease. This case report documents the probable occurrence of a rare but life-threatening drug reaction following its use in the hope of creating awareness amongst clinicians. A high index of suspicion and quick withdrawal of the offending drug with institution of the appropriate supportive care could possibly improve patient outcomes.

Abbreviations

NK

Natural killer cells

NSAID

Non-steroidal anti-inflammatory drug

TEN

Toxic Epidermal Necrolysis

TNF

Tumor necrotic factor

USA

United States of America

Author contributions

D.G wrote the initial draft of this case report and was involved in editing the manuscript. I.G. contributed to the writing of the discussion section and was engaged in proofreading and editing the manuscript. C.N contributed to conceptualizing the case report, supervised the writing, and edited the manuscript.

Funding

We did not receive any funding for this article.

Data availability

All data supporting our findings are available from the author upon request.

Declarations

Ethics approval and consent to participate

None was needed for this single case report, in accordance with the institutional policy.

Consent for publication

Written informed consent was obtained from the patient's legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors disclosed no competing interests.