DRUG-INDUCED HYPERSENSITIVITY SYNDROME CAUSED BY LAMOTRIGINE, A CASE REPORT

SUMMARY

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is an under-recognized and potentially life-threatening hypersensitivity reaction associated with a variety of medications, many of them anti-epileptics. Patients with DRESS syndrome typically present with rash, swelling, fever, and systemic manifestations. We report a case of a patient admitted to out hospital after the administration of an anticonvulsive drug lamotrigine. She was presented with high fever, rash, face oedema and elevated liver enzymes. At admission, all previous medications were discontinued, systemic corticosteroid therapy was administered, and the patient was monitored for signs of clinical recovery. This case report suggests that in patients presenting with skin rash and systemic abnormalities after a recent change in medications, physicians should consider DRESS syndrome as a possible diagnosis and switch to a more aggressive therapy if removal of the offending agent does not result in clinical improvement. Early diagnosis can reduce the risk of complications and the mortality rate.

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is an under-recognized and potentially life-threatening hypersensitivity reaction associated with a variety of medications, many of them anti-epileptics. Patients with DRESS syndrome typically present with rash, swelling, fever, and systemic manifestations such as a severe transaminitis. (1)

Isolated elevation of liver transaminases is the most common laboratory manifestation of hepatitis in DRESS syndrome. In severe cases it can progress to fulminant liver failure, occurring in as many as 10% of cases and accounting for the principle cause of mortality in patients affected by DRESS syndrome. (1)

These patients are typically found to have started one of a few select medications in the past two to eight weeks with aromatic anti-epileptics being the most commonly implicated. (2, 3)

Drug group’s associates with DRESS/DIHS are shown in the table (Table 1.).

Table 1. Drug groups associated with DRESS/DIHS.

Drug groups:
Anticonvulsants
Antidepressants
Sulfonamides/sulfones
Anti-infammatories
Anti-infectives
Angiotensin-converting enzyme inhibitors
Beta-blockers
Specific Examples:
phenytoin, carbamazepine, phenobarbital, lamotrigine, valproate
despiramine, amitriptyline, fluoxetine
dapsone, sulfasalazine, trimethoprim-sulfamethoxazole
piroxicam, naproxen, diclofenac, sulindac, ibuprofen
abacavir, nevirapine, linezolid, doxycycline, nitrofurantoin
captopril, enalapril
atenolol, celiprolol

Although its true incidence is unknown, DRESS syndrome has been estimated to occur in approximately one out of 1,000 to 10,000 new users of anti-epileptic medications. (4, 5)

Case report

A 52-year-old woman was presented at the Emergency Department (ED) of the Clinical Hospital Sveti Duh with a high fever (40°C), maculopapular rash prominent on most parts of the chest, back, extremities, and face oedema and erythema (Fig. 1,2).

Figure 1.

Maculopapular rash

Figure 2.

Face erythema and swelling

Two days prior she was administered for first time an anticonvulsive drug (lamotrigine) during the modification of chronic psychiatric therapy at the University Psychiatric Hospital Vrapče. She was referred to the Clinical Hospital Sveti Duh for further evaluation.

There was no involvement of the oral mucosa, palms, or soles. The patients past medical history included hypertension, diabetes type II and depression. There were no previously known allergies to drugs. Physical examination showed that heart rhythm is normal. No murmurs, gallops, or rubs were auscultated. There were no signs of respiratory distress. Lung sounds were clear in all lobes bilaterally without rales, rhonchi, or wheezes. The abdomen was soft, symmetric, and non-tender and without distention. No masses, hepatomegaly, or splenomegaly were noted. No focal deficits were appreciated on neurological examination. The initial laboratory results revealed elevated liver enzymes and leukocytosis, but no eosinophilia. The chest X-ray showed normal size and shape of the chest wall and the main structures in the chest. Covid19 infection was excluded after negative reverse-transcription of a polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus (SARS COV2). The diagnostic panel for hepatitis serology showed past HBV infection. Other diagnostic tests that excluded the possible causes of the symptoms were also carried out - anti-nuclear antibodies (ANA), blood cultures, serology for chlamydia and/or mycoplasma.

She was admitted to the Clinical Hospital Sveti Duh with a presumptive diagnosis of a drug-induced hypersensitivity. At admission, systemic corticosteroid therapy was started, all previous medications were discontinued and the patient was monitored for signs of clinical recovery.

Although no formal diagnostic criteria for DRESS syndrome have been widely accepted, the Kardaun et al. of the Severe Cutaneous Adverse Reactions (RegiSCAR) study group published a scoring system in 2007 that has been widely used to evaluate potential cases of DRESS syndrome (Table 2.) (6)

Table 2. Scoring system by RegiSCAR.

Criteria	No	Yes	Unknown
Fever greater than 38.5°C	-1	0	-1
Enlarged lymph nodes	0	1	0
Atypical lymphocytosis	0	1	0
Eosinophilia 10-19,9% >20%	0	1 2	0
Skin rash > 50% of the skin surface morphology suggestive of DRESS biopsy suggestive of DRESS	0 -1 -1	1 1 0	0 0 0
Organ involvement 1 2 or more	0	1 2	0
Resolution greater than 15 days	-1	0
Evaluation of other causes (ANA, blood cultures, serology for hepatitis A virus, hepatitis B virus, hepatitis C virus, and chlamydia and/or mycoplasma)	0	1	0

DRESS= Drug reaction with eosinophilia and systemic symptoms, ANA= Anti-nuclear antibodies

The criteria for this system include: first, fever greater than 38.5°C; second, enlarged lymph nodes; third, eosinophilia; fourth, atypical lymphocytosis; fifth, skin involvement; sixth, organ involvement; seventh, resolution greater than 15 days; and eighth, evaluation of other causes (ANA, blood cultures, serology for hepatitis A virus, hepatitis B virus, hepatitis C virus, and chlamydia and/or mycoplasma). Using this scoring system, a final score of less than two indicates no case, a final score of between two and three indicates a possible case, and a final score of between four and five indicates a probable case, and a final score of greater than five indicates a definite case.

The patient in this case report had a score of five points (one each for fever greater than 38.5°C, skin rash suggestive of DRESS, affecting >50% of the skin surface, liver involvement, and evaluation of other potential causes), indicating a ‘probable case’ of DRESS per the RegiSCAR scoring guidelines.

Within five days of admission and corticosteroid treatment, the laboratory results showed a slight progression of elevated liver enzymes. Other laboratory results were without significant change. Confluent configuration of the rash was noticed (Fig. 3,4).

Figure 3.

Confluent configuration of the rash

Figure 4.

Confluent configuration of the rash

On 10th day of the admission, the clinical improvement was obvious. There was no face erythema or swelling, and the skin rash had begun to resolve (Fig. 5, 6 and 7). The levels of transaminases began to improve, and she was discharged home, with metilprednizolon still in the therapy until a follow-up with an immunologist within four weeks.

Figure 5.

Rash resolution

Figure 6.

Resolution of the face oedema and erythema

Figure 7.

Rash resolution

Discussion

As with most severe allergic reactions, DRESS syndrome involves a rash, diffuse swelling, and eosinophilia. (2, 6, 7) The hallmark of DRESS syndrome, however, is the presence of systemic manifestations, such as inflammation of the liver, kidneys, heart, or other organs. (8) Prompt recognition of the adverse drug reaction and discontinuation of the offending medications are imperative steps in limiting the progression of DRESS syndrome. Systemic corticosteroids have become a mainstay of therapy in severe cases and often produce a marked improvement in clinical symptoms and laboratory measures within just a few days of the initiation of the treatment. (9) If symptoms continue to progress despite the use of corticosteroids, other options include intravenous immunoglobulin (IVIG) and/or plasmapheresis. (10) The mortality rate in patients affected by DRESS syndrome is about 10%, with the principle cause of mortality being fulminant liver failure. (1)

Conclusion

In patients presenting with skin rash and systemic abnormalities after a recent change in medications, physicians should consider DRESS syndrome as a possible diagnosis and switch to more aggressive therapy if removal of the offending agent does not result in clinical improvement. Early diagnosis can reduce the risk of complications and the mortality rate.