Drug Reaction with Eosinophilia and Systemic Symptoms and Agranulocytosis Presenting as Cervical Lymphadenopathy

Abstract

Objective: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare cause of cervical lymphadenopathy. It is a potentially life-threatening hypersensitivity reaction, commonly characterized by fever, rash, hematological abnormalities, and multi-organ involvement. Its association with agranulocytosis is even rarer, with fewer than 10 cases describing the coexistence of DRESS with agranulocytosis reported in the English literature. Case Summary: An otherwise well 40-year-old female presented with a sore throat and cervical lymphadenopathy, with investigations revealing DRESS and agranulocytosis secondary to carbamazepine. Conclusion: DRESS and agranulocytosis are serious, potentially life-threatening adverse drug reactions which can initially present as cervical lymphadenopathy. As carbamazepine is considered first-line therapy for certain chronic neuropathic conditions such as trigeminal neuralgia, clinicians should be aware of the varying clinical presentations of both conditions.

Background

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity reaction (DIHS), is a rare but potentially life-threatening hypersensitivity reaction. It is commonly characterized by rash, fever, lymphadenopathy, hematological abnormalities, and multi-organ involvement. ¹ Histopathological findings, such as interface dermatitis, apoptotic bodies, dermal neutrophils, and atypical lymphocytes may be present, however, due to its varying clinical presentations, diagnosis can be challenging. ²

Eosinophilia, leukocytosis, and atypical lymphocytes are the most common blood dyscrasias associated with DRESS. ³ Rarer are other hematological conditions, such as aplastic anemia, agranulocytosis, and thrombocytopenia. In particular, agranulocytosis is a potentially life-threatening event, and death can occur if treatment is delayed.

Agranulocytosis is very rarely associated with DRESS, with fewer than 10 cases described in the English literature.^4-9 Although both conditions are typically independent adverse effects, the possibility cannot be excluded that one condition could have precipitated the other. To the best of the authors’ knowledge, this is the first case report in literature reporting the coexistence of both DRESS and agranulocytosis, associated with carbamazepine in an adult patient.

Case Summary

An otherwise well 40-year-old woman presented to the emergency department with 3 days of worsening sore throat, fevers, and cervical lymphadenopathy, on the background of a 1-month history of dental pain with referred otalgia. She denied dysphagia, dysphonia, and dyspnea, and was a lifelong non-smoker. The patient had been previously investigated by the general medical practitioner for concurrent facial pain, and had been started on oral carbamazepine 100 mg twice a day for 2 weeks prior for presumed trigeminal neuralgia.

On examination, the patient was febrile at 38.2°C, with diffuse, painful bilateral cervical lymphadenopathy over the submandibular and submental regions. Carious upper and lower left third molars, and a carious lower right first molar was noted, with no significant oral swelling suggestive of an odontogenic source, or any mucosal or dermal lesions. The dental pain could not be replicated by palpation or percussion of the carious teeth, and flexible nasendoscopy was unremarkable.

Contrast-enhancing CT imaging of the neck showed marked retropharyngeal edema with no definitive peripheral enhancement to suggest abscess formation, and significant bilateral cervical lymphadenopathy. A dental abscess was present relating to the upper left third molar, however this did not correlate to the clinical features, and the degree of inflammatory change present was disproportionate and anatomically remote to the area, suggestive of another primary cause.

Laboratory testing on admission revealed: white cell count 3.0 × 10⁹/L (range 4-11), neutrophils 1.80 × 10⁹/L (range 2-8), lymphocytes 0.90 × 10⁹/L (range 1-4), and C-reactive protein 17 mg/L (range 0-5). Biochemical studies showed deranged liver function tests (LFT): ALP 233 U/L (range 30-110), GGT 793 U/L (range 5-35), and ALT 350 (range 5-35). Red blood cells, hemoglobin, and platelet counts were normal.

The patient was admitted for monitoring and further evaluation. Serology for EBV, mumps, HIV, ANCA, and ENA were negative. Thyroid function tests and serum electrolytes also did not reveal any abnormalities. An ultrasonic guided lymph node biopsy was performed, with non-diagnostic results. During the hospital stay, the patient developed further progressive derangement of LFT with a normal liver ultrasound and negative hepatic screen, and a progressive neutropenia with undetectable neutrophil levels. Agranulocytosis secondary to carbamazepine was suspected, and the drug was suspended as a result. Treatment with Granulocyte colony-stimulating factor (G-CSF) and corticosteroids were commenced with good response.

The patient reported a diffuse erythematous pruritic rash affecting the trunk and upper arms immediately following cessation of carbamazepine. A skin biopsy was performed and confirmed mild superficial perivascular lymphocytic dermatosis. The diagnosis of DRESS was immediately suspected. The patient received a score of “5” on the Registry of Severe Cutaneous Adverse Reactions scale (Regi-SCAR), ¹⁰ and satisfied the criteria of atypical DIHS using the Japanese consensus group DIHS criteria ¹¹ (Tables 1 and 2). An excisional biopsy of an enlarged axillary lymph node revealed features of dermatopathic lymphadenoma, adding further confirmation of DRESS. The patient clinically improved throughout inpatient stay, with no further hematological abnormalities and complete resolution of dermatological symptoms on outpatient follow up.

Table 1.

Results of the Registry of Severe Cutaneous Adverse Reactions Scale (Regi-SCAR) Scoring System.

Criteria	Score			Patient score
	No	Yes	Unknown
Fever (≥38.5°C)	−1	0	−1	0
Enlarged lymph nodes (≥2 sites, >1 cm)	0	1	0	1
Atypical lymphocytes	0	1	0	1
Eosinophilia
700 to 1499 or 10% to 19.9%	0	1	0	0
≥1500 or ≥20%	0	2	0
Skin rash
Extent >50%	0	1	0	0
At least 2: edema, infiltration, purpura, scaling	−1	1	0	1
Biopsy suggesting DRESS	−1	0	0	0
Internal organ involvement
One	0	1	0	1
Two or more	0	2	0
Resolution in ≥15 d	−1	0	−1	0
Evaluation of other potential causes (ANA, blood culture, serology for HAV/HBV/HCV, chlamydia/mycoplasma)	0	1	0	1
If none of these are positive and >3 are negative
Total score <2 no case; 2 to 3 possible case; 4 to 5 probable case; >5 definite case				5

Table 2.

Results of the Japanese Drug-Induced Hypersensitivity Syndrome Scoring System.

Maculopapular rash developing 3 wk after starting with a limited number of drugs	1
Prolonged clinical symptoms 2 wk after discontinuation of the causative drug	1
Fever (≥38°C)	1
Liver abnormalities (ALT ≥ 100 U/L)	1
Leukocyte abnormalities (at least 1 present)	1
Leukocytosis (>11 × 109/L)
Atypical lymphocytosis (≥5%)
Eosinophilia (≥1.5 × 109/L)
Lymphadenopathy	1
Human herpesvirus 6 reactivation	0
The diagnosis is confirmed by the presence of the 7 criteria above (typical DIHS) or of 5 of the 7 (atypical DIHS)	6

Discussion

This case report identifies DRESS as a rare cause of cervical lymphadenopathy, and emphasises the importance of a detailed, systematic framework for the investigation of causes of cervical lymphadenopathy.

Carbamazepine is a common anticonvulsant medication, used primarily for the treatment of seizure disorders and neuropathic pain. It is considered as the first drug of choice for patients with trigeminal neuralgia. Adverse hematological reactions attributed to carbamazepine have been well-documented in literature, however most effects are mild, transient and reversible. Only 1% to 2% of patients taking carbamazepine progress to develop more serious conditions of aplastic anemia, agranulocytosis, or thrombocytopenia. ¹²

Agranulocytosis is a rare, but potentially life-threatening event, characterized by a complete absence of blood granulocytes, resulting in an absolute neutrophil count of below 500/mm³. The pathophysiology of carbamazepine-induced agranulocytosis is unknown and has not previously been investigated. It appears to be an unpredictable complication with a variable time of onset. Patients with low leukocyte or neutrophil counts prior to carbamazepine treatment may be at an increased risk for developing blood dyscrasias, and hematological monitoring may be particularly useful in these cases. ¹² Untreated, agranulocytosis can lead to life-threatening complications, and death can occur due to uncontrolled septicemia, septic shock, or severe deep infections. With appropriate management, such as the use of G-CSF, systemic corticosteroids, and intravenous broad-spectrum antibiotic therapy, the mortality rate is around 5%. ¹³ Hence rapid diagnosis, appropriate management and prompt cessation of the offending drug is crucial.

DRESS is a rare Type IV hypersensitivity reaction, typically presenting within 2 to 8 weeks following drug initiation. Carbamazepine is a known offending drug, and treatment is similar to agranulocytosis, which includes prompt withdrawal of the medication. ¹⁴ Typical characteristics of DRESS include rash, fever, lymphadenopathy, facial edema, hematological abnormalities, and multi-organ involvement. The liver is the most commonly affected visceral organ, with previous reports of up to 87% of cases showing signs of liver damage. ¹⁵ Involvement can range from a transient increase in liver enzymes, to fulminant liver failure. The mortality rate of DRESS is around 5% to 10%, with liver failure being the most common cause of death. ¹⁵

The pathogenesis of DRESS is unclear, however, the late onset of symptoms suggests a delayed hypersensitivity reaction mediated by drug-specific T cells. ¹⁶ It has been proposed that variations in drug metabolism and abnormalities in the production and/or detoxification of active drug metabolites may play a role in the pathophysiology of the condition. ¹⁵

In this case report, all of the initial presenting symptoms of fever, lymphadenopathy, and liver dysfunction are all typical for DRESS. Differential diagnosis for the patient’s bilateral cervical lymphadenopathy with neck swelling on initial presentation included a spreading odontogenic infection, tuberculosis, mumps and EBV, all of which were proven negative through serology and imaging. The Naranjo algorithm was used to determine the causality of the adverse drug reaction, and received a score of “7”, indicating a probable association between carbamazepine and the patients’ clinical status ¹⁷ (Table 3). Following the onset of the rash, other serious cutaneous drug reactions needed to be excluded, such as Stevens Johnson syndrome and toxic epidermal necrolysis. Both of these conditions were excluded due to the lack of mucosal involvement and the absence of epidermal necrosis on pathology.

Table 3.

Results of the Naranjo Adverse Drug Reaction Probability Scale.

	Yes	No	Don’t know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse event appear after the suspected drug was administered?	+2	−1	0	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	+1
Did the adverse event reappear when the drug was re-administered?	+2	−1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	−1	+2	0	+2
Did the reaction reappear when a placebo was given?	−1	+1	0	0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score ≤0 doubtful case; 1 to 4 possible case; 5 to 8 probable case, ≥9 definite case				+7

Although no gold standard diagnosis criteria for DRESS has been recognized, this case report used 2 common criteria sets to confirm the diagnosis. The RegiSCAR scoring guideline classifies patients into 4 categories as “possible,” “probable,” “definite,” or “no,” depending on how many of the criteria are fulfilled ¹⁰ (Table 1). As eosinophilia is not always present and not mandatory for the diagnosis, a Japanese consensus group in 2006 established a 7-point diagnostic criterion for DIHS. ¹¹ For a “typical DIHS” diagnosis, all 7 criteria need to be satisfied, whilst a diagnosis of “atypical DIHS” is given if the case meets the first 5 (1-5) criteria (Table 2). However, both criteria sets contain criteria which can only be determined later in the disease course, and thus their use may be limited for real-time diagnosis.

The use of corticosteroids for DRESS, although a widely accepted treatment, remains controversial due to the lack of randomized controlled trials assessing their efficacy. ¹⁸ The ideal dosage and treatment duration remains unknown and continues to be debated. Frequently used anecdotally to control cutaneous inflammation, it has also been suggested for patients with liver or renal involvement. Skin biopsies may also help to confirm the diagnosis and can often show interface dermatitis, eczematous changes, apoptotic bodies, and the presence of dermal neutrophils and atypical lymphocytes. ²

Although agranulocytosis is a well described adverse effect of carbamazepine therapy, it is unknown whether the appearance of agranulocytosis was a direct adverse reaction from carbamazepine or a symptom of DRESS. However, the concurrence of both of these conditions is unlikely to be coincidental. It is quite possible that one of the conditions had caused immune alterations which may have facilitated the development of the other. Due to the rarity of DRESS with agranulocytosis, the pathogenesis behind this association has not been investigated.

Conclusion

Although rarely seen concurrently, DRESS and agranulocytosis are serious, potentially life-threatening adverse drug reactions which can initially present as cervical lymphadenopathy. As carbamazepine is considered first-line therapy for certain chronic neuropathic conditions such as trigeminal neuralgia, clinicians should be aware of the varying clinical presentations of both conditions. Prompt diagnosis and removal of the offending drug is crucial for effective treatment and successful management.