DRESS syndrome is a rare yet serious condition that can manifest in both children and adults as a morbilliform cutaneous rash accompanied by fevers, lymphadenopathy, hematological abnormalities, and visceral organ involvement [10]. It was historically referred to as phenytoin hypersensitivity syndrome, yet the name was changed when a multitude of additional culprit medications were elucidated [10]. While research seeks to further explain the pathogenesis, DRESS syndrome appears to be attributed to a delayed immunological reaction to the causative agent, a transient state of immunosuppression, and potential reactivation of latent herpes virus infections [10]. Visceral organ failure is often the cause of death in patients who succumb to the condition, and fulminant hepatitis with concomitant hepatic necrosis is commonly observed in these cases [3, 11].
Immunogenetic factors can raise a patient’s risk of developing DRESS syndrome [12]. Certain human leukocyte antigen (HLA) haplotypes have been linked to it [12]. For instance, there is a heightened susceptibility to reactions to carbamazepine in patients with the HLA-B*1502 variant [12]. Additionally, allopurinol can induce reactions among patients harboring the HLA-B*5801 allele [12]. Interleukin (IL)-17 is overexpressed in DRESS syndrome, including IL-17E, which can further raise circulating eosinophils, eotaxin, IL-4 level, IL-5 level, and IgE, thereby enhancing the eosinophilic immune response [12]. Genetic variants of IL-17 pathways can influence the development of atopy [13]. This patient had environmental allergies, eczema, and sensitivity to multiple hair/skin products. It would not be surprising if dysregulation of IL-17 rendered her susceptible to developing DRESS syndrome.
DRESS syndrome is recognized as a clinical diagnosis, which can be facilitated by the RegiSCAR criteria ([1], Table 1). A score above 5 solidifies the diagnosis [1]. This patient had a score of 7 for hospitalization, reaction suspected to be drug-related, acute rash, fever > 38 °C, enlarged lymph nodes at multiple sites, involvement of at least one internal organ (lung in the form of a pleural effusion), and blood count abnormalities ([1], Table 1). The lymphocyte toxicity assay (LTA) is a new diagnostic modality [14]. In LTA, the patient’s lymphocytes are isolated from the peripheral blood sample and incubated with the suspected culprit drug in the presence of a source of cytochrome p450 monooxygenase activity. [14]. Enhanced cell death correlates with a patient’s risk of having a hypersensitivity reaction to the drug used in the test [14]. This case did not warrant use of the LTA. The RegiSCAR criteria cemented the diagnosis.
The differential for DRESS syndrome includes SJS, TEN, AGEP, lupus, lymphomas, hypereosinophilic syndromes, and Kikuchi disease [5,6,7,8,9]. DRESS syndrome, SJS, and TEN all represent forms of severe cutaneous drug-induced eruptions [12]. While DRESS syndrome is associated with a morbilliform rash, SJS and TEN are severe mucocutaneous eruptions marked by diffuse erythema, blistering, and desquamation of the skin along with two or more other mucosal surfaces [3]. SJS and TEN are treated by removing the inciting drug and implementing supportive care measures [3].
AGEP is distinguished from DRESS syndrome by its nonfollicular small pustules surrounded by edema and erythema [5, 15]. This, coupled with epidermal acanthosis, spongiosis, and microvesicle and pustule formation on biopsy, makes the diagnosis [5, 15]. Immunophenotypical features identify DRESS syndrome: cutaneous effector lymphocytes represent a large quantity of the polyclonal CD8+ granzyme B+ T lymphocytes [15, 16]. AGEP and DRESS syndrome are managed by withdrawal of the culprit drug and initiation of steroids [5, 15, 16]. Lupus’ heterogeneous presentation requires satisfaction of 4/11 American College of Rheumatology criteria [6]. Treatment modalities for lupus include nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, steroids, and immunosuppressive agents [6].
Extensive lymphadenopathy made it necessary to rule out a lymphoproliferative disorder. Cutaneous T-cell lymphomas are the most common type of cutaneous lymphoma, including mycosis fungoides, Sézary syndrome, cutaneous CD30+ T-cell lymphoproliferative disorders, and primary cutaneous peripheral T-cell lymphoma [7]. Lymph node biopsy showed a reactive process rather than malignancy. Hypereosinophilic syndromes are defined by eosinophilia > 1.5 × 109 cells/L for > 6 consecutive months, eosinophil-induced organ damage, and exclusion of allergic, parasitic, and malignant etiologies for hypereosinophilia [8]. Kikuchi disease, or histiocytic necrotizing lymphadenitis, is a rare etiology of lymphadenopathy [9]. It is a benign, self-limited disease presenting with fever, fatigue, and night sweats, sometimes accompanied by joint pain and a rash [9]. Diagnosis requires analysis of clinical and histopathologic characteristics, subdivided into three types: early proliferative, necrotizing, and xanthomatous [9].
This particular case of DRESS syndrome was novel owing to multiple aspects of the presentation and clinical course. It has been discovered that internal organ involvement frequently impacts the hematopoietic, hepatic, and renal systems [17]. While the patient displayed evidence of hematopoietic involvement via leukocytosis and eosinophilia, along with hepatic involvement given the transaminitis, she also showed signs of pulmonary involvement given the cough and dyspnea in the setting of a new pleural effusion. Visceral organ involvement is typically a delayed manifestation of DRESS syndrome that can occur weeks to months after the appearance of the skin rash [17]. In this patient, the leukocytosis, transaminitis, and pleural effusion were noted on day 1 of the hospital stay, and the eosinophilia became evident on hospital day 2. In fact, the early organ involvement associated with this case facilitated the rapidity of the diagnosis by helping to fulfill elements of the RegiSCAR criteria.
Some of the hematologic manifestations of this patient’s case highlight the novelty of the clinical presentation. Although cytopenias are infrequently reported in conjunction with DRESS syndrome, this patient’s hemoglobin (Hb) dropped to 8.7 g/dL during the hospital stay despite having a baseline Hb of 12.4 g/dL [17]. Of note, no evidence of bleeding was found. Another unique hematological feature in this case was the lymphadenopathy in the absence of an association with nonsteroidal anti-inflammatory medications (NSAIDs) [17]. While it is known that lymphadenopathy is observed in 54–71% of cases of DRESS syndrome, it is more commonly witnessed with NSAIDs [17]. In contrast, this presentation involved diffuse lymphadenopathy on presentation, despite the lack of association with NSAID use.
In up to 80% of patients with DRESS syndrome, a concomitant finding of human herpesvirus reactivation is noted [17]. A few of the commonly encountered human herpesviruses implicated in DRESS syndrome include human herpesvirus (HHV)-6, EBV, HHV-7, and CMV [17]. Although the infectious workup completed included EBV and CMV PCR, viral detection might not be present until 3–5 weeks following symptom onset [17]. Since the human herpesviruses are ubiquitous, there is a possibility that reactivation of one of them was involved in this case, despite the fact that this was not pinpointed in the workup.
One of the feared complications that needed to be investigated in this case was the possibility of cardiac involvement. One retrospective analysis detected a prevalence of cardiac involvement among 19.1% of patients diagnosed with DRESS syndrome [17]. Some of the most severe cases display evidence of hypersensitivity myocarditis, acute necrotizing eosinophilic myocarditis, and restrictive cardiomyopathy [17]. However, patients with cardiac involvement may experience symptoms that could be shared by other organ pathologies, such as shortness of breath, hypotension, chest pain, and tachycardia [17]. For this reason, it was critically important to rule out the presence of any structural heart disease in the syncope workup, which returned negative. In some instances, cardiac manifestations can be delayed, which necessitates close follow-up for the patient.