Phloroglucinol-Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome with Subsequent Fulminant Type 1 Diabetes (FT1D): A Rare Case and Literature Review

This study reported a woman with drug reaction with eosinophilia and systemic symptom (DRESS) syndrome induced by phloroglucinol who developed fulminant type 1 diabetes as sequelae. The literature review emphasized the necessity of at least seven months of follow-up for better management of DRESS syndrome.


Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a hypersensitivity reaction characterized by fever, facial edema, erupting skin rash, eosinophilia, lymphadenopathy, and internal organ involvement [1].Te most frequently involved organs were the liver (75%), the kidneys (37%), and the lungs (32%) [2,3].Hepatic involvement could result in transaminitis, hepatic necrosis, and even failure.Renal involvement could result in elevated creatinine, which may progress to renal failure [3].Pulmonary involvement could result in interstitial pneumonitis and may progress to acute respiratory distress syndrome and respiratory failure [4].Gastrointestinal tract, including esophagus, stomach, small intestine, pancreas, and colon, could also be involved in DRESS syndrome, which is less common but also underreported [5].Te acute phase of pancreatic involvement in DRESS can manifest as acute pancreatitis and fulminant type 1 diabetes (FT1D) [6].It is noted that patients with DRESS syndrome may not only experience internal organ involvement during the acute phase but also develop new-onset diseases due to immune dysregulation after recovery, among which FT1D is rarely reported [7].Here, we report a case of DRESS syndromeinduced FT1D, review the published cases, and summarize the clinical manifestation thereof.

Main Text
A 42-year-old woman presented to our hospital complaining of intermittent fever (T max 39.0 °C) and malaise.A review of her medical history revealed abdominal pain two weeks ago and a phloroglucinol application for four days.She denied any other medications during this period.Te nonpruritic erythematous macules and papules were found on the face and abdomen ten days before, progressing rapidly to the extremities.Physical examination revealed facial erythematous edema, scaly erythematous macules, and papules on the trunk and extremities, covering over 80% of the body surface area (Figures 1(a .63E + 04 copies/ml, normal antinuclear antibody, blood culture, and hepatitis virus B. Otherwise, the biochemistry, blood glucose, and abdominal ultrasound results were unremarkable.Dermatopathology examination revealed dyskeratosis, interface dermatitis, melanin pigment incontinence, and eosinophils in the superfcial dermis, indicating drug-induced manifestation (Figure 2).Based on the RegiSCAR diagnostic criteria, a score of 6 was made, indicating defnite drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) syndrome.Methylprednisolone 40 mg intravenously daily was prescribed and gradually tapered after the lesions and liver dysfunction recovered.Te patient was discharged with recovery after 20 days of hospitalization.
Twelve days later, the patient experienced muscle weakness and nausea, resulting in an emergency department visit.Laboratory studies showed hyperglycemia (42.6 mmol/ L), urine ketone body of 10 mmol/L (3+), urine glucose of 111 mmol/L (4+), metabolic acidosis (pH: 7.34; HCO 3 − 18 mm/L; PCO 2 : 22.5 mmHg), and glycated hemoglobin (HbA 1c ) of 7.6%.Terefore, the diagnosis of diabetic ketoacidosis (DKA) was made, and she was transferred to the Department of Endocrinology.Te subsequent test revealed abnormality of autoimmune type 1 diabetes-related antibodies, among which the anti-insulin antibody was 153.80 IU/ml and the antiglutamic acid decarboxylase antibody and the anti-islet cell cytoplasmic antibody were negative.Levels of C-peptide were <0.01 nmol/L in 0′-30″-120′ examination.Pancreatic enzymes were within a normal range.According to the criteria for the diagnosis of FT1D from the Committee of the Japan Diabetes Society [8], the patient was diagnosed with FT1D and insulin replacement therapy was prescribed, which induced rapid remission of symptoms.

Discussion
DRESS syndrome is characterized by lymphocyte activation, peripheral eosinophilia, reactivation of herpes viruses, and multiorgan involvement.Te pathogenesis is hypothesized to be multifactorial, involving a combination of impaired    [4].Common DRESS syndrome culprits contain anticonvulsant, antimicrobial, antiviral, antidepressant, antihypertensive, biologic, NSAID, and miscellaneous drugs, while no case of phloroglucinol-induced DRESS syndrome has been reported [4].DRESS syndrome-induced immune system dysregulation may result in several autoimmune sequelae, including autoimmune thyroiditis, reactive arthritis, systemic lupus erythematosus, and diabetes mellitus [9].FT1D is a subtype of type 1 diabetes mellitus characterized by the rapid onset of ketoacidosis within a few days after developing hyperglycemic symptoms.Te pathogenesis of FT1D involves a complex interplay between genetic background, virus infection, and immune dysregulation [10].Kano et al. [9] reported that the prevalence of FT1D was 3.45% (5/145) according to the survey on sequelae of DRESS syndrome patients.Onuma et al. [11] reported an elevated frequency of FT1D in DRESS syndrome patients compared with the general Japanese population (0.54% vs. 0.010%).Considering the susceptibility of DRESS syndrome-induced FT1D, it is imperative for both physicians and patients to remain aware of regular follow-up care.

Case Reports in Dermatological Medicine
We conducted a literature review to summarize the characteristics of DRESS syndrome-induced FT1D.A total of 30 case reports (our case contained) were included (Table 1; see more details in Supplementary Table 1).Onset age ranged from 9 months to 78 years, with the mean age of 52.35 years.Te frequent causative drugs included carbamazepine, mexiletine, dapsone, and allopurinol, which were consistent with the common culprits in DRESS syndrome.Endocrine system, digestive system, and cardiovascular system were mostly associated with complications.Te involvement of the endocrine system (thyroiditis) and digestive system (pancreatitis) may suggest the development of FT1D in patients with DRESS might share some pathogenesis with the autoimmune polyendocrine syndrome [12].It is noted that the average interval between the onset of DRESS syndrome and the development of FT1D was 35.51 days (ranging from 0 days to 199 days).Our study highlights the need for long-term follow-up after DRESS syndrome recovery for better management.In light of the fndings regarding the time interval, we recommend a 5week follow-up after DRESS syndrome recovery, followed by ongoing monitoring for at least seven months.
Te pathogenesis of DRESS syndrome-induced FT1D was still unclear, although they shared similar pathogenic aspects, including genetic susceptibility, viral infections, and immune dysregulation.
Diferent HLA haplotype classes were reported in FT1D and DRESS syndrome.Growing evidence has shown the association of specifc class II human leukocyte antigen (HLA) haplotypes and FT1D [13,14] Viral infections were involved in both mechanisms of FT1D and DRESS syndrome [15,16].Previous research revealed that HHV-6 infection could strongly induce both proliferation of CD4 + and CD8 + T cells [17,18].Activated T lymphocytes produced large amounts of tumor necrosis factor-α, interleukin-2, and interferon-c and considered key mediators of the cytokine release that induces the symptoms found in DRESS syndrome patients [15].Te accelerated innate immune response by viral reactivation may result in the rapid destruction of pancreatic β-cells in FT1D with DRESS syndrome [9].A recent study verifed that the

Conclusion
DRESS syndrome could be accompanied by autoimmune sequelae, among which the FT1D was characterized by acute onset and rapid progression of hyperglycemia and DKA.Educating patients to follow up regularly for at least seven months is worthwhile, especially for patients with positive results for viral tests and susceptible HLA haplotypes.

Figure 1 :
Figure 1: Clinical manifestation of the patient.(a) Facial erythema, edema, and (b) scaly erythematous macules and papules on the trunk and extremities.Te total lesions cover over 80% of the body surface area.