Severe hypocalcemia and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome under deferasirox therapy for myelodysplasic syndrome

Abstract

To the editor: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare life-threatening adverse drug reaction. The culprit drugs are dominated by Allopurinol and anticonvulsants [1]. The efficiency of deferasirox (DFX) has been reported in the treatment of iron overload secondary to myelodysplastic syndrome (MS) management [2]. We report the first case of DRESS during DFX treatment, associated with severe hypocalcemia. In 2010, a 75-year-old woman, followed for MS since 2004, was admitted in ICU, for exanthema associated with skin necrosis aeras, facial edema, and fever, 15 days after starting DFX therapy. Blood tests revealed no eosinophilia, leukocytosis (13,5 × 109 L−1 (N < 10)), atypical lymphocytes, increased liver enzymes (ALAT until 10 N), prothrombin time at 30% (N > 70%), disseminated intravascular coagulation (DIC) signs (low fibrinogen 0.5 g L−1 (N > 1.8), thrombopenia until 17 × 109 L−1), and severe hypocalcemia (ionized calcemia at 0.92 mmol L−1 (N > 1.4 mmol L−1). Ferritin level was high (12,546 μg L−1 (n < 322)), and triglycerides were normal. Serum calcium concentration before DFX therapy was normal. Bone marrow biopsy revealed eosinophils infiltrate (20%) and iron overload. without any sign of hemophagocytic syndrome, leukemia, or MS. VIH,VHB, VHC, HHV6, CMV, and EBV serology and blood polymerase chain reaction were negative. Repeated blood cultures and mycoplasma pneumoniae serology were negative. The evolution was complicated rapidly by cardiac arrest without any etiology except severe hypocalcemia. The vitamin D level (1.25OH D3) was low (<10 ng mL−1 (N > 50)). Parathormone level was normal. Histologic analysis of skin and necrosis areas biopsy revealed perivascular lymphocytes infiltrates with eosinophils, compatible with DRESS and intracapillary thrombosis, compatible with cutaneous lesions of DIC. The diagnosis score, according to criteria published by Kardaun et al. [3], was calculated at 6 and confirm the diagnosis of probable DRESS. At admission, DFX was immediately stopped and systemic intravenous corticosteroid treatment by methylprednisolone 60 mg day−1 and calcium supplementation, without antibiotics, were started. Under this therapy, the cutaneous rash, necrosis, and visceral involvement slowly improved. Nevertheless, electroencephalogram assay revealed the diagnosis of definitive chronic vegetative state probably secondary to cardiac arrest. DRESS is characterized by clinical criterias such as later onset, skin rash, multiorgan involvement, atypical lymphocytes, and eosinophilia [1]. DRESS is a lethal disease with an estimated mortality of 10%. Nevertheless, eosinophilia is often absent or delayed for 1 to 2 weeks, as reported by Chen et al. [4] with only 50% of eosinophilia or atypical lymphocytes in 60 DRESS cases. In our case, corticosteroids were started immediately before admission, which could also rapidly decrease or hide blood anomalies. Furthermore, even if eosinophils level were not high in blood, they could infiltrate other organs, such as the skin or bone marrow, as in our case. Only two cases of DFX allergic reactions have been reported including acute renal failure and delayed hypersensitivity syndrome [5]. DRESS is not well known as being responsible for profound hypocalcemia. Furthermore, hypocalcemia under DFX therapy with recurrence after re-exposure have been reported and suggest that DFX could be a risk factor of hypocalcemia in this case [6]. The suspected pathophysiology is an “hungry bone syndrome.” Under DFX, iron chelation in bone's patient lead to an increase of bones calcium uptake and in consequence to serum calcium anomalies. In conclusion, clinicians should be aware of the risk of (i) severe hypocalcemia during DFX therapy and (ii) potentially lethal DRESS under DFX therapy, which is being more and more prescribed. All the authors disclose any financial relationship with a biotechnology and/or pharmaceutical manufacturer that has an interest in the subject matter or materials discussed in the submitted article. Benoit Ben Said [email protected]*, A. Rozieres , Olivier Martin , Jean-Francois Nicolas*, Frederic Berard*, * Severe Cutaneous Drug Reaction Regional Center, Allergology and Clinical Immunology, CHU Lyon Sud, Hospices Civils de Lyon, Inserm U851, Université Claude Bernard Lyon 1, 69495 Pierre Benite Cedex, France, Intensive Care Unit, CHU Edouard Herriot, Hospices Civils de Lyon, 69003 Lyon, France.