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    • TTP has been associated with

    2019-04-28

    TTP has been associated with a deficiency in plasma ADAMTS13 activity, which is caused by genetic mutations in or acquired autoantibodies to this enzyme. In the idiopathic form, TTP is an autoimmune disease and, thus, may be triggered by immunological stimuli such as vaccination or viral infection. It has been hypothesized that a cross-reactive stimulation between vaccinal or virus rac inhibitor and ADAMTS13 protease or the bystander activation of a vaccination or virus with ADAMTS13-specific IgG causes a response. Furthermore, inflammatory responses caused by immunological factors represent another pathway linking endothelial injury and TTP [2]. EBV may rescue autoreactive B cells to produce autoantibodies that contribute to the development of TTP. The present case had a transient ADAMTS13 deficiency that was attributed to autoantibodies against ADAMTS13. The increased EBV load suggested active EBV lytic replication in the presence of TTP. Since the viral load was associated with ADAMTS13 activity, the reactivation of EBV may be associated with the development of TTP.
    Conflict of interest
    Acknowledgement
    Case description Fusariosis in patients with prolonged neutropenia have a dismal prognosis and survival is extremely low at 4% [2]. Fusarium species are plant pathogens found in air and soil, and enter the human body through inhalation, ingestion, and heel or toe fissures. Early detection of Fusarium infections is difficult due to lack of specific laboratory assays. Management is challenging due to variability of anti-fungal susceptibilities and lack of optimal treatment strategy [1]. We report the successful treatment of a patient with relapsed AML and invasive sino-pulmonary and cutaneous Fusarium solani infection during a course of salvage chemotherapy and subsequent allogeneic SCT. A 66-year-old Caucasian male with diabetes, hyperlipidemia and obstructive sleep apnea presented to the NIH Clinical Center with relapsed AML. At the time of presentation, he was noted to have firm, non-tender, erythematous subcutaneous nodules on his bilateral anterior lower limbs and painful edematous feet (Fig. 1A/B). A skin biopsy of one of these nodules was interpreted as septal panniculitis. The patient was consented to treatment on clinical trial NCT02527447 and received treatment with salvage chemotherapy of mitoxantrone 12mg/m2/day IV on days 1–3, etoposide 200mg/m2/day continuous IV infusion (CIV) on days 8–10, and cytarabine 500mg/m2/day CIV on days 1–3 and 8–10 (EMA). Infectious prophylaxis with caspofungin was given during chemotherapy and oral posaconazole was started after chemotherapy as per institutional standard. During the third week after chemotherapy, new painful nodules appeared on his trunk, neck, upper arm and the plantar aspect of his foot. In addition, there was interval development of bilateral focal patchy nodular pulmonary infiltrates with ground glass and reticular appearance on chest CT imaging (Fig. 1C/D), followed by development of paranasal sinusitis. The patient underwent bronchoscopy with broncho-alveolar lavage, skin biopsy of a palpable nodule, and sinus biopsy. Fusarium solani was isolated from all three of these sites (Fig. 1F/G). Fungal susceptibilities showed amphotericin minimum inhibitory concentration (MIC): 2mcg/mL and terbinafine MIC: 2mcg/mL and resistance to micafungin, posaconazole and voriconazole. The patient was initially treated with amphotericin, however, subsequent CT chest one week later showed progression of pulmonary infiltrates, and terbinafine and voriconazole were added despite fungal susceptibilities. Bone marrow examination on day 35 showed a hypocellular (5%) marrow with trilineage hypoplasia and no definitive evidence of AML. Peripheral blood neutrophils were absent. A course of filgrastim daily injections was administered for ten days, at which time his absolute neutrophil count (ANC) recovered to greater than 2.0 × 109/L. The total duration of severe neutropenia with ANC less than 0.1 × 109/L was 40 days. At the time of ANC recovery, the result of his Fungitell serum assay (Beacon diagnostics) was positive (167pg/mL, positive = > 80pg/mL), however, the appearance of his skin nodules improved, and pulmonary and sinus radiographic abnormalities stabilized during this time. Complete remission with no evidence of minimal residual disease was confirmed on bone marrow examination on day 73. At day 100 following salvage chemotherapy, the CT showed resolution of the nodules (Fig. 1E) and Fungitell result normalized (< 60pg/mL, Fig. 2A). He received consolidation chemotherapy with clofarabine 20mg/m2 IV on days 1–5, followed by haplo-identical SCT 10 days later. A two-step approach [3] was used as a myeloablative conditioning regimen including fludarabine 120mg/m2, total body irradiation (12Gy), and a donor lymphocyte infusion (2 × 108/kg CD3+T cells) which was followed by cyclophosphamide 120mg/kg prior to CD34+ selected peripheral blood stem cell infusion. GVHD prophylaxis was with sirolimus (trough goal 5–12ng/mL) along with ultra-low dose interleukin-2 (ULD-IL2) 100,000 international units/m2(clinical trial NCT02226861). Micafungin was used as anti-fungal prophylaxis until day 33 following post-transplant. No other anti-fungal prophylaxis therapy was used.