Miliaria Crystallina Type Rash as an Unusual Presentation of Acute Graft Versus Host Disease (GVHD) After Hematopoietic Stem Cell Transplant’

To The Editor, Acute graft versus host disease (aGVHD) is a frequent complication seen after allogeneic hematopoietic stem cell transplant (HSCT). It is an immune reaction of the donor cells against the host tissues. The incidence being 30-50% post fully matched allo-HSCT.[1] It accounts for 15% of mortality post-HSCT.[2] GVHD commonly affects the skin, liver and gastrointestinal tract. Several cutaneous manifestations of aGVHD such as erythematous maculopapular morbilliform eruptions, follicular erythema, epidermolysis, pityriasis rubra pilaris and psoriasis vulgaris-like eruption have been previously reported in the literature.[3] Miliaria crystallina are rapidly evolving noninflammatory vesicles. They are subcorneal or intracorneal vesicles resulting from superficial obstruction of eccrine sweat ducts. These eruptions are frequently observed among neonates due to the immaturity of the eccrine glands. However, they may also develop in hot, humid and tropical climates. However, miliaria crystallina as a presenting symptom of aGVHD following stem cell transplant has not been documented well in the medical literature. We hereby report a case of miliaria crystallina as the presenting manifestation of aGVHD in a young girl with Fanconi anaemia undergoing T cell replete haploidentical bone marrow HSCT using post-transplant cyclophosphamide from father donor. A 6-year-old girl, the second born of a non-consanguineous marriage resident of Kenya, Africa presented with the chief complaints of recurrent episodes of epistaxis for two years. She suffered from frequent nose bleeds on occasions requiring hospitalization and multiple platelet transfusions. On examination, she had several dysmorphic features in the form of microcephaly, “Bird”-like facies, bilateral microphthalmia, single left palmar crease, bilateral malformed thumbs and perioral hyper-pigmentation. Systemic examination was normal. She was suspected to have a primary bone marrow failure syndrome with dysmorphic features likely Fanconi anaemia and was evaluated for the same. On evaluation, her complete blood counts showed pancytopenia and bone marrow aspiration and biopsy showed hypocellular bone marrow. Chromosomal fragility test for Fanconi anaemia was positive and genetic test revealed FANCG homozygous mutation. She was diagnosed to have Fanconi anaemia, and the family was counselled for a HSCT. On receiving informed consent from her parents, the pre-transplant workup was carried out. As there were no suitable fully matched related or unrelated donors available, father was identified as a suitable haploidentical donor. She received transplant conditioning with Fludarabine, anti-thymocyte globulin (ATG) and total body irradiation. A bone marrow harvest was performed from the donor and was transfused to the patient on day 0. Post-transplant GVHD prophylaxis with cyclophosphamide (on day +3 and +5), cyclosporine and mycophenolate mofetil (MMF) was added. During the course of her HSCT, she had several issues such as cyclosporine-induced liver toxicity, grade 3 mucositis and febrile neutropenia with Candida parapsilosis sepsis for which she received broad-spectrum antibiotics and symptomatic treatment was given. On day +16, she developed persistent high-grade fever spikes and her oxygen requirement increased. On evaluation, the inflammatory parameters and serum ferritin showed a rising trend, and blood and urine cultures were sterile and viral workup (Adenovirus, CMV, EBV, Parvovirus, HHV6 PCR) was negative. A possibility of hemophagocytic lymphohistiocytosis (HLH) was considered and she was treated with IV Methylprednisolone (1 mg/kg/day), and subsequently, Inj Anakinra (2 mg/kg/dose) was added. Following treatment, the fever subsided immediately; however, serum ferritin continued to remain elevated. On day +21, she developed persistent loose motions containing large quantity blood in stools. Around the same time, she also developed a micro-vesicular rash (Day +22) initially involving the face, scalp and flexures of the arms, axilla and inguinal region which later spread to involve the entire face, neck, chest and extremities. She was reviewed by the dermatologist and the rash was described to be miliaria crystallina like eruptions [Figure 1]. In view of persistent loose motions, bleeding per rectum and skin rash, a possibility of acute GVHD was considered. On evaluation, her complete blood counts showed anaemia and progressive thrombocytopenia (1,18,000 to 42,000/cumm) with deranged liver function tests. The stool workup for infections was negative and the blood culture was sterile. Skin biopsy showed presence of anisonucleosis of keratinocytes, few scattered apoptotic keratinocytes in the lower layers of the epidermis with extensive basal vacuolar degeneration and few scattered lymphocytes [Figure 2]. These features were suggestive of aGVHD. A sigmoidoscopy and gut biopsy were performed which also showed features suggestive of acute GVHD. Hence, the dose of steroids was increased (2 mg/kg/day), and MMF was continued. Following treatment, the loose motions and bleeding per rectum subsided and the rash slowly healed [Figure 3]. Although she improved clinically, serum ferritin continued to increase (29491 to 48672 ng/ml). Hence, the immunosuppression was increased and Ruxolitinib was added (Day +25) and Inj anakinra was withheld. She continued to improve clinically, and ferritin levels gradually decreased to normal limits. Post-engraftment, whole blood chimerism on day +22 showed 99% donor cells. On day +34, she was discharged from the BMT unit, and she remains on close follow-up.Figure 1: Miliaria crystallina rashFigure 2: Skin biopsy HPE image showing features of Miliaria crystallinaFigure 3: Healed rash after treatmentMiliaria is a self-limiting skin rash triggered by blocked eccrine sweat glands, also known as “prickly heat” or a “sweat rash”. The three main types of miliaria are profunda, rubra and crystallina, classified based on the degree of obstruction of the eccrine gland leading to clinical and histological features.[4] Miliaria crystallina or sudamina affects 5-9% of neonates in the first 2 weeks of life.[5] On histology, subcorneal or intracorneal vesicles from the intraepidermal portion of the duct are seen.[6] Miliaria crystallina though uncommon can rarely be associated with aGVHD. Bae K et al. reported a 50-year old man who developed whole body flaccid fluid-filled eruptions 6 weeks after undergoing a liver donor liver transplantation. However, despite treatment with immunosuppressives, this patient succumbed due to hematologic complications and brain damage.[7] Our report suggests that Miliaria crystallina-type skin rash can rarely be a manifestation of acute GVHD in the post-transplant setting. Awareness of this atypical manifestation may help in the early diagnosis and improved survival of patients with aGVHD. Abbreviations aGVHD = Acute graft verus host disease ATG = Anti-thymocyte globulin BMT = Bone marrow transplant HSCT = Hematopoietic stem cell transplant MMF = Mycophenolate mofetil HLH = Hemophagocytic lymphohistiocytosis G-CSF = Granulocyte colony-stimulating factor Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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