A 3-year-old female received an unrelated cord blood stem cell transplantation (URCBT) for the treatment of neuroblastoma of the adrenal gland in February 2010. She developed graft-versus-host disease (GVHD) on day 4 post-URCBT and was treated with oral corticosteroids. On day 17 post-URCBT, she manifested abnormal lacrimation from her left eye. On day 26 post-URCBT, she also manifested considerable salivation and multiple ulcers of her lips and oral mucosa, which was diagnosed as gingivostomatitis by a dentist. On day 30 post-URCBT, several millet-sized vesicles and light red papules emerged in the perioral region. We treated them as irritant dermatitis. At that point, serum level of anti-herpes simplex virus (HSV) immunoglobulin (Ig)G was 18.4 (normal, <2.0), and that of serum anti-HSV IgM was 0.27 (normal, <0.8), although there was no apparent clinical history of HSV infection. However, on day 33 post-URCBT, ulcerative lesions appeared around the left side of her lip and spread to the periphery rapidly. We found viral giant cells in these lesions by the Tzanck test. The administration of i.v. acyclovir (25 mg/kg per day) was re-started, because the prophylactic administration of acyclovir (12.5 mg/kg per day) had ended 14 days after URCBT. Her peripheral leukocyte counts were under 200/μL at that time, and this level persisted until she died. The administration of Ig exhibited no beneficial effects, and the ulcers expanded to cover almost her entire face and had turned black toward the peripheral portion (Fig. 1). Histopathological examinations by staining using anti-HSV antibodies and periodic acid-Schiff staining revealed infection with HSV in the peripheral white necrotic area, and infection with both HSV and fungus in the central black necrotic area (Fig. 2). Candida gulliemondii and Aspergillus species were detected in her blood. The i.v. administration of amphotericin was not effective. She finally developed multiple organ failure and died, although whether HSV infection occurred systemically could not be explored.
Atypical cutaneous manifestations lacking in inflammatory findings were one of the clinical features of this case, presumably reflecting poor inflammatory infiltration (Fig. 2a) due to her severe bone marrow suppression. A rapidly spreading black necrosis was another notable feature in this case. A significant invasion of the endothelium by HSV (Fig. 2b) presumably contributed to the blood vessel damage. An overgrowth of fungus into the dermis might have played a part in the formation of the black necrotic skin. Colonizing oral flora including fungi might have spread systemically through the mucosal ulceration in the present case.
The administration of acyclovir failed in treating the HSV infection, probably due to the prolonged severe immunosuppressive state which was caused by the failure of grafting of the transplanted stem cells. In addition, substantial bone marrow suppression might have affected the wound healing in this case, because recent studies suggested that mesenchymal stem cells derived from bone marrow could significantly impact wound healing.2 Another possibility is that she was infected with acyclovir-resistant HSV. The emergence of acyclovir-resistant HSV has become more common, particularly in unrelated human leukocyte antigen (HLA)-mismatched family transplant recipients and in patients with GVHD.
Patients who have undergone hematopoietic stem cell transplantation (HSCT) and are in the pre-engraftment phase have two major risk factors for infection: (i) prolonged neutropenia; and (ii) breaks in the mucocutaneous barrier due to the HSCT preparative regimens. The abnormal lacrimation from her left eye and left corneal epithelium disorder, which were thought to be caused by HSV reactivation, emerged only a few days after the prophylactic administration of acyclovir was stopped. This case suggests that the duration of antiviral prophylaxis should be adjusted for each patient and each situation, as previously advocated. According to the guidelines, the antiviral prophylaxis should have continued throughout the aplastic phase, although no treatment could have prevented the mortality in the severely immunocompromised state of the present case.