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Fatal pulmonary hemorrhage associated with early immune reaction after reduced intensity stem cell transplantation.

Several types of immune reactions have been reported after cord blood transplantation (CBT) (1). With the exception of acute graft-versus-host disease (GVHD), little information is available on them (2– 4). We report a patient who developed fatal pulmonary hemorrhage associated with preengraftment immune reaction (PIR) after reduced-intensity CBT (RI-CBT). A 60-year-old man with chemorefractory multiple myeloma (IgG type) underwent RI-CBT using two-antigen mismatched single-unit cord blood in April 2005. He had received multiple courses of chemotherapies, including melphalan. Both respiratory function test and chest computed tomography scan showed normal findings at pretransplant evaluation. The preparative regimen comprised fludarabine 30 mg/kg for 6 days and busulfan 4 mg/kg for 2 days. GVHD prophylaxis was intravenous tacrolimus 0.03 mg/kg. Infused number of all nucleated cells was 2.0 10E7/kg. Ciprofloxacin, acyclovir, and itraconazole were given as bacterial, viral, and fungal prophylaxis, respectively. His clinical courses had been uneventful until day 8, when he developed a high-grade fever. Skin eruption and weight gain also were documented. Blood culture was negative. CMV antigenemia was not conducted because he had not achieved engraftment. Clinical diagnosis of PIR was established based on these findings, and he received oxygen, hydration, and cefepime. He developed progressive dyspnea and massive hemoptysis on day 9, resulting in hypovolemic shock. His conditions deteriorated rapidly, and he died of respiratory failure on day 10. His platelet count was 2.1 10E3/ L, and he required platelet transfusion. Coagulation test was not conducted. Postmortem examination of the lung showed diffuse alveolar hemorrhage (DAH) with pulmonary congestion (Fig. 1a). Pulmonary effusion was presented. We failed to find any evidence of bacterial, fungal, and viral infection or that of disseminated intravascular coagulation (DIC). There were no signs suggesting myeloma or lymphocytes infiltration in the lung, and no hemorrhage was documented except for the lung. We, however, cannot deny the possibility that unrecognized infection and/or DIC might have contributed to the development of DAH. Bone marrow examination showed hypocellular marrow with residual myeloma cells. Except for the lung, no hemorrhage was documented. DAH is a regimen-related toxicity associated with infection and thrombocytopenia (5). Considering the intensity of the preparative regimen, it is unlikely that DAH was attributable to regimen-related toxicity alone. Interestingly, there was a short interval between the development of PIR and that of DAH. These findings suggest an association between them. PIR is usually self-limiting or responds well to corticosteroid, and it rarely becomes fatal (1). The patient had received long-term administration of melphalan before RICBT, which might have caused underlying damages of the lung, leading to the development of DAH (6). We should recognize that PIR could be fatal in elderly patients or those with organ damages. In serious case of PIR, corticosteroid should be started immediately after evaluation of infection and DIC. There is little information on the pathogenesis of PIR; however, several hypotheses, including hyperacute GVHD, cytokine storms, and homeostasis-driven proliferation of T cells have been postulated (1). Narimatsu et al. reported that intensive GVHD prophylaxis could reduce the incidence of PIR (7), suggesting that immunological mechanism plays a role in its pathogenesis. Considering that lymphocyte infiltration in the lung was not documented in this patient, hyperacute GVHD might not be a probable cause of fatal PIR. Further basic and clinical studies are required to elucidate its pathogenesis. FIGURE 1. (A) Microscopic findings of the lung showing diffuse alveolar hemorrhage (HE stain; 100). There was no finding of lymphocyte infiltration.