Although transplant-associated
thrombotic microangiopathy (TA-TMA) commonly complicates pediatric hematopoietic cellular
therapy (HCT), pulmonary manifestations and histology of TA-TMA (pTA-TMA) are rarely reported, with scant data available on timing, risk factors, pathogenesis, and outcomes.
Pulmonary hypertension (PH) and diffuse alveolar
hemorrhage (DAH) are recognized manifestations of pTA-TMA. The objective of this study was to characterize the pathologic findings, outcomes, and coincident diagnoses preceding biopsy-proven pTA-TMA. In Institutional Review Board- approved retrospective studies, available lung tissue was reviewed at 2 institutions between January 2016 and August 2021 to include those with pulmonary vascular pathology. Histologic features of pTA-TMA were present in 10 children with prior respiratory decline after an allogeneic HCT (allo-HCT; n = 9) or autologous HCT (n = 1). Pathologic lesions included muscular medialization, microthrombi, and red cell fragments, in addition to perivasculitis and intimal
arteritis. Parenchymal findings included diffuse alveolar damage,
organizing pneumonia, and plasmocytic infiltrates. Six children were clinically diagnosed with TA-TMA, and all were treated with
eculizumab, at a median of 2.5 days after clinical diagnosis (range, 0 to 11 days). Four were identified postmortem. Coincident pulmonary
infection was confirmed in 8 of the 10 patients. Five allo-HCT recipients (56%) experienced
graft-versus-host disease (GVHD; 4 acute, 1 chronic) prior to the onset of respiratory symptoms. Two patients (20%) had clinically recognized DAH, although 9 (90%) had evidence of DAH on histology. Although all 10 patients underwent echocardiography at the time of symptom onset and 9 had serial echocardiograms, only 2 patients had PH detected. Treatments varied and included
sildenafil (n = 3),
steroids (n = 1), and
eculizumab (n = 6). One patient was alive at the time of this report; the remaining 9 died, at a median of 52 days after onset of respiratory symptoms (range 4 to 440 days) and a median of 126 days post-HCT (range, 13 to 947 days). pTA-TMA is a heterogeneous histologic disease characterized by arteriolar
inflammation, microthrombi, and often DAH. pTA-TMA presented with respiratory decline with systemic TA-TMA in all patients. Clinicians should maintain a high degree of suspicion for DAH in patients with TA-TMA and pulmonary symptoms. Coincident rates of GVHD and pulmonary
infections were high, whereas the rate of PH identified by echocardiography was 20%. Outcomes were poor despite early use of
eculizumab and other
therapies. Our data merit consideration of pTA-TMA in patients with acute respiratory decline in the setting of systemic TA-TMA, GVHD, and
infection. Investigation of additional
therapies for pTA-TMA is needed as well. © 2022 American Society for
Transplantation and Cellular
Therapy. Published by Elsevier Inc.