PMC8718506_01
(A) Timeline of major events pre- and post-HSCT. (B) BK viremia and viruria with therapeutic interventions denoted in the pre- and post-transplant period. (C) Blood ferritin, CRP, and (D) plasma cytokine levels pre- and post-onset of CRS, with arrows indicating VST infusion (blue) and delivery of each of 4 total doses of tocilizumab (black). Notably, the first dose of tocilizumab was administered after cytokine levels were drawn on day +45. AKI, acute kidney injury; Bu, busulfan; CDV, cidofovir; CRP, C-reactive protein; CRS, cytokine release syndrome; Cy, cyclophosphamide; DLBCL, Diffuse large B-cell lymphoma; Flu, fludarabine; HSCT, hematopoietic stem cell transplantation; IFN-gamma, interferon gamma; IL-6, interleukin-6; VST, quadrivalent anti-CMV, -EBV, -ADV, and -BK virus specific T-cells; PT/Cy, post-transplant cyclophosphamide; RIC, reduced intensity conditioning; SOS, sinusoidal obstructive syndrome; TBI, total-body irradiation; Toci, tocilizumab; TNF-alpha, Tumor Necrosis Factor alpha; VOD, veno-occlusive disease.
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BK viremia simultaneously increased from 588,844 copies/mL (3 days pre-HSCT) to 6,456,542 copies/mL on day +4 ( Figure 1A ). Grade IV gross hematuria, managed with daily blood product transfusions, persisted alongside worsening acute kidney injury (AKI, day +14) ( Figure 1A ). BK viremia measured 5,754,399 copies/mL at third infusion, nearly a full log increase from viral load with pre-transplant VSTs ( Figure 1B ). A rapid rise in ferritin was seen from 4,641 mcg/mL pre-VSTs (day +40) to 5,313 mcg/mL post-infusion (day +45) and 17,456 mcg/mL on day +47 ( Figure 1C ). CRS onset and prior to initiation of the IL-6R (receptor) blocker tocilizumab ( Figure 1D ). Concurrent blood, urine, and viral testing remained negative for any signs of new infection.
Interventional radiology findings. (A) Selective left renal arteriogram demonstrating active arterial bleeding in the midpole area (white arrow). (B) Superselective left renal arteriogram confirming active bleeding source (white arrow). (C) Superselective left renal arteriogram showing coil occlusion of arterial bleeding source (white arrowhead), as well as suspicious second bleeding source (white arrow). (D) Superselective left renal arteriogram (parenchymal phase) showing slower extravasation from same location as image C (white arrow), as well as third potential bleeding source (white arrowhead). (E) Superselective left renal arteriogram performed 72 hours after embolization redemonstrating bleeding sources (white arrows) in early arterial phase and delayed (F) images. (G) Superselective left upper pole renal arteriogram performed during second embolization showing distal vessel narrowing (white arrowheads) and occlusions (white arrows). (H) Right renal arteriogram performed during second left renal embolization showing a lower pole arteriovenous fistula (white arrow). Pathology findings. (I) Exudative phase diffuse alveolar damage with hyaline membrane formation (arrows) (H&E, 200x). (J) Acute tubular injury with tubular dilation (TD) and reactive atypia of surviving tubular epithelial cells (arrowheads) (H&E, 400x). (K) Hepatic necrosis (N) and apoptosis (arrow), (H&E, 400x). (L) Occluded hepatic vein filled with loose blue-stained collagen (arrows) (Masson trichrome, 400x).
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Complete left renal artery embolization on day +42, followed by initiation of intravenous cidofovir ( Figures 2A-H ), stabilized the patient for transport to receive an additional infusion of third-party VSTs (day +43) produced using the same donor as his second pre-HSCT infusion (NCT02532452). Autopsy was declined but limited postmortem single core liver, kidney, and lung biopsies demonstrated hepatic SOS/VOD with zone 3 hemorrhagic necrosis, acute renal tubular injury, and early pulmonary exudative phase diffuse alveolar damage ( Figures 2I-L ).