Hepatic sinusoidal obstructive syndrome (SOS), also known as veno-occlusive disease, is a
complication of hematopoietic stem cell transplant (HCT) that is associated with high
morbidity and mortality. 57,000 patients in the United States and Europe undergo HCT
annually and SOS affects up to 15% of these patients. SOS pathogenesis is thought to be
caused by damage to the hepatic venous endothelium due to the preparative regimen used
before HCT. This damage results in obstruction of blood flow through the liver. Pathology
shows collagen deposition in the sinusoids and fibrosis of venous lumens. The severity of
the disease is not correlated to the number and severity of the histological changes.
Mild and moderate SOS can resolve with supportive treatment. Severe SOS (30% of SOS) is
commonly associated with multi-organ failure and has a mortality rate of 80% despite
available prophylaxis and treatment.
SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and
the Baltimore criteria. The modified Seattle criteria state that at least two of the
following criteria must be present within 20 days of HCT: bilirubin > 2mg/dL;
hepatomegaly and/or ascites; and/or weight gain > 5% above baseline weight (6). Pediatric
SOS incidence in HCT is 20% and is higher compared to adults. Death or multi-organ
dysfunction affects 30-60% children who develop SOS. The most common definition of severe
SOS is retrospective, namely death from SOS-related causes or persistent multi-organ
dysfunction at 100 days post HCT. However, the European Society for Blood and Marrow
Transplantation has proposed new prospective SOS diagnosis and grading schemes that could
become standard of care since it can be performed prospectively and thus can guide
treatment.
Defibrotide is a DNA derivative from porcine intestine that protects and repairs
endothelial cells. Prior trials showed that defibrotide decreased the incidence of
multi-organ failure and death from SOS. The main caveat is that treatment must be
initiated very close to the time of clinical diagnosis using the Baltimore criteria to be
effective (14). A study showed that 31/33 (94%) patients had complete remission of their
SOS when treated with defibrotide <3 days after diagnosis, whereas only 3/12 (25%)
patients had complete remission when treated >3 days of diagnosis. However, universal
prophylaxis is difficult due to high drug costs ($155,000 for 21-day course). There is a
critical need for an early and effective SOS diagnostic test that can identify patients
who would benefit from defibrotide treatment.
Several adult and pediatric prospective studies have evaluated the efficacy of grayscale
and Doppler ultrasound (US) in diagnosing SOS and have concluded that the clinical
criteria are superior to US criteria for SOS diagnosis. The main reason for this
conclusion is that conventional US is able to diagnose SOS only after the clinical
diagnosis. This research has resulted in multiple recent guidelines recommending US only
for confirming clinical diagnoses or following disease progression and not for primary
diagnosis. Ultrasound shear wave elastography (SWE) has been shown to effectively
diagnose passive hepatic congestion. Fontan physiology is the best studied example. SWE
values markedly increased after the Fontan operation. This surgery connects the hepatic
venous circulation to the pulmonary arteries exposing the liver to increased resistance
from the pulmonary circulation thereby increasing hepatic venous congestion.
Additionally, the effect sizes in the Fontan studies are large compared with the effect
sizes in hepatic fibrosis studies. The common thread of hepatic venous congestion between
Fontan physiology and SOS physiology led us to hypothesize that SWE could be useful in
SOS diagnosis. Additionally, preliminary SWE studies in adults showed that it might be
useful in the setting of SOS.
The investigators of this study recently conducted a single site prospective cohort study
involving 25 patients undergoing myeloablative HCT patients from December 2015 through
June 2017. The investigators found increased velocities in all patients who developed
SOS. US SWE velocity values showed no difference between pre-conditioning median US SWE
velocity in the SOS group (1.24 + 0.09 m/s) and non-SOS group (1.41 + 0.18 m/s) (p=0.06).
By day +5, patients with SOS had US SWE velocities that significantly increased by 0.25 +
0.21 m/s from baseline compared to 0.02 + 0.18 m/s in patients without SOS from baseline
(p=0.02). By day +14, patients with SOS had US SWE velocities that significantly
increased by 0.91 + 1.14 m/s from baseline compared to 0.03 + 0.23 m/s in patients
without SOS from baseline (0.01). These values are both clinically and statistically
significant, demonstrating that patients with SOS have significantly increased liver
stiffness as measured by US SWE compared to patients without SOS. Additionally, SWE
changes happened on average 9 to 11 days before clinical diagnostic criteria became
positive. The sensitivity and specificity of this test were 60-80% and 67-93% in our
small cohort of 25 patients depending on the threshold used and the test timing.
Data Collection Procedures: Candidates for the study will be identified by a HCT
physician taking care of the patient and will be identified as a potential candidate for
the study. Subjects will be approached for consent by a member of the research team prior
to start of conditioning regimen. Consented subjects will have demographic, laboratory
and clinical data collected from the chart at each ultrasound time point.
Consented subjects will have an US SWE within two weeks prior to starting their
conditioning regimen and at the following time points based on disease course:
All Patients: patients will undergo ultrasound elastography within two-weeks prior
to admission for conditioning AND twice per week through Day +30 or discharge,
whichever comes first.
Patients whom are still an inpatient after Day +30, and are not clinically
suspicious for SOS/VOD, will undergo ultrasound elastography every 30 days (Day +60
and Day +90) until discharge.
Late Onset SOS/VOD as INPATIENT (AFTER DAY +30): patients will undergo ultrasound
elastography twice a week during course of SOS/VOD treatment. If patient is still
admitted at end of treatment, patient will undergo ultrasound elastography once
every 30 days through day +100 or discharge, whichever comes first.
Late Onset SOS/VOD as OUTPATIENT (DAY +30 - DAY + 100): patients will undergo
ultrasound elastography once a week during course of SOS/VOD treatment