Ultrasound Elastography to Predict Development of SOS
Condition: Bone Marrow Transplant Complications; Sinusoidal Obstruction Syndrome; Veno-occlusive Disease; Stem Cell Transplant Complications
MeSH terms: Hepatic Veno-Occlusive Disease; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      The long-term goal of our research is to accurately identify SOS patients who would benefit
      from defibrotide treatment using US SWE. The overall objective of this study is to validate
      SWE as an early diagnostic marker for SOS. Our central hypothesis is that SWE changes will
      precede clinical and conventional US diagnostic criteria for SOS. Our hypothesis has been
      formulated on the basis of our own preliminary data. The investigators completed the first
      prospective cohort trial demonstrating that US SWE provides SOS diagnosis (80% sensitivity
      and 67% specificity) nine days earlier than current clinical criteria. SWE is widely
      available, has no known side effects, and is easy to learn and interpret. Our study enrolled
      25 high-risk BMT patients over 18 months (five with SOS and two with severe SOS). More data
      is needed to determine the optimal window for testing to balance between improved test
      characteristics and early detection of disease. The investigators propose conducting a
      prospective cohort study with 80 additional patients, 12 of which will likely develop SOS
      (including four with severe SOS) to optimize SWE timing. This study will increase the
      confidence in the findings from our preliminary study and allow us to test SWE against newly
      published clinical criteria. The rationale for the proposed research is that, if SWE can
      diagnose SOS earlier than clinical criteria, then SWE can guide early initiation of SOS
      treatment.
    

Detailed description: 
      Hepatic sinusoidal obstructive syndrome (SOS) is a complication of blood and marrow
      transplant (BMT) that is associated with high morbidity and mortality. 57,000 patients in the
      United States and Europe undergo BMT 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 BMT. 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 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 (Table 1).

      SOS is most commonly defined by two clinical criteria: the modified Seattle criteria and the
      Baltimore criteria (Table 2). The modified Seattle criteria state that at least two of the
      following criteria must be present within 20 days of BMT: bilirubin > 2mg/dL; hepatomegaly
      and/or ascites; and/or weight gain > 5% above baseline weight. Pediatric SOS incidence in BMT
      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 BMT.
      However, the European Society for Blood and Marrow Transplantation has proposed a new
      prospective SOS grading scheme that will likely become standard of care since it is pediatric
      patient specific and it is can be performed prospectively and thus can guide treatment.

      Recently, a promising drug for SOS treatment has been discovered, defibrotide, which 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. 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 infeasible due to high drug costs ($155,000 for
      patient) (2016). 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.

      Data Collection Procedures Candidates for the study will be identified by a BMT 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.

      Ultrasound Examinations and Timeline After enrollment and within two weeks prior to starting
      their conditioning regimen, a limited abdominal US with Doppler measurements of the hepatic
      arteries, hepatic and portal veins, as well as SWE will be performed.

      Subjects will be undergo US examinations based on disease course as outlined below:

        1. All Patients: Patients will undergo limited abdominal US with Doppler and SWE once a
           week upon admission for conditioning until the patient day +30 BMT or discharge,
           whichever comes first.

        2. Inpatient SOS: patients will undergo limited abdominal US with doppler and SWE once a
           week upon admission for conditioning until resolution of SOS.

        3. Late Onset SOS: patients will undergo limited abdominal US with Doppler and SWE once a
           week upon admission for conditioning until resolution of SOS.

      Clinically indicated US and SWE exams for suspicion for SOS will be included in our analysis.
      All imaging will be performed using General Electric Logiq E9 US machines by dedicated
      pediatric sonographers and interpreted by board-certified pediatric radiologists. Twelve
      shear wave velocity measurements will be taken 2-3 cm below the liver capsule at the
      mid-clavicular line in the right hepatic lobe and another 12 will be taken in the left
      hepatic lobe near midline avoiding areas of vasculature. By necessity, the sonographer and
      interpreting radiologist will not be blinded to the clinical status of the patient. US and
      clinical data will be collected weekly and managed using REDCap electronic data capture tools
      hosted at Children's Mercy Hospital.
    

Intervention name(s): Ultrasound Examination
Intervention type(s): Diagnostic Test
Intervention description(s): Grayscale ultrasound, Doppler ultrasound, ultrasound elastography with or without ultrasound intravenous contrast will be performed.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Ultrasound elastography