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Elastography in sinusoidal obstruction syndrome
(above 4 mg/dL or 68 μmol/L) after allo-HSCT.3 More recently, even after reduced-intensity conditioning (RIC), 20% to 26% of patients were reported to have a bilirubin peak above 4 mg/dL, which was also associated with poor outcomes.1,4 Clinical, biological and imaging data are weekly correlated and can lead to delayed or wrong diagnoses.5 Although liver biopsy is useful to establish diagnosis, it has limitations including its feasibility in severely-ill patients and bleeding risk in case of severe thrombocytopenia.5 Several clinical scores have been developed to diagnose SOS after allo-HSCT6,7 but cur- rently lack of specificity and sensibility.8 We previously observed that among patients who fulfilled clinical crite- ria for SOS diagnosis, less than a half had a final diagnosis of SOS after liver biopsy.5 Pitfall associated with ultra- sonography and Doppler are due to heterogeneity and lack of reproducibility8,9 and to the late onset of some radiological signs (e.g., reverse flow in the portal vein) that can occur in SOS. There are currently no early ultra- sonography specific signs that are able to discriminate these various hepatic complications.8 Liver stiffness measurement using elastography is widely used and rec- ommended for the assessment of liver fibrosis, cirrhosis and portal hypertension.11,12 Different techniques have been described: transient elastography (TE with FibroScan®), point shear wave with acoustic radiation force impulse (ARFI), and two-dimensional real-time shear wave (2D-SWE).1,13 The objective of this study was to determine the feasibility and interest of sequential measures of liver elastography for the diagnosis of early hepatic complications after allo-HSCT.
Methods
Patients
Between July 2017 and July 2019, 212 patients underwent an allo-HSCT in the Saint Louis Hospital (Paris, France). A total of 161 patients were included. This study has been conducted in compli- ance with the Declaration of Helsinki. All patients gave their writ- ten consent for the registration of clinical and biological data (CNIL number 2093819), were collected and processed anony- mously in a dedicated study (CNIL number 2211540), with authorization of the IRB 00003888 (study number 20-697).
Ultrasonography and elastography
Ultrasonography, Doppler, and elastography were performed at baseline, at day+7, and at day+14. Two methods were used for elastography for all patients: transient elastography with Fibroscan® (Echosens, Paris, France) and 2D-SWE (Aixplorer, SuperSonic Imaging SA, Aix-en-Provence, France) with a 3.5 MHz convex ultrasound probe (SCX-6-1) and a 7.5 Mhz linear ultra- sound probe (SL-10-2). For all ultrasonography and Doppler exam- ination, the following criteria, were assessed: liver and splenic measurements, measurement of the gallbladder wall, ascites, por- tal vein diameter, portal vein direction flow and maximal flow velocity, spectral waveforms of the hepatic veins. Based on Lassau et al.,6 and European Society for Blood and Marrow Transplantation (EBMT) classification, an ultrasound-Doppler score based on seven criteria was performed: (i) hepatomegaly, (ii) splenomegaly, (iii) gall bladder wall thickening, (iv) dilatation of main portal vein, (v) ascites, (vi) decrease mean velocity of portal vein, (vii) hepatofugal flow or no flow in portal vein. An additional ultrasonography and elastography could be performed at the dis- cretion of the physician.
Liver test and definition of liver involvements
Liver involvement was considered if increased serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level above twice the upper limit of normal values or hyperbilirubine- mia (above 17 μmol/L) occurred in two consecutive measures. All medical records were retrospectively reviewed to determine the final liver diagnosis. GvHD was graded according to the modified Glucksberg’s classification.17 When patients had no other organ involvement than suspected liver GvHD, a biopsy was performed to ascertain the diagnosis (n=3). SOS diagnosis was suspected when EBMT, Baltimore or modified Seattle clinical criteria were present in patients.18–20 Diagnosis was retained only if proven on liver biopsy (n=3), or using ultrasonography and Doppler criteria, as described in EBMT classification.20 If not proven on biopsy or ultrasonography, SOS diagnosis was considered only in the absence of infectious disease, drug toxicity or GvHD (n=3), as rec- ommended by the European Association for the Study of the Liver (EASL) guidelines.8,21 Drug-induced liver injury (DILI) was defined according to EASL guidelines.22
Statistical analysis
Two-group comparisons were performed with Mann-Whitney U test and multiple comparisons were performed with Kruskal- Wallis test followed by a Dunn’s correction for multiple compar- isons. Two-way ANOVA test followed by Dunnet correction was used for multiple comparisons of data with normal distribution and equal variance. ROC curves were built for continuous variable and area under the ROC curve (AUROC) was calculated for SOS diagnosis using all ultrasound and Doppler criteria, 2D-SWE and TE measurements at baseline, day+7 and day+14. Best cutoff value was determined using Youden index. Scores performance were calculated using an intention to diagnose approach using 3x2 table, as previously described to assess performance of diagnostic tests.21,23 All statistical tests were two-tailed with a significance level of 0.05.
Results
Population overview
Over two years, 146 patients out of 161 consecutive patients were analyzed (Figure 1). Fifteen patients were excluded for analysis due to incomplete ultrasonography evaluations. Main patient, disease and transplant features are summarized in Table 1 and Table 2. Median follow-up was 9.2 months (range, 3-19). Five donors had prior hepa- titis B virus (HBV) hepatitis, but none had viral replication at the time of stem cell collection. None of the patients had detectable HBV DNA or hepatitis C virus (HCV) RNA. Two patients had Child-Pugh A cirrhosis (previous HBV infection and telomeropathy, one each). Eighteen (12%) and seven (5%) patients had prior cholecystectomy or splenectomy, respectively and could not be evaluated for all the ultrasonography criteria. During follow-up, 32 patients (22%) died, including 16 (11%) early deaths (before day+100). The leading cause of early death was TRM (93%), including three patients with SOS and two with liver GvHD who had all received a RIC regimen.
Incidence of hepatic involvements after allogeneic hematopoietic stem cell transplantation
Eighty-one (55%) patients had a hepatic involvement defined by an elevation of liver enzymes and/or hyper- bilirubinemia during the first 100 days after allo-HSCT (Figure 2). Hepatic GvHD was diagnosed in 11 patients
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