Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled ...into the Spanish DILI Registry over a 20-year time period.
Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected.
A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio aOR per year 0.983; 95% CI 0.974–0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994–0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy’s law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%).
AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management.
Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.
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•Clinical parameters can help predict DILI phenotype and outcome.•Older patients with cytolitic DILI and those with liver disease have worse outcome.•Serum AST at DILI onset should be assessed as it strongly predicts poor outcome.•Prognostic potential of Hy’s law in DILI varies between causative agents.
Background. The benefit of the combination of serum galactomannan (GM) assay and polymerase chain reaction (PCR)–based detection of serum Aspergillus DNA for the early diagnosis and therapy of ...invasive aspergillosis (IA) in high-risk hematological patients remains unclear. Methods. We performed an open-label, controlled, parallel-group randomized trial in 13 Spanish centers. Adult patients with acute myeloid leukemia and myelodysplastic syndrome on induction therapy or allogeneic hematopoietic stem cell transplant recipients were randomized (1:1 ratio) to 1 of 2 arms: "GM-PCR group" (the results of serial serum GM and PCR assays were provided to treating physicians) and "GM group" (only the results of serum GM were informed). Positivity in either assay prompted thoracic computed tomography scan and initiation of antifungal therapy. No antimold prophylaxis was permitted. Results. Overall, 219 patients underwent randomization (105 in the GM-PCR group and 114 in the GM group). The cumulative incidence of "proven" or "probable" IA (primary study outcome) was lower in the GM-PCR group (4.2% vs 13.1%; odds ratio, 0.29 95% confidence interval, .09–.91). The median interval from the start of monitoring to the diagnosis of IA was lower in the GM-PCR group (13 vs 20 days; P = .022), as well as the use of empirical antifungal therapy (16.7% vs 29.0%; P = .038). Patients in the GM-PCR group had higher proven or probable IA–free survival (P = .027). Conclusions. A combined monitoring strategy based on serum GM and Aspergillus DNA was associated with an earlier diagnosis and a lower incidence of IA in high-risk hematological patients.
Immune thrombocytopenia (ITP) is an autoimmune disorder that induces a decrease in the number of circulating platelets due to spleen destruction and inability of megakaryocytes to restore normal ...counts. Immunosuppressive therapy with glucocorticoid drugs constitutes the first line of treatment. However, lack of response to these agents is not uncommon, and the management of refractory patients is a matter of controversy. In fact, day-to-day clinical practice shows that, in spite of the current guidelines, splenectomy, which is currently considered a suitable second-choice therapy, is being replaced by treatment with thrombopoietin receptor agonists. These boost platelet production by megakaryocytes. The use of one of these, namely eltrombopag, has been permitted for ITP patients refractory to first-line drugs or splenectomy, for the last 10 years. This review summarizes the experience reported using eltrombopag in ITP, paying attention to efficacy and safety. Results from clinical trials will be discussed, and studies performed in the course of daily clinical practice will also be reviewed, as these are useful to assess the potential of the drug in real-world settings. The management of adverse events and the use of eltrombopag in particular situations will also be covered. The experience reported so far permits us to suggest that eltrombopag efficiently induces recovery of platelet counts. Furthermore, recent papers have demonstrated that a sustained response after discontinuation, initially thought to be problematic, may be possible in a nonnegligible number of cases. The safety profile is satisfactory, although patients presenting with thromboembolism risk factors should be treated with caution until the eltrombopag-associated prothrombotic risk is fully established. In summary, although larger studies are still needed to clarify some issues, eltrombopag may be a useful alternative tool for ITP patients refractory to conventional medical management or splenectomy.
Summary
Currently, molecular diagnosis of haemophilia A and B (HA and HB) highlights the excess risk-inhibitor development associated with specific mutations, and enables carrier testing of female ...relatives and prenatal or preimplantation genetic diagnosis. Molecular testing for HA also helps distinguish it from von Willebrand disease (VWD). Next-generation sequencing (NGS) allows simultaneous investigation of several complete genes, even though they may span very extensive regions. This study aimed to evaluate the usefulness of a molecular algorithm employing an NGS approach for sequencing the complete
F8, F9
and
VWF
genes. The proposed algorithm includes the detection of inversions of introns 1 and 22, an NGS custom panel (the entire
F8, F9
and
VWF
genes), and multiplex ligation-dependent probe amplification (MLPA) analysis. A total of 102 samples (97 FVIII- and FIX-deficient patients, and five female carriers) were studied. IVS-22 screening identified 11 out of 20 severe HA patients and one female carrier. IVS-1 analysis did not reveal any alterations. The NGS approach gave positive results in 88 cases, allowing the differential diagnosis of mild/moderate HA and VWD in eight cases. MLPA confirmed one large exon deletion. Only one case did have no pathogenic variants. The proposed algorithm had an overall success rate of 99 %. In conclusion, our evaluation demonstrates that this algorithm can reliably identify pathogenic variants and diagnose patients with HA, HB or VWD.
Supplementary Material to this article is available online at
www.thrombosis-online.com
.
Allogeneic hematopoietic stem cell transplantation recipients have an increasing risk of both hemorrhagic and thrombotic complications. However, the competing risks of two of these life-threatening ...complications in these complex patients have still not been well defined. We retrospectively analyzed data from 431 allogeneic transplantation recipients to identify the incidence, risk factors and mortality due to thrombosis and bleeding. Significant clinical bleeding was more frequent than symptomatic thrombosis. The cumulative incidence of a bleeding episode was 30.2% at 14 years. The cumulative incidence of a venous or arterial thrombosis at 14 years was 11.8% and 4.1%, respectively. The analysis of competing factors for venous thrombosis revealed extensive chronic graft-versus-host disease to be the only independent prognostic risk factor. By contrast, six factors were associated with an increased risk of bleeding; advanced disease, ablative conditioning regimen, umbilical cord blood transplantation, anticoagulation, acute III-IV graft-versus-host disease, and transplant-associated microangiopathy. The development of thrombosis did not significantly affect overall survival (P=0.856). However, significant clinical bleeding was associated with inferior survival (P<0.001). In allogeneic hematopoietic stem cell transplantation, significant clinical bleeding is more common than thrombotic complications and affects survival.
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Specific scoring systems developed for patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) (Garc'a-Manero G et al. Leukemia 2008; Falantes J et al. Clin Lymphoma Myeloma Leuk 2013) ...are able to identify a significant fraction of pts with a poorer (median OS, 13 months) than expected outcome (Greenberg P et al. Blood 1997). Retrospective data of azacitidine (AZA) in LR-MDS showed hematological improvement and survival when compared to non-responder pts (Lyons R et al. J Clin Oncol 2009; Musto P et al. Cancer 2010). However, the impact of AZA treatment in the group of LR-MDS with poor prognosis by a LR-specific score (LR-S) is uncertain.
To evaluate the impact of AZA treatment in LR-MDS pts with more adverse LR-S by multivariable time-dependent analysis.
Eighty-eight LR-MDS pts (IPSS Low/Int-1 or <10% bone marrow blast with no unfavorable karyotype according to Schanz J et al. J Clin Oncol 2012) with the most adverse specific LR-S were retrospectively analyzed. Patients were separated in two cohorts: Non-AZA cohort (n=61), that included pts who received only best supportive care (BSC; n=46) or BSC plus erythroid stimulating agents (ESA; n=15) at Hospital Universitario Virgen del Roc'o (Seville, Spain) from 2000-2010 who were the core for the development of the LR specific model, versus AZA-cohort (n=27), that included pts treated with AZA (75 mg/m2/day for 5 or 7 days every 4 weeks subcutaneously) in a compassionate use program in Spain
Median age was 71 years (range, 48-86). Patients in the AZA cohort were older and included more RAEB-1, transfusion dependent and elevated LR-S pts. Baseline characteristics and differences between cohorts are shown in Table 1. Median time from diagnosis to AZA therapy was 4 months (range, 0.5-21). At last follow-up, 72 pts (81%) had died (Non-AZA cohort: 55/61; 90% and 17/27; 63% in the AZA group). Median OS for the overall series was 18 months. The actuarial probabilities of OS at 1 and 2 years were 62.4% and 45% for AZA and 25.4% and 11% for Non-AZA cohort (P=10-4). In a multivariable analysis including blast % (<4% vs 4-9%), neutropenia (<0.5 vs >0.5x10e9/L), thrombocytopenia (<50 vs >50x10e9/L) and AZA treatment as time-dependent covariate, the later did not significantly influenced OS (HR, 1.502; 95% CI, 0.258-3; P=0.258) and only severe thrombocytopenia (<50x109/L) showed an independent association with OS (HR, 1.690; 95% CI, 1.036-2.756; P=0.03. Table 2). However, a 3-month landmark analysis showed a survival advantage for pts treated with AZA as compared to non-AZA cohort (median OS, 10m Non-AZA vs 23 months AZA; P=0.019) and estimated OS rate at 12 and 24 months were 31.5% and 5.7% for Non-AZA vs 50.2% and 41.1% for AZA cohort respectively. Progression to acute myeloid leukemia (AML) occurred in 24.6% (Non-AZA) vs 14.8% (AZA)(P=0.19).
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Table 1Patient«s characteristicsParameterNon-AZA (N; %)AZA (N; %)PAge (median)70 (48-86)74 (62-83)0.26WHO<0.001RA/RARS14 (22.9)1 (3.7)RCMD/RS25 (41)7 (25.9)RAEB-112 (19.7)17 (63)CMML10 (16.4)0LR-MDS score0.075 pt28 (46)12 (44)6 pt27 (44)8 (30)7 pt6 (10)7 (26)Transfusion dependency49 (80)24 (96)0.06IPSS0.0103 (4.8)00.535 (57.1)8 (30.4)123 (38.1)18 (69.6)Platelet (<50x10e9/L)29 (47.5)13 (48)0.7ANC <0.5x10e9/L11 (18)7 (26)0.06BM blast (4-9%)18 (29.5)18 (67)<0.001
Azacitidine appeared to increase survival in LR-MDS pts within the most adverse LR-S although differences in OS were not statistically significant in a multivariable time-dependent analysis. Larger number of pts and prospective randomized trials are needed to better address this issue. Thrombocytopenia (<50x10e9/L) is confirmed as the most significant clinical parameter with impact on outcome in LR-MDS.
Off Label Use: 5 azacitidine. Treatment for lower-risk MDS in Europe.
To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort.
A cross-sectional followup of 120 patients from an ...initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014-2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases.
Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness.
To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.
Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE ...consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
Highlights • A community-based trial of the HPV-16/18 vaccine was conducted among 7466 women. • Vaccine efficacy was 89.8% for HPV-16/18 CIN2+ and 61.4% for any CIN2+. • The vaccine had an acceptable ...safety profile and induced robust antibody responses. • Results confirm the safety, immunogenicity and efficacy of the HPV-16/18 vaccine.
Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral ...contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R² > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.
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