Covid-19 in liver transplant recipients: the French SOT COVID registry.

BACKGROUND: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in organ transplant recipients remains limited. The aim of this registry-based observational study was to report the characteristics and clinical outcomes of liver transplant (LT) recipients included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. METHODS: COVID-19 was diagnosed in patients who had a positive PCR assay for SARS-CoV-2 or in presence of typical lung lesions on imaging or specific SARS-CoV-2 antibodies. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. RESULTS: Of the 104 patients, 67 were admitted to hospital and 37 were managed at home (including all 13 children). Hospitalized patients had a median age of 65.2 years (IQR: 58.1 - 73.2 years) and two thirds were men. Most common comorbidities included overweight (67.3%), hypertension (61.2%), diabetes (50.7%), cardiovascular disease (20.9%) and respiratory disease (16.4%). SARS-CoV-2 infection was identified after a median of 92.8 months (IQR: 40.1 - 194.7 months) from LT. During hospitalization, antimetabolites, mTOR inhibitor, and CNIs were withdrawn in 41.9%, 30.0% and 12.5% of patients, respectively. The composite endpoint of severe Covid-19 within 30 days after diagnosis was reached by 33.0% of the adult patients. The 30-day mortality rate was 20.0%, and 28.1% for hospitalized patients. Multivariate analysis identified that age was independently associated with mortality. CONCLUSION: In our large nationwide study, Covid-19 in LT recipients was associated with a high mortality rate.

Pharmacokinetic-pharmacodynamic modeling of manganese after a single intravenous infusion of mangafodipir in patients with acute alcoholic hepatitis.

To determine the pharmacokinetic (PK) profile of manganese (Mn) after a 2-hour intravenous infusion of mangafodipir at 5 micromol/kg body weight and to correlate Mn concentrations with oxidative stress, early decrease in serum total bilirubin concentration, and prothrombin time (PT) in chronic alcoholic patients with acute alcoholic hepatitis. In 7 patients, a total of 49 serum Mn concentrations were determined on day 1 (before the start of the infusion and 15, 30, and 45 minutes after the end of the infusion) and on days 2, 7, 14, and 21. Fifty-seven PTs, reflecting liver activity, were measured on days 1, 2, 7, 14, and 21 and at months 1, 2, and 3. A population PK-pharmacodynamic model was developed to describe the kinetics of serum Mn concentrations and PT, to estimate interpatient variability, and to test covariate influence. A 2-compartment model with zero-order absorption and first-order elimination best described the data, and a signal transduction model with 2 transit compartments best described PT. Mean PK estimates and the corresponding interindividual variabilities (%) were clearance 23.1 L/h (34%), central and peripheral volume of distribution 35.4 and 1090 L, respectively, intercompartmental clearance 27.3 L (34%), endogenous Mn concentrations 15.8 nmol/L, slope-relating effect to concentration 141 nmol x L(-1) x s(-1) (52%), and mean transit time (tau) 3.8 days (34%). When patients had an early decrease in bilirubin at day 7, tau increased to 28.2 days. Serum Mn concentrations could be related to a decrease in PT; the effect was longer in patients with an early decrease in total bilirubin serum concentrations.

Validation of body mass index for the diagnosis of malnutrition in patients with liver cirrhosis.

OBJECTIVES: Simple clinical tools are needed to detect malnutrition in cirrhotic patients. We have validated optimal body mass index (BMI) cut-offs for the diagnosis of malnutrition in accordance with the importance of ascites. METHODS: BMI, mid-arm muscle circumference (MAMC) and triceps skinfold thickness (TST) were measured before paracentesis in study (SP) and validation (VP) populations of 875 and 294 cirrhotic patients, respectively with no ascite (NA), mild (MA), tense ascites (TA) (NA/MA/TA: SP: 327, 270, 278; VP: 111, 69, 114). Preserved nutritional status (SP: 259; VP: 93), malnutrition including severe and moderate malnutrition (SP: 251 and 365; VP: 92 and 109) were defined from MAMC and TST measurements. RESULTS: Optimal BMI cut-off values were 22, 23 and 25 kg/m2 in NA, MA and TA patients, respectively. In the whole SP and VP, sensitivities of these cut-offs were 86.2% and 89.1%, respectively; the corresponding negative predictive values (NPV) for the diagnosis of severe malnutrition were 92.3% and 93.2%; specificities and positive predictive values (PPV) were 87.7% and 89.9%, 92.7% and 93.6%, respectively for the diagnosis of malnutrition. In the entire VP, peripheral oedema did not change sensitivity and NPV of BMI cut-offs for the diagnosis of severe malnutrition and tended to increase specificity and PPV for the diagnosis of malnutrition. 96.7% of the malnourished TA patients in the VP before paracentesis were correctly identified after removal of ascites. CONCLUSION: BMI is a reliable parameter to detect malnutrition in cirrhotic patients with the above mentioned cut-offs. Peripheral oedema and removal of ascites do not affect its diagnostic performance.

Combined polymorphisms of tumour necrosis factor alpha and interleukin-10 genes in patients with alcoholic hepatitis.

OBJECTIVES: The development and progression of alcoholic hepatitis are controlled by an extensive cytokine network which involves pro-inflammatory and anti-inflammatory cytokines. Genetic variations determining production of these cytokines have been described and the susceptibility to the disease may be determined by an imbalance in the expression of several candidate genes. METHODS: We have studied biallelic single nucleotide polymorphisms at positions (-308) and (-238) in the promoter region of the pro-inflammatory tumour necrosis factor alpha (TNF-alpha) and at positions (-1,082) and (-592) in the promoter of anti-inflammatory interleukin-10 (IL-10) in 134 patients with severe biopsy-proven alcoholic hepatitis and 145 healthy subjects. RESULTS: The frequency distribution of isolated cytokine genotypes did not differ between the two groups. The combination of at least one A or A allele for TNF-alpha, associated with a TNF-alpha high-producer phenotype, and one A or A allele for IL-10, associated with an IL-10 low-producer phenotype, was less frequent in patients (20.9 vs 33.8%, P=0.016, OR (95% CI)=0.52 (0.30-0.89)). The same combination in patients was associated with a higher risk of septic complications (32.5 vs 16.0%, P=0.031, OR (95% CI)=1.79 (1.07-6.00)) but not with in-hospital mortality. CONCLUSIONS: We have not found any relationship between the isolated polymorphisms and the risk of alcoholic hepatitis. Moreover, the imbalance between the pro-inflammatory and anti-inflammatory responses leading to high TNF-alpha production and low IL-10 was uncommon in alcoholic hepatitis. However, patients with this particular genotype appeared more susceptible to severe septic complications.

Diagnostic value of two reagent strips (Multistix 8 SG and Combur 2 LN) in cirrhotic patients with spontaneous bacterial peritonitis and symptomatic bacterascites.

OBJECTIVE: Spontaneous bacterial peritonitis is a life-threatening complication in patients with liver cirrhosis requiring a rapid diagnosis. We have tested two reagent strips, Multistix 8 SG and Combur 2 LN for bedside diagnosis of spontaneous bacterial peritonitis and symptomatic bacterascites, a variant of spontaneous bacterial peritonitis. METHODS: Responses of the two strips in colorimetric scale were compared with results given by cyto-bacteriological analysis of ascitic fluid. Results with positivity in grades 1 and 2 of colorimetric scale were analyzed. RESULTS: Four hundred and forty three paracentesis were performed in 116 patients including 46 samples of ascitic fluid with spontaneous bacterial peritonitis occurring in 25 patients and 20 samples of ascitic fluid with symptomatic bacterascites occurring in 17 patients. Forty two percent of spontaneous bacterial peritonitis were culture-negative neutrocytic ascites, gram-positive pathogens and enterobacteriaceae were responsible for 36% and 21% episodes of spontaneous bacterial peritonitis and 71% and 29% episodes of symptomatic bacterascites respectively. Fifty seven percent of spontaneous bacterial peritonitis had polymorphonuclear cell count<1000/mm3. For spontaneous bacterial peritonitis diagnosis, grade 1 positive Multistix and Combur tests had a sensitivity of 69.6% and 80.4% respectively, and a negative predictive value of 96% and 97.3%. Grade 2 positivity increased specificity to 98% and 99.2% and positive predictive value to 75% and 91% for the two strips respectively. Grade 1 positive tests had a sensitivity of 100% and 90% and a negative predictive value of 100% and 99.4% respectively for diagnosis of spontaneous bacterial peritonitis with polymorphonuclear count > 1000/mm3. For symptomatic bacterascites diagnosis, grade 1 positive tests had a sensitivity of 22.4% and 44.4% respectively and a negative predictive value of 96% and 97%. CONCLUSION: Although Combur had a higher sensitivity than Multistix for the diagnosis of spontaneous bacterial peritonitis, sensitivity of the two strips remains low with polymorphonuclear cell count<1000/mm3. Grade 2 positive Combur test had an acceptable positive predictive value. Sensitivity of both strips is insufficient for diagnosis of symptomatic bacterascites. Rapid cyto-bacteriological analysis of ascitic fluid remains necessary for diagnosis of these complications.

Enteral nutrition in severely malnourished and anorectic cirrhotic patients in clinical practice.

OBJECTIVES: To determine among severely malnourished cirrhotic patients remaining anorectic during hospital stay which patients may benefit from enteral nutrition in clinical practice. METHODS: A prospective study including malnourished cirrhotic patients fed by enteral nutrition because of inadequate dietary intake after one-month hospitalization was carried out in a department receiving patients from other hospitals. Patients who died during hospital stay (N=35, group I) were compared to surviving patients (N=28, group II). RESULTS: Nutritional status and spontaneous dietary intake on admission to our department were in the same range in the two groups, Pugh score was higher in group I (11.1 +/- 1.9 vs 9.1 +/- 2.0, P=0.0001). The delay between previous hospital admission and the outset of enteral nutrition was comparable in the two groups. Its duration and total dietary intake during enteral nutrition were higher in group II (respectively 42.2 +/- 30.9 vs 15.2 +/- 33.1 days, P=0.0016 and 41.1 +/- 13.0 vs 29.9 +/- 10.0 kcal/kg/d, P=0.0004). Prevalence of side effects was higher in group I (54.3 vs 17.9%, P=0.0031). Multivariate analysis showed that Pugh score and septic complications were negatively associated with survival (respectively P=0.0196 and P=0.0078) while duration of enteral nutrition was positively associated (P=0.0435). Eighty six per cent of patients receiving enteral nutrition with bilirubin levels above 74 micromol/L on admission to our department died during hospital stay. Mid-term effects of enteral nutrition in surviving patients were improvement in Pugh score (7.5 +/- 2.0 vs 9.1 +/- 2.0, P<0.0001) and increase in spontaneous caloric and protein intake (29.7 +/- 15.3 vs 18.1 +/- 10.1 kcal/kg/d, P=0.0150 and 1.0 +/- 0.5 vs 0.6 +/- 0.3 g/kg/d, P=0.0049). CONCLUSIONS: In severely malnourished cirrhotic patients remaining anorectic after one-month hospitalization, patients with bilirubin level below 74 micromol/L may benefit from six-week enteral nutrition with mid-term improvement in liver function and increase in spontaneous dietary intake.

Low-grade steatosis and major changes in portal flow as new prognostic factors in steroid-treated alcoholic hepatitis.

The aim of this study was to assess the prevalence and prognostic value of major alterations of portal flow in patients with steroid-treated alcoholic hepatitis. Fifty patients with severe, histologically proven alcoholic hepatitis were enrolled. Clinical data, liver test results, and hepatic Doppler ultrasound findings were collected at inclusion and at month 2. Patients were followed for 1 year or until death. Major changes in portal flow were defined as reversed or alternating flow in the portal trunk and/or in intrahepatic portal branches. Changes in portal flow were observed in 24 (48.0%) of 50 and 17 (39.5%) of 43 patients at inclusion and month 2, respectively. Univariate analysis showed that age older than 50 years, steatosis less than 20% on initial liver biopsy, presence of major changes in portal flow, Child-Turcotte-Pugh score higher than 12, factor V level higher than 45%, and hepatofugal splenic blood flow were associated with a lower 1-year survival. Cox regression analysis showed that steatosis < 20% (relative hazard [RH] = 9.3, P = .0009) and major changes in portal flow (RH = 3.1, P = .04), were independently associated with poor survival. In conclusion, major changes in portal flow are frequent in patients with severe alcoholic hepatitis. Altered portal flow and steatosis < 20% are new prognostic factors in steroid-treated alcoholic hepatitis and must be taken into account in patient management.

Gastroduodenal ulcer and erosions are related to portal hypertensive gastropathy and recent alcohol intake in cirrhotic patients.

Gastroduodenal ulcers and gastroduodenal erosions are particularly frequent in cirrhotic patients, but their precise cause is unclear. The aim of this study was to identify pathogenic factors associated with ulcers and erosions in patients with cirrhosis. We studied 64 consecutive patients with cirrhosis referred for gastroscopy. The severity of portal hypertensive gastropathy was graded with an endoscopic score. H. pylori status was determined by histological examination of gastric biopsy samples or by the [13C] urea breath test. The daily alcohol intake within the preceding week was recorded. The Child-Pugh score was determined. Fifteen patients had gastroduodenal ulcer and 20 had gastroduodenal erosions. Cirrhosis was related to alcohol in 44 patients and hepatitis B or C virus in 14 patients. The portal hypertensive gastropathy was graded as severe in 12 patients and mild in 25 patients. H. pylori infection, found in 37 patients, was not related to the gastroduodenal lesions. Univariate and multivariate analysis showed the links between gastroduodenal erosions and hypertensive gastropathy and recent heavy drinking. Gastroduodenal ulcer was independently associated only with the severity of the gastropathy. In conclusion, in these patients with cirrhosis, the presence of gastroduodenal ulcer was significantly related to hypertensive gastropathy but not to H. pylori infection. Recent alcohol intake favored the occurrence of gastroduodenal erosions.

Evaluation of nutritional practice in hospitalized cirrhotic patients: results of a prospective study.

OBJECTIVE: We evaluated the impact of malnutrition and nutrition practice in 396 hospitalized cirrhotic patients (Child stages A, B, and C: 60, 169, and 167 patients) in a readaptative unit for liver diseases. METHODS: Triceps skinfold thickness and mid-arm muscle circumference were measured at admission, and spontaneous dietary intake was evaluated at admission and during hospital stay. RESULTS: Ascites was associated with impairment of nutrition status: 49% and 30.4% of non-ascitic patients, 49.1% and 40.5% of patients with mild ascites, and 65.5% and 48.3% of patients with tense ascites had mid-arm muscle circumferences and triceps skinfold thicknesses, respectively, below the fifth percentile of a reference population (P < 0.05 and P = 0.02, respectively). Decrease in dietary intake paralleled worsening of liver failure: 48% and 34% of Child A patients, 51.7% and 35.8% of Child B patients, and 80.3% and 62.9% of Child C patients at admission had caloric intakes below 30 kcal/kg of body weight and protein intakes below 1 g/kg of body weight, respectively (P < 0.001). Mortality rate was 15.4% during hospital stay; Child-Pugh score (P = 0.0014), age (P = 0.0029), severe septic complications (P = 0.0050), and decrease in caloric intake during hospital stay (P = 0.0072) were independently associated with mortality. Twenty-four patients received enteral feeding that was initiated before admission in four patients and after 12.4 +/- 8.3 d of hospitalization in 20 patients because of low caloric intake (<25 kcal/kg) despite oral supplements. Patients receiving enteral feeding were older (P < 0.01), had a higher Child-Pugh score (P < 0.01), and a higher mortality rate (P < 0.001) than other patients. CONCLUSIONS: Hospitalized cirrhotic patients have a high prevalence rate of malnutrition, and most do not satisfy their nutritional requirements. Decrease in caloric intake is an independent risk factor of short-term mortality. Enteral nutrition after failure of oral supplementation has no clinical benefit. Tube feeding may be indicated earlier in the course of the disease.

[Prognosis factors of short and long-term survival in elderly hospitalized patients after percutaneous endoscopic gastrostomy]. / Facteurs pronostiques de la survie à court et long terme après pose d'une gastrostomie percutanée endoscopique chez des malades âgés hospitalisés.

OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is the procedure of choice to achieve long-term enteral nutrition. The risks and benefits of PEG in elderly hospitalized patients have been poorly documented. The objective of this study was to describe the outcome of elderly patients one-year after insertion of a PEG tube. PATIENTS AND METHODS: Hospital records of 73 patients who underwent PEG for enteral nutrition were reviewed retrospectively. Data on patient age and sex, preexisting medical conditions such as dementia or pressure sores, indication for PEG, concomitant infection, complications of PEG and death were obtained from the hospital charts. RESULTS: The main indication for PEG was anorexia (49%). Before insertion of the gastrostomy tube, 44% of the patients had pressure scores, 30% had concomitant infection, 45% had dementia. PEG complications were observed in 51 patients. The survival rate at 1, 6 and 12 months was 0.68 [95% confidence interval - CI 95%: 0.56-0.78], 0.48 [CI 95%: 0.36-0.59] and 0.37 [CI 95%: 0.26-0.48] respectively. The presence of an infectious disease or of pressure sores at the time of PEG tube insertion were independently associated with mortality. Median survival of patients with these two factors was 32 days [CI 95%: 11-98]. CONCLUSION: According to these results, the PEG tubes should be inserted with a delay from infectious diseases and before the occurrence of pressure sores.

Nosocomial spontaneous bacterial peritonitis and bacteremia in cirrhotic patients: impact of isolate type on prognosis and characteristics of infection.

The characteristics of and prognosis for nosocomial spontaneous bacterial peritonitis (SBP) and bacteremia were examined in a prospective study that included data from 194 consecutive episodes of SBP and 119 episodes of bacteremia, 93.3% of which were nosocomial, in 200 hospitalized cirrhotic patients. Gram-positive pathogens were predominant (70% of the total) among isolates from nosocomial infections; the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was 24.8%. Nosocomial and staphylococcal infections were associated with a higher mortality rate than were community-acquired infections (P=.0255) and nonstaphylococcal infections (P<.001), respectively. In comparison with non-MRSA infections, MRSA infections were more likely to recur and occurred in a greater number of sites other than ascitic fluid and blood (P=.0004). Older age (P=.0048), higher Child-Pugh score (P=.0011), and infection with staphylococci (P=.0031) were independently associated with a higher mortality rate. The emergence of MRSA is important because of the recurrence and poor outcome associated with infection with such organisms.