V. Moal

Infection with hepatitis E virus in kidney transplant recipients in southeastern France

Hepatitis E virus (HEV) is an emerging cause of acute hepatitis in Europe, particularly in southern France, and HEV is a new causative agent of chronic hepatitis and cirrhosis in immunocompromised patients. However, the data regarding HEV infection after kidney transplantation are still scarce with respect to the clinical issues that have been raised, and no study has specifically focused on kidney transplant recipients. This study described the clinical features and outcomes of HEV infections in a cohort of kidney transplant recipients living in southeastern France. The epidemiological, clinical, and virological characteristics of HEV infections diagnosed by PCR over a 53‐month period were retrospectively analyzed in a cohort of 1,350 kidney transplant recipients monitored at the Marseille University Hospital. Sixteen HEV infections were diagnosed, all of which were autochthonous and involved genotype 3 viruses (HEV‐3). Chronic infections occurred in 80% of these patients and resolved in half of the cases after a median time of 39 months. The rate of HEV clearance was 54% after a decrease in the dose of immunosuppressants. One patient developed liver cirrhosis 14 months after infection and experienced acute rejection after a decrease in the dose of immunosuppressants. Autochthonous HEV‐3 infections in kidney transplant recipients progress to chronicity in most cases and might be complicated by early liver cirrhosis. Chronic HEV infection can resolve following the reduction of immunosuppressive therapy, but ribavirin may be required if reduction of the immunosuppressant dose is not associated with HEV clearance or is inappropriate for the patient management. J. Med. Virol. 85:462–471, 2013.

Chronic Hepatitis E Virus Infection Is Specifically Associated With an Interferon-Related Transcriptional Program

BACKGROUND Hepatitis E virus (HEV) is a new causative agent of chronic hepatitis in solid organ transplant recipients. Clinical studies suggest that the occurrence and persistence of chronic HEV infection are related to the immunological status of patients. METHODS We used whole-genome microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to compare the transcriptional profiles of whole blood from 8 kidney transplant recipients with chronic HEV infection and 8 matched kidney transplant recipients without HEV infection. RESULTS We found that 30 genes in HEV-infected patients were upregulated, compared with those in control patients, as determined by microarray analysis. In contrast, no genes were downregulated. The 30 upregulated genes included 25 interferon-stimulated genes. Increased expression of the genes that encode IFIT1, IFI44L, RSAD2, EPSTI1, and ISG15 was confirmed by qRT-PCR. Interestingly, the expression levels of these genes were associated with the persistence of HEV infection. CONCLUSIONS Increased expression of interferon-stimulated genes may favor the persistence of an HEV infection. Whether the expression of interferon-stimulated genes is a marker of ongoing viremia or independent prognostic marker of HEV clearance needs further investigations. CLINICAL TRIALS REGISTRATION NCT01090232.

Hepatitis E Virus of Subtype 3i in Chronically Infected Kidney Transplant Recipients in Southeastern France

ABSTRACT Hepatitis E virus (HEV) is a leading cause of waterborne acute hepatitis in developing countries. In Europe, HEV causes a zoonotic disease and is hyperendemic in southern France. Four HEV genotypes (1 to 4) have been defined, and the most used classification divides them into 24 subtypes. Autochthonous European HEV strains belong in majority to genotype 3. Subtypes 3c, 3f, and 3e are representative of the HEV diversity in France. HEV causes chronic hepatitis in solid-organ transplant recipients in Europe, and viral characteristics associated with chronicity are poorly documented. We sequenced 343-nucleotide-long HEV genomic fragments from the serum of eight chronically infected kidney transplant recipients and a near-full-length genome in one case. We identified in four patients (50%) HEV of subtype 3i, not described previously in France. If shorter genomic fragments were used in phylogenetic analyses, these HEV sequences were clustered with open reading frame 2 (ORF2) fragments labeled as subtype 3c. At least five of the eight HEV 3i sequences recovered from humans in our phylogenetic analyses were from chronically infected kidney transplant recipients. These data show that the description of the prevalence and geographical distribution of HEV subtypes may be partially inaccurate and that criteria for classification as 3i and 3c should be clarified. Extended molecular virology analyses are required to improve knowledge of HEV epidemiology and determinants of chronic HEV infection.

Hepatitis E virus serological testing in kidney transplant recipients with elevated liver enzymes in 2007–2011 in southeastern France

Hepatitis E virus (HEV) is an emerging cause of acute and chronic hepatitis in Europe, particularly in solid organ transplant recipients. Anti-HEV IgG/IgM testing in kidney transplant recipients with liver biological disturbances indicated high HEV exposure in our geographical area and led to diagnose HEV infection in 6% of cases.

Considerable decrease in antibodies against hepatitis B surface antigen following kidney transplantation

BACKGROUND Immunization against hepatitis B virus (HBV) in kidney transplantation (KT) candidates and recipients is recommended. If anti-HBV surface antigen antibody (anti-HBsAb) titer of 10 IU/L is admitted to be protective, the optimal threshold, at and after KT, is unknown. In addition, the natural evolution of anti-HBsAb titers after KT is not reported. OBJECTIVES To describe rates of protective immunity to HBV at time of KT (baseline) and evolution of anti-HBsAb titers during the following year. STUDY DESIGN We retrospectively analyzed HBV serology at baseline, 15 days, and 4 and 12 months post-KT. No patient received vaccination during the study period, but information about previous vaccination was unavailable. RESULTS At baseline 80% of 141 recipients had anti-HBsAb titer ≥10 IU/L. Among these 113 patients, 84 had subsequent HBV serologies at day 15 and month 4, and 67 had also serology at month 12. At month 12, 25% of patients had lost protective anti-HBsAb titers (p<0.001). The duration of protective anti-HBsAb titers was significantly longer when the initial titer was ≥ 100 IU/L versus <100 IU/L (log-rank test p<0.0001). Protective titers at month 12 persisted in 93% of patients with initial titer ≥100 IU/L compared to 33% with 10-100IU/L titer (p<0.0001). In contrast, duration of protective titers did not differ according to the anti-HBV core antigen antibody status at baseline. CONCLUSIONS Despite a high prevalence of protective anti-HBsAb titer at KT, the loss of protective immunity during the following year was considerable, particularly when initial anti-HBsAb titer was <100 IU/L.

Systematic Serological Testing for Hepatitis E Virus in Kidney Transplant Recipients

ABSTRACT Hepatitis E virus (HEV) genotype 3 is endemic in Europe and hyperendemic in southern France. Recent reports of a high prevalence of HEV RNA in blood donations and in culinary specialties from this geographical area confirmed the endemicity of HEV and sources of viral transmission in this geographical area. HEV causes acute and chronic hepatitis in solid organ transplant recipients. Since March 2012, we have implemented systematic HEV serological testing in our cohort of kidney transplant recipients (KTRs) in Marseille in southeastern France. The aim of our study was to assess HEV exposure in this cohort between March 2012 and May 2014. During these 27 months, we found that 39% of the patients who underwent kidney transplantation had an anti-HEV IgG response using a sensitive microplate enzyme immunoassay. This seroprevalence was approximately 43% at both 1 and 8 years after, using the same assay. In addition, systematic HEV serological testing detected 6 cases of HEV infection among 578 KTRs (1%) during the 27 months of the study, with 5 at an acute stage and 1 at a chronic stage. In conclusion, continuous HEV monitoring in this population is useful for better understanding the epidemiology of HEV in France, because these patients are a well-monitored population. Moreover, HEV monitoring in KTRs is clinically relevant because HEV represents a clinical threat in these patients. Nevertheless, HEV serological testing may be more fruitful for identifying HEV infections when performed in cases of biological liver abnormalities than when performed systematically.

Hepatitis E virus genotype 4 in Southeastern France: still around.

To the Editor: We read with interest Nakano et al.’s article on the history of hepatitis E virus genotype 4 (HEV-4) (1). These authors identified pig trade as the main cause of HEV-4 dispersal and determined that HEV-4 likely originated from Japan around the 1900s, and may have migrated from China to Denmark in the 1980s, then possibly to Italy, but dispersal routes to Europe remain unclear. We previously diagnosed in 2011– 2012 in Southeastern France 10 autochthonous infections with HEV-4b, whose sequences were 98.9–100% identical between each other and with others described in autochthonous infections in France (2, 3). In addition, autochthonous HEV-4b, 4d and 4f infections occurred in Denmark (2012), Italy (2011) and Germany (2006–2007), respectively (Figure 1; https:// www.google.com/maps/d/edit?mid=zA3X4ljlz-uM.kbtYyqEiPYpY) (1–4). We detected in June 2015 a new autochthonous HEV-4b infection, the first one diagnosed at our laboratory since August 2012 and to involve a transplant recipient. The case-patient is a 62-year-old kidneytransplanted man. He presented pruritus and dark urine. Alanine aminotransferase level was 264 IU/L.

Nocardiosis in the south of France over a 10-years period, 2004–2014

BACKGROUND Nocardiosis is a rare disease with polymorphic presentations. The epidemiology and clinical presentation could change with the increasing number of immunocompromised patients. METHODS The medical records and microbiological data of patients affected by nocardiosis and treated at the university hospitals of Marseille between 2004 and 2014 were analyzed retrospectively. RESULTS The cases of 34 patients infected by Nocardia spp during this period were analyzed. The main underlying conditions were transplantation (n=15), malignancy (n=9), cystic fibrosis (n=4), and immune disease (n=3); no immunodeficiency condition was observed for three patients. No case of AIDS was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations were identified, depending on the underlying condition: the disseminated form (50.0%) and the visceral isolated form (26.5%) in severely immunocompromised patients, the bronchial form (14.7%) in patients with chronic lung disease, and the cutaneous isolated form (8.8%) in immunocompetent patients. Nocardia farcinica was the main species identified (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% underwent surgery. Mortality was 11.7%, and the patients who died had disseminated or visceral nocardiosis. CONCLUSIONS The clinical presentation and outcome of nocardiosis depend on the patients initial immune status and underlying pulmonary condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system.

Delayed diagnosis of fibrinogen Aα-chain amyloidosis after dual heart-kidney transplantation.

Dear Sir, Besides light-chain and amyloid A amyloidosis, hereditary autosomal dominant amyloidosis is considered a rare disease. Nevertheless, it is frequently misdiagnosed [1]. Fibrinogen Aa-chain (AFib) amyloidosis involves the kidneys and causes proteinuria, hypertension, and progression to endstage renal disease (ESRD). Isolated renal transplantation has been proposed when ESRD is reached, but it is associated with risk of recurrence and premature graft loss [2,3]. Moreover, cardiac amyloidosis has been recently described among mutated patients [4] but its precise pathogenesis remains debated [2,5]. Heart transplantation in the course of AFib amyloidosis has, to our knowledge, never been reported. A 55-year-old smoker Caucasian male presented with a large inaugural anterior myocardial infarction in 2003 with coronary angiography showing an atherosclerotic plaque of the left anterior descending artery. Despite angioplasty and stent implantation, severe heart failure appeared (left ventricular ejection fraction = 20% with dilated left ventricle) without other echocardiographic signs suggestive of amyloid cardiopathy. Moderate renal failure [serum creatinine level (SCr) = 130 lmol/l] with proteinuria at 1.4 g/l and hypertension were contemporaneously noticed but not explored. In 2004, deterioration of kidney function (SCr = 245 lmol/l) and massive albuminuria at 6 g/day led the patient to the first nephrological assessment. Renal ultrasound evaluation revealed two small kidneys of 8 cm that did not allow renal biopsy. Family tree was unremarkable and immunological or infectious tests failed to explain this glomerulonephritis. Decline of renal and cardiac functions was prompt. He started hemodialysis at the end of 2004 and was placed on the waiting list for combined heart –kidney transplantation. In November 2005 he received a combined heart–kidney transplant from a deceased 51-year-old male donor with no medical history. Transplantation was successful: the lowest SCr was 108 lmol/l at month 1. He received cyclosporin A, mycophenolate mofetil, and prednisone after an initial induction with anti-thymocyte globulin. At M6, a first kidney transplant biopsy (performed for SCr increased to 145 lmol/l with proteinuria at 0.7 g/day) showed chronic aspecific vascular endarteritis lesions. SCr then stabilized between 150 and 190 lmol/l with low proteinuria. Annual coronary angiographies were normal until 2009, when a nonsignificant stenosis of the right coronary artery and a mild elevation of pulmonary capillary wedge pressure (18 mmHg) were suggestive of chronic rejection. Repeated cardiac protocol biopsies revealed asymptomatic cardiac rejections grade 1R between 2007 and 2009. Repeated echocardiographs showed septum wall thickening (14 mm), an impaired relaxation pattern with restrictive profile, and a normal ejection fraction (65%). Interestingly, the septum had a granular sparkling appearance. Finally, he received a pacemaker in 2010 for repeated episodes of complete atrioventricular block. In 2011, he was admitted for acute diarrhea secondary to intestinal cryptosporidiosis complicated by acute pre-renal failure (SCr: 625 lmol/l). He was treated by a high-volume of parenteral fluid and nitazoxanide. Despite his improved clinical status, we observed a stagnation of SCr at 260 lmol/l, without hypertension, hematuria, or proteinuria. A second renal biopsy revealed glomerular deposits of amorphous eosinophilic material without interstitial or vascular deposits. Congo red staining was positive with reddish-brown material that showed red birefringence under polarized light (Fig. 1, panels a and b). Immunofluorescence study showed no reactivity for j and k light-chain, AA protein, transthyretin, lysosyme, apolipoprotein, leukocyte chemotactic factor 2, and b2-microglobulin but glomerular deposits were labeled with anti-AFib antibodies. Genetic analysis confirmed a heterozygous p.E526V mutation of the AFib gene. Interestingly, careful retrospective examination of his native explanted heart also revealed mild amyloid deposits within small myocardial vessels (Fig. 1, panels c and d). However, retrospective examination of graft endomyocardial biopsies did not show amyloidosis. Our patient is currently well; Scr has stabilized at 230 lmol/l with mild proteinuria (0.5 g/day) under ACE inhibition.

Emerging viral diseases in kidney transplant recipients

Viruses are the most important cause of infections and a major source of mortality in Kidney Transplant Recipients (KTRs). These patients may acquire viral infections through exogenous routes including community exposure, donor organs, and blood products or by endogenous reactivation of latent viruses. Beside major opportunistic infections due to CMV and EBV and viral hepatitis B and C, several viral diseases have recently emerged in KTRs. New medical practices or technologies, implementation of new diagnostic tools, and improved medical information have contributed to the emergence of these viral diseases in this special population.