Increased Prevalence of Antibodies to Hepatitis E Virus in Patients with Neurocysticercosis.

We explored the association between serological status for hepatitis E and neurocysticercosis (NCC) in neurologic patients attending a national neurological referral center in Lima, Perú, between the years 2008 and 2012. Anti-hepatitis E antibodies were evaluated in patients with and without NCC, and a control group of rural general population. Anti-hepatitis E IgG was found in 23.8% of patients with NCC, compared with 14.3% in subjects without NCC from a general rural population (P = 0.023) and 14.4% in subjects with neurological complaints without NCC (P = 0.027). Seropositive patients had a median age of 44 years compared with 30 years in seronegative patients (P <0.001). No significant differences in sex, region of residence, or liver enzyme values were found. Seropositivity to hepatitis E was frequent in this Peruvian population and higher in patients with NCC, suggesting shared common routes of infection.

Evaluation of an automated platform for the detection of HEV RNA in plasma and stool.

INTRODUCTION: We evaluated the performance of the automated Altostar HEV RNA platform for detecting HEV RNA. METHODS AND RESULTS: Clinical performance was determined by testing 81 plasma samples and 10 fecal samples manually quantified previously with the Realstar RT-PCR assay using the Magnapure instrument for extraction. The assays were concordant for 79/81 plasma samples (97.5%) and 10/10 (100%) fecal samples. The two plasma samples that tested negative with the Altostar assay had a very low HEV RNA concentration (1.6 and 1.4 log10 IU/ml). Quantitative results obtained with the automated platform and the manual workflow were highly correlated (ρ= 0.98, p<0.01). The intra-run and inter-run standard deviation were 0.09 IU/ml and 0.13 IU/ml respectively. The assay was linear from 2 to 6 log IU/ml. The limit of detection determined by Probit analysis with the WHO HEV RNA standard was 7.6 [95% CI: 4.4-52.5] IU/ml. CONCLUSIONS: The Altostar platform enables highly accurate testing for the detection of HEV RNA in stool and the quantification of HEV RNA in plasma. This allowed us to shorten turnaround times and to save time for the technical staff.

Clustered Cases of Waterborne Hepatitis E Virus Infection, France.

The identification of seven cases of hepatitis E virus infection in a French rural hamlet in April 2015 led to investigations confirming the clustering and identifying the source of the infection. Laboratories and general practitioners in the area actively searched for other cases based on RT-PCR and serological tests. The environment, including water sources, was also checked for HEV RNA. Phylogenetic analyses were performed to compare HEV sequences. No other cases were found. Six of the seven patients lived in the same hamlet, and the seventh used to visit his family who lived there. All HEV strains were very similar and belonged to the HEV3f subgenotype, confirming the clustering of these cases. All the patients drank water from the public network. A break in the water supply to the hamlet was identified at the time the infection probably occurred; HEV RNA was also detected in a private water source that was connected to the public water network. The water flowing from the taps was quite turbid during the break. The private water supply containing HEV RNA was the likely source of the contamination. Private water supplies not disconnected from the public network are still frequent in rural areas, where they may contribute to public water pollution.

Glucocorticoids selectively affect the memory T cell response to SARS-Cov2 spike in vaccinated and post-infected patients with systemic lupus erythematosus.

Immune response to vaccines and pathogens remains unclear in patients with systemic lupus erythematosus (SLE). To investigate this, a single-center retrospective study was conducted with 47 SLE patients vaccinated against COVID-19, including 13 who subsequently developed an asymptomatic/mild disease. As compared to controls, post-vaccine response against Spike was reduced in SLE patients when considering both memory T-cells in a whole blood interferon gamma release assay (IGRA-S) and IgG anti-Spike antibody (Ab) responses. The SLE-associated defective IGRA-S response was associated with a serum albumin level below 40 g/L and with the use of glucocorticoids, while a defective IgG anti-Spike Ab response was associated with lower levels of anti-dsDNA and anti-SSA/Ro 52 kDa Abs. IGRA-S and IgG anti-Spike responses were independent from SLE activity and clinical phenotype, low complement, hypergammaglobulinemia, and lymphopenia. As compared to controls, SLE patients showed a rapid decay of anti-Spike T-cell memory and stable IgG anti-Spike Ab responses. In conclusion, both T cell and humoral anti-Spike responses were independently affected in our SLE patients cohort, which supports the exploration of both responses in the follow-up of SLE patients and especially in those receiving glucocorticoids.

Diagnostic and management strategies for chronic hepatitis E infection.

INTRODUCTION: Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus. AREAS COVERED: We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China. EXPERT OPINION: HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.

Influence of Nasopharyngeal Viral Load on the Spread of the Omicron BA.2 Variant.

We used variant typing polymerase chain reaction to describe the evolution of severe acute respiratory syndrome coronavirus 2 Omicron sublineages between December 2021 and mid-March 2022. The selective advantage of the BA.2 variant over BA.1 is not due to greater nasopharyngeal viral loads.

Seven years (2015-2021) of blood donor screening for HEV-RNA in France: lessons and perspectives.

BACKGROUND: The French health authorities are considering expanding the current selective hepatitis E virus (HEV)-RNA testing procedure to include all donations in order to further reduce transfusion-transmitted HEV infection. Data obtained from blood donors (BDs) tested for HEV-RNA between 2015 and 2021 were used to assess the most efficient nucleic acid testing (NAT) strategy. MATERIALS AND METHODS: Viral loads (VLs) and the plasma volume of blood components, as well as an HEV-RNA dose of 3.85 log IU as the infectious threshold and an assay with a 95% limit of detection (LOD) at 17 IU/mL, were used to assess the proportion of: (i) HEV-RNA-positive BDs that would remain undetected; and (ii) blood components associated with these undetected BDs with an HEV-RNA dose >3.85 log IU, considering 4 NAT options (Individual testing [ID], MP-6, MP-12, and MP-24). RESULTS: Of the 510,118 BDs collected during the study period, 510 (0.10%) were HEV-RNA-positive. Based on measurable VLs available in 388 cases, 1%, 15.2%, 21.8%, and 32.6% of BDs would theoretically pass undetected due to a VL below the LOD of ID, MP-6, MP-12, and MP-24 testing, respectively. All BDs associated with a potentially infectious blood component would be detected with ID-NAT while 13% of them would be undetected with MP-6, 19.6% with MP-12, and 30.4% with MP-24 depending on the plasma volume. No red blood cell (RBC) components with an HEV-RNA dose >3.85 log IU would enter the blood supply, regardless of the NAT strategy used. DISCUSSION: A highly sensitive ID-NAT would ensure maximum safety. However, an MP-based strategy can be considered given that: (i) the risk of transmission is closely related to the plasma volume of blood components; (ii) RBC are the most commonly transfused components and have a low plasma content; and (iii) HEV-RNA doses transmitting infection exceed 4 log IU. To minimise the potential risk associated with apheresis platelet components and fresh frozen plasma, less than 12 donations should be pooled using an NAT assay with a LOD of approximately 20 IU/mL.

Unmet Needs for the Treatment of Chronic Hepatitis E Virus Infection in Immunocompromised Patients.

Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.

Glucocorticoid use as a cause of non-cellular immune response to SARS-Cov2 Spike in patients with immune system diseases.

Disease modifying therapies compromise immune response to SARS-Cov2 or its vaccine in patients with immune system diseases (ISD). Therefore, analysis of the humoral and cellular responses against Spike is of utmost importance to manage ISD patients. A single-center retrospective study was conducted to evaluate the impact of COVID-19 immunization in 87 ISD patients and 81 healthy controls. We performed a whole blood interferon gamma release assay using SARS-Cov2 Spike and Nucleocapsid recombinant proteins in order to evaluate T-cell memory response, and an IgG anti-Spike ELISA to evaluate humoral response. Cellular (26.4%) and humoral (44.8%) responses were negative against Spike in ISD patients following COVID-19 immunization. In univariate analysis, an anti-Spike T cell defective response was associated with the use of glucocorticoids (Odds ratio [OR] = 10.0; p < 10-4), serum albumin level ≤40 g/L (OR = 18.9; p < 10-4), age over 55 years old (OR = 3.9, p = 0.009) and ≤2 vaccine injections (OR = 4.9; p = 0.001). The impact of glucocorticoids persisted after adjustment for age and number of vaccine injections (OR = 8.38, p < 0.001). In contrast, the humoral response was impacted by the use of anti-CD20 mAb (OR = 24.8, p < 10-4), and an extended time since immunization (≥75 days; OR = 4.3, p = 0.002). Double defective cellular/humoral responses (6.9%) were typically encountered in glucocorticoids and/or anti-CD20 mAb treated ISD with a serum albumin level ≤40 g/L (OR = 17.5; p = 0.002). Glucocorticoid usage, B cell depleting therapies, and a low serum albumin level were the main factors associated with a non-response to COVID-19 immunization in ISD patients. These results need further confirmation in larger studies.

Humoral and Cellular Responses to a Delayed Fourth SARS-CoV-2 mRNA-Based Vaccine in Weak Responders to 3 Doses Kidney Transplant Recipients.

While kidney transplant recipients (KTRs) represent a high-risk population for severe SARS-CoV-2 infection, almost half of them do not develop adequate levels of antibodies conferring clinical protection despite 3 doses of the mRNA vaccine. In the present study we retrospectively analyzed the humoral and cellular responses resulting from a fourth dose of vaccine administered to KTRs having an anti-SARS-CoV-2 antibody titer below 142 binding antibody unit (BAU)/mL at 3 months post-third-dose. We observed a significant increase in anti-SARS-CoV-2 antibody concentration from 6.1 (Q1 4.3; Q3 12.7) BAU/mL on the day of the fourth dose to 1054.0 (Q1 739.6; Q3 1649.0) BAU/mL one month later (p = 0.0007), as well as neutralizing antibody titers (from 0.0 (Q1 0.0; Q3 2.0) to 8 (4; 16) IU/mL, p = 0.01) and CD3+ T cell response (from 37.5 (Q1 12.5; Q3 147.5) to 170.0 (Q1 57.5; Q3 510.0) SFUs per 106 PBMCs, p = 0.001). Hence, delaying the fourth dose seems to improve vaccine immunogenicity in KTRs, compared with previously reported data obtained in respect of a fourth dose one month after the third dose. Nevertheless, antibody concentrations seem to remain insufficient to confer clinical protection, especially for Omicron, for which breakthrough infections occur even at very high concentrations.

Diagnostic Performance of an Automated System for Assaying Anti-Hepatitis E Virus Immunoglobulins M and G Compared with a Conventional Microplate Assay.

To evaluate the diagnostic performance of the Liaison® Murex anti-HEV IgM and IgG assays running on the Liaison® instrument and compare the results with those obtained with Wantai HEV assays. We tested samples collected in immunocompetent and immunocompromised patients during the acute (HEV RNA positive, anti-HEV IgM positive) and the post-viremic phase (HEV RNA negative, anti-HEV IgM positive) of infections. The specificity was assessed by testing HEV RNA negative/anti-HEV IgG-IgM negative samples. The clinical sensitivity of the Liaison® IgM assay was 100% for acute-phase samples (56/56) and 57.4% (27/47) for post-viremic samples from immunocompetent patients. It was 93.8% (30/32) for acute-phase (viremic) samples and 71%% (22/31) for post-viremic samples from immunocompromised patients. The clinical sensitivity of the Liaison® IgG assay was 100% for viremic samples (56/56) and 94.6% (43/47) for post-viremic samples from immunocompetent patients. It was 84.3% (27/32) for viremic samples and 93.5% (29/31) for post-viremic samples from immunocompromised patients. Specificity was very high (>99%) in both populations. We checked the limit of detection stated for the Liaison® IgG assay (0.3 U/mL). The clinical performance of the Liaison® ANTI-HEV assays was good. These rapid, automated assays for detecting anti-HEV antibodies will greatly enhance the arsenal for diagnosing HEV infections.

Novel T cell interferon gamma release assay (IGRA) using spike recombinant protein for COVID19 vaccine response and Nucleocapsid for SARS-Cov2 response.

We explored the performance of a whole blood interferon gamma release assay (IGRA) based on the stimulation of SARS-Cov2-specific T cells by purified recombinant proteins. Twenty volunteers vaccinated with BNT162b2 were selected first for T cell response evaluation using an in-house IGRA, a commercial IGRA, and ELISpot showing a S2 > S1 poly-epitopic response. Next, 64 vaccinated and 103 non-vaccinated individuals were tested for humoral and T cell response (IGRA-Spike/-nucleocapsid recombinant proteins). Following the second vaccine injection, humoral (100%) and IGRA-Spike T cell (95.3%) responses took place irrespective of sex, age, and vaccine type. The humoral response declined first, followed by IGRA-Spike T cell response after the second vaccine injection. Altogether, this study confirms the utility of the IGRA-Spike/-nucleocapsid assay to complement serology in COVID19 vaccinated individuals and those who have recovered from SARS-Cov2.

Humoral and Cellular Immune Responses of Solid Organ Transplant Patients on Belatacept to Three Doses of mRNA-Based Anti-SARS-CoV-2 Vaccine.

BACKGROUND: Two doses of anti-SARS-CoV-2 mRNA-based vaccines are poorly immunogenic in solid organ transplant recipients (SOT). METHODS: In total, 68 belatacept-treated SOT recipients followed at the Toulouse University Hospital were investigated. They were given three injections of the BNT162b2 mRNA COVID-19 vaccine. Their humoral response was assessed by determining anti-spike antibodies and neutralizing antibodies. The T-cell responses were assessed using an enzyme-linked immunospot assay that measured the interferon-γ produced by specific SARS-CoV-2 T-cells in a subgroup of 17 patients. RESULTS: Only 23.5% of these patients developed a detectable anti-spike response. Moreover, the cellular and the humoral responses were well correlated. Patients with no humoral response were also without a detectable cellular response. Those belatacept-treated patients who developed an Anti-SARS-CoV-2 humoral response were younger, had been transplanted for longer, and had a higher lymphocyte count and a better glomerular filtration rate than those with no response. Finally, patients on tacrolimus plus belatacept produced a lower immune response. CONCLUSIONS: Belatacept-treated SOT recipients have a reduced immune response to anti-SARS-CoV-2 mRNA vaccination. The vaccine should be given quite separately from the belatacept infusion to improve immunogenicity. Studies to assess whether switching to another immunosuppressive regimen can improve the post-vaccination immune response would be useful.

Hepatitis E infection in adults with primary immunodeficiency with or without immunoglobulin replacement therapy.

BACKGROUND: In a context of secondary immunodeficiency, hepatitis E virus (HEV) infection can be responsible for chronic liver disease. MATERIALS AND METHODS: We investigated HEV infection in patients with primary immunodeficiency treated (or not) with immunoglobulin (Ig) replacement therapy (IgRT) in France, a country with a high seroprevalence of HEV. In a nationwide study of individuals with primary immunodeficiency, 533 patients (349 and 184 receiving IgRT or not, respectively) were tested for HEV RNA and anti-HEV antibodies. In addition, 23 batches of five different commercially available immunoglobulin preparations were screened for anti-HEV IgG. RESULTS: Three of the 533 patients displayed markers of a recent HEV infection (HEV RNA in one case, and anti-HEV IgG and IgM in two) but no evidence of chronic liver disease. The overall seroprevalence of HEV was 50% (266 out of 533), with values of 68% and 16% in patients receiving IgRT or not, respectively (p<0.001). Anti-HEV IgG were detected in all batches of immunoglobulin preparations, although the titer varied from 3 to 127 IU/g IgG. Seroconversion was observed in 15 of the 22 (68%) patients tested before and after IgRT. DISCUSSION: No cases of chronic HEV-related disease were detected among patients with primary immunodeficiency and hypogammaglobulinemia, whether they received IgRT or not. This confirms that patients with primary immunodeficiency have a low risk of chronic infection despite a seroprevalence close to that observed in the French general population and that IgRT, which confers a high HEV seroprevalence, might play a key role in protection against chronic infection.

Influence of the Delta Variant and Vaccination on the SARS-CoV-2 Viral Load.

Studies comparing SARS-CoV-2 nasopharyngeal (NP) viral load (VL) according to virus variant and host vaccination status have yielded inconsistent results. We conducted a single center prospective study between July and September 2021 at the drive-through testing center of the Toulouse University Hospital. We compared the NP VL of 3775 patients infected by the Delta (n = 3637) and Alpha (n = 138) variants, respectively. Patient's symptoms and vaccination status (2619 unvaccinated, 636 one dose and 520 two doses) were recorded. SARS-CoV-2 RNA testing and variant screening were assessed by using Thermo Fisher® TaqPath™ COVID-19 and ID solutions® ID™ SARS-CoV-2/VOC evolution Pentaplex assays. Delta SARS-CoV-2 infections were associated with higher VL than Alpha (coef = 0.68; p ≤ 0.01) independently of patient's vaccination status, symptoms, age and sex. This difference was higher for patients diagnosed late after symptom onset (coef = 0.88; p = 0.01) than for those diagnosed early (coef = 0.43; p = 0.03). Infections in vaccinated patients were associated with lower VL (coef = -0.18; p ≤ 0.01) independently of virus variant, symptom, age and sex. Our results suggest that Delta infections could lead to higher VL and for a longer period compared to Alpha infections. By effectively reducing the NP VL, vaccination could allow for limiting viral spread, even with the Delta variant.

Anti-SARS-CoV-2 spike protein and neutralizing antibodies at 1 and 3 months after three doses of SARS-CoV-2 vaccine in a large cohort of solid organ transplant patients.

The immunogenicity of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccine was improved by the administration of a third dose. The aim of our retrospective study was to assess the evolution of binding and neutralizing antibody concentration until 3 months after the third dose in a large cohort of solid organ transplant (SOT) patients (n = 872). At 1 month after the third dose, anti-SARS-CoV-2 antibodies were detected by means of enzyme-linked immunosorbent assay tests in 578 patients (66.3%). In a subgroup of patients, 70% (180 out of 257) had anti-SARS-CoV-2 antibody concentrations ranging from 1.2 to 18 411 binding antibody units (BAU)/ml and 48.5% (115 out of 239) had a neutralizing antibodies titer that can confer clinical protection against SARS-CoV-2. Three-hundred ninety-three patients out of the 416 (94.5%) who were seropositive at month 1 and were tested at 3 months after vaccination remained seropositive. Between months 1 and 3 after vaccination, binding and neutralizing antibodies concentrations decreased significantly. The proportion of protected patients against the SARS-CoV-2 also slightly decreased. In conclusion, this study shows that although two-third of SOT develop anti-SARS-CoV-2 antibodies after three doses, one-third of them remain weak or non-protected. It is important to measure anti-SARS-CoV-2 antibodies to define the strategy that can optimize SOT protection against SARS-CoV-2.

Predictive Factors for Humoral Response After 2-dose SARS-CoV-2 Vaccine in Solid Organ Transplant Patients.

BACKGROUND: A weak immunogenicity has been reported in solid organ transplant (SOT) recipients after 2 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The aim of this retrospective study was to identify the predictive factors for humoral response in SOT patients. METHODS: Three hundred and ninety-three SOT patients from our center with at least 4 wk of follow-up after 2 doses of mRNA-based vaccine were included in this study. Anti-SARS-Cov-2 spike protein antibodies were assessed before and after vaccination. RESULTS: Anti-SARS-CoV-2 antibodies were detected in 34% of the patients: 33.7% of kidney transplant patients, 47.7% of liver transplant patients, and 14.3% of thoracic transplant patients (P = 0.005). Independent predictive factors for humoral response after vaccination were male gender, a longer period between transplantation and vaccination, liver transplant recipients, a higher lymphocyte count at baseline, a higher estimated glomerular filtration rate and receiving the tacrolimus + everolimus ± steroids combination. Conversely, the nondevelopment of anti-SARS-CoV-2 antibodies after vaccination was associated with younger patients, thoracic organ recipients, induction therapy recipients, and tacrolimus + mycophenolic acid ± steroids recipients. CONCLUSIONS: The immunosuppressive regimen is a modifiable predictive factor for humoral response to SARS-CoV-2 vaccine.