High Incidence of Acute Liver Failure among Patients in Egypt Coinfected with Hepatitis A and Hepatitis E Viruses.

Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are transmitted through the fecal-oral route. HAV outbreaks and one HEV outbreak have been reported in Egypt. However, the impact of HAV-HEV co-infection is not known. In this study, we assessed HEV markers in acute HAV-infected patients (n = 57) enrolled in Assiut University hospitals. We found that 36.8% of HAV-infected patients were also positive for HEV markers (anti-HEV IgM and HEV RNA), while 63.2% of the patients were HAV mono-infected. Demographic and clinical criteria were comparable in both HAV mono-infected patients and HAV-HEV co-infected patients. Although liver enzymes were not significantly different between the two groups, liver transaminases were higher in the co-infected patients. Six patients developed acute liver failure (ALF); five of them were HAV-HEV-co-infected patients. The relative risk of ALF development was 8.5 times higher in HAV-HEV co-infection compared to mono-infection. Three cases of ALF caused by HAV-HEV co-infection were reported in children (below 18 years) and two cases were reported in adults. All patients developed jaundice, coagulopathy, and encephalopathy; all were living in rural communities. In conclusion: HAV-HEV co-infection can be complicated by ALF. The risk of ALF development in HAV-infected patients is higher when coinfection with HEV is present.

Elevated CD39+T-Regulatory Cells and Reduced Levels of Adenosine Indicate a Role for Tolerogenic Signals in the Progression from Moderate to Severe COVID-19.

Viral infections trigger inflammation by controlling ATP release. CD39 ectoenzymes hydrolyze ATP/ADP to AMP, which is converted by CD73 into anti-inflammatory adenosine (ADO). ADO is an anti-inflammatory and immunosuppressant molecule which can enhance viral persistence and severity. The CD39-CD73-adenosine axis contributes to the immunosuppressive T-reg microenvironment and may affect COVID-19 disease progression. Here, we investigated the link between CD39 expression, mostly on T-regs, and levels of CD73, adenosine, and adenosine receptors with COVID-19 severity and progression. Our study included 73 hospitalized COVID-19 patients, of which 33 were moderately affected and 40 suffered from severe infection. A flow cytometric analysis was used to analyze the frequency of T-regulatory cells (T-regs), CD39+ T-regs, and CD39+CD4+ T-cells. Plasma concentrations of adenosine, IL-10, and TGF-ß were quantified via an ELISA. An RT-qPCR was used to analyze the gene expression of CD73 and adenosine receptors (A1, A2A, A2B, and A3). T-reg cells were higher in COVID-19 patients compared to healthy controls (7.4 ± 0.79 vs. 2.4 ± 0.28; p < 0.0001). Patients also had a higher frequency of the CD39+ T-reg subset. In addition, patients who suffered from a severe form of the disease had higher CD39+ T-regs compared with moderately infected patients. CD39+CD4+ T cells were increased in patients compared to the control group. An analysis of serum adenosine levels showed a marked decrease in their levels in patients, particularly those suffering from severe illness. However, this was paralleled with a marked decline in the expression levels of CD73. IL-10 and TGF-ß levels were higher in COVID-19; in addition, their values were also higher in the severe group. In conclusion, there are distinct immunological alterations in CD39+ lymphocyte subsets and a dysregulation in the adenosine signaling pathway in COVID-19 patients which may contribute to immune dysfunction and disease progression. Understanding these immunological alterations in the different immune cell subsets and adenosine signaling provides valuable insights into the pathogenesis of the disease and may contribute to the development of novel therapeutic approaches targeting specific immune mechanisms.

Evidence of a Link between Hepatitis E Virus Exposure and Glomerulonephritis Development.

Viruses can trigger glomerulonephritis (GN) development. Hepatitis viruses, especially Hepatitis C virus and Hepatitis B viruses, are examples of the viruses that trigger GN initiation or progression. However, the proof of a correlation between GN and Hepatitis E virus infection is not clear. Some studies confirmed the development of GN during acute or chronic HEV infections, mainly caused by genotype 3. While others reported that there is no relation between HEV exposure and GN development. A recent study showed that a reduced glomerular filtration rate was developed in 16% of acute HEV genotype 1 (HEV-1) infections that returned to normal during recovery. HEV-1 is endemic in Egypt with a high seroprevalence among villagers and pregnant women. There is no available data about a link between HEV and GN in Egypt. METHODS: GN patients (n = 43) and matched healthy subjects (n = 36) enrolled in Assiut University hospitals were included in this study. Blood samples were screened for hepatotropic pathogens. Tests for HEV markers such as HEV RNA and anti-HEV antibodies (IgM and IgG) were performed. Laboratory parameters were compared in HEV-seropositive and HEV-seronegative GN patients. RESULTS: Anti-HEV IgG was detected in 26 (60.5%) out of 43 GN patients. HEV seroprevalence was significantly higher in GN than in healthy controls, suggesting that HEV exposure is a risk factor for GN development. None of the GN patients nor the healthy subjects were positive for anti-HEV IgM or HEV RNA. There was no significant difference between seropositive and seronegative GN patients in terms of age, gender, albumin, kidney function profiles, or liver transaminases. However, anti-HEV IgG positive GN patients had higher bilirubin levels than anti-HEV IgG negative GN patients. HEV-seropositive GN patients had a significantly elevated AST level compared to HEV-seropositive healthy subjects. CONCLUSION: exposure to HEV infection could be complicated by the development of GN.

Unusual pattern of thrombotic events in young adult non-critically ill patients with COVID-19 may result from an undiagnosed inherited and acquired form of thrombophilia.

In 145 previously healthy non-critically ill young adults, coronavirus disease 2019 (COVID-19)-related symptoms, risk factors for thrombosis, coagulation and inflammatory parameters were compared, with 29 patients reporting unusual thrombotic events (UTEs) and 116 not having thrombotic events. The inflammatory indices, coagulation and prothrombotic platelet phenotype (PTPP) were significantly higher in patients with UTEs versus those without. Patients with UTEs were categorised according to detection of thrombophilic genes (TGs), coagulation and inflammatory markers to the non-TG and TG subcohort. A total of 38 UTEs were identified, which included splanchnic vein thrombosis (SVT; 11), stroke (six), cerebral vein thrombosis (five), thrombotic microangiopathy (four), limb ischaemia and inferior vena cava thrombosis (three each), ST-segment elevation myocardial infarction (two), superior vena cava thrombosis (two), upper limb deep venous thrombosis and retinal vein thrombosis, one each. We found a 55% prevalence of TGs mainly heterozygous coagulation factor II, thrombin (FII)-G20210A, Janus kinase 2 (JAK2)-V617F, protein-S, and antithrombin III deficiency with a high (76·9%) prevalence of venous UTEs, multiple vessels thrombosis, and recurrence rate among the TG versus non-TG subcohort. The presence of JAK2-V617F, and FII-G20210A mutations was linked with SVT. Thrombosis in the non-TG subcohort was associated with more haemorrhagic problems, thrombosis progression and a significantly higher level of inflammatory markers, PTPP, mean platelet volume, von Willebrand factor, and factor VIII, which remained high for up to 6 months, as well as elevated D-dimer. Acquired and inherited thrombophilia with endotheliopathy appeared to be a relevant mechanism to explain the occurrence of UTEs that are not correlated to COVID-19 severity.

Clinical and immunological assessment of children with ataxia telangiectasia attending Sohag university hospital in Upper Egypt.

Ataxia Telangiectasia (AT) is a very rare autosomal recessive primary immune deficiency (PID) disease that affects 1 in 10,000-40,000 new births per year in the world. It is caused by biallelic mutations in ataxia telangiectasia mutated (ATM) gene and characterized by a progressive cerebellar ataxia. The clinical profile of AT children in Upper Egypt in missing. Herein, we evaluated the clinical characteristics and immunological profiles of patients with AT attending Sohag University Hospital. This was a cross-sectional study, included 21 AT patients attending the Neurological and Immunological Units, Pediatric Department, Sohag University Hospital, starting April 2018 to the end of March 2019. AT represented 20.5% of all PID patients attending the hospital. The most common type of humoral immune deficiency in patients with AT was specific IgA deficiency (52.3%) followed by hypogammaglobulinemia (23.8%). Recurrent sinopulmonary infection with different degrees of severity was the common immunological problem. The most common neurological manifestations in our studied patients, other than the ataxia, were language delay and eye movement abnormalities followed by developmental delay and head nodding. None of our patients had developed malignancy till the end of the study.

"Clinical Aspects of Chronic Granulomatous Disease in Upper Egypt".

Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency disorder that affects phagocytes and is characterized by a marked increased susceptibility to severe bacterial and fungal infections. We aimed to describe the clinical presentations of pediatric patients with CGD in Upper Egypt and to identify the defective component of NADPH oxidase. Pediatric patients diagnosed with CGD within one year from January 2018 to January 2019 were enrolled in the study. Patient history, clinical and laboratory investigations were carried out, including nitroblue tetrazolium test and flow cytometry DHR analysis. Infectious microorganisms were isolated from infected sites to identify the causative agents and their resistance profile. A total of 15 patients were diagnosed with CGD. Failure to thrive and lymphadenopathy were the most common presentations. The median age of clinical onset was 1.17 years of age. The most common gene mutations were observed in the CYBA gene. All cases showed pulmonary infections followed by abscesses. Staphylococcus aureus and Klebsiella pneumoniae were the most frequently isolated bacterial pathogens, Aspergillus spp and Candida spp were isolated from fungal infections. 4/15 (26.7%) children died due to severe serious infections. We concluded that CGD is common in Upper Egypt, and we recommend raising the awareness and testing for CGD in pediatric patients with recurrent or persistent infections, especially those with a familiar history of similar manifestations to avoid delays in proper diagnosis and deterioration of cases. Abbreviations: CGD: chronic granulomatous disease; XL: X-linked; AR: autosomal recessive.

Enhancement of the Molecular and Serological Assessment of Hepatitis E Virus in Milk Samples.

Hepatitis E virus (HEV) infection is endemic in developing and developed countries. HEV was reported to be excreted in the milk of ruminants, raising the possibility of transmission of HEV infection through the ingestion of contaminated milk. Therefore, the detection of HEV markers in milk samples becomes pivotal. However, milk includes inhibitory components that affect HEV detection assays. Previously it was reported that dilution of milk matrix improves the performance of HEV molecular assay, however, the dilution of milk samples is not the best strategy especially when the contaminated milk sample has a low HEV load. Therefore, the objective of this study is to compare the effect of extraction procedures on the efficiency of HEV RNA detection in undiluted milk samples. In addition, we assessed the effect of the removal of milk components such as fats and casein on the performance of the molecular and serological assays of HEV. Phosphate buffered saline (PBS) and different milk matrices (such as whole milk, skim milk, and milk serum) were inoculated with different HEV inoculums and subjected to two different extraction procedures. Method A includes manual extraction using spin column-based extraction, while method B includes silica-based automated extraction. Method A was more sensitive than method B in the whole milk and skim milk matrices with a LoD95% of 300 IU/mL, and virus recovery yield of 47%. While the sensitivity and performance of method B were significantly improved using the milk serum matrix, with LoD95% of 96 IU/mL. Interestingly, retesting HEV positive milk samples using the high sensitivity assay based on method B extraction and milk serum matrix increased the HEV RNA detection rate to 2-fold. Additionally, the performance of HEV serological assays such as anti-HEV IgG and HEV Ag in the milk samples was improved after the removal of the fat globules from the milk matrix. In conclusion, HEV RNA assay is affected by the components of milk and the extraction procedure. Removal of inhibitory substances, such as fat and casein from the milk sample increased the performance of HEV molecular and serological assays which will be suitable for the low load HEV milk with no further dilutions.

Hepatitis C Virus Affects Tuberculosis-Specific T Cells in HIV-Negative Patients.

The occurrence of tuberculosis (TB) and hepatitis C virus (HCV) infections in the same patient presents a unique clinical challenge. The impact of HCV infection on the immune response to TB remains poorly investigated in TB+/HCV+ patients. This study was conducted to evaluate the impact of HCV on the T-cell-mediated immune response to TB in coinfected patients. Sixty-four patients with active TB infections were screened for coinfection with HCV. The expression of immune activation markers IFN-γ, CD38, and HLA-DR on TB-specific CD4+ T cells was evaluated by flow cytometry in TB-monoinfected patients, TB/HCV-coinfected patients, and healthy controls. IL-2, IL-4, IFN-γ, TNF-α, and IL-10 levels were measured using ELISA. The end-of-treatment response to anti-TB therapy was recorded for both patient groups. Significantly lower levels of CD4+IFN-γ+CD38+ and CD4+IFN-γ+HLA-DR+ T cells were detected in TB/HCV-coinfected patients compared to TB monoinfected patients and controls. TB+/HCV+-coinfected patients showed higher serum levels of IL-10. The baseline frequencies of TB-specific activated T-cell subsets did not predict the response to antituberculous therapy in TB+/HCV+ patients. We concluded that different subsets of TB-specific CD4+ T cells in TB/HCV-infected individuals are partially impaired in early-stage HCV infection. This was combined with increased serum IL-10 level. Such immune modulations may represent a powerful risk factor for disease progression in patients with HCV/TB coinfection.