Asymptomatic Chronic Infection Research Articles

Mixed Leptospira infections in domestic animals from a rural community with high leptospirosis endemicity.

Leptospirosis is one of the most common zoonoses in the world which is associated with a severe febrile disease in humans causing a variety of syndromes including meningitis, interstitial nephritis, hepatitis, and sometimes death. Leptospirosis is caused by different pathogenic Leptospira species divided into almost 30 serogroups and more than 300 serovars which are carried by some animal asymptomatic chronic infections. Humans can become infected through direct contact with animal urine or indirectly by coming into contact with fresh water or mud contaminated with urine. In this research, we looked for leptospiral DNA in urine samples from dogs living in a rural, low-income and highly endemic community in the coast of Ecuador. We used molecular biology and next-generation sequencing for the detection. Our results showed evidence of two Leptospira species, L interrogans and L. santarosai, genomes in three dogs. It has been widely known that animal carriers are typically infected with a single leptospiral strain. However, recent reports, including the present one, indicate that carrier animals may be coinfected with two or more leptospiral species.

Seropositivity and coinfection of hepatitis B and hepatitis C viruses in Central India: A hospital-based study

ABSTRACT Background: Hepatitis B virus (HBV) and Hepatitis C virus (HCV) show similarity in the transmission, distribution, hepatotropism, and leading to chronic asymptomatic infection. Coinfection of HBV and HCV can lead to more severe liver disease and an increased risk for progression to hepatocellular carcinoma (HCC). Most of the people with chronic infection are unaware of their HBV and HCV infections, hence facilitating these to go undiagnosed until these viruses have caused serious liver damage and they act as a potential source of infection for the community at large. Therefore, the present study aimed to find the prevalence of HBV and HCV along with incidences of coinfection of HBV and HCV in patients seeking hospital care in central India. Methods: A five-year hospital-based study was carried out at the tertiary care hospital in Central India from 2018 to 2022. A total of 72402 patients attending the outdoor patients and admitted indoor patients who were advised for HBV and HCV for screening before any invasive/surgical procedure and patients who presented with symptoms of acute or chronic liver disease were included in this study. Screening was done by immunochromatography-based card test followed by the confirmation of all samples by enzyme immunoassay. Results: Seroprevalence of HBV and HCV was found to be 3.71% and 1.91%, respectively. Coinfection with HBV/HCV was seen in 0.13% of the individuals. The overall prevalence of HBV, HCV, and HBV-HCV coinfection was significantly higher in the male population as compared to females. Conclusion: The study findings of seroprevalence of HBV and HCV among the hospital-based population will help to get a baseline understanding of the disease burden in central India. The HBV/HCV coinfection rate also raises serious concerns owing to its high prevalence rate among the younger age.

An evaluation of a lateral flow rapid diagnostic test for Strongyloides stercoralis infection

Strongyloides stercoralis in humans often presents as a chronic asymptomatic infection. Diagnosis can be challenging due to the limited sensitivity of faecal-based parasitological techniques. A prototype lateral flow rapid diagnostic test (RDT) for the detection of specific antibodies against Strongyloides stercoralis (SsRapid) was evaluated using 143 samples from the serum bank of the Swiss Tropical and Public Health Institute. Group 1 (n = 30) comprised serum samples from larvae-positive individuals; the RDT's diagnostic sensitivity was 97 % (29/30). Group II comprised serum samples from patients with other parasitic infections (n = 86) and Swiss blood donors (n = 27); the RDT's diagnostic specificity for this group was 90 % (102/113). The RDT showed good diagnostic performance and is a promising point-of-care test for detecting human Strongyloides stercoralis infection.

The frequency and associated factors of typhoid carriage in patients undergoing cholecystectomy for gallbladder disease in Pakistan: A cross-sectional study.

Enteric fever is caused by Salmonella enterica serovars Typhi (S. Typhi) and Paratyphi A, B, and C. It continues to be a significant cause of morbidity and mortality worldwide. In highly endemic areas, children are disproportionately affected, and antimicrobial resistance reduces therapeutic options. It is estimated that 2-5% of enteric fever patients develop chronic asymptomatic infection. These carriers may act as reservoirs of infection; therefore, the prospective identification and treatment of carriers are critical for long-term disease control. We aimed to find the frequency of Salmonella Typhi carriers in patients undergoing cholecystectomy. We also compared the detection limit of culturing versus qPCR in detecting S. Typhi, performed a geospatial analysis of the carriers identified using this study, and evaluated the accuracy of anti-Vi and anti-YncE in identifying chronic typhoid carriage. We performed a cross-sectional study in two centers in Pakistan. Gallbladder specimens were subjected to quantitative PCR (qPCR) and serum samples were analyzed for IgG against YncE and Vi by ELISA. We also mapped the residential location of those with a positive qPCR result. Out of 988 participants, 3.4% had qPCR-positive gallbladder samples (23 S. Typhi and 11 S. Paratyphi). Gallstones were more likely to be qPCR positive than bile and gallbladder tissue. Anti-Vi and YncE were significantly correlated (r = 0.78 p<0.0001) and elevated among carriers as compared to qPCR negative controls, except for anti-Vi response in Paratyphi A. But the discriminatory values of these antigens in identifying carriers from qPCR negative controls were low. The high prevalence of typhoid carriers observed in this study suggests that further studies are required to gain information that will help in controlling future typhoid outbreaks in a superior manner than they are currently being managed.

Plasmodium vivax spleen-dependent protein 1 and its role in extracellular vesicles-mediated intrasplenic infections.

Recent studies indicate that human spleen contains over 95% of the total parasite biomass during chronic asymptomatic infections caused by Plasmodium vivax. Previous studies have demonstrated that extracellular vesicles (EVs) secreted from infected reticulocytes facilitate binding to human spleen fibroblasts (hSFs) and identified parasite genes whose expression was dependent on an intact spleen. Here, we characterize the P. vivax spleen-dependent hypothetical gene (PVX_114580). Using CRISPR/Cas9, PVX_114580 was integrated into P. falciparum 3D7 genome and expressed during asexual stages. Immunofluorescence analysis demonstrated that the protein, which we named P. vivax Spleen-Dependent Protein 1 (PvSDP1), was located at the surface of infected red blood cells in the transgenic line and this localization was later confirmed in natural infections. Plasma-derived EVs from P. vivax-infected individuals (PvEVs) significantly increased cytoadherence of 3D7_PvSDP1 transgenic line to hSFs and this binding was inhibited by anti-PvSDP1 antibodies. Single-cell RNAseq of PvEVs-treated hSFs revealed increased expression of adhesion-related genes. These findings demonstrate the importance of parasite spleen-dependent genes and EVs from natural infections in the formation of intrasplenic niches in P. vivax, a major challenge for malaria elimination.

Proteomic profiles of Leptospira borgpetersenii serovar Hardjo strains JB197 and HB203 cultured at different temperatures

Leptospirosis is a global zoonotic disease affecting humans, domestic, and wild animals. Leptospira are typically shed in the urine of reservoir hosts which persist in suitable environments where incidental host transmission occurs after direct contact with infected urine or contaminated environments. Interestingly, serologically identical L. borgpetersenii serovar Hardjo strains JB197 and HB203 show divergent disease severity in the hamster model; JB197 causes severe acute infection while HB203 causes persistent chronic infection. Historically, serovar Hardjo was limited to culture at 29 °C, but utilization of HAN media allows propagation from host tissues at 37 °C. Here, the proteome of strains JB197 and HB203 were characterized after culture from experimentally challenged hamsters at 29 °C and 37 °C. Comparative analyses of JB197 and HB203 samples cultured at 29 °C yielded 425 significantly differentially expressed (DE) proteins, while strains at 37 °C yielded 613 DE proteins including prominent outer membrane proteins and known virulence factors. In agreement, membrane protein GO terms were identified by STRING network analyses along with numerous metabolic KEGG pathways consistent with condition differences. Within strain, JB197 cultured at 29 °C vs 37 °C identified 529 DE proteins, while HB203 identified 524 DE proteins. Investigating differential protein profiles provide insights into strain specific behaviors with implications for better understanding host-pathogen interactions, disease transmission, and response to environmental conditions which can contribute to vaccine development, diagnostic improvement, and ultimately leptospirosis control. SignificanceLeptospirosis is a devastating zoonotic disease affecting humans, wild and domestic animals around the globe. Different species and serovars of Leptospira can affect various animal host species differently; for instance, a serovar that is asymptomatic in the rat may cause severe disease in a dog or human. These differences in host response are not only found at the species and serovar level for Leptospira, but also at the strain level. A prime example comes from strains JB197 and HB203, both species L. borgpetersenii, both serovar Hardjo. Interestingly, JB197 causes a severe acute infection in the hamster while HB203 causes an asymptomatic chronic infection. Understanding these unique relationships between pathogen and host species is important, especially in the context of prevention technologies such as vaccine design, where the strain of Leptospira used as a bacterin might have different efficiencies in different hosts. In this study, proteomic profiles of strains JB197 and HB203 were analyzed, and results revealed diverse protein expression profiles of outer membrane proteins, as well as proteins functioning in motility and growth.

Strongyloides stercoralis Infestation Manifesting as Protein Losing Enteropathy and Dyselectrolytaemia in an Immunocompetent Adult: A Case Report

Strongyloides stercoralis is an intestinal nematode which persists as chronic asymptomatic infection for several years. Clinical manifestations become apparent long after initial infection which includes non specific gastrointestinal (GI) symptoms like pain abdomen, nausea, vomiting, altered bowel habits or weight loss. Larval reproduction can lead to disseminated infection in the immunocompromised. Very rarely, hyperinfection or disseminated strongyloides can lead to ulceration, bleeding, small bowel obstruction, colitis or ascites. In severe cases, electrolyte disturbances and protein losing enteropathy may occur. We present a unique case of intestinal infestation of Strongyloides stercoralis in a 42-year-old immunocompetent male with a rare manifestation of protein losing enteropathy and dyselectrolytaemia without any GI symptoms at the outset, whose presentation was anasarca and initial investigations including work-up for cardiovascular, hepatic and renal causes of anasarca were unremarkable except for hypoalbuminaemia and electrolyte abnormalities and notable absence of peripheral eosinophilia. The diagnosis was arrived at by simple and conventional investigations like stool microscopy which demonstrated the Strongyloides larvae and upper GI endoscopy aided the biopsy which was confirmatory. He responded to appropriate medical treatment. Helminthic infestation should be kept in mind as a rare cause of malabsorption syndrome manifesting as protein losing enteropathy in a tropical and endemic country like India. These are treatable causes and respond to specific cost-effective antihelminthic treatments.

Incidence, Risk Factors and Clinical Impact of Sars-Cov-2 Prolonged Viral Shedding in Patients Diagnosed with Hematologic Malignancies

Patients with hematologic malignancies (HM) infected by SARS-CoV-2 present a higher risk of prolonged viral shedding, severe infection and mortality. However, data regarding clinical outcomes and viral evolution of prolonged COVID-19 in HM are still scarce. Our aim was to describe the incidence, risk factors, clinical outcomes and viral evolution of the protracted SARS-CoV-2 infection in patients with HM. We collected clinical data and respiratory samples of patients with HM who consulted at Vall d´Hebron Universitary Hospital and were diagnosed with a laboratory-confirmed SARS-CoV-2 infection between March 2020 and March 2023. Prolonged COVID-19 was defined as a positive real-time reverse transcription polymerase chain reaction (rRT-PCR) with a cycle threshold (Ct) &amp;lt;35 beyond 30 days since microbiological diagnosis with the same genotyped viral variant. Whole-genome sequencing of the virus was performed following the ARTIC, v4.1 protocol on a MiSeq platform. We considered an exacerbation of persistent COVID-19 the reappearance of symptoms and/or a positive SARS-CoV-2 rRT-PCR after initial clinical improvement or a previous negative rRT-PCR. Results: Among a total of 400 patients with HM developed COVID-19, 269 patients (67.25%) were eligible for prolonged COVID-19 assessment, whereas 52 patients (13%) died due to COVID-19 before day 30 and 79 patients (19.5%) did not have follow-up rRT-PCR. Prolonged COVID-19 was documented in 126 of 269 evaluable patients (46.8%) with a median time of rRT-PCR positivity of 60 days (IQR 43-95). Median age of patients with prolonged COVID-19 was 68 years and 46.8% were female. The main HM was lymphoma (58.7%), the majority of patients were under active treatment (78.6%), and the most frequent active therapy was anti-CD20 monoclonal antibodies+/- chemotherapy (25.4%). In the univariate analysis, active treatment with bispecific T-cell engagers antibodies (BiTEs) (OR 9.2; p=0.048) and anti-CD38 monoclonal antibodies (mAb) (OR 4.9; p=0.02), heavily pretreated patients (&amp;gt; 2 previous lines of therapy) (OR 3.1; p=0.02), and severe/critical acute COVID-19 (OR 7.4; p=&amp;lt;0.01) were significantly associated with prolonged viral shedding. Vaccination (OR 0.2; p=&amp;lt;0.01) and the development of an optimal humoral vaccine-induced immunogenicity (anti-spike IgG &amp;gt;260 BAU/mL) (OR 0.1; p=&amp;lt;0.01) were significantly associated with an inferior risk of developing prolonged COVID-19. In the multivariate analysis, active treatment with anti-CD20 mAb, BiTEs, and BTK inhibitors; lack of vaccination; an impaired humoral vaccine-induced immunogenicity and severe acute COVID-19 remained significantly associated with prolonged COVID-19 (Figure 1). CAR T-cell therapy also showed a trend to develop prolonged COVID-19 but did not reach statistical significance (OR 14.4; p=0.08). Prolonged COVID-19 clinical spectrum in HM ranged from a chronic asymptomatic infection in 29.4% of cases (37/126) to severe infection and COVID-19 related death in 16.7% of cases (21/126). During prolonged COVID-19, 51.6% of patients (65/126) experienced an increase in the severity of the infection, 54% (68/126) patients suffered a delay/interruption of their hematologic treatment, and 22.2% (28/126) had to suspend it indefinitely. A 55.6% of patients (70/126) experienced an exacerbation of persistent COVID-19 with a median of 1 episode (IQR 1-2) per patient. Through those exacerbations, 84.3% (59/70) required hospital readmission with a median of 17 days of length of stay (IQR 9-27). To treat prolonged COVID-19, 55.6% of patients (70/126) required a median of 1 course of antiviral treatment and 31% (39/126) received convalescent plasma. Of note, 37.3% of prolonged COVID-19 patients (47/126) developed a pneumopathy being organizing pneumonia the most frequent one in 28.6% (36/126) of cases. Finally, data of the kinetics of viral load and intra-host viral mutations in prolonged COVID-19 patients with a positive rRT-PCR beyond 90 days will be available for the congress. In conclusion, prolonged COVID-19 is frequent in patients with HM and clinical repercussion are severe. Patients with risk factors for prolonged viral replication, particularly those with a suboptimal humoral vaccine-induced immunogenicity and acute severe disease, require a personalized diagnostic, therapeutic and follow-up.

Clinical significance of Bacteroides fragilis as a potential prognostic factor in colorectal cancer

IntroductionBacteroides fragilis (B. fragilis) is considered to act in an anti-inflammatory manner on the intestinal tract. On the contrary, enterotoxigenic B. fragilis (ETBF), a subtype of B. fragilis, produces an enterotoxin (BFT; B. fragilis toxin), leading to asymptomatic chronic infections and colonic tumor formation. However, the impact of B. fragilis and ETBF on the clinical outcome of colorectal cancer (CRC) remains unclear. We aim to assess whether their presence affects the outcome in patients with CRC after curative resection. MethodsWe obtained 197 pairs of matched formalin-fixed paraffin-embedded samples from cancerous and adjacent non-cancerous tissues of patients with pathological stage (pstage) II and III CRC after curative resection. The presence of B. fragilis and ETBF were estimated using real-time polymerase chain reaction, and recurrence-free survival (RFS) and overall survival (OS) of the patients were analyzed. Results16S rRNA for B. fragilis and bft DNA were detected in 120 (60.9%) and 12 (6.1%) of the 197 patients, respectively. B. fragilis-positive patients had better RFS than B. fragilis-negative patients, although that was not statistically significant. In subgroup analysis, better outcomes on RFS were observed in the presence of B. fragilis in pstage II and left-sided CRC. The association of B. fragilis positivity on OS was accentuated in the depth of T4 subgroup. No significant differences were observed in RFS and OS between ETBF and non-toxigenic B. fragilis. ConclusionsOur findings suggest that the presence of B. fragilis is associated with better outcomes in patients with pstage II and III CRC after curative resection.

Signature of cardiac alterations in early and late chronic infections with Trypanosoma cruzi in mice.

Chagas disease by Trypanosoma cruzi (T. cruzi) infection is a leading cause of myocarditis worldwide. Chagas cardiomyopathy is presented with a wide variety of conduction abnormalities including arrhythmias, first- and second-degree atrioventricular blockade, left ventricular systolic dysfunction and some cases heart failure leading to the death. Currently, there are no effective treatments available against advanced Chagas disease. With the advance in the development of novel therapies, it is important to utilize an animal model that can effectively replicate the diverse stages of Chagas disease, including chronic asymptomatic and symptomatic infection, that are akin to those observed in humans. Therefore, to characterize the cardiac alterations during the evolution of the infection, we evaluated the progression of cardiomyopathy caused by T. cruzi H1 infection in both BALB/c and ICR mouse models by performing electrocardiogram (ECG) studies in unanesthetized mice every month until 210 days post-infection (dpi). In the late chronic phase of infection, we also performed echocardiogram (ECHO) studies to further assess cardiac function. In conclusion, we demonstrated that ICR mice were more susceptible to cardiac alterations compared to BALB/c mice and both mouse strains are suitable experimental models to study chronic T. cruzi infection and novel treatments.

HTLV-1 Proliferation after CD8+ Cell Depletion by Monoclonal Anti-CD8 Antibody Administration in Latently HTLV-1-Infected Cynomolgus Macaques.

Human T-cell leukemia virus type 1 (HTLV-1) induces chronic asymptomatic latent infection with a substantial proviral load but without significant viral replication in vivo. Cumulative studies have indicated involvement of CD8-positive (CD8+) cells, including virus-specific CD8+ T cells in the control of HTLV-1 replication. However, whether HTLV-1 expression from latently infected cells in vivo occurs in the absence of CD8+ cells remains unclear. Here, we examined the impact of CD8+ cell depletion by monoclonal anti-CD8 antibody administration on proviral load in HTLV-1-infected cynomolgus macaques. Five cynomolgus macaques were infected with HTLV-1 by inoculation with HTLV-1-producing cells. Administration of monoclonal anti-CD8 antibody in the chronic phase resulted in complete depletion of peripheral CD8+ T cells for approximately 2 months. All five macaques showed an increase in proviral load following CD8+ cell depletion, which peaked just before the reappearance of peripheral CD8+ T cells. Tax-specific CD8+ T-cell responses were detected in these recovered CD8+ T cells. Importantly, anti-HTLV-1 antibodies also increased after CD8+ cell depletion, indicating HTLV-1 antigen expression. These results provide evidence indicating that HTLV-1 can proliferate from the latent phase in the absence of CD8+ cells and suggest that CD8+ cells are responsible for the control of HTLV-1 replication. IMPORTANCE HTLV-1 can cause serious diseases such as adult T-cell leukemia (ATL) in humans after chronic asymptomatic latent infection with substantial proviral load. Proviruses are detectable in peripheral lymphocytes in HTLV-1 carriers, and the association of a higher proviral load with a higher risk of disease progression has been observed. However, neither substantial viral structural protein expression nor viral replication was detectable in vivo. Cumulative studies have indicated involvement of CD8+ cells, including virus-specific CD8+ T cells in the control of HTLV-1 replication. In the present study, we showed that CD8+ cell depletion by monoclonal anti-CD8 antibody administration results in HTLV-1 expression and an increase in proviral load in HTLV-1-infected cynomolgus macaques. Our results indicate that HTLV-1 can proliferate in the absence of CD8+ cells, suggesting that CD8+ cells are responsible for the control of HTLV-1 replication. This study provides insights into the mechanism of virus-host immune interaction in latent HTLV-1 infection.

Strongyloides and COVID-19: Challenges and Opportunities for Future Research.

Strongyloides stercoralis is a soil transmitted helminth endemic to tropical and subtropical areas that can persist for decades in immunocompetent human hosts as a chronic asymptomatic infection. The use of corticosteroids, a mainstay of treatment for patients hospitalized with severe coronavirus disease (COVID-19), can trigger a life-threatening Strongyloides hyperinfection syndrome and disseminated disease. We identified 22 previously published cases of strongyloidiasis occurring in individuals with COVID-19, with one death reported among the seven patients who had Strongyloides hyperinfection syndrome. A total of seventeen patients had previously received corticosteroids, and of the five with no prior corticosteroid use, one presented with hyperinfection syndrome. We identify the key challenges in the diagnosis and treatment of Strongyloides within the context of COVID-19, including our imprecise knowledge of the global distribution of Strongyloides, the overlapping symptoms and signs of COVID-19 and Strongyloides hyperinfection syndrome, the limited utility of eosinophilia as a clinical marker for strongyloidiasis in this setting, the lack of validated algorithms to screen for Strongyloides prior to corticosteroid use, and the paucity of treatment options for critically ill patients with COVID-19 who cannot take oral ivermectin. Future research should focus on improved diagnostic methods and population prevalence estimates, optimizing the approaches for Strongyloides screening in persons with COVID-19 (including clinical trial participants and strategies for resource-limited settings) and better defining the role of pre-emptive treatment.

A case of apparent ART-associated immune reconstitution inflammatory syndrome in a patient with Strongyloides stercoralis infection

Introduction: Strongyloides infection is most commonly caused by Strongyloides stercoralis (S. stercoralis). It often causes asymptomatic chronic infection but through the translocation of the parasite into the bloodstream, it can lead to disseminated strongyloidiasis (DS). We describe a case of a patient with human immunodeficiency virus (HIV) who developed Strongyloidiasis with the complication of vancomycin-resistant Enterococcus (VRE) meningitis. Notably, the clinical condition of the patient worsened after commencing anti-retroviral therapy (ART), raising concern for ART-associated immune reconstitution inflammatory syndrome (IRIS) to S. stercoralis. Case Report: A 51-year-old African female with a past medical history of HIV presented with a 1-week history of abdominal pain and a 2-month history of generalized malaise, constipation, and weight loss. She improved with symptomatic management and commenced Biktarvy. She re-presented one month later with worsening gastrointestinal symptoms. Her hospital course was complicated by septicemia with worsening mentation. Her repeat abdominal imaging showed ascending and transverse colitis and cerebrospinal fluid analysis was positive for vancomycin-resistant Enterococcus faecium (VRE). During her re-admission, the patient developed persistent watery diarrhea which was found to be positive for S. stercoralis. Despite medical therapy she demised on day 28 of admission. Conclusion: Literature is very scarce concerning the progression of S. stercoralis infection to Strongyloides disseminated strongyloidiasis (DS) as a result of IRIS. As clinicians, we must have a high index of suspicion in our HIV population as DS can lead to fatal complications. It can also help guide management decisions concerning ART until complete eradication of S. stercoralis infection is obtained.

Importance of CHB's grey zone: analysis of patients with HBeAg negative chronic hepatitis B virus infection.

HBeAg-negative chronic HBV infection is defined by viremia < 2,000 IU/ml (or < 20,000 IU/ml), normal ALT activity and minimal liver fibrosis. Some patients do not meet all the criteria and belong to the so-called grey zone. The aim of the work was to analyse a group of patients with asymptomatic chronic HBV infection, divide them according to the levels of HBV DNA during follow-up and to compare the clinical and laboratory parameters of the patients within the groups. We retrospectively analysed patients with HBeAg-negative chronic HBV infection examined in the Centre for Viral Hepatitis of the Department of Infectology in Košice, Slovakia, from September 2018 to December 2021. Patients were divided into three groups based on HBV DNA levels ​​during long-term follow-up ( 2,000 IU/ ml). We evaluated selected demographic, anamnestic and laboratory data (HBV DNA, ALT, fibrosis stage). Of the 280 enrolled patients, 160 were men (57.1 %), the average age was 48.0 years, and the mean length of follow-up was 4.7 years. HBV DNA levels ​​were consistently 2,000 IU/ml in 62 patients. 165 patients had normal ALT activity, 74 had fluctuating ALT activity, and permanently increased ALT in 41 patients. 139 patients underwent transient elastography examination, 16 of them had stage F2 fibrosis, two stage F3 and 1 had cirrhosis. When comparing the three groups divided according to HBV DNA, patients with fluctuating HBV DNA had the longest follow-up, but patients with HBV DNA permanently over 2,000 IU/ml were the youngest and the highest proportion of them had elevated ALT activity. 165 patients (58.9%) met the extended criteria of asymptomatic carriers, 115 were in the grey zone. Patients with HBeAg-negative chronic HBV infection often have fluctuating HBV DNA and ALT values ​​during follow-ups. Statistically significantly higher proportion of abnormal ALT activity in patients with HBV DNA > 2,000 IU/ml may suggest higher risk of adverse outcomes. Initiation of treatment in such patients is not always necessary unless they also meet the other indication criteria for treatment. The exact definition of the grey zone is currently absent (Tab. 2, Fig. 2, Ref. 16).

Identification of antibodies cross-reactive with woodchuck immune cells and activation of virus-specific and global cytotoxic T cell responses by anti-PD-1 and anti-PD-L1 in experimental chronic hepatitis B and persistent occult hepadnaviral infection.

Woodchuck (Marmota monax) infected with woodchuck hepatitis virus (WHV) is the most pathogenically compatible naturally occurring model of human hepatitis B virus (HBV) infection, chronic hepatitis B, and HBV-induced hepatocellular carcinoma. This system plays a crucial role in discovery and preclinical evaluation of anti-HBV therapies. Its utilization remains tempered by the relatively narrow range of validated immunologic and molecular tools. We evaluated commercial antibodies against immune cell phenotypic markers and T cell molecules for cross-reactivity with woodchuck antigenic equivalents. The confirmed antibodies against programed cell death protein-1 (PD-1) and its ligand (PD-L1) were examined for ex vivo ability to activate WHV-specific, global and bystander cytotoxic T cells (CTLs) in chronic hepatitis and asymptomatic infection persisting after self-resolved acute hepatitis. Examination of 65 antibodies led to identification or confirmation of 23 recognizing woodchuck T, regulatory T, B and natural killer cells, T cell-associated PD-1, PD-L1, CTLA-4 and TIM-3 molecules, CD25 and CD69 markers of T cell activation, and interferon gamma (IFNγ). Antibodies against woodchuck PD-1 and PD-L1 triggered in vitro highly individualized WHV-specific and global activation of CTLs in both chronic hepatitis and persistent occult infection. WHV-specific CTLs were more robustly augmented by anti-PD-1 than by anti-PD-L1 in chronic hepatitis, while global IFNγ-positive CTL response was significantly suppressed in chronic hepatitis compared to persistent occult infection. Anti-PD-1 and anti-PD-L1 also occasionally activated CTLs to specificities other than those tested suggesting their potency to trigger side effects. This was particularly apparent when T cells from chronic hepatitis were treated with anti-PD-L1. The current findings indicate that inhibition of the PD-1/PD-L1 pathway could reactivate virus-specific and global T cell responses in both chronic hepatitis and asymptomatic persistent infection. They suggest a mechanism of potential reactivation of clinically silent infection during anti-PD-1/PD-L1 treatment and indicate that this therapy may also subdue occult HBV infection.

How to Effectively Monitor Aging Patients with Chronic Hepatitis B: A Review.

Hepatitis B virus (HBV) infection is a major global public health challenge associated with significant morbidity and mortality. Due to worldwide population aging, HBV infection in the elderly will become increasingly prevalent. Effective universal vaccination programs exist but these are largely targeted towards the younger population. Therefore, the elderly population remains at risk of higher disease burden. New diagnoses of HBV infection in the elderly are usually asymptomatic chronic infections which increases their risk of developing cirrhosis, hepatocellular carcinoma, and liver disease-related mortality, especially if left untreated. Physiological changes and the increasing prevalence of multimorbidity associated with aging also potentially worsen outcomes in elderly patients with chronic HBV infection. Therefore, this cohort of patients should be monitored closely and effectively. Current international clinical practice guidelines unfortunately do not provide hard treatment endpoints specific to elderly patients with chronic HBV infection. Management of these patients is complex and requires an individualized approach. Multiple factors such as physiological changes, comorbidities, compliance, treatment tolerability and efficacy, burden of treatment, and realistic treatment goals need to be considered. Shared decision-making between patient and clinician is essential to ensure that the final decision for or against treatment aligns with the patient's values and preferences. This review article aims to summarize the monitoring and management of chronic HBV infection in the aging population.

Toxoplasma gondii infection and peripheral-blood gene expression profiling of older people reveals dysregulation of cytokines and identifies hub genes as potential therapeutic targets

Infections of humans with the protozoan parasite Toxoplasma gondii (T. gondii) can lead to the disease's development, even in an asymptomatic status. However, the mechanisms that result in these clinical outcomes after infection are poorly understood. This study aimed to explore the molecular pathogenesis of toxoplasmosis-related inflammation through next-generation sequencing, to assess RNA expression profiles in peripheral blood from 5 female patients with chronic toxoplasmosis and 5 healthy female controls. All plasma samples were analyzed for anti-Toxoplasma IgG and IgM antibody titers by using electrochemiluminescence. Detection of acute and chronic toxoplasmosis was carried out using the ELISA IgG avidity. We evaluated the levels of INF-γ, IL-2, IL-12, TNF-α, IL-10, and IL-1β in culture supernatants of Peripheral Blood Mononuclear Cells infected with Toxoplasma lysate antigen (TLA) prepared with tachyzoites of strain T. gondii RH. Differential expression analysis was performed using DESeq2, pathway and enrichment analysis of DEGs was done on WEB-based Gene SeT AnaLysis Toolkit (WebGestalt) and Protein-protein interaction was carried out using NetworkAnalyst with STRING. In older people with chronic asymptomatic infection, a significant difference in the levels of inflammatory cytokines INF-γ and IL-2 was observed compared to seronegative individuals. Our results revealed differences in the regulation of critical biological processes involved in host responses to chronic T. gondii infection. Gene ontology analysis revealed several biologically relevant inflammatory and immune-related pathways.

Unveiling the Pathologic Response of Cardiac Fibroblasts During Aspergillus fumigatus Pulmonary Infections

Various adverse cardiovascular events have been associated with lung damage as a result of pathological infections followed by chronic inflammation. In this context, several recent studies report severe cardiovascular complications after pulmonary infection by SARS‐CoV‐2. Therefore, determining the physiological link between abnormal pulmonary and cardiac function is an emerging clinical need in the cardiovascular field. The main limitation of these studies has been the lack of specific genetic tools and mouse models to study the cellular and molecular mechanisms that regulate the lung‐heart interactions. To induce lung damage we utilized a common airborne environmental fungus, Aspergillus fumigatus (AF), which is an opportunistic pathogen that establishes pathological infection in the lung if the immune system is compromised. However, in immunocompetent animals, transient stress to the lung is still detectable before clearance via immune cells. Our lab has discovered that pulmonary fibroblasts (PFs), typically associated with the maintenance and production of the extracellular matrix, activate in response to inhaled AF spores and modulate the immune response. Moreover, we have also observed activation of cardiac fibroblasts (CFs) in response to the pulmonary AF infection. Therefore, we hypothesized that pulmonary infection leads to cardiac stress, resulting in the activation and pathological response of CFs, and subsequently result in myocardial remodeling, fibrosis, and disease. To test our hypothesis we used our recently developed and described in vivo cre‐loxP lineage tracing mouse lines to specifically tag and manipulate all activated fibroblast during infection, clearing and reinfection. Our data show that CFs can activate after an acute inhalation of AF spores which are quickly cleared in immunocompetent mice with no pathological lung damage. Moreover, subsequent asymptomatic chronic AF infections result in the accumulation of PF and CF pathologic activation. These results reveal a cellular novel link between pulmonary infection and its impact on cardiovascular events.

Strongyloides stercoralis.

Strongyloidiasis has been estimated to affect over 600 million people worldwide. It is caused by Strongyloides stercoralis, a roundworm endemic to the tropics and subtropics, especially areas where sanitation is suboptimal Autochthonous transmission has been documented in rural areas of the USA and Europe. Humans are infected when larvae penetrate the skin or are ingested. Autoinfection, in which larvae generated in the host go on to re-infect the host, leads to a state of chronic asymptomatic infection often with eosinophilia. Hyperinfection syndrome may develop when patients develop immune suppression, due to medications such as corticosteroids or following solid-organ transplantation. Hyperinfection is characterized by exponential increase in parasitic burden, leading to tissue invasion and life-threatening disease and associated bloodstream infections due to enteric organisms. Cases following use of corticosteroids for COVID-19 pneumonia have been described. Strongyloidiasis can be diagnosed by direct visualization of larvae in stool or other body fluids, or by serology. Ivermectin is highly effective in treating the disease. Patients with exposure to endemic areas and those expected to become immune suppressed should be screened and treated before starting immune suppressive agents. Empiric treatment should be considered when timely testing is not readily available.

Distinct N-Linked Immunoglobulin G Glycosylation Patterns Are Associated With Chronic Pathology and Asymptomatic Infections in Human Lymphatic Filariasis.

Lymphatic filariasis presents a complex spectrum of clinical manifestations ranging from asymptomatic microfilariaemic (MF+) to chronic pathology (CP), including lymphedema and elephantiasis. Emerging evidence suggests a link between the physiopathology of filarial infections and antibody properties. Post-translational glycosylation has been shown to play a key role in the modulation of antibodies’ effector functions. Here, we investigated the link between total IgG-N-glycosylation patterns and the physiopathology of human lymphatic filariasis using UPLC-FLD/ESI-MS comparison of N-glycan profiles of total IgG purified from endemic normals (EN), MF+, and CP patients. We detected a total of 19 glycans released from all IgG samples. Strikingly, agalactosylated glycan residues were more prominent in EN, whereas sialylation and bisecting GlcNac correlated with asymptomatic infections. While IgG from all three clinical groups expressed high levels of fucosylated residues, significantly lower expressions of afucosylated IgG were seen in MF+ individuals compared to EN and CP. Our data reveal distinct N-linked IgG glycan profiles in EN, MF+, and CP and suggest that IgG galactosylation and sialylation are associated with chronic pathology, whereas agalactosylation correlates with putative immunity. The results also indicate a role for sialylation, fucosylation, and bisecting GlcNac in immune tolerance to the parasite. These findings highlight the link between N-glycosylation and the physiopathology of lymphatic filariasis and open new research avenues for next-generation therapeutic formulations against infectious diseases.