Infected deep vein thrombophlebitis in people who inject drugs: missed opportunities and potential for alternative antimicrobial approaches.

Infected deep vein thrombophlebitis (i-DVT) in people who inject drugs (PWID) is a clinically challenging but poorly characterised disease. We undertook a retrospective observational study of 70 PWID presenting acutely with i-DVT to improve the clinical and microbiological characterisation of this disease. i-DVT was frequently associated with bacteraemia (59.1% patients with blood cultures obtained), groin abscesses (in 34.3%; of which 54.2% required surgical drainage), and septic pulmonary emboli (38.6%) requiring anticoagulation. Network analysis identified a cluster of patients presenting with respiratory symptoms but lacking typical DVT symptoms, more likely to have septic pulmonary emboli. A microbiologic diagnosis was frequently achieved (70%). Causative pathogens were predominantly gram-positive (S. aureus and streptococci, especially anginosus group), whereas gram-negative pathogens were identified very infrequently (in 6.1% of microbiological diagnoses). This suggests routine empiric therapy against gram-negative bacteria, though commonly administered, is not required. High rates of clinical cure (88.6%) were observed despite the complex nature of infections and independently of the highly variable intravenous and total antimicrobial durations received. There exists a rationale to devise pragmatic approaches to implement novel individualised treatment plans utilising oral antimicrobial therapy for i-DVT. Despite frequent healthcare interactions, opportunities to address HCV treatment and opioid substitution therapy were frequently missed during these acute admissions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s15010-021-01725-3

Changing Face of Vaccination in Immunocompromised Hosts

Infection prevention is a key component of care and an important determinant of clinical outcomes in a diverse population of immunocompromised hosts. Vaccination remains a fundamental preventative strategy, and clear guidelines exist for the vaccination of immunocompromised individuals and close contacts. Unfortunately, adherence to such guidelines is frequently suboptimal, with consequent missed opportunities to prevent infection. Additionally, vaccination of immunocompromised individuals is known to produce responses inferior to those observed in immunocompetent hosts. Multiple factors contribute to this finding, and developing improved vaccination strategies for those at high risk of infectious complications remains a priority of care providers. Herein, we review potential factors contributing to vaccine outcomes, focusing on host immune responses, and propose a means for applying modern, innovative systems biology technology to model critical determinants of vaccination success. With influenza vaccine in solid organ transplants used as a case in point, novel means for stratifying individuals using a host "immunophenotype” are explored, and strategies for individualizing vaccine approaches tailored to safely optimize vaccine responses in those most at risk are discussed

Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination

Background. Influenza vaccine immunogenicity is suboptimal in immunocompromised patients. However, there are limited data on the interplay of T- and B- cell responses to vaccination with simultaneous immunosuppression. Methods. We collected peripheral blood mononuclear cells from transplant recipients before and 1 month after seasonal influenza vaccination. Before and after vaccination, H1N1-specific T- and B-cell activation were quantified with flow cytometry. We also developed a mathematical model using T- and B-cell markers and mycophenolate mofetil (MMF) dosage. Results. In the 47 patients analyzed, seroconversion to H1N1 antigen was demonstrated in 34%. H1N1-specific interleukin 4 (IL-4)-producing CD4+ T-cell frequencies increased significantly after vaccination in 53% of patients. Prevaccine expression of H1N1-induced HLA-DR and CD86 on B cells was high in patients who seroconverted. Seroconversion against H1N1 was strongly associated with HLA-DR expression on B cells, which was dependent on the increase between prevaccine and postvaccine H1N1-specific IL-4+CD4+ T cells (R2 = 0.35). High doses of MMF (≥2 g/d) led to lower seroconversion rates, smaller increase in H1N1-specific IL-4+CD4+ T cells, and reduced HLA-DR expression on B cells. The mathematical model incorporating a MMF-inhibited positive feedback loop between H1N1-specific IL-4+CD4+ T cells and HLA-DR expression on B cells captured seroconversion with high specificity. Conclusions. Seroconversion is associated with influenza-specific T-helper 2 and B-cell activation and seems to be modulated by MM

Immunomodulatory Function of Interleukin 28B During Primary Infection With Cytomegalovirus

Background. Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication. Methods. We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs). Results. Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher "antiviral” ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01). Conclusions. We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication contro

Changing Face of Vaccination in Immunocompromised Hosts

Infection prevention is a key component of care and an important determinant of clinical outcomes in a diverse population of immunocompromised hosts. Vaccination remains a fundamental preventative strategy, and clear guidelines exist for the vaccination of immunocompromised individuals and close contacts. Unfortunately, adherence to such guidelines is frequently suboptimal, with consequent missed opportunities to prevent infection. Additionally, vaccination of immunocompromised individuals is known to produce responses inferior to those observed in immunocompetent hosts. Multiple factors contribute to this finding, and developing improved vaccination strategies for those at high risk of infectious complications remains a priority of care providers. Herein, we review potential factors contributing to vaccine outcomes, focusing on host immune responses, and propose a means for applying modern, innovative systems biology technology to model critical determinants of vaccination success. With influenza vaccine in solid organ transplants used as a case in point, novel means for stratifying individuals using a host “immunophenotype” are explored, and strategies for individualizing vaccine approaches tailored to safely optimize vaccine responses in those most at risk are discussed

The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections

Type-III interferons (IFN-lambda, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor alpha-subunit genes have been strongly associated with IFN-alpha-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response

Cross-sectional study of the characteristics, healthcare usage, morbidity and mortality of injecting drug users attending an inner city emergency department.

Background: The affliction of injecting drug use (IDU) has resulted in the emergence of a subgroup of people with a unique set of medical issues. We aimed to describe the emergency department (ED) presentations of IDUs. Methods: In a prospective observational study over a 3-month period, we identified characteristics of patients with a history of active IDU presenting to the ED. Results: From 1 January 2010 to 31 March 2010, 146 patients with a history of IDU were identified. These contributed to 222 acute presentations to the ED. Baseline characteristics revealed that patients were predominantly male, of Irish nationality, with high levels of homelessness, unemployment and lack of stable family or intimate partner relationships. 45% of presentations occurred as a result of infection (95% CI 38.5% to 51.5%). Trauma, pure toxicological issues, thromboembolic phenomena and psychiatric issues comprised the other common acute diagnoses. The burden of comorbid medical illness was substantial with high rates of hepatitis C infection (74%) and HIV infection (13.8%). Healthcare utilisation indices for this cohort are extreme on multiple measures. We found an ED attendance rate of 445 per 100 patient-years, an admission rate of 68.8 per 100 patient-years and mortality rate of 4.86 per 100 patient-years. Conclusions Our study characterises the emergency presentations of active IDUs. We describe considerable acute and chronic medical consequences and high healthcare utilisation associated with IDU. This study is of particular relevance to any institution that provides acute medical care to this group of patients

Variation in both IL28B and KIR2DS3 genes influence pegylated interferon and ribavirin hepatitis C treatment outcome in HIV-1 co-infection.

Pegylated-IFN and ribavirin remains the current treatment for chronic HCV infection in patients co-infected with HIV-1, but this regimen has low efficacy rates, particularly for HCV genotype 1/4 infection, has severe side effects and is extremely costly. Therefore, accurate prediction of treatment response is urgently required. We have recently shown that the NK cell gene, KIR2DS3 and a SNP associated with the IL28B gene synergise to increase the risk of chronic infection in primary HCV mono-infected patients. Identification of SNPs associated with the IL28B gene has also proven very powerful for predicting patient response to treatment. Patients co-infected with HIV-1 are of particular concern given they respond less well to HCV treatment, have more side effects and suffer a more rapid liver disease progression. In this study, we examined both IL28B and KIR2DS3 for their ability to predict treatment response in a cohort of HIV-1/HCV co-infected patients attending two treatment centres in Europe. We found that variation in both host genetic risk factors, IL28B and KIR2DS3, was strongly associated with sustained virological response (SVR) to treatment in our co-infected cohort (n = 149). The majority of patients who achieved a rapid virological response (RVR) achieved a SVR. However, it is currently impossible to predict treatment outcome in patients who fail to achieve an RVR. In our cohort, the presence of host genetic risk factors, IL28B-T and KIR2DS3 alleles, resulted in increased odds of treatment failure in these RVR negative patients (n = 88). Our data suggests that testing for host genetic factors will improve predicting treatment responsiveness in the clinical management of co-infected patients, and provides further evidence of the importance of the innate immune system in the immune response to HCV

An analysis of regulatory T-cell and Th-17 cell dynamics during cytomegalovirus replication in solid organ transplant recipients.

BACKGROUND: CMV-specific T-cells are crucial to control CMV-replication post-transplant. Regulatory T-cells (T-regs) are associated with a tolerant immune state and may contribute to CMV-replication. However, T-cell subsets such as T-regs and IL-17 producing T-cells (Th-17) are not well studied in this context. We explored T-regs and Th-17 frequencies during CMV-replication after transplantation. METHODS: We prospectively evaluated 30 transplant patients with CMV-viremia. We quantified CMV-specific CD4(+) and CD8(+) T-cells, T-regs (CD4(+)CD25(+)FoxP3(+)) and Th-17 frequencies using flow-cytometry and followed patients requiring anti-viral treatment. Two subsets were compared: anti-viral treatment requirement (n = 20) vs. spontaneous clearance of viremia (n = 10). RESULTS: Higher initial CMV-specific CD4(+) T-cells and lower T-regs were observed in patients with spontaneous clearance (p = 0.043; p = 0.021 respectively). Using a ratio of CMV-specific CD4(+) T-cells to T-regs allowed prediction of viral clearance with 80% sensitivity and 90% specificity (p = 0.001). One month after stop of treatment, the same correlation was observed in patients protected from CMV-relapse. The ratio of CMV-specific CD4(+) T-cells to T-regs allowed prediction of relapse with 85% sensitivity and 86% specificity (p = 0.004). Th-17 responses were not correlated with virologic outcomes. CONCLUSIONS: This study provides novel insights into T-regs and Th-17 subpopulations during CMV-replication after transplantation. These preliminary data suggest that measurement of CMV-specific CD4(+) T-cells together with T-regs has value in predicting spontaneous clearance of viremia and relapse