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Vitexin-2-O-rhamnoside (VR) is an important active substance in hawthorn, which is widely used as a food or functional food raw material; however, its immunomodulatory activities have not been extensively studied. In this study, BALB/c mice immunocompromised by cyclophosphamide (CY) were used as models to explore the effects of VR on the immunity and antioxidant capacity of mice. The results revealed that VR can restore weight to the immunosuppressed mice to varying degrees, improve spleen and thymus injury, and restore peripheral blood levels. Furthermore, it can effectively promote the proliferation of T and B lymphocytes, natural killer (NK) and cytotoxic T lymphocyte (CTL) cell activities, and the secretion and mRNA expression of cytokines IFN-γ, IL-2, IL-6, and IL-12 to 0.36, 0.34, 50.25%, 45.74%, 28.36 pg/mL or 0.68, 31.81 pg/mL or 0.74, 20.40 pg/mL or 0.75, and 19.81 pg/mL or 0.55, respectively. Moreover, it can upregulate the phosphorylation level of PI3K/Akt signaling pathway in mice immunosuppressed by CY, increase the activities of glutathione peroxidase (GSH-Px), chloramphenicol acetyltransferase (CAT), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC), and decrease the level of malondialdehyde (MDA). This study provides a theoretical and experimental basis for the research and development of health products with targeted efficacy, and the development of diversified products in the hawthorn deep-processing industry., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A severe pandemic of Coronavirus Disease (COVID-19) has been sweeping the globe since 2019, and this time, it did not stop, with frequent mutations transforming into virulent strains, for instance, B.1.1.7, B.1.351, and B.1.427. In recent months, a fungal infection, mucormycosis has emerged with more fatal responses and significantly increased mortality rate. To measure the severity and potential alternative approaches against black fungus coinfection in COVID-19 patients, PubMed, Google Scholar, World Health Organization (WHO) newsletters, and other online resources, based on the cases reported and retrospective observational analysis were searched from the years 2015-2021. The studies reporting mucormycosis with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) coinfection and/or demonstrating potential risk factors, such as a history of diabetes mellitus or suppressed immune system were included, and reports published in non-English language were excluded. More than 20 case reports and observational studies on black fungus coinfection in COVID-19 patients were eligible for inclusion. The results indicated that diabetes mellitus, hyperglycemic, and immunocompromised COVID-19 patients with mucormycosis were at a higher risk. We found that it was prudent to assess the potential risk factors and severity of invasive mycosis via standardized diagnostic and clinical settings. Large-scale studies need to be conducted to identify early biomarkers and optimization of diagnostic methods has to be established per population and geographical variation. This will not only help clinicians around the world to detect the coinfection in time but also will prepare them for future outbreaks of other potential pandemics., (© 2021 Wiley Periodicals LLC.)

Background & Aims: Our previous genomic whole-exome sequencing (WES) data identified the key ErbB pathway mutations that play an essential role in regulating the malignancy of gallbladder cancer (GBC). Herein, we tested the hypothesis that individual cellular components of the tumor microenvironment (TME) in GBC function differentially to participate in ErbB pathway mutation-dependent tumor progression., Methods: We engaged single-cell RNA-sequencing to reveal transcriptomic heterogeneity and intercellular crosstalk from 13 human GBCs and adjacent normal tissues. In addition, we performed WES analysis to reveal the genomic variations related to tumor malignancy. A variety of bulk RNA-sequencing, immunohistochemical staining, immunofluorescence staining and functional experiments were employed to study the difference between tissues with or without ErbB pathway mutations., Results: We identified 16 cell types from a total of 114,927 cells, in which epithelial cells, M2 macrophages, and regulatory T cells were predominant in tumors with ErbB pathway mutations. Furthermore, epithelial cell subtype 1, 2 and 3 were mainly found in adenocarcinoma and subtype 4 was present in adenosquamous carcinoma. The tumors with ErbB pathway mutations harbored larger populations of epithelial cell subtype 1 and 2, and expressed higher levels of secreted midkine (MDK) than tumors without ErbB pathway mutations. Increased MDK resulted in an interaction with its receptor LRP1, which is expressed by tumor-infiltrating macrophages, and promoted immunosuppressive macrophage differentiation. Moreover, the crosstalk between macrophage-secreted CXCL10 and its receptor CXCR3 on regulatory T cells was induced in GBC with ErbB pathway mutations. Elevated MDK was correlated with poor overall survival in patients with GBC., Conclusions: This study has provided valuable insights into transcriptomic heterogeneity and the global cellular network in the TME, which coordinately functions to promote the progression of GBC with ErbB pathway mutations; thus, unveiling novel cellular and molecular targets for cancer therapy., Lay Summary: We employed single-cell RNA-sequencing and functional assays to uncover the transcriptomic heterogeneity and intercellular crosstalk present in gallbladder cancer. We found that ErbB pathway mutations reduced anti-cancer immunity and led to cancer development. ErbB pathway mutations resulted in immunosuppressive macrophage differentiation and regulatory T cell activation, explaining the reduced anti-cancer immunity and worse overall survival observed in patients with these mutations., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Several vaccine candidates have been developed using different platforms, including nucleic acids (DNA and RNA), viral vectors (replicating and non-replicating), virus-like particles, peptide-based, recombinant proteins, live attenuated, and inactivated virus modalities. Although many of these vaccines are undergoing pre-clinical trials, several large clinical trials investigating the clinical efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines have produced promising findings., Areas Covered: In this review, we provide a status update on COVID-19 vaccines currently undergoing clinical trials and discuss issues of concern beyond vaccine efficacy and safety, including dosing regimens, the mixed vaccine strategy, prior severe acute respiratory syndrome coronavirus-2 infection, antibody levels, cellular immunity and protection, variants of concern, COVID-19 vaccine distribution, vaccination willingness, herd immunity, immunity passports, and vaccine indications., Expert Opinion: Four vaccines have obtained emergency use authorization, 87 are at the clinical development stage, and 186 are in pre-clinical development. While the knowledge and development of COVID-19 vaccines is rapidly expanding, the benefits of COVID-19 vaccines must outweigh the potential risks of adverse events. To combat the COVID-19 pandemic, clinicians should consistently update COVID-19-associated information, and healthcare authorities and manufacturers should work together to provide adequate and appropriate vaccinations for the prevention of COVID-19., Plain Language Summary: What is the context? Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic: the coronavirus disease 2019 (COVID-19) outbreak. The development and implementation of the COVID-19 vaccine could be an important measure to control the COVID-19 pandemic. What is new? Several phase 3 clinical trials have demonstrated the effectiveness and safety of COVID-19 vaccines for the prevention of SARS-CoV-2 infections. Several COVID-19 vaccines have obtained emergency use authorization and been implemented in many countries. Although concerns regarding unusual blood clots and low platelet counts have been raised, the benefits of COVID-19 vaccines outweigh the potential risks of adverse events. What is the impact? Except for children, the COVID-19 vaccine is recommended for all people, including those pregnant or immunocompromised. Healthcare authorities should advise people receiving the vaccine that they must seek medical attention if they have associated thromboembolism and thrombocytopenia symptoms. More studies are necessary to determine the appropriate vaccine dose and regimen strategy, as well as the effectiveness of COVID-19 vaccines against variants of concerns. A global effort must be made to achieve widespread vaccination and herd immunity.

Rationale: Cryptococcal infection has been documented in immunocompromised patients. AIDS and renal transplant recipients account for majority of the cases. Most cases present with central nervous system or disseminated disease, with only few presenting soft tissue, bone, and joint manifestations., Patient Concerns: We present a case of soft tissue mass in a 66-year-old female renal transplant recipient and that of arthritis in a 64-year-old immunocompetent man who presented pseudogout arthropathy. Chest radiographies of both cases were negative. Biopsy revealed cryptococcal organisms. Blood culture or cerebrospinal fluid sampling indicated positive results for cryptococcal antigen., Diagnosis: Cryptococcus neoformans was recovered in the wound culture., Interventions: The patients received intravenous fluconazole and flucytosine, followed by oral fluconazole administration., Outcomes: Symptomatic improvements were achieved and no subsequent relapses were observed., Lessons: The authors experienced 2 cases of cryptococcosis with very unusual clinical presentation. Early clinical suspicion and serum cryptococcal antigen testing can help in rapid appropriate diagnosis in immunocompetent as well as immunocompromised patients even in the absence of pulmonary involvement., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population., Competing Interests: Competing interests: JDG reports research support from Gilead Sciences, Eli Lilly and Regeneron Pharmaceuticals and advisory board and consulting from Gilead and Eli Lilly. PCR reports personal fees from Abbvie, Atom Biosciences, Eli Lilly, Gilead, Janssen, Novartis, UCB, Roche, Pfizer; meeting attendance support from Roche, Pfizer, Lilly and BMS and grant funding from Janssen, UCB and Novartis. TSU receives research support from Celgene/BMS, Merck and Roche and consults for AbbVie and Seattle Genetics. TSU is a co-inventor on US Patent 10 001,483, “Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers”. PL reports personal fees from Pfizer and Bristol Myers Squibb, about the topic covered in the review; grants and personal fees from MSD, personal fees from AiCuris, Takeda, and Enanta pharmaceuticals, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Coronavirus disease 2019 (COVID-19) was first detected in December 2019. In March 2020, the World Health Organization declared COVID-19 a pandemic. People with underlying medical conditions may be at greater risk of infection and experience complications from COVID-19. COVID-19 has the potential to affect People living with HIV (PLWH) in various ways, including be increased risk of COVID-19 acquisition and interruptions of HIV treatment and care. The purpose of this review article is to evaluate the impact of COVID-19 among PLWH. The contents focus on 4 topics: (1) the pathophysiology and host immune response of people infected with both SARS-CoV-2 and HIV, (2) present the clinical manifestations and treatment outcomes of persons with co-infection, (3) assess the impact of antiretroviral HIV drugs among PLWH infected with COVID-19 and (4) evaluate the impact of the COVID-19 pandemic on HIV services.

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors ( KIR ) and HLA class I ) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor-ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor-ligand interactions.

Objective: Pneumocystis jirovecii pneumonia (PCP) is a fatal respiratory infection, mostly associated with immunocompromised conditions. Several reports have described PCP development in patients who were not immunocompromised, but the clinical course and prognosis of PCP are not well understood. We compared the clinical characteristics and prognoses between patients with and without immunocompromised conditions who developed PCP., Methods: We retrospectively analyzed patients who had been treated for PCP from three hospitals. We defined immunocompromised (IC) status as following: human immunodeficiency virus (HIV) infection; hematological malignancy; solid organ tumor under chemotherapy; rheumatic disease; medication with immunosuppressive agents. Patients without immunocompromised status were defined as being non-immunocompromised (non-IC)., Results: The IC and non-IC groups comprised 173 and 14 patients. The median ages were 62.0 and 74.0 years in the IC and the non-IC group, respectively. The median interval between admission and anti-PCP treatment was significantly longer for patients in the non-IC group than that for patients in the IC group (7 vs. 2 days). The in-hospital mortality rates were significantly higher for patients in the non-IC group than that for patients in the IC group (71.4% vs. 43.9%; P = 0.047). A longer interval between admission and anti-PCP therapy was associated with increased 90-day mortality rate in patients with PCP (hazard ratio, 1.082; 95% confidence interval, 1.015-1.153; P = 0.016)., Conclusions: Patients with PCP with no predisposing illnesses were older and had higher mortality rates than IC patients with PCP. Delayed anti-PCP treatment was associated with increased 90-day mortality., Competing Interests: The authors have declared that no competing interests exist.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection with high mortality rate usually seen in the context of immunosuppression. Although cases have been reported largely in patients with HIV/AIDS, following the use of monoclonal antibodies and occasionally in haematological malignancies, there is no review to date of patients with smouldering or treated myeloma who developed PML. Here, we conducted a literature search of PML cases in patients with multiple myeloma (MM), analyse patient and disease characteristics and describe the possible mechanisms that could lead to the development of PML. The lack of data and case reports until 2010 may indicate that PML in MM is underdiagnosed. Simultaneously, with an expanding field of new therapeutic options, patients with MM live longer, albeit continually immunosuppressed, and at risk of opportunistic infections. Emerging new treatments for PML in the horizon render the need to look out for this complication mandatory, and more case reports are needed to enrich our knowledge in this field.

Ascites due to Mycobacterium avium intracellulare (MAI) infection is extremely rare and associated with a poor outcome. The cytomorphology of this condition has not been previously reported. We present a unique case of a 45-year-old woman with iatrogenic immunodeficiency who developed MAI-associated chylous ascites. The ascitic fluid cytology showed numerous lymphocytes and foamy histiocytes with abundant intracytoplasmic MAI organisms. The diagnosis was confirmed by tissue biopsy showing MAI mesenteritis. It is important to consider MAI-associated ascites in the differential diagnosis whenever ascitic fluid shows a predominant population of lymphocytes and macrophages, especially in immunocompromised patients., (© 2020 Wiley Periodicals LLC.)

Objectives: To describe the Children's Hospital Association's Improving Pediatric Sepsis Outcomes sepsis definitions and the identified patients; evaluate the definition using a published framework for evaluating sepsis definitions., Design: Observational cohort., Setting: Multicenter quality improvement collaborative of 46 hospitals from January 2017 to December 2018, excluding neonatal ICUs., Patients: Improving Pediatric Sepsis Outcomes Sepsis was defined by electronic health record evidence of suspected infection and sepsis treatment or organ dysfunction. A more severely ill subgroup, Improving Pediatric Sepsis Outcomes Critical Sepsis, was defined, approximating septic shock., Interventions: Participating hospitals identified patients, extracted data, and transferred de-identified data to a central data warehouse. The definitions were evaluated across domains of reliability, content validity, construct validity, criterion validity, measurement burden, and timeliness., Measurements and Main Results: Forty hospitals met data quality criteria across four electronic health record platforms. There were 23,976 cases of Improving Pediatric Sepsis Outcomes Sepsis, including 8,565 with Improving Pediatric Sepsis Outcomes Critical Sepsis. The median age was 5.9 years. There were 10,316 (43.0%) immunosuppressed or immunocompromised patients, 4,135 (20.3%) with central lines, and 2,352 (11.6%) chronically ventilated. Among Improving Pediatric Sepsis Outcomes Sepsis patients, 60.8% were admitted to intensive care, 26.4% had new positive-pressure ventilation, and 19.7% received vasopressors. Median hospital length of stay was 6.0 days (3.0-13.0 d). All-cause 30-day in-hospital mortality was 958 (4.0%) in Improving Pediatric Sepsis Outcomes Sepsis; 541 (6.3%) in Improving Pediatric Sepsis Outcomes Critical Sepsis. The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated strengths in content validity, convergent construct validity, and criterion validity; weakness in reliability. Improving Pediatric Sepsis Outcomes Sepsis definitions had significant initial measurement burden (median time from case completion to submission: 15 mo [interquartile range, 13-18 mo]); timeliness improved once data capture was established (median, 26 d; interquartile range, 23-56 d)., Conclusions: The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated feasibility for large-scale data abstraction. The patients identified provide important information about children treated for sepsis. When operationalized, these definitions enabled multicenter identification and data aggregation, indicating practical utility for quality improvement.

Objectives: To assess the response to initial oxygenation strategy according to clinical variables available at admission., Design: Multicenter cohort study., Setting: Thirty French and Belgium medical ICU., Subjects: Immunocompromised patients with hypoxemic acute respiratory failure., Interventions: None., Measurements and Main Results: Data were extracted from the Groupe de Recherche en Reanimation Respiratoire du patient d'Onco-Hématologie database. Need for invasive mechanical ventilation was the primary endpoint. Secondary endpoint was day-28 mortality. Six-hundred forty-nine patients were included. First oxygenation strategies included standard oxygen (n = 245, 38%), noninvasive ventilation (n = 285; 44%), high-flow nasal cannula oxygen (n = 55; 8%), and noninvasive ventilation + high-flow nasal cannula oxygen (n = 64; 10%). Bilateral alveolar pattern (odds ratio = 1.67 [1.03-2.69]; p = 0.04), bacterial (odds ratio = 1.98 [1.07-3.65]; p = 0.03) or opportunistic infection (odds ratio = 4.75 [2.23-10.1]; p < 0.001), noninvasive ventilation use (odds ratio = 2.85 [1.73-4.70]; p < 0.001), Sequential Organ Failure Assessment score (odds ratio = 1.19 [1.10-1.28]; p < 0.001), and ratio of PaO2 and FIO2 less than 100 at ICU admission (odds ratio = 1.96 [1.27-3.02]; p = 0.0002) were independently associated with intubation rate. Day-28 mortality was independently associated with bacterial (odds ratio = 2.34 [1.10-4.97]; p = 0.03) or opportunistic infection (odds ratio = 4.96 [2.11-11.6]; p < 0.001), noninvasive ventilation use (odds ratio = 2.35 [1.35-4.09]; p = 0.003), Sequential Organ Failure Assessment score (odds ratio = 1.19 [1.10-1.28]; p < 0.001), and ratio of PaO2 and FIO2 less than 100 at ICU admission (odds ratio = 1.97 [1.26-3.09]; p = 0.003). High-flow nasal cannula oxygen use was neither associated with intubation nor mortality rates., Conclusions: Some clinical characteristics at ICU admission including etiology and severity of acute respiratory failure enable to identify patients at high risk for intubation.

Background: The use of potent immunosuppressant medications is becoming more common, particularly the use of biologicals for a range of conditions such as rheumatoid arthritis and inflammatory bowel disease., Objective: This article focuses on the implications of immunosuppressant medications for travel, including pre-travel vaccinations, minimising risks during travel and travelling with medicines., Discussion: Pre-travel risk assessment is essential to prepare for safe travel. Live vaccines are contraindicated in people with significant immunosuppression because of the higher risk of adverse events and vaccine-associated disease. Inactivated vaccines can be used but may be less effective. Assessing the degree of immunocompromise in patients taking immunosuppressants includes considering both the medications and the underlying conditions. An individualised approach, often involving expert input, is needed to provide pre-travel health advice and immunisation. Planning ahead for travel is needed to minimise risks.

With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.

Background: The aim of the study was to determine clinical manifestations and outcome of Listeria monocytogenes meningitis (LM) and to compare with other forms of bacterial meningitis (BM)., Material and Methods: We analyzed records of all adult patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland., Results: Out of 343 analyzed patients with BM 24 were diagnosed to have LM. Patients with LM were older compared to patients with other forms of BM (62 years vs. 57 years, p=0.039), were more likely to have cancer (16.7% vs. 4.7%, p=0.045), receive immunosuppressive treatment (45.8% vs. 10.7%, p<0.001), or be immunocompromised in any way (62.5% vs. 35.5%, p=0.016). Blood tests showed lower WBC (10.7 × 103 cells/µl vs. 15.5 × 103 cells/µl, p=0.004), C-reactive protein (150 mg/L vs. 221 mg/L, p=0,019) and procalcitonin (1.27 ng/mL vs. 3.78 ng/mL, p=0.003) in LM group. Analysis of cerebrospinal fluid showed lower cell count (531.5 cells/µL vs. 1100 cells/µL, p<0.001) and lower chloride (113 mmol/L vs. 117 mmol/L, p=0.036) in patients with LM. In the multiple logistic regression analysis, immunosuppressive therapy was the only variable independently associated with LM (OR:8.72, CI 95%:1.41-64.34, p=0.024)., Conclusions: LM is associated with older age, cancer and immunosuppressive therapy. However, in multivariate analysis only immunosuppressive therapy turned out to be an independent risk factor for LM.

Idiopathic hyperammonemia is a rare complication with a high mortality rate that occurs in persons with hematologic malignancies or hematopoietic stem cell or solid organ transplant. Patients present with encephalopathy and hyperammonemia in the absence of liver disease or inborn errors of metabolism. Several etiologies have been proposed, including chemotherapeutic agents, medications, and a catabolic state with an elevated nitrogen load in the setting of acute illness. Recently, cases of hyperammonemia in adult lung transplant recipients have been attributed to infection from Ureaplasma parvum or U urealyticum Herein, we report a 12-year-old girl with acute myeloid leukemia and neutropenic fever who developed acute encephalopathy. Laboratory testing revealed severe hyperammonemia (blood ammonia level >1609 μmol/L) with normal liver function studies. U parvum was detected in blood, urine, and respiratory specimens by polymerase chain reaction testing. After antibiotic therapy directed against U parvum , blood ammonia levels normalized, the infection was eradicated, and the patient recovered. We propose that clinicians should test for invasive infection from Ureaplasma species in immunocompromised children with unexplained hyperammonemia., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Pneumocystis jirovecii pneumonia (PJP) has emerged as a main issue in non Human Immunodeficiency Virus (HIV) immunocompromised hosts, exposing patients to high mortality rates, especially when the diagnosis is delayed. Since microbiological confirmation is often unfeasible or difficult to obtain, High-resolution Computed Tomography (HRCT) represents a main tool for guiding the diagnosis in the appropriate clinical scenario. Nevertheless, radiologists must be aware that PJP at HRCT is a multifaceted process, with a variety of common and less frequent findings, along with a broad spectrum of infectious (e.g., viral and certain fungal and bacterial pneumonias) and non-infectious (e.g., pulmonary oedema, diffuse alveolar haemorrhage, and drug toxicity) differential diagnoses. In this review we resume background clinical information on PJP in non-HIV immunocompromised patients, illustrate both typical and less frequent HRCT findings, and present the spectrum of infectious and non-infectious mimickers at HRCT, highlighting the similarities with PJP and providing clues for the differential diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose of Review: This article reviews infections associated with cancer treatments and immunosuppressive/immunomodulatory therapies used in both neoplastic and non-neoplastic conditions, including hematopoietic cell transplantation and solid organ transplantation. It provides a clinical approach to the most commonly affected patient groups based on clinicoanatomic presentation and disease-specific risks resulting from immune deficits and drugs received., Recent Findings: The clinical presentations, associated neuroimaging findings, and CSF abnormalities of patients with central nervous system infections who are immunocompromised may differ from those of patients with central nervous system infections who are immunocompetent and may be confused with noninfectious processes. Triggering of brain autoimmunity with emergence of neurotropic antibodies has emerged as a recognized parainfectious complication. New unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity., Summary: Despite evidence-based prophylactic regimens and organism-specific antimicrobials, central nervous system infections continue to cause significant morbidity and mortality in an increasing range of patients who are immunocompromised by their conditions and therapies. Multiple new drugs put patients at risk for progressive multifocal leukoencephalopathy, which has numerous imaging and clinical manifestations; patients at risk include those with multiple sclerosis, for whom infection risk is becoming one of the most important factors in therapeutic decision making. Efficient, early diagnosis is essential to improve outcomes in these often-devastating diseases.

Background: Capnocytophaga canimorsus is a bacterium of the normal oral flora of dogs and cats. Human infection is caused by animal bite but is rarely observed, mainly in immunocompromised patients. We present 2 cases of C. canimorsus infection that occurred in immunocompetent patients and caused multiorgan failure and in both cases severe neurologic involvement., Case Report: In the first case, we present a 69-year-old immunocompetent woman with septic shock derived from skin and soft tissue infection after a dog's bite. She developed ischemic necrosis evolving to gangrene of both forefeet and hands, infective aortic endocarditis, and neurologic involvement caused by large hemispheric hypodense lesions compatible with ischemic septical lesions. In the second case, we present a 65-year-old immunocompetent man with meningitis after a dog's bite. Despite antibiotic therapy, he developed neurologic clinical deterioration, with right sensitive hemisyndrome associated with lack of strength and motor skills of the right hand. Radiologic findings were consistent with the diagnosis of cerebritis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Clinicians should always be aware of this pathogen, both in immunocompromised and immunocompetent patients, and consider prophylactic antibiotics after exposure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Herpes zoster is a major health burden that can affect individuals of any age. It is seen more commonly among individuals aged ≥50 years, those with immunocompromised status, and those on immunosuppressant drugs. It is caused by a reactivation of varicella zoster virus infection. Cell-mediated immunity plays a role in this reactivation. Fever, pain, and itch are common symptoms before the onset of rash. Post-herpetic neuralgia is the most common complication associated with herpes zoster. Risk factors and complications associated with herpes zoster depend on the age, immune status, and the time of initializing treatment. Routine vaccination for individuals over 60 years has shown considerable effect in terms of reducing the incidence of herpes zoster and post-herpetic neuralgia. Treatment with antiviral drugs and analgesics within 72 hours of rash onset has been shown to reduce severity and complications associated with herpes zoster and post-herpetic neuralgia. This study mainly focuses on herpes zoster using articles and reviews from PubMed, Embase, Cochrane library, and a manual search from Google Scholar. We cover the incidence of herpes zoster, gender distribution, seasonal and regional distribution of herpes zoster, incidence of herpes zoster among immunocompromised individuals, incidence of post-herpetic neuralgia following a zoster infection, complications, management, and prevention of herpes zoster and post-herpetic neuralgia., Competing Interests: There are no conflicts of interest.

Bacillus cereus is a widely-distributed, gram-positive or variable, rod-shaped bacterium frequently considered a contaminant in clinical specimens. It is recognized as a potential pathogen inducing self-limiting emetic or diarrheal food poisoning or localized infection in immunocompetent patients. True B. cereus bacteremia is uncommon and mainly observed in fragile patients, notably in immunocompromised individuals. We report clinical, radiological, and pathological findings of a 64-year-old patient with a history of acute myeloid leukemia who initially presented a fever while neutropenic after the induction of a second cycle of chemotherapy. He developed B. cereus bacteremia with invasive infection and a fatal outcome. The clinical and radiological data of this case are compared to a previously-published series of 21 patients from our institution with B. cereus bacteremia. This study highlights the clinical challenge to diagnose B. cereus and the importance of the delay between the detection of B. cereus and the initiation of an effective targeted antibiotic therapy. This case presented an aggressive evolution with multiple necrotic and hemorrhagic foci in the brain. Upon histological examination, B. cereus virulence was notably reflected by the dissection of blood vessel walls by the bacilli and luminal occlusion, a pattern that has not been yet reported.
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Background: Animal models are often used to assess interventions that might improve fat grafting outcomes; however, there is great variability in the models. The authors sought to determine the predictive value of the immunocompromised mouse model for fat grafting so that experiments could be standardized and optimized., Methods: Human lipoaspirate injections at different volumes and time points were assessed in a nude mouse model and compared with control injections of nonviable fat. Volume retention and explant histologic score were compared. In a separate study, interanimal reproducibility was determined by implanting a highly consistent hydrogel and measuring variability in volume retention., Results: Injection volume significantly affects adipose resorption kinetics at 6 and 12 weeks. Masson trichrome staining revealed that macrophages were unable to infiltrate large (1 ml) grafts, and oil cysts were not absorbed by 18 weeks, which interfered with interpretation of volume retention data. Nonviable tissue was resorbed when grafts were 0.3 ml, and quantification of graft histologic viability correlated well with graft retention at all study time points. Interanimal variability was measured to be 8.44 percent of the mean retention volume for small graft volumes., Conclusions: Human fat graft retention in the immunodeficient mouse correlates with graft viability in small, 0.3-ml-volume grafts. However, centralized oil cysts in nonviable 1.0-ml grafts were not resorbed by 18 weeks and thus volume measurements were confounded and not significantly different from viable samples. In addition, tissue injury scores increased in initially healthy fat grafts at 18 weeks, possibly because of a delayed immune reaction.

Background: Immunosuppressed inflammatory bowel disease (IBD) patients have an increased risk of herpes zoster virus (HZV) infection. The existing live-attenuated HZV vaccine is contraindicated in some of these patients and can only be used with caution in others., Aims: To describe characteristics of IBD patients suffering HZV to enable implementation of risk mitigation strategies for those at highest risk., Methods: Gastroenterologists completed a proforma for IBD patients who experienced HZV infection: IBD phenotype, details of HZV infection, immunosuppression and any change to treatment upon diagnosis of HZV., Results: A total of 30 cases was identified: Crohn disease (CD) (n = 25) and ulcerative colitis (n = 5). In total, 80% (20/25) of the CD patients had penetrating, stricturing or perianal disease. Time from commencement of immunosuppression to HZV infection was highly variable (range: 3 months to over 10 years). A total of 90% (27/30) of patients was on at least one immunosuppressive therapy; of those, one-third was on monotherapy (9/27) and two-thirds (18/27) on dual therapy. A total of 89% (24/27) of immunosupressed patients was on a thiopurine (monotherapy; 6/27) or in combination (18/27). Complications of HZV occurred in 27% (8/30) of patients., Conclusion: Our series is consistent with existing epidemiological analysis that identified more severe IBD and the use of multiple immunosuppressive therapies as risk factors for HZV. If the promise of an investigational subunit HZV vaccine is realised in immunocompromised patients, better protection may be possible in the future. Thiopurine medications were the most commonly used immunosuppressant in this series. Age and duration of immunosuppressive therapy do not appear to predict HZV infection., (© 2017 Royal Australasian College of Physicians.)

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) remain two of the most commonly diagnosed nosocomial infections. Both are responsible for significant morbidity and mortality in hospitalized patients. The development of HAP and VAP is related to bacterial colonization of the oropharynx (and endotracheal tube in VAP) with subsequent microaspiration and development of clinical infection. Diagnosis is made based on the clinical presentation and can be confirmed by obtaining either noninvasive or invasive microbiology culture specimens. Decisions addressing initiation of antimicrobial therapy can be divided into clinical and bacteriological strategies. These strategies differ in the criteria used to determine the timing of empiric therapy, with the clinical strategy basing the decision on radiographic evidence of infection plus clinical signs and symptoms and the bacteriological strategy requiring growth of pathogens above a certain threshold from invasively obtained culture specimens. Despite the delineated pathways, these decisions remain multifactorial and should also include consideration of patient-related factors, such as immunocompetence, the risk of multidrug-resistant infection, and overall clinical condition. Patients with risk factors or signs of clinical decompensation should have empiric therapy initiated at a lower threshold. However, when possible, therapy should be directed at a confirmed infection following a positive culture result. Decisions regarding specific empiric regimens should be based on the local prevalence of infectious microorganisms along with their associated antimicrobial susceptibilities. Patients deemed at risk of infection with multidrug-resistant pathogens merit broader spectrum therapy, and immunosuppressed patients should have consideration of antifungal coverage., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Herpes group viruses (herpes simplex virus, HSV; varicella-zoster virus, VZV; cytomegalovirus, CMV; and Epstein-Barr virus, EBV) remain an important cause of morbidity in immunocompromised persons. The aim of the study was to analyze the prevalence of HSV-1, HSV-2, VZV, CMV and EBV in patients undergoing hemodialysis. During a three-year period (2013-2015), 152 consecutive serum samples from hemodialysis patients and 150 healthy subjects (control group) were tested for the presence of IgM/IgG antibodies to herpes group viruses. Serologic tests were performed using a commercial enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunofluorescent assay (ELFA). Hemodialysis patients showed significantly higher CMV IgG seropositivity compared to controls (88.2% vs. 78.7%, p=0.011). In addition, seroprevalence rates of HSV-1 and VZV were higher in hemodialysis patients; however, these differences did not reach statistical significance (85.5% vs. 80.0%, p=0.054 and 99.3% vs. 96.0%, p=0.051, respectively). The prevalence of HSV-2 and EBV was similar in both groups (12.5% vs. 12.7%, p=0.137 and 98.0% vs. 95.3%, p=0.113, respectively). There was no difference in IgG seropositivity according to gender and place of residence. Logistic regression showed that older age was a significant predictor for CMV and EBV IgG seropositivity (increase in age by one year: CMV OR=1.055; 95%CI=1.030-1.080 and EBV OR=1.075, 95%CI=1.023-1.130).

Background: Pneumocystis jirovecii pneumonia (PCP) is a frequent opportunistic infection in immunocompromised patients. In literature, presentation and outcome of PCP differs between patients with human immunodeficiency virus (HIV) infection and renal transplant recipients (RTRs)., Methods: We conducted a cross-sectional study of patients with PCP based on the HIV and renal transplant registries at our institution. Radiological and clinical data from all confirmed PCP cases between 2005 and 2012 were compared., Results: Forty patients were included: 16 with HIV and 24 RTRs. Radiologically, HIV patients had significantly more areas of diffuse lung affection (81% HIV vs. 25% RTR; p = 0.02), more ground glass nodules 5-10 mm (69% vs. 4%; p = <0.001) and enlarged hilar lymph nodes were found only in HIV patients (44%). Cough and dyspnea were the most common clinical signs (>80%) in both groups. Duration from illness onset to hospital presentation was longer in the HIV patients (median of 18 vs. 10 days (p = 0.02)), implying a less fulminant clinical course. Sixty percent of PCP cases in RTRs occurred >12 months after transplantation. Lengths of hospitalization, admission rates to the intensive care unit, and requirements for mechanical ventilation were similar. Outcome in both groups was favourable., Conclusions: While important differences in radiological presentation of PCP between HIV patients and RTRs were found, clinical presentation was similar. PCP only rarely presented with fulminant respiratory symptoms requiring ICU admission, with similar results and outcomes for HIV patients and RTRs. Early diagnosis and treatment is mandatory for clinical success., Competing Interests: The authors have declared that no competing interests exist.

Pulmonary nocardiosis is a rare but potentially serious infection typically in immunosuppressed patients (ISPs). It is also known to occur in immunocompetent patients (ICPs). However, little is currently known regarding the clinical characteristics and radiographic findings of pulmonary nocardiosis specifically in ICPs. In this study, 30 patients with pulmonary nocardiosis were identified and 10 were considered to be colonized. Of all patients with pulmonary nocardiosis, 12 patients were ICPs and 18 were ISPs. Although half of ISPs were infected by Nocardia nova, ICPs were affected by various Nocardia species. Compared with ISPs, chest CT findings of ICPs showed a higher prevalence of bronchiectasis (67% vs 6%, p < .01) and centrilobular nodular opacities (67% vs 11%, p < .01), both of which are often seen in pulmonary nontuberculous mycobacterial disease. Additionally, nontuberculous mycobacterium was isolated from 6 of 21 ICPs with positive Nocardia species culture. Therefore, we recommend that physicians carefully differentiate pulmonary nocardiosis from pulmonary nontuberculous mycobacterial disease in ICPs., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever disease in humans and pose serious public health concerns in their regions of endemicity. Moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a neglected human pathogen of clinical significance. We have documented that a recombinant LCMV containing the glycoprotein (GPC) gene of LASV within the backbone of the immunosuppressive clone 13 (Cl-13) variant of the Armstrong strain of LCMV (rCl-13/LASV-GPC) exhibited Cl-13-like growth properties in cultured cells, but in contrast to Cl-13, rCl-13/LASV-GPC was unable to establish persistence in immunocompetent adult mice, which prevented its use for some in vivo experiments. Recently, V459K and K461G mutations within the GP2 cytoplasmic domain (CD) of rCl-13/LASV-GPC were shown to increase rCl-13/LASV-GPC infectivity in mice. Here, we generated rCl-13(GPC/VGKS) by introducing the corresponding revertant mutations K465V and G467K within GP2 of rCl-13 and we show that rCl-13(GPC/VGKS) was unable to persist in mice. K465V and G467K mutations did not affect GPC processing, virus RNA replication, or gene expression. In addition, rCl-13(GPC/VGKS) grew to high titers in cultured cell lines and in immunodeficient mice. Further analysis revealed that rCl-13(GPC/VGKS) infected fewer splenic plasmacytoid dendritic cells than rCl-13, yet the two viruses induced similar type I interferon responses in mice. Our findings have identified novel viral determinants of Cl-13 persistence and also revealed that virus GPC-host interactions yet to be elucidated critically contribute to Cl-13 persistence., Importance: The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), provides investigators with a superb experimental model system to investigate virus-host interactions. The Armstrong strain (ARM) of LCMV causes an acute infection, whereas its derivative, clone 13 (Cl-13), causes a persistent infection. Mutations F260L and K1079Q within GP1 and L polymerase, respectively, have been shown to play critical roles in Cl-13's ability to persist in mice. However, there is an overall lack of knowledge about other viral determinants required for Cl-13's persistence. Here, we report that mutations K465V and G467K within the cytoplasmic domain of Cl-13 GP2 resulted in a virus, rCl-13(GPC/VGKS), that failed to persist in mice despite exhibiting Cl-13 wild-type-like fitness in cultured cells and immunocompromised mice. This finding has uncovered novel viral determinants of viral persistence, and a detailed characterization of rCl-13(GPC/VGKS) can provide novel insights into the mechanisms underlying persistent viral infection., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Opisthorchiasis caused by Opisthorchis viverrini infection, is a serious public health problem in Lao PDR, Cambodia, Vietnam and Thailand. Cyprinid fish are required for the transmission of O. viverrini metacercariae to fish eating-mammal hosts including humans. The transmission of infective metacerariae is an important event, potentially resulting in the development of cholangiocarcinoma in cases of chronic opisthorchiasis. For a better understanding of the development of O. viverrini metacercariae in the second intermediate host, Barbonymus gonionotus (Cyprinidae), the immune response of infected B. gonionotus through fibrous tissue formation and superoxide dismutase (SOD) activity were investigated. The immunosuppressant (prednisolone) was administered to B. gonionotus infected with O. viverrini cercariae to study infectivity and development of the metacercariae. Additionally, the effects of prednisolone were studied by the investigation of fibrous tissue formation around the metacercariae, as well as SOD activity. In our study, prednisolone administered prior to infection in B. gonionotus had higher metacercarial recovery when compared to the non-administered control group. On the other hand, the administration of prednisolone after the O. viverrini infection allowed metacercariae to develop to the infective stage. Energy consumption from encystation to the infective stage required 443.9-463.7degree-days. The results show that immunosuppression decreases fibrous tissue and SOD activity in infected fish, and also affects the ability of O. viverrini metacercariae to develop to the infective stage. The immune response to metacercarial development of O. viverrini in cyprinid fish should be further studied to gain a greater understanding of this process, and hence, a better understanding of the mechanism(s) involved in metacercarial wall formation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tuberculous pyomyositis is a rare manifestation of extrapulmonary tuberculosis, most common in immunosuppressed patients, with clinical manifestations similar to pyomyositis of other etiologies, although with a lower age of presentation; notable risk factors include prior tuberculosis infection and pharmacological immunosuppression. Diagnosis depends on a high clinical suspicion of the infection in a susceptible population, given that microbiological isolation is often impossible. The response to treatment and prognosis are good. The case presented here is noteworthy given the rarity of this manifestation of tuberculosis and the slow response to first-line TB management in an HIV patient, despite susceptible microbiological isolation.

Achromobacter xylosoxidans is a rare, opportunistic infection most commonly encountered in immunocompromised patients during hospitalization. Primary uncomplicated bacteremia, catheter-associated infections, and pneumonia have been reported as the most common clinical presentations; skin and soft tissue infections from A. xylosoxidans are rare. We describe a case of A. xylosoxidans presenting as cellulitis and bacteremia in an immunocompromised patient., (© 2015 Wiley Periodicals, Inc.)

Q fever has rarely been reported and can be difficult to diagnose, especially in immunocompromised patients. In the present report, we describe an unusual case of Q fever that presented as peritonitis and was treated with long-term combination therapy with doxycycline, ciprofloxacin and rifampicin for five weeks in a patient who had been on peritoneal dialysis for six years due to hypertensive nephropathy., (Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.)

Background: Parainfluenza virus (PIV), a common pediatric pathogen, is associated with significant morbidity in immunocompromised (IC) hosts. DAS181, a novel sialidase fusion protein inhibitor, seems to be effective against PIV in vitro and in vivo; its use in IC children has not been evaluated., Methods: Patients were diagnosed with PIV infection using a quantitative reverse transcription-polymerase chain reaction. DAS181 was obtained under emergency investigational new drug applications and was administered via aerosol chamber or nebulizer. Patients were assessed daily for their clinical condition and adverse outcomes., Results: Four pediatric hematopoietic cell transplantation (HCT) patients with PIV detected in respiratory specimens were identified and treated with DAS 181. Patients 1 and 2 were diagnosed with PIV lower respiratory tract infection (LRTI) by bronchoalveolar lavage at 9 months and 2 days after allogeneic transplantation, respectively. Patient 3 was on chemotherapy prior to planned autologous HCT at time of PIV diagnosis from a nasal swab. Patient 4 was diagnosed with PIV via nasal wash 2 days after HCT. Patients 1-3 had clinical symptoms and chest imaging consistent with LRTI. Inhaled DAS181 was administered for 5-10 days. All 4 patients tolerated therapy well. Clinical improvement in oxygen requirement and respiratory rate was observed in all patients who required oxygen at therapy initiation. Viral load decreased in all patients within 1 week of therapy and became undetectable by day 3 of therapy in patient 3., Conclusion: DAS181 was used to treat 4 severely IC pediatric patients with PIV disease. The drug was well tolerated. Improvement in both viral loads and symptoms after initiation of therapy was observed in all cases. This report supports prospective, randomized studies in IC patients with PIV infection.

Background: SIAscopy (Spectrophotometric Intracutaneous Analysis) enables non-invasive analysis of the skin., Objective: We wanted to determine whether SIAscopy is able to detect and differentiate the skin chromophores melanin, collagen and haemoglobin and the influence of immunosuppressive drugs and other known risk factors for non-melanoma skin cancer (NMSC)., Methods: Volunteers and patients were measured by SIAscopy at six spots on sun-exposed and two spots on sun-protected skin. Measurements were transformed by SIAmetrics into arbitrary units and statistically analysed., Results: Melanin was shown to be higher with age (+1.73759 a.u.; P < 0.0001), sun exposure (+47.03998 a.u.; P < 0.0001), immunosuppression (+10.48526 a.u.; P < 0.0001) and lower in males (-26.50952 a.u.; P < 0.0001). Collagen was lower with increasing age (-0.29162 a.u.; P < 0.0001) and sun exposure (-6.85586 a.u.; P < 0.0001) but higher with male sex (+8.34251 a.u.; P < 0.0001) and immunosuppression (+5.79171 a.u.; P = 0.0001). Haemoglobin was lower with increasing age (-0.23833 a.u.; P = 0.0005), but higher with male sex (+18.51976 a.u.; P < 0.0001) and sun exposure (+13.74523 a.u.; P < 0.0001). Haemoglobin content was not associated to immunosuppression., Conclusion: Our results encourage the use of SIAscopy as a tool to better gauge an individual patient's NMSC risk factors. Further studies should help to better delineate SIAscopy as a prognostic tool., (© 2014 European Academy of Dermatology and Venereology.)

Graft rejection in transplant patients is managed clinically by suppressing T-cell function with immunosuppressive drugs such as prednisolone and methylprednisolone. In such immunocompromised hosts, human cytomegalovirus (HCMV) is an important opportunistic pathogen and can cause severe morbidity and mortality. Currently, the effect of glucocorticosteroids (GCSs) on the HCMV life cycle remains unclear. Previous reports showed enhanced lytic replication of HCMV in vitro in the presence of GCSs. In the present study, we explored the implications of steroid exposure on latency and reactivation. We observed a direct effect of several GCSs used in the clinic on the activation of a quiescent viral major immediate-early promoter in stably transfected THP-1 monocytic cells. This activation was prevented by the glucocorticoid receptor (GR) antagonist Ru486 and by shRNA-mediated knockdown of the GR. Consistent with this observation, prednisolone treatment of latently infected primary monocytes resulted in HCMV reactivation. Analysis of the phenotype of these cells showed that treatment with GCSs was correlated with differentiation to an anti-inflammatory macrophage-like cell type. On the basis that these observations may be pertinent to HCMV reactivation in post-transplant settings, we retrospectively evaluated the incidence, viral kinetics and viral load of HCMV in liver transplant patients in the presence or absence of GCS treatment. We observed that combination therapy of baseline prednisolone and augmented methylprednisolone, upon organ rejection, significantly increased the incidence of HCMV infection in the intermediate risk group where donor and recipient are both HCMV seropositive (D+R+) to levels comparable with the high risk D+R- group., (© 2015 The Authors.)

Purpose of Review: With the majority of deaths from cancer because of their metastases, strategies to reduce this from occurring are at the forefront of treatment. It has been hypothesized that morphine may result in an increase in cancer metastases, following many in-vitro and animal studies, but the evidence from human retrospective data is inconclusive. This article will explore the possible mechanisms by which opioids can impact on the natural history of the cancer cell and whether they are likely to be harmful in individuals with cancer., Recent Findings: Although there have been trials demonstrating benefits with regional anaesthesia techniques (opioid sparing) in the surgical population, it is not clear whether the source of the benefit arises directly from the avoidance of opioids or an added benefit afforded by regional anaesthesia. Research has shown that in particular cancer cell types, morphine may actually be beneficial and that the μ-opioid receptor (MOR) plays a role in cancer disease. With the crystal structure of the MOR having recently been elucidated, this may offer new opportunities for treatments aimed at reducing cancer metastasis., Summary: The role opioids play in the development of cancer metastasis and recurrence is far from clear and appears to differ depending on the cancer cell type in question. Prospective randomized controlled trials are currently underway in humans to help clarify the situation further and there results are awaited with anticipation. The negative impact of pain on the immune system is well documented and it appears that appropriate analgesia is paramount in minimizing this. Opioids still constitute a central role in the management of moderate-to-severe cancer pain.

Background/aims: There is an increased risk for inflammatory bowel disease (IBD) patients to develop infections due to the use of immunomodulators and biologics. Several infections are preventable by immunizations. This study investigated the knowledge and awareness of Korean gastroenterologists regarding the vaccination of patients with IBD., Methods: A self-reported questionnaire was sent by e-mail to the faculty members of tertiary hospitals. Gastroenterologists were asked ten questions regarding the immunization of patients with IBD. A total of 56 gastroenterologists completed the questionnaire., Results: A majority of gastroenterologists (>60%) had rarely or never recorded an immunization history from their patients with IBD. Moreover, 50% to 70% of the gastroenterologists did not know that live vaccines should be avoided in immunosuppressed patients. The most commonly mentioned resistance to vaccinations was "the lack of concern and knowledge regarding vaccination." Gastroenterologists more frequently asked about the immunization history of influenza, pneumococcal, hepatitis A, and hepatitis B vaccines and recommended these vaccines more often than others., Conclusions: Korean gastroenterologists' awareness and knowledge regarding the vaccination of patients with IBD were very poor. Intensive educational programs on immunization guidelines directed toward gastroenterologists who care for patients with IBD are required to ensure that these patients receive the necessary vaccinations.

Background: Diabetic foot (DF) can be defined as an infection and/or an ulceration with or without destruction of deep tissues associated with neurological abnormalities and varying degrees of peripheral vascular disease of the lower limb in patients with diabetes. Both neuropathy and vascular disease, along with the well-known impairment of immune function in patients with diabetes, contribute to polymicrobial foot infections, which further aggravate the already severe clinical manifestations of diabetes., Discussion: The immunocompromised district (ICD) is a novel pathogenic concept referring to a site in which there is an obstacle to the normal trafficking of immunocompetent cells through lymphatic channels, and/or interference with the signals that neuropeptides and neurotransmitters, released by peripheral nerves, send to cell membrane receptors of immunocompetent cells. These loci minoris resistentiae have the propensity to develop a secondary disease, which may occur after an extremely variable length of time., Conclusions: In this work, we provide an overview of etiopathogenetic mechanisms of DF and propose a unifying view of this topic based on the concept of the ICD., (© 2013 The International Society of Dermatology.)

Infection with various human polyomaviruses (HPyVs) is prevalent, with rates as high as 80 % within the general population. Primary infection occurs during childhood through respiratory or urino-oral transmission. While the majority of individuals exhibit asymptomatic latent infection, those immunocompromised persons are at risk for viral reactivation and disease progression resulting in conditions such as progressive multifocal leukoencephalopathy (PML), trichodysplasia spinulosa, Merkel cell carcinoma, and polyomavirus associated nephropathy. Individuals with altered immune systems due to HIV, organ transplantation, lymphoproliferative diseases, and monoclonal antibody therapy are particularly susceptible to reactivation of various HPyVs. While the specific factors that induce lytic infection have yet to be defined, it is evident that dysfunctional host cellular immune responses allow active infection to occur. Immunosuppressant conditions, such as in chronic alcohol abuse, may serve as added risk factors for reactivation of HPyVs. Since the human HPyV family is rapidly expanding, continuing studies are needed to characterize the role that known and newly discovered HPyVs play in human disease.