Zearalenone and deoxynivalenol inhibited IL-4 receptor-mediated Th2 cell differentiation and aggravated bacterial infection in mice.

The immunotoxicity of zearalenone (ZEA) and deoxynivalenol (DON), two of the most common environmental mycotoxins, has been well investigated. However, due to the complexity of the immune system, especially during bacterial infection, many types of immune cells are involved in invasion resistance and bacterial clearance. Of these, T helper 2 (Th2) cells, which are members of the helper T cell family, assist B cells to activate and differentiate into antibody-secreting cells, participate in humoral immune response, and, ultimately, eliminate pathogens. Thus, it is important to identify the stage at which these toxins affect the immune function, and to clarity the underlying mechanisms. In this study, mice infected with Listeria monocytogenes (Listeria) were used to study the effects of ZEA, DON, and ZEA + DON on Th2 differentiation, Interleukin-4 Receptor (IL-4R) expression, costimulatory molecules expression and cytokine secretion after Listeria infection. Naive CD4+ T cells, isolated from mice, were used to verify the in vivo effects and the associated mechanisms. In vivo experiments showed that these toxins aggravated spleen damage after Listeria infection and reduced the differentiation of Th2 cells by affecting the synthesis of IL-4R of CD4+ T cells. In addition, the level of the costimulatory molecule CD154 decreased. Consistent with this, in vitro studies showed that these toxins inhibited the differentiation of mouse naive CD4+ T cell into Th2 subtype and decreased IL-4R levels. In addition, the levels of costimulatory molecules CD154, CD278 and the Th2 cells secrete cytokines IL-4, IL-6, and IL-10 decreased. Based on our in vivo and in vitro experiments, we suggest that ZEA, DON, and ZEA + DON inhibit the expression of costimulatory molecules on CD4+ T cell, and inhibit the IL-4R-mediated Th2 cell differentiation. This may indicate that the body cannot normally resist or clear the pathogen after mycotoxin poisoning.

Listeria infection after treatment with alemtuzumab: a case report and literature review. Would antibiotic prophylaxis be considered?

Few cases of complicated infections with Listeria monocytogenes (LM) have been reported to date in patients with multiple sclerosis (MS) treated with alemtuzumab. Primary prevention strategies may be suggested in such patients to avoid infections. However, these may be ineffective because patients may already be carriers of LM. We report herein a case of bloodstream infection due to LM in a 25-year-old woman with MS treated with alemtuzumab. We searched the UMC/WHO Vigibase system for all reported cases of LM in patients treated with alemtuzumab and found 29 cases overall up to 21 July 2019. We also performed a literature review of MS cases with LM on alemtuzumab, in order to evaluate epidemiology, clinical characteristics, and outcome of this complication. Since the published cases (N=8) were mainly reported in recent years but more cases were found in the UMC/WHO Vigibase system (although not necessarily in patients with MS), we hypothesize that this complication is more frequent than currently believed and may become even more important in the future. Therefore, it is worth reaching a consensus on appropriate algorithms to stratify individuals by risk so as to implement targeted prevention strategies (whether primary or secondary).

Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis.

OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.

Fatal Chemotherapy-induced Combined Infection in a Hodgkin's Disease Patient: a Case Report.

Multimodal therapy, used for the treatment of patients with Hodgkin's disease (HD), makes them prone to life-threatening infections, attributed mainly to febrile neutropenia. Herein, we present a case report of fatal combined bacterial and viral infection in a 49-year-old female patient, subject to polychemotherapy for HD. Rapid microbiological diagnosis performed by multiplex polymerase chain reaction elucidated the causes of the infection within hours. Listeria monocytogenes was detected in both the cerebrospinal fluid and blood samples. Nasopharyngeal swabs returned positive for two swine-derived strains of influenza A virus. We aimed to emphasize the importance of these pathogens and draw attention to their association in the aetiology of infections among patients receiving chemotherapy. In conclusion, better surveillance is needed to improve the early diagnosis of infectious complications in these patients.

Propofol Increases Host Susceptibility to Microbial Infection by Reducing Subpopulations of Mature Immune Effector Cells at Sites of Infection.

Anesthetics are known to modulate host immune responses, but separating the variables of surgery from anesthesia when analyzing hospital acquired infections is often difficult. Here, the bacterial pathogen Listeria monocytogenes (Lm) was used to assess the impact of the common anesthetic propofol on host susceptibility to infection. Brief sedation of mice with physiologically relevant concentrations of propofol increased bacterial burdens in target organs by more than 10,000-fold relative to infected control animals. The adverse effects of propofol sedation on immune clearance of Lm persisted after recovery from sedation, as animals given the drug remained susceptible to infection for days following anesthesia. In contrast to propofol, sedation with alternative anesthetics such as ketamine/xylazine or pentobarbital did not increase susceptibility to systemic Lm infection. Propofol altered systemic cytokine and chemokine expression during infection, and prevented effective bacterial clearance by inhibiting the recruitment and/or activity of immune effector cells at sites of infection. Propofol exposure induced a marked reduction in marginal zone macrophages in the spleens of Lm infected mice, resulting in bacterial dissemination into deep tissue. Propofol also significantly increased mouse kidney abscess formation following infection with the common nosocomial pathogen Staphylococcus aureus. Taken together, these data indicate that even brief exposure to propofol severely compromises host resistance to microbial infection for days after recovery from sedation.

CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15.

Innate CD8(+) T cells are a heterogeneous population with developmental pathways distinct from conventional CD8(+) T cells. However, their biology, classification, and functions remain incompletely understood. We recently demonstrated the existence of a novel population of chemokine (C-X-C motif) receptor 3 (CXCR3)-positive innate CD8(+) T cells. Here, we investigated the functional properties of this subset and identified effector molecules and pathways which mediate their function. Adoptive transfer of IL-15 activated CXCR3(+) innate CD8(+) T cells conferred increased protection against Listeria monocytogenes infection in susceptible IFN-γ(-/-) mice compared with similarly activated CXCR3(-) subset. This was associated with enhanced proliferation and IFN-γ production in CXCR3(+) cells. Further, CXCR3(+) innate cells showed enhanced cytotoxicity against a tumor cell line in vitro. In depth analysis of the CXCR3(+) subset showed increased gene expression of Ccl5, Klrc1, CtsW, GP49a, IL-2Rß, Atp5e, and Ly6c but reduced IFN-γR2 and Art2b. Ingenuity pathway analysis revealed an up-regulation of genes associated with T-cell activation, proliferation, cytotoxicity, and translational initiation in CXCR3(+) populations. Our results demonstrate that CXCR3 expression in innate CD8(+) T cells defines a subset with enhanced cytotoxic potential and protective antibacterial immune functions. Immunotherapeutic approaches against infectious disease and cancer could utilize CXCR3(+) innate CD8(+) T-cell populations as novel clinical intervention strategies.

Emergence of sporadic non-clustered cases of hospital-associated listeriosis among immunocompromised adults in southern Taiwan from 1992 to 2013: effect of precipitating immunosuppressive agents.

BACKGROUND: Sporadic non-clustered hospital-associated listeriosis is an emerging infectious disease in immunocompromised hosts. The current study was designed to determine the impact of long-term and precipitating immunosuppressive agents and underlying diseases on triggering the expression of the disease, and to compare the clinical features and outcome of hospital-associated and community-associated listeriosis. METHODS: We reviewed the medical records of all patients with Listeria monocytogenes isolated from sterile body sites at a large medical center in southern Taiwan during 1992-2013. Non-clustered cases were defined as those unrelated to any other in time or place. Multivariable regression analysis was used to determine factors associated with prognosis. RESULTS: Thirty-five non-clustered cases of listeriosis were identified. Twelve (34.2%) were hospital-associated, and 23 (65.7%) were community-associated. The 60-day mortality was significantly greater in hospital-associated than in community-associated cases (66.7% vs. 17.4%, p = 0.007). Significantly more hospital-associated than community-associated cases were treated with a precipitating immunosuppressive agent within 4 weeks prior to onset of listeriosis (91.7% vs. 4.3%, respectively p < 0.001). The median period from the start of precipitating immunosuppressive treatment to the onset of listeriosis-related symptoms was 12 days (range, 4-27 days) in 11 of the 12 hospital-associated cases. In the multivariable analysis, APACHE II score >21 (p = 0.04) and receipt of precipitating immunosuppressive therapy (p = 0.02) were independent risk factors for 60-day mortality. CONCLUSIONS: Sporadic non-clustered hospital-associated listeriosis needs to be considered in the differential diagnosis of sepsis in immunocompromised patients, particularly in those treated with new or increased doses of immunosuppressive agents.

[Neurological complications during treatment of the tumor necrosis alpha inhibitors]. / Powiklania neurologiczne w przebiegu leczenia inhibitorami przeciwcial monoklonalnych.

Medications with TNF-alpha inhibitors family are successfully applicable in rheumatology, gastroenterology, dermatology and neurology. Still, the ongoing research on the safety assessment of their application, also due to neurological complications. The vast majority of these complications is associated with an increased risk of serious virus (Herpes simplex--JC) and bacterial (Listeria monocytogenes) neuroinfections. They can cause the occurrence of progressive multifocal leukoencephalopathy--PML with a severe clinical course and poor prognosis or herpes simplex encephalitis--HSE. Meta-analysis revealed a number of cases of PML and the HSE in the first 6 months of treatment with natalizumab, efalizumab, rituximab, abatacept and infliximab. Common complication occasionally turning on this biologics is chronic demyelinating polyneuropathy or Lewis-Sumner syndrome. Described are cases of central and peripheral demyelination typical of multiple sclerosis (MS). Are also reported cases of motor multifocal neuropathy with conduction block acute encephalithis with polyneuropathy or mononeuropathy in the form of anterior optic neuropathy Guillen-Barre' syndrome and its variant, Miller-Fisher syndrome have been confirmed as adverse events following treatment with infliximab. Also revealed several cases of myasthenia gravis after using etanercept. In the few cases of systemic lupus CNS involvement caused by treatment with TNF inhibitors, the mechanism of these disorders is still considered too vague. Due to the emerging reports on the number of neurological adverse events of TNF antagonists, significantly higher than those described in the literature, the safety of their use requires further monitoring and multicenter studies.

Existing medications among non-pregnancy-related listeriosis patients in England, 2007-2009.

To identify which medications were most commonly taken by non-pregnancy-related listeriosis patients prior to illness, we compared the medications reported by 512 cases identified via national surveillance in England between 2007 and 2009 with national prescription data, using British National Formulary (BNF) coding. Relative risks and corresponding confidence intervals were calculated, as appropriate, for BNF chapters and sections. Among listeriosis cases, the rates for cytotoxic drugs, drugs affecting the immune response and corticosteroids were significantly higher than for other medications. However, interactions between medications and how medications might confound or be confounded by concurrent medical conditions need to be investigated further. Nevertheless our findings suggest that targeting food-safety advice to prevent this foodborne disease in certain treatment groups is warranted.

Listeria monocytogenes cholecystitis: a possible new syndrome.

The U.S. Food and Drug Administration recently added potentially fatal Listeria monocytogenes infection to the list of opportunistic infections that can occur in patients who receive tumor necrosis factor inhibitor therapy. In this study, the first reported case of L monocytogenes cholecystitis associated with etanercept use is described. It also appears that tumor necrosis factor inhibitor therapy likely increases the risk for Listeria cholecystitis. Clinicians need to be aware of this association when selecting antimicrobial therapy for these patients.

Listeria monocytogenes septic arthritis in a patient treated with mycophenolate mofetil for polyarteritis nodosa: a case report and review of the literature.

Listeriosis can be a cause of arthritis. Here, we present a case of Listeria monocytogenes septic arthritis of the right hip in a 66-year-old male treated with mycophenolate mofetil for polyarteritis nodosa. So far, septic arthritis due to this microorganism has not been reported in patients treated with mycophenolate mofetil. We review the literature of L. monocytogenes septic arthritis and discuss the role of mycophenolate mofetil treatment in precipitating listeriosis.

[Listeriosis in non-Hodgkin's lymphoma following outpatient R-CHOP therapy].

Non-Hodgkin's lymphoma, a hematolymphoid malignancy, puts subjects at risk for complete infection. A 65-year-old man with non-Hodgkin's lymphoma Stage IV had undergone 5 R-CHOP courses in May 2008. Six days later, he was hospitalized for a high fever for which he was initially administered cefepime. When blood culture was positive for Listeria monocytogenes, he was administered ampicillin. His medical interview indicated that he had gone hunting and dressed wild animal meat at his mountain retreat, where he was exposed to wild animals and their excreta following R-CHOP course 5. CSF was not checked because his general condition was good. On hospital day 2, his fever dropped, and he was discharged following two weeks of ampicillin administration. Listeriosis cases reported in Japan number far fewer than in the United States, France or Germany. From January 1983 to February 2009, 153 cases were reported in Japan, 12 of whom were cancer patients. Despite the high incidence of meningitis with listeriosis, 7 of the 12 were not examined for CSF--an examination necessary in listeriosis, however well the subject appears.

Listeria infections associated with infliximab: case reports.

Infliximab is a human-murine chimeric monoclonal antibody directed against tumor necrosis factor alpha (TNFalpha). Infliximab and other TNF blockers are used to treat inflammatory diseases such as rheumatoid arthritis (RA). TNF blockers are suspected to play a key role in some infections. We report here two cases of Listeria monocytogenes sepsis associated with infliximab treatment for RA. The first patient developed a terminal ileitis and a bacteraemia after three doses of infliximab; the second RA patient presented a bacteraemia associated with a prosthetic joint arthritis of the left hip, both related to Listeria. Those two cases occurred in a population of 518 patients treated with TNF blockers in our hospitals since the year 2000. Those events are of particular interest because of the severity of the infection, because the treatment differs from other infections, and because that, in the rheumatology unit, septic arthritis can mimic RA symptoms. They enhance the likelihood for this drug to increase the risk for infections with germs like Listeria.

Enhancement of mice susceptibility to infection with Listeria monocytogenes by the treatment of morphine.

The effect of morphine on the susceptibility of BALB/c mice to diarrheagenic Escherichia coli, Shigella flexneri, Listeria monocytogenes, Salmonella Enteritidis, Yersinia enterocolitica, was examined via the intraperitoneal inoculation. Morphine treatment increased the susceptibility to S. Enteritidis and L. monocytogenes, resulting in bacteremia and central nervous system (CNS) invasion (for L. monocytogenes), while the infection with other bacteria did not show the systemic dissemination in the morphinetreated mice. Notably, L. monocytogenes infection caused 100% mortality with a mean survival time (MST) of 1.3 days in morphine-treated mice, but untreated mice did not die. The present data suggested that individuals using heroin or treated with morphine derivatives might be at high risk for listeriosis, especially those who are immunocompromised. Recent increasing consumption of morphine may propose the necessity for further epidemiological surveillance on infectious diseases.

Listeria brain abscess, Pneumocystis pneumonia and Kaposi's sarcoma after temozolomide.

BACKGROUND: A 55-year-old man with glioblastoma multiforme was treated with continuous, dose-dense temozolomide. This therapy was curtailed after three cycles because of nausea, asthenia, and neuropsychological deterioration. During a subsequent course of radiotherapy, the patient developed fever, headaches, and cutaneous lesions. INVESTIGATIONS: Physical examination, cerebral MRI, brain biopsy, skin biopsy, immunohistochemistry, bronchoscopy with bronchoalveolar lavage, and laboratory tests. DIAGNOSIS: Severe temozolomide-induced immunosuppression, exacerbated by corticosteroids, with profound T-cell lymphocytopenia and simultaneous opportunistic infections with Pneumocystis jiroveci pneumonia, brain abscess with Listeria monocytogenes, and cutaneous Kaposi's sarcoma. MANAGEMENT: Discontinuation of temozolomide, discontinuation of radiotherapy, antibiotic treatment with amoxicillin and gentamicin, and administration of atovaquone and pentamidine.