[Functional immunoassays in the setting of infectious risk and immunosuppressive therapy of non-HIV immunocompromised patients]. / Place des tests immunitaires fonctionnels dans la prise en charge du risque infectieux et de la gestion des thérapies immunosuppressives chez les patients immunodéprimés non-VIH.

The holistic approach of the human immune system is based on the study of its components collectively driving a functional response to an immunogenic stimulus. To appreciate a specific immune dysfunction, a condition is mimicked ex vivo and the immune response induced is assessed. The application field of such assays are broad and expanding, from the diagnosis of primary and secondary immunodeficiencies, immunotherapy for cancer to the management of patients at-risk for infections and vaccination. These assays are immune monitoring tools that may contribute to a personalised and precision medicine. The purpose of this review is to describe immune functional assays available in the setting of non-HIV acquired immune deficiency. First, we will address the use of theses assays in the diagnosis of opportunistic infections such as viral reactivation. Secondly, we will report the usefulness of these assays to assess vaccine efficacy and to manage immunosuppressive therapies.

Effects of Corynebacterium bovis on Engraftment of Patient-derived Chronic-Myelomonocytic Leukemia Cells in NSGS Mice.

Modeling chronic myelomonocytic leukemia (CMML) in immunodeficient NSGS mice relies on unique human CMML specimens and consistent murine engraftment. Only anecdotal comments have thus far supported the notion that research data may be altered by Corynebacterium bovis, an opportunistic cutaneous pathogen of immunodeficient mice. C. bovis disseminated by asymptomatic and clinically affected mice with hyperkeratotic dermatitis, resulting in resilient facility contamination and infectious recurrence. Herein we report that, compared with C. bovis PCR-negative counterparts, C. bovis PCR-positive NSGS mice developed periocular and facial hyperkeratosis and alopecia and had reduced metrics indicative of ineffective human CMML engraftment, including less thrombocytopenia, less splenomegaly, fewer CMML infiltrates in histopathologic sections of murine organs, and fewer human CD45+ cells in samples from murine spleen, bone marrow, and peripheral blood that were analyzed by flow cytometry. All CMML model metrics of engraftment were significantly reduced in the C. bovis PCR-positive cohort compared with the - negative cohort. In addition, a survey of comprehensive cancer center practices revealed that most murine facilities do not routinely test for C. bovis or broadly decontaminate the facility or its equipment after a C. bovis outbreak, thus increasing the likelihood of recurrence of invalidated studies. Our findings document that CMML engraftment of NSGS mice is diminished-and the integrity of murine research data jeopardized-by C. bovis infection of immunodeficient mice. In addition, our results indicate that C. bovis should be excluded from and not tolerated in murine facilities housing immunodeficient strains.

Risk of opportunistic infections in patients with antineutrophil cytoplasmic antibody-associated vasculitis, using a Japanese health insurance database.

AIM: Opportunistic infections (OIs) adversely affect outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study aimed to identify the incidence proportion of risk factors for OIs in patients with AAV who were on remission-induction therapy, using a Japanese health insurance database. METHOD: This retrospective longitudinal population-based study was conducted using claims data provided by Medical Data Vision Co., Ltd. We defined individuals as AAV cases receiving remission-induction therapy if they met all of the following criteria: (a) having OIs with at least 1 specified International Statistical Classification of Diseases and Related Health Problems, 10th Revision code (M300, M301, M313, or M318); (b) receiving at least 1 prescription of oral corticosteroids (CS) with prednisolone (PSL)-equivalent dosage ≥30 mg/d, CS pulse therapy, immunosuppressive agents or rituximab during hospitalization between April 2008 and April 2017; and (c) at least 7 days of hospitalization while on the above-mentioned therapies. We calculated incidence and proportion of OIs during the year following remission-induction therapy and the adjusted odds ratio (OR) using a logistic regression model. RESULTS: We included 2299 patients with AAV in this study. OIs occurred in 460 patients (20.0%), with the most frequently occurring OI being cytomegalovirus infection (n = 122, 6.5%). After adjusting for covariates, age by decade (OR 1.24, 95% CI: 1.12-1.36), daily PSL dose per 10 mg (OR 1.16, 95% CI: 1.08-1.25), and CS pulse therapy (OR 1.29, 95% CI: 1.04-1.60) were found to be significantly associated with occurrence of OIs. CONCLUSION: Older age and corticosteroid use were found to be significant risk factors for OIs in patients with AAV on remission-induction therapy, using a health insurance database.

Infección urinaria por Aerococcus sanguinicola. Patógeno emergente oportunista / Urinary tract infection by aerococcus sanguinicola. An emerging opportunistic pathogen

Los pacientes ancianos con enfermedad urológica de base tienen mayor riesgo de infecciones del trato urinario por patógenos infrecuentes. Previamente se ha infraestimado la enfermedad causada por Aerococcus, pero la espectrometría de masas podría ser un método sencillo para su identificación. En este trabajo se describen 2 casos de infección urinaria por Aerococcus sanguinicola (A. sanguinicola). Se realizó un estudio descriptivo clínico-microbiológico de la presencia de A. sanguinicola produciendo infecciones urinarias. La presencia de A. sanguinicola ocurrió en pacientes ancianos con enfermedad urológica previa y con un recuento significativo en orinas obtenidas mediante sondaje vesical. La identificación fue correcta mediante espectrometría de masas. La evolución clínica fue satisfactoria mediante el uso de amoxicilina y cefuroxima. En este trabajo informamos de la capacidad patógena de A. sanguinicola. En el urocultivo, ante un recuento significativo de microorganismos alfa-hemolíticos, deberíamos descartar que se trate de A. sanguinicola antes de informar un resultado como microbiota urogenital

Elderly patients with underlying urological disease have a greater risk of urinary tract infections due to uncommon pathogens. The disease caused by Aerococcus has been underestimated, but mass spectrometry could be a simple method for identifying this pathogen. In this study, we report 2 cases of urinary tract infection by Aerococcus sanguinicola. A descriptive clinical-microbiological study was conducted on the presence of A. sanguinicola causing urinary tract infections. The presence of A. sanguinicola occurred in elderly patients with previous urological disease and a significant count in urine obtained through bladder catheterisation. Correct identification was achieved through mass spectrometry, and the clinical outcome of administering amoxicillin and cefuroxime was satisfactory. In this study, we also report the pathogenic capacity of A. sanguinicola. When there is a significant number of alpha-haemolytic microorganisms in the urine cultures, A. sanguinicola should be ruled out before reporting a result as urogenital microbiota

Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance.

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

Successful management of Mycobacterium haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Nontuberculous mycobacterial infections can often occur in individuals with adequate immune function. Such infections typically have cutaneous involvement and are caused by rapidly growing mycobacterium. Other nontuberculous mycobacteria species, like Mycobacterium haemophilum, almost always present as opportunistic infections occurring in severely immunocompromised hosts. Here, we present a complicated and protracted course of diagnosing M. haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

[Generation of Antibiotic Tolerant Bacterial Persisters in Immunocompromized Patients with Hematologic and Malignant Diseases: A New Problem of Health-Care Associated Infections].

Background: Antibiotic tolerance (AT) represents one of the causes of the phenomenon of antibiotic resistance that allows escape of non-replicating metabolically inert microorganisms (persisters) from any antibiotics attack because molecular targets of antibiotics are lacking thereby creating the potential for chronic infections. Aims: Determine the heterogeneity of the strains of opportunistic pathogens E. coli and P. aeruginosa isolates from children with hematologic malignancies containing bacterial persisters that cause the AT phenomenon. Methods: Children with hematological malignancies were divided into 2 groups according to the intensity of antibiotic treatment of infectious complications. Ciprofloxacin-induced persisters were quantitatively determined in the biological materials obtained from sick children. Results: Within the clinical isolates of E. coli and P. aeruginosa, about a third of the strains belong to high-persisting. The numbers of persistent forms of bacteria did not correlate with a minimal inhibitory concentration values ciprofloxacin (r=0.148, n=25, p>0.05). Interestingly, higher level of formation of persistent E. coli and P. aeruginosa, is associated with higher frequencies of infection attacks, massive antibiotic use and unfavorable course of the disease in children. Conclusions: Therefore, detecting the persistent forms of bacterial pathogens including those associated with the health-care associated infection, specifically, in immunocompromised patients, should be included into the contemporary algorithms of microbiological observation and monitoring of patients and intrahospital environment.

Prevalence and antifungal susceptibility patterns of dermatophytes isolated from patients with neoplastic diseases: a case control study.

Patients with neoplasia who are severely immunocompromised have a higher risk of fungal infections. There are limited data in the literature regarding the frequency of dermatophyte infections and efficacy of antifungals in patients with malignancies. Objective was assessment of the incidence of dermatophyte infections and antifungal susceptibility, determination of dermatophyte species isolated from patients with neoplastic diseases. 138 patients diagnosed with various malignancies and 160 immunocompetent patients who were referred to the Department of Dermatology in Brasov, Romania, for suspicion of dermatophyte infections were included in the study. Nail clippings or skin scrapings were examined by direct microscopy and cultures in Sabouraud agar medium. Susceptibility tests for antifungals were conducted in vitro using a method of broth microdilution. Infections with dermatophytes were identified in 30.4% of patients with neoplastic diseases and in 29.37% in the control group. There was a significantly higher frequency of dermatophyte infections in patients with hematologic malignancies (52%) compared to those with solid cancers (25.66%) (P=0.01). The clinical aspects of dermatophyte infections in patients with neoplastic diseases were not different from those of patients without cancer; though in some cases the infections were more extensive. There were no statistically significant differences between mean values of minimum inhibitory concentration of antifungals compared with controls. Terbinafine had the highest antidermatophyte activity for all tested dermatophyte species isolated from patients with neoplastic diseases. There were no differences in frequency of dermatophyte infections and antifungal susceptibility to dermatophytes between patients with neoplastic diseases and immunocompetent patients.

Fungaemia caused by Fusarium proliferatum in a patient without definite immunodeficiency.

Recent literature has shown the growing importance of opportunistic fungal infections due to Fusarium spp. However, disseminated fusariosis remains rare in patients without neutropenia. We report a case of fungaemia in a 78-year-old French woman without definite immunodeficiency. Fusarium proliferatum grew from both central and peripheral blood cultures. Fever was the only clinical sign of the infection. An appropriate antifungal therapy with voriconazole led to the recovery of the patient. An environmental investigation was undertaken but failed to find a reservoir of Fusarium spores. A contaminated central venous catheter might have been the source of fungaemia.

[Molecular markers: an important tool in the diagnosis, treatment and epidemiology of invasive aspergillosis]. / Marcadores moleculares: una herramienta importante en el diagnóstico, tratamiento y epidemiología de la aspergilosis invasora.

Increase in the incidence of invasive aspergillosis has represented a difficult problem for management of patients with this infection due to its high rate of mortality, limited knowledge concerning its diagnosis, and therapeutic practice. The difficulty in management of patients with aspergillosis initiates with detection of the fungus in the specimens of immunosuppressed patients infected with Aspergillus fumigatus; in addition, difficulty exists in terms of the development of resistance to antifungals as a consequence of their indiscriminate use in prophylactic and therapeutic practice and to ignorance concerning the epidemiological data of aspergillosis. With the aim of resolving these problems, molecular markers is employed at present with specific and accurate results. However, in Mexico, the use of molecular markers has not yet been implemented in the routine of intrahospital laboratories; despite the fact that these molecular markers has been widely referred in the literature, it is necessary for it to validated and standardized to ensure that the results obtained in any laboratory would be reliable and comparable. In the present review, we present an update on the usefulness of molecular markers in accurate identification of A. fumigatus, detection of resistance to antifugal triazoles, and epidemiological studies for establishing the necessary measures for prevention and control of aspergillosis.

El incremento en la incidencia de la aspergilosis invasora representa un grave problema para el tratamiento de pacientes con esta micosis, debido a su elevada tasa de mortalidad por deficiencias diagnósticas y terapéuticas. Éstas se han atribuido a la dificultad para detectar Aspergillus fumigatus, principal agente etiológico de esta micosis, en las muestras biológicas de pacientes inmunosuprimidos, que son los principales afectados por el hongo; además por la resistencia a los antifúngicos como consecuencia del uso incontrolado de éstos, a nivel profiláctico y terapéutico, y el desconocimiento de aspectos epidemiológicos de la aspergilosis. En la actualidad, para superar estas limitaciones se han empleado marcadores moleculares. En México su uso aún no está implementado en la rutina de los laboratorios intrahospitalarios, porque a pesar de que se han reportado ampliamente en la bibliografía, hace falta validarlos y estandarizarlos para asegurar que los resultados que se obtengan en cualquier laboratorio sean confiables y comparables. En este trabajo se presenta una revisión actualizada de la utilidad de los marcadores moleculares en la identificación certera de A. fumigatus en la detección de resistencia a los antifúngicos triazólicos y en estudios epidemiológicos para establecer las medidas necesarias en la prevención y control de la aspergilosis.

Sporopachydermia cereana fungaemia in refractory leukaemia presenting as breakthrough infection during micafungin therapy.

The Sporopachydermia cereana species lives in decaying stems of cactus and is exceptionally rare as a human pathogen. A 57-year-old man with therapy-refractory acute promyelocytic leukaemia developed severe neutropaenia. After about 3 weeks of micafungin used as prophylaxis, he developed high fever, multiple pulmonary nodular infiltrates and a painful leg lesion. Blood culture yielded a yeast which was not identified by the Vitek 2 system. On ITS1-5.8S-ITS2 gene sequencing, the isolate was identified as S. cereana. Antifungal sensitivity by the Etest showed that the minimum inhibitory concentration for fluconazole was 0.75 µg/mL, and for anidulafungin, it was >32 µg/mL. He responded to liposomal amphotericin B but later died of Escherichia coli septicaemia. There were no cactus plants in the vicinity, suggesting that S. cereana might have alternative habitats.

Severe combined immunodeficiency resulting from mutations in MTHFD1.

Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

[Screening for opportunistic infections and vaccination before introduction of biologic therapy]. / Probir na oportunisticke infekcije i cijepljenje prije pocetka bioloske terapije.

Patients on anti-TNFalpha medications carry a higher risk for developing opportunistic infections. In order to introduce anti-TNFalpha therapy, screening for hepatitis viruses B and C, HIV, EBV, HPV, TBC, bacterial, fungal and parasitic infections should be performed. Screening involves patient's history of earlier infectious diseases, vaccinations and traveling to parts of the world with endemic diseases. Clinical examination should be supplemented with stomatologic and gynecologic exams. Laboratory results include leukogram, transaminases, C-reactive protein, urine analysis, hepatitis B, C, HIV and EBV serology. Varicella zoster virus serology depends on past medical history. If the patient has traveled to tropical areas, both stool analysis and strongiloidiasis serology should be performed. Other mandatory examinations include chest radiography, PPD and TBC serology using interferon gamma release test (IGRA). If suspecting intra-abdominal abscess, magnetic resonance of the abdomen is recommended. In case of abscess, CMV or Clostridium difficile colitis anti-TNF-alpha therapy is contraindicated. Live vaccine application is contraindicated in patients receiving anti-TNFalpha therapy. All seronegative patients should be vaccinated against hepatitis B virus. Seasonal flu vaccination is recommended to be applicated yearly and pneumococcal polysaccharide vaccine once in every five years. Based on the past medical history and serologic results, patients are vaccinated against VZV with extra precaution. Human papilloma virus vaccination is performed in a group of women under 23 years of age, after gathering cervical smear sample analysis.

Onychomycosis: modern diagnostic and treatment approaches.

The medical term onychomycosis should be understood as chronic infection of the nails caused by a fungus. The most common causative agents are the dermatophytes and Candida species. The less common are certain types of moulds (nondermatophyte moulds or NDMs). In approximately 60-80 % of the cases, onychomycosis is due to dermatophytes. Among dermatophytes, the most often isolated causative pathogen is Trichophyton (T.) rubrum. Other common species are T. interdigitale (formerly T. mentagrophytes), Epidermophyton floccosum, and T. tonsurans. The most significant yeasts causing onychomycosis are Candida albicans and Candida parapsilosis. Predisposing factors for onychomycosis include mainly diseases such as diabetes mellitus, peripheral vascular arterial disease, chronic venous insufficiency, polyneuropathies of diverse etiologies, and immunosuppression, e.g., myeloproliferative diseases (such as lymphoma and paraproteinemia), HIV/AIDS, etc. Other factors facilitating the fungal infection are frequent trauma in professional sportsmen, often accompanied by excessive perspiration. The diagnostic methods that are often applied in different dermatologic departments and ambulatory units are also different. This precludes the creation of a unified diagnostic algorithm that could be used everywhere as a possible standard. In most of the cases, the method of choice depends on the specialist's individual experience. The therapeutic approach depends mostly on the fungal organism identified by the dermatologist or mycologist. This review hereby includes the conventional as well as the newest and most reliable and modern methods used for the identification of the pathogens causing onychomycosis. Moreover, detailed information is suggested, about the choice of therapeutic scheme in case whether dermatophytes, moulds, or yeasts have been identified as causative agents. A thorough discussion of the schemes and duration of the antifungal therapy in certain groups of patients have been included.

¿Cómo manejar al paciente con artritis reumatoide y serología virus de hepatitis B, hepatitis C, virus de la inmunodeficiencia humana? / How does one manage patients with rheumatoid arthritis and positive serology to hepatitis B, hepatitis C, human immunodeficiency virus?

Las infecciones virales crónicas en un paciente reumático constituyen un reto diagnóstico y terapéutico. Algunos de los fármacos antirreumáticos modificadores de la enfermedad (FAME) más utilizados en la artritis reumatoide, como el metotrexato y la leflunomida, presentan riesgo de hepatotoxicidad. Con la terapia biológica, que es hoy en día ampliamente utilizada en pacientes refractarios a estos y otros FAME, se han descrito casos de reactivación de hepatitis B, incluso fulminante, especialmente con los antagonistas del TNF y rituximab, por lo que su utilización ha de ser cuidadosamente valorada y, generalmente, administrada junto con tratamiento antiviral. Sin embargo, no se han descrito casos de reactivación de hepatitis C tras terapia inmunosupresora. En los pacientes con serología VIH la administración de tratamiento inmunosupresor conlleva un elevado riesgo de infecciones oportunistas, aunque la nueva terapia antiviral altamente activa permite utilizar algunos fármacos en casos seleccionados (AU)

Chronic viral infections in rheumatic patients are a diagnostic and therapeutic challenge. Some of the disease-modifying antirheumatic drugs (DMARD) commonly used in rheumatoid arthritis, such as methotrexate and leflunomide, are hepatotoxic. With biological therapy, which is now widely used in patients refractory to these and other DMARD, some cases of reactivation of hepatitis B, even fulminant cases, have been reported, especially when employing TNF antagonists and rituximab, so their use must be carefully assessed and usually accompanied by antiviral therapy. However, there have not been reports of reactivation of hepatitis C after immunosuppressive therapy. In patients with HIV infection, administration of immunosuppressive therapy carries a high risk of opportunistic infections, although the new highly active antiviral therapy allows the use of some drugs in selected cases (AU)

Rhodotorula fungemia: two cases and a brief review.

Rhodotorula is emerging as an important cause of nosocomial and opportunistic infections. We present two cases of Rhodotorula mucilaginosa fungemia diagnosed over a period of 3 months at our hospital. The first case was of a pre-term neonate in the neonatal ICU who presented with respiratory failure and sepsis. The second involved an adult female who had been injured in a road traffic accident requiring an operation for a hematoma and was later shifted to the medical ICU. For a new hospital like ours, finding two cases of Rhodotorula fungemia within a span of 3 months prompted us to describe them in this report. These cases emphasize the emerging importance of Rhodotorula mucilaginosa as a pathogen and the importance of identification and MIC testing for all fungal isolates recovered from the blood stream.

[Urosepsis and treatment]. / Urosepsis und Therapie.

Urosepsis is one of the most frequent sepsis entities. Mortality from urosepsis is nowadays mostly lower than from other entities. Sepsis syndrome is pathophysiologically characterized by a generalized infection and immune dysregulation. Exogenous microbiological and active or passive endogenous factors released from body cells initiate and accompany the immune dysregulation. Diagnosis and therapy of urosepsis need to be instigated as early as possible (within the first hour), in order to prevent cell and tissue damage in the early phase. For this reason a series of measures is started, aimed at achieving early control of the focus of infection, providing antibiotic treatment, and stabilizing respiratory and cardiovascular function in order to optimize tissue oxygenation. A significant clinical problem ensues due to increasing antibiotic resistance mainly of enterobacteria. The choice of antibiotic therefore is made on the basis of local antibiotic resistance statistics. Dosage is determined on an individual basis, as well as according to current pharmacokinetic/pharmacodynamic knowledge. The intensive care of the septic patient needs to be started as early as on patient admission and, where necessary, continued on the intensive care ward.