Scedosporium boydii finding in an immunocompromised patient and review of the literature / Hallazgo de Scedosporium boydii en un paciente inmunocomprometido y revisión de la literatura

Background Scedosporiasis is an emerging mycosis that has gained importance in recent years due to its worldwide prevalence. It is caused by species of the Scedosporium apiospermum complex. These species can cause opportunistic infections in immunocompromised patients and, occasionally, in immunocompetent patients as well. The high intrinsic antifungal resistance make these infections difficult to manage. Aims The objective of this study was to interpret the mycological findings in a transplant patient, together with the images obtained in the radiological studies, in order to provide an early and effective antifungal therapy. Methods The mycological analysis of samples taken from a heart transplant patient with radiological images suggesting a fungal infection was performed. Computed tomography scan of the head and thorax showed space-occupying lesions in both the frontal lobe and cerebellum, and multiple pulmonary nodules. The nodules were punctured and the samples obtained were analyzed according to the procedures for mycological analysis. The identity of the isolates was confirmed by nucleotide sequencing. Eventually, the antifungal susceptibility was studied. Results The fungal isolates obtained, whose identity was confirmed by sequencing, belonged to the species Scedosporium boydii. Injured tissues were surgically removed and a treatment with amphotericin B and voriconazole-minimum inhibitory concentration (MIC) 0.5μg/mL and ≥0.5μg/mL respectively – was administered. Conclusions Although the patient died due to complications of a Klebsiella pneumoniae sepsis refractory to treatment, the progression of the fungal disease, although slow, was favourable in the early phases of the treatment due to a correct diagnosis and the antifungal susceptibility test carried out. ... (AU)

Antecedentes La escedosporiasis es una micosis emergente de relevancia en los últimos años por su prevalencia mundial. Es causada por especies del complejo Scedosporium apiospermum (S. apiospermum), que pueden provocar infecciones oportunistas de difícil tratamiento en pacientes inmunocomprometidos y, ocasionalmente, en inmunocompetentes. El alto grado de resistencia intrínseca de las especies de este complejo dificulta el manejo de las infecciones. Objetivos Interpretar los hallazgos micológicos en un paciente trasplantado, en conjunción con los estudios radiológicos, a fin de instaurar una terapia antifúngica precoz y efectiva. Métodos Se realizó el estudio micológico de muestras de un paciente con trasplante cardiaco, cuyos exámenes radiológicos eran compatibles con una infección fúngica. La tomografía axial computarizada de cabeza y tórax mostró masas ocupantes en el lóbulo frontal y el cerebelo, así como múltiples nódulos pulmonares. Se punzaron las mismas y se procesó de acuerdo con el protocolo de análisis micológico de rutina; la identidad de los aislamientos se confirmó por secuenciación nucleotídica. Finalmente se evaluó la sensibilidad antifúngica. Resultados La identidad de los aislamientos fúngicos obtenidos fue Scedosporium boydii (S. boydii). Se procedió a la remoción quirúrgica del tejido afectado y se puso un tratamiento con anfotericina B y voriconazol, para los cuales los valores de concentración inhibitoria mínima del aislamiento fueron 0,5 μg/mL y ≥ 0,5 μg/mL, respectivamente. Conclusiones Si bien el paciente falleció por complicaciones asociadas a sepsis por Klebsiella pneumoniae (K. pneumoniae) refractaria al tratamiento, la evolución del cuadro micológico, aun siendo lenta, progresó favorablemente en las primeras fases del tratamiento. Esto se atribuye a un correcto diagnóstico y evaluación de la sensibilidad antifúngica del hongo aislado. ... (AU)

Scedosporium boydii finding in an immunocompromised patient and review of the literature.

BACKGROUND: Scedosporiasis is an emerging mycosis that has gained importance in recent years due to its worldwide prevalence. It is caused by species of the Scedosporium apiospermum complex. These species can cause opportunistic infections in immunocompromised patients and, occasionally, in immunocompetent patients as well. The high intrinsic antifungal resistance make these infections difficult to manage. AIMS: The objective of this study was to interpret the mycological findings in a transplant patient, together with the images obtained in the radiological studies, in order to provide an early and effective antifungal therapy. METHODS: The mycological analysis of samples taken from a heart transplant patient with radiological images suggesting a fungal infection was performed. Computed tomography scan of the head and thorax showed space-occupying lesions in both the frontal lobe and cerebellum, and multiple pulmonary nodules. The nodules were punctured and the samples obtained were analyzed according to the procedures for mycological analysis. The identity of the isolates was confirmed by nucleotide sequencing. Eventually, the antifungal susceptibility was studied. RESULTS: The fungal isolates obtained, whose identity was confirmed by sequencing, belonged to the species Scedosporium boydii. Injured tissues were surgically removed and a treatment with amphotericin B and voriconazole-minimum inhibitory concentration (MIC) 0.5µg/mL and ≥0.5µg/mL respectively - was administered. CONCLUSIONS: Although the patient died due to complications of a Klebsiella pneumoniae sepsis refractory to treatment, the progression of the fungal disease, although slow, was favourable in the early phases of the treatment due to a correct diagnosis and the antifungal susceptibility test carried out. Clinical cases of this nature highlight the need to increase the epidemiological study of these microorganisms, as well as the proper treatment of the diseases caused, in order to achieve early diagnoses that reduce the morbidity and mortality of patients.

Differential expression of genes regulated by the glucocorticoid receptor pathway in patients with pulmonary tuberculosis.

AIMS: Previous studies in TB patients showed an immuno-endocrine imbalance characterized by a disease-severity associated increase in plasma levels of proinflammatory cytokines and glucocorticoids (GCs). To analyze the potential immunomodulatory effect of circulating GCs over peripheral blood mononuclear cells (PBMC) from TB patients, we investigated the expression of positively (anti-inflammatory-related genes ANXA1; FKBP51; GILZ, NFKBIA, and NFKBIB) and negatively (inflammatory genes: IL-6, IL-1ß, and IFN-γ) Glucocorticoids Receptors (GR)-regulated genes. Plasma concentrations of cytokines and hormones, together with specific lymphoproliferation were also assessed. MATERIALS AND METHODS: Gene expression was quantified by RT-qPCR, specific lymphoproliferation by 3H-thymidine incorporation, whereas plasma cytokines and hormones levels by ELISA. KEY FINDINGS: Transcripts of ANXA1, GILZ, NFKBIB, and NFKBIA appeared significantly increased in patients, whereas FKBP51, IL-6, IL-1ß, and NF-κB remained unchanged. Upon analyzing according to disease severity, mRNA levels for ANXA1 and NFKBIB were even higher in moderate and severe patients. GILZ was increased in moderate cases, with NFKBIA and IL-1 ß being higher in severe ones, who also displayed increased GRß transcripts. TB patients had reduced plasma DHEA concentrations together with increased pro and anti-inflammatory cytokines (IFN-γ, IL-6, and IL-10) cortisol and cortisol/DHEA ratio, more evident in progressive cases, in whom their PBMC also showed a decreased mycobacterial-driven proliferation. The cortisol/DHEA ratio and GRα expression were positively correlated with GR-regulated genes mainly in moderate patients. SIGNIFICANCE: The increased expression of cortisol-regulated anti-inflammatory genes in TB patients-PBMC, predominantly in progressive disease, seems compatible with a relatively insufficient attempt to downregulate the accompanying inflammation.

Increased levels of circulating LPS during Tuberculosis prevails in patients with advanced pulmonary involvement.

Our earlier studies in tuberculosis (TB) patients indicate that in those where the process evolves to a larger pulmonary involvement, the immune endocrine response may promote an unfavorable environment. Chronic infectious diseases, and their persistent proinflammatory response, may affect mucosal barriers integrity favoring the translocation of gastrointestinal bacteria, leading to an increase of circulating lipopolysaccharides (LPS). Consequently, we quantified LPS levels in TB patients, with different degrees of pulmonary involvement, and controls (Co) and analyzed the possible relationship between LPS and inflammatory mediators i.e., C reactive protein (CRP), interleukin 6 (IL-6) and Interferon-gamma (IFN-γ), Erythrocyte Sedimentation Rate (ESR), steroid hormones (Cortisol and Dehydroepiandrosterone, DHEA), and inflammatory transcripts from peripheral blood mononuclear cells (IL-1ß, IL-6, IFN-γ). LPS was assessed by the Limulus amoebocyte lysate assay and the ELISA technique was used to quantify hormones and cytokines in the plasma samples. Cytokine transcripts from PBMC were evaluated by qRT-PCR. Non-parametric tests were used. LPS levels were increased in TB patients, as did levels of CRP, IL-6, IFN-γ, cortisol and ESR. Severe patients had the highest amounts of circulating LPS; with moderate and severe cases showing much higher levels of CRP, ESR, IL-6, IFN-γ and cortisol/DHEA ratio, as an endocrine imbalance. Only in PBMC from severe cases was mRNA for IL-1ß increased. Correlation analysis showed that levels of LPS from severe patients were positively associated with IL-6 and IFN-γ plasma concentrations and with IL-1ß transcripts, while IL-6 had a positive correlation with the cortisol/DHEA ratio. The higher levels of circulating LPS during progressive TB may emerge as a contributing factor for the persistence of the greater immune endocrine imbalance distinctive of advanced disease, which might suggest a vicious cycle among LPS, inflammation and endocrine imbalance.

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity.

Pulmonary tuberculosis (PTB), caused by Mycobacterium tuberculosis (Mtb), is a major health problem worldwide, further aggravated by the convergence of type 2 diabetes mellitus (DM) which constitutes an important risk factor for TB development. The worse scenario of patients with PTB and DM may be partly related to a more unbalanced defensive response. As such, newly diagnosed PTB patients with DM (TB+DM, n = 11) or not (TB, n = 21), as well as DM (n = 18) patients and pair matched controls (Co, n = 22), were investigated for the circulating immuno-endocrine-metabolic profile (ELISA), along with studies in peripheral blood mononuclear cells (PBMC) analyzing transcript expression (RT-qPCR) of mediators involved in glucocorticoid functionality. Given the hyperglycemic/hypercortisolemic scenario of TB+DM patients, PBMC were also exposed to stress-related cortisol concentrations (0.1 and 1 µM) and supraphysiologic glucose doses (10, 20, and 40 mM) and assessed for the specific response against Mtb stimulation (lymphoproliferation, -thymidine incorporation-, and cytokine production -bead-cytometry). All TB patients displayed increased plasma amounts of cortisol, growth hormone -hGH-, and proinflammatory mediators. In turn, TB+DM showed even higher levels of interferon gamma -IFN-γ- and hGH (vs. TB), or IL-6, C reactive protein, cortisol and hGH (vs. DM). Both DM groups had equally augmented values of IL-10. All TB patients showed decreased dehydroepiandrosterone- sulfate concentrations, even more in TB+DM cases. Leptin was also decreased in both TB cases, particularly in the TB group, revealing a lower body mass index, as well. Unlike PBMC from TB cases showing a decreased relationship between the glucocorticoids receptor (GR) isoforms (GRα/GRß; functional isoform/negative isoform), cells from TB+DM patients had no changes in this regard, along with an increased expression of 11-beta hydroxysteroid dehydrogenase type-1, the enzyme facilitating intracellular cortisone to cortisol conversion. TB+DM patients also showed an increased Mtb antigen-driven lymphoproliferation. Compared to TB, DM and HCo counterparts, PBMC from TB+DM patients had a biased Th1 response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.

Evidence that changes in antimicrobial peptides during tuberculosis are related to disease severity, clinical presentation, specific therapy and levels of immune-endocrine mediators.

Given the role of host defense peptides (HDPs) in the defensive response against mycobacteria, we analyzed the circulating levels of LL-37, ß-defensin-2 and -3 in newly diagnosed patients with pulmonary (PTB) or pleural tuberculosis (PLTB) in whom measurements of pleural fluids were also performed. Severe PTB patients displayed higher circulating amounts of ß-defensin-3, statistically different from controls, further decreasing upon antimycobacterial treatment. LL-37 concentrations appeared within the normal range at diagnosis, but tended to increase during treatment, becoming statistically upon its completion in moderate cases. PLTB patients revealed decreased levels of ß-defensin-2 in presence of increased amounts of ß-defensin-3 and LL-37; in their plasma or pleural fluids. Considering the immune-endocrine dysregulation of tuberculosis, we also performed correlation analysis detecting positive associations between levels of cortisol, IL-6 and ß-defensin-3 in plasma from untreated severe patients as did their dehydroepiandrosterone and LL-37 values. Increased presence of ß-defensins, may represent an attempt to improve defensive mechanisms; which also take part in the inflammatory reaction accompanying TB, reinforced by the association with immune-endocrine mediators. The divergent profile of PLTB patients, decreased ß-defensin-2 but increased ß-defensin-3 and LL-37 levels, suggests a differential role of these HDPs in a situation characterized for its better protective response.

Espondilodiscitis: análisis de 19 casos internados en un hospital de tercer nivel / Spondylodiscitis: analiysis of 19 inpatients at a referral hospital in Rosario, Argentina

Introducción: la espondilitis representa un desafío diagnóstico, ya que el dolor lumbar, su principal manifestación clínica, constituyeun motivo de consulta muy frecuente en la práctica cotidiana y carece de especificidad. Por lo tanto, resulta indispensablemantener una elevada sospecha clínica. Objetivo: Analizar las características clínicas, analíticas, microbiológicas e imagenológicas,el tratamiento, la evolución y los factores pronósticos de pacientes internados por espondilodiscitis en el Hospital Provincial delCentenario, desde enero de 2011 a marzo de 2015, excluyéndose los casos postquirúrquicos. Resultados: Se analizaron 19 pacientescon una edad media 48±11 años, 63% varones. Se identificaron como comorbilidades: diabetes (37%), obesidad (16%), etilismo(21%), insuficiencia renal crónica en hemodiálisis (16%), HIV (11%), adicción EV (11%). Los gérmenes más frecuentes fueron losestafilococos (52%). Al ingreso el 94% presentó dolor, 73% fiebre y 36% foco neurológico. La media de tiempo de evolución desíntomas hasta ingreso fue 62±80 días (rango 4-360 días). La velocidad de eritrosedimentación fue elevada en todos los pacientes,y sólo 37% presentaban leucocitosis. La vancomicina fue el antibiótico más utilizado. El 37% de los pacientes presentaba infeccióndiseminada. La mortalidad fue del 26%. Los pacientes que tuvieron un tiempo de evolución al ingreso mayor a 25 días presentaronpeor evolución (colecciones, foco neurológico o muerte) (p<0,05). Conclusiones: en esta serie, la asociación de la consulta tardíacon la mala evolución destaca la importancia de considerar las pautas de alarma en centros de atención primaria para posibilitar undiagnóstico más temprano.

Introduction: Spondylodiscitis represents a diagnostic challenge since the main clinical manifestation, low back pain, is very frequent andnonspecific, and often impedes a timely diagnosis. Clinical suspicion is essential. Objective: to analyze the clinical, analytical, microbiological,and radiological features, as well as outcome and prognostics factors, in patients with spondylodiscitis admitted to the Hospital Provincialdel Centenario (Rosario, Argentina), from January 2011 to March 2015. Postsurgical cases were excluded. Results: Nineteen patients wereincluded. Mean age was 48±11 years, 63% were males. We identified the following comorbid diseases: diabetes (37%), obesity (16%),alcoholism (21%), hemodialysis-dependent chronic kidney disease (16%), HIV (11%), intravenous drug abuse (11%). The most frequentcausative organism was Staphylococcus sp. (52%). Upon admission 94% of patients presented pain, 73% fever, and 36% neurologicalinvolvement. The average time from the onset of symptoms to diagnosis was 62±80 days (range 4-360). The erythrocyte sedimentation ratewas raised in all the patients, and only 37% had leukocytosis. Vancomycin was the most frequently prescribed antibiotic. Disseminatedinfection was present in 37% of patients. The mortality rate was 26%. Patients with a time lag to diagnosis higher than 25 days had worseoutcome (suppurative collections, neurological involvement, or death) compared to those with earlier diagnosis (p <0.05). Conclusions:The association of late consultation with poor outcome in this study emphasizes the importance of educating the general population toencourage attendance to medical centers. Physicians in primary care settings must be trained to identify pain pattern, and incorporateclinical perspectives capable of recognizing a defined syndrome at first contact, in other to achieve a better outcome.Key words: Spondylodiscitis, comorbid conditions, diagnostic delay, outcome.

Recomendación de abandono del tabaquismo en una muestra de adultos de la ciudad de Rosario / Recommendation of Smoking Cessation in an Adult Sample of the City of Rosario

Introducción: El tabaquismo es la principal causa de muerte prevenible en el mundo; pese a ello, muchos médicos no aconsejan a sus pacientes dejar de fumar. Objetivos: Evaluar las características del consumo de tabaco y la frecuencia en la recomendación de su abandono en adultos de la ciudad de Rosario mediante un estudio transversal realizado entre julio y diciembre de 2010. Material y métodos: Encuesta cerrada prefijada realizada mediante muestreo no probabilístico por conveniencia a individuos mayores de edad concurrentes a los seis distritos de la ciudad de Rosario, a los cuales asistían por cuestiones no relacionadas con el cuidado de su salud. Resultados: Se encuestaron 1.217 voluntarios; el 57% fueron mujeres y el 11% trabajaban en ámbitos relacionados con la atención de la salud. La edad promedio fue de 48 años; fumaban el 28% de los encuestados y el 24% eran extabaquistas. La mediana de intentos para dejar de fumar fue menor en extabaquistas (1 vs. 3 veces; p < 0,0001). El 72,5% de los que recibieron la recomendación de dejar de fumar durante el año precedente intentaron hacerlo, mientras que de los que no recibieron consejo lo intentó el 57% (p = 0,003). Se realizó un análisis factorial de correspondencias múltiples y posterior clasificación, que mostró que los tabaquistas que no intentaron dejar de fumar comenzaron a edades mayores y consumían menos cigarrillos diarios. Conclusiones: La calidad de la recomendación de abandonar el hábito de fumar y la autopercepción del riesgo que esta adicción supone son aspectos no jerarquizados en forma sistemática al abordar esta temática. Consideramos que el presente estudio pone de relieve la importancia de estos aspectos, los cuales se deberán profundizar en el futuro para una mejor aproximación a la complejidad del logro del cese del consumo de tabaco.

Backgroung: Smoking is the leading cause of preventable death worldwide; nevertheless, many physicians do not advice to quit smoking. Objectives: The goal of this cross-sectional study was to evaluate the characteristics of tobacco use and the frequency of smoking cessation recommendation in adults in the city of Rosario between July and December 2010. Methods: A closed survey was performed to adults attending the seven districts of the city of Rosario for reasons not related to health care, using a prearranged questionnaire based on non-probability convenience sampling. Results: A total of 1,217 volunteers were surveyed; 57% were women and 11% worked in health care sectors. Mean age was 48 years; 28% were current smokers and 24% were former smokers. The median number of attempts to quit smoking was lower in former smokers (1 vs. 3 times; p < 0.0001). Of those who received advice to quit smoking, 72.5% attempted to do so during the preceding year, while 57% of those not receiving advice tried to quit smoking (p = 0.003). A multiple correspondence factor analysis with subsequent classification showed that current smokers who did not attempt cessation started smoking later in life and smoked fewer cigarettes per day. Conclusions: The quality of the recommendation for smoking cessation and the self-perception of the risk associated with this addiction are aspects that are not systematically taken into account when this topic is raised. We consider that the present study emphasizes the importance of theses aspects, which should undergo further evaluation in the future for a better approach to the complexity of achieving tobacco cessation.

Recomendación de abandono del tabaquismo en una muestra de adultos de la ciudad de Rosario / Recommendation of Smoking Cessation in an Adult Sample of the City of Rosario

Introducción: El tabaquismo es la principal causa de muerte prevenible en el mundo; pese a ello, muchos médicos no aconsejan a sus pacientes dejar de fumar. Objetivos: Evaluar las características del consumo de tabaco y la frecuencia en la recomendación de su abandono en adultos de la ciudad de Rosario mediante un estudio transversal realizado entre julio y diciembre de 2010. Material y métodos: Encuesta cerrada prefijada realizada mediante muestreo no probabilístico por conveniencia a individuos mayores de edad concurrentes a los seis distritos de la ciudad de Rosario, a los cuales asistían por cuestiones no relacionadas con el cuidado de su salud. Resultados: Se encuestaron 1.217 voluntarios; el 57% fueron mujeres y el 11% trabajaban en ámbitos relacionados con la atención de la salud. La edad promedio fue de 48 años; fumaban el 28% de los encuestados y el 24% eran extabaquistas. La mediana de intentos para dejar de fumar fue menor en extabaquistas (1 vs. 3 veces; p < 0,0001). El 72,5% de los que recibieron la recomendación de dejar de fumar durante el año precedente intentaron hacerlo, mientras que de los que no recibieron consejo lo intentó el 57% (p = 0,003). Se realizó un análisis factorial de correspondencias múltiples y posterior clasificación, que mostró que los tabaquistas que no intentaron dejar de fumar comenzaron a edades mayores y consumían menos cigarrillos diarios. Conclusiones: La calidad de la recomendación de abandonar el hábito de fumar y la autopercepción del riesgo que esta adicción supone son aspectos no jerarquizados en forma sistemática al abordar esta temática. Consideramos que el presente estudio pone de relieve la importancia de estos aspectos, los cuales se deberán profundizar en el futuro para una mejor aproximación a la complejidad del logro del cese del consumo de tabaco.(AU)

Backgroung: Smoking is the leading cause of preventable death worldwide; nevertheless, many physicians do not advice to quit smoking. Objectives: The goal of this cross-sectional study was to evaluate the characteristics of tobacco use and the frequency of smoking cessation recommendation in adults in the city of Rosario between July and December 2010. Methods: A closed survey was performed to adults attending the seven districts of the city of Rosario for reasons not related to health care, using a prearranged questionnaire based on non-probability convenience sampling. Results: A total of 1,217 volunteers were surveyed; 57% were women and 11% worked in health care sectors. Mean age was 48 years; 28% were current smokers and 24% were former smokers. The median number of attempts to quit smoking was lower in former smokers (1 vs. 3 times; p < 0.0001). Of those who received advice to quit smoking, 72.5% attempted to do so during the preceding year, while 57% of those not receiving advice tried to quit smoking (p = 0.003). A multiple correspondence factor analysis with subsequent classification showed that current smokers who did not attempt cessation started smoking later in life and smoked fewer cigarettes per day. Conclusions: The quality of the recommendation for smoking cessation and the self-perception of the risk associated with this addiction are aspects that are not systematically taken into account when this topic is raised. We consider that the present study emphasizes the importance of theses aspects, which should undergo further evaluation in the future for a better approach to the complexity of achieving tobacco cessation.(AU)