Frailty Could Predict Death in Older Adults after Admissionat Emergency Department? A 6-month Prospective Study from a Middle-Income Country.

BACKGROUND: The number of older adults attending emergency department (ED) is increasing all over the world. Usually, those patients are potentially more complex due to their greater number of comorbidities, cognitive disorders, and functional or physical disabilities. Frailty is a vulnerable state that could predict adverse outcomes of those patients. There are very few studies that addressed this topic in the ED, and none of them used a simple instrument for frailty assessment. OBJECTIVES: The primary outcome was to evaluate the association between frailty identified through the FRAIL questionnaire at baseline and death after a 6-month follow-up period after hospital discharge from the ED. Secondary outcomes were readmission to the ED and disability after 6 months. METHODS: A 6-month follow-up prospective study (FASES study) was conducted at a university-based trauma-center ED in Jundiaí, southwestern of Brazil. A total of 316 older adults aged 60 or older were randomly included based on a lottery of their medical record admission number. Frailty was evaluated through the FRAIL questionnaire. The association between frailty and death was estimated through a binary logistic regression adjusted for age, sex, and cognitive performance. RESULTS: From the total sample, the mean age was 72.11±8.0 years, and 51.6% were women. Participants presented 2.28±1.4 comorbidities and 25.6% were frail. Mean hospital stay was 5.43±5.6 days. Death occurred in 52 participants, readmission to the emergency in 55, and new disability in 16 after 6 months. Frailty was associated with an odds ratio of 2.18 for death after 6 months (95% CI = 1.10-4.31; p = 0.024). This association lost significance after multivariate analysis taking into account cognitive performance. There was no association between frailty status at baseline and readmission to the ED or disability. CONCLUSION: The identification of frailty using the FRAIL at admission was not predictive of death after a 6-month period after discharge from the ED. Simple frailty assessment could identify patients at higher risk for death in the follow-up.

Monocytes of patients with unstable angina express high levels of chemokine and pattern-recognition receptors.

BACKGROUND AND AIMS: Macrophages derived from monocytes play an important role in atherosclerosis progression. Subpopulations of circulating classical, intermediate, and non-classical monocytes possess distinct functions and phenotypes, and participate in the pathogenesis of disease. The aim of this study was to compare the quantity and phenotypes of circulating monocyte subpopulations in patients with established atherosclerosis and healthy control individuals. Additionally, the study aimed to provide insight into the functional activity of monocytes against a heat shock protein (HSP60). METHODS: Chemokine and pattern recognition receptors in monocyte subsets obtained from peripheral blood of acute and chronic coronary artery disease patients and controls were quantified by flow cytometry. Furthermore, monocytes from healthy controls were stimulated in vitro with HSP60, and the cytokines produced by them were evaluated by flow cytometry. RESULTS: Eighteen controls (C), 34 individuals with risk factors for cardiovascular disease (RF), 32 patients with stable angina (SA), and 16 patients with unstable angina (UA) were enrolled in the study. The absolute count of intermediate monocytes was found to be increased in patients of the UA group; high frequencies of the chemokine receptors CCR2, CCR5, and CX3CR1 were also observed in this subpopulation. Moreover, the pattern recognition receptors TLR2 and TLR4 were more frequent in intermediate monocytes from the UA group. Furthermore, the intermediate monocytes from healthy individuals produced IL-12p70 after stimulation with HSP60. CONCLUSIONS: Our results show that intermediate monocytes of UA patients exhibited an enhanced expression of the receptors involved in the recognition of damage-associated molecular patterns (DAMPs) and enhancement of the migratory function. Hence, they might contribute to the propagation and progression of inflammation observed in atherosclerosis, especially in the acute setting.

Severe Paracoccidioidomycosis in a 14-Year-Old Boy.

Paracoccidioidomycosis (PCM) is the most important systemic mycoses in Latin America. We describe a severe case of paracoccidioidomycosis in a 14-year-old boy, with a rapid disease progression. The fungal strain was isolated and inoculated into a T and/or B cell immunocompromised mice, which revealed a highly virulent strain. The case report presented herein emphasizes the importance of considering PCM in the differential diagnosis of patients with other infectious diseases in endemic areas and highlights a novel isolate.

Frequency and characteristics of circulating CD4(+) CD28(null) T cells in patients with psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory disease that affects the skin. CD4(+) CD28(null) cells are a subset of T lymphocytes associated with systemic inflammation and increased cardiovascular disease risk, and may be involved in the pathogenesis of psoriasis. OBJECTIVES: To study the features of circulating CD4(+) CD28(null) cells in patients with psoriasis, adjusted for the influence of known cardiovascular disease risk factors. METHODS: Forty-two patients with psoriasis and 42 controls entered the study. Peripheral blood mononuclear cells were analysed for the frequency of CD4(+) CD28(null) T lymphocytes and their expression of cytotoxic granules and homing receptors. Immunostaining for cutaneous cytotoxic granules was assessed in skin biopsies from 11 patients. RESULTS: There were no differences in the frequency of CD4(+) CD28(null) T cells between groups in all situations analysed. However, there was an increased number of cells expressing cytotoxic granules and a decreased number expressing CXCR3 in ex vivo samples of patients with psoriasis. A negative correlation was observed between the frequency of ex vivo CD4(+) CD28(null) cells and psoriasis severity. After clinical remission in nine patients, ex vivo CD4(+) CD28(null) lymphocytes expressing cytotoxic granules decreased. Perforin-, granzyme B- and granulysin-containing cells were found in skin lesions. Patients with psoriasis also had increased plasma levels of C-reactive protein. CONCLUSIONS: These data suggest that cytotoxic cells, such as CD4(+) CD28(null) lymphocytes, within an inflammatory environment may play a role in the pathogenesis of psoriasis.

Expression of activation and cytotoxic molecules by peripheral blood lymphocytes of patients with paracoccidioidomycosis.

In a previous study, we reported an increased number of T CD8(+) cells in the bronchoalveolar lavage (BAL) of patients with pulmonary paracoccidioidomycosis, suggesting a role for these cells in the local immune response. The aims of this study were to verify, by flow cytometry, the activation state, as well as the production of cytotoxic molecules by peripheral blood lymphocytes (CD8(+) and CD4(+)). Specimens were obtained from patients with paracoccidioidomycosis (PCM), individuals with PCM-infection, i.e., healthy individuals with demonstrated strong cellular response against the fungus (PI) and controls, with studies conducted both ex-vivo and in vitro, after stimulation with Paracoccidioides brasiliensis yeast cells. The ex-vivo analysis demonstrated that PCM patients presented a lower frequency of granzyme A, B and perforin-positive cells, as compared to individuals with PCM infection (PI). P. brasiliensis stimulation led to a discrete increase in CD69(+) cells and a reduction in cytotoxic granule expression in all groups. The addition of IL-15 induced an increase in the frequency of CD69(+) cells only in PI individuals and controls. The effect of IL-15 on granzyme A and B expression was low, but a higher frequency of CD8(+) perforin(+) was detected in PI individuals than in patients with active PCM. IL-15Ralpha expression was lower in CD4(+) T cells from patients, in relation to the PI group. Furthermore, low levels of granulysin were detected in sera from PCM patients, but a tendency for an increase in these levels was observed after antifungal therapy. Taken together, these results indicate that lymphocytes from PCM patients are poorly activated, express low levels of IL-15Ralpha and produce basal levels of cytotoxic granules. These findings may account for the defective cytotoxic activity in patients and, consequently, a low capacity to kill the fungus.

Anaemia in patients with cancer: role of inflammatory activity on iron metabolism and severity of anaemia.

Hepcidin has been proposed as an important factor in the pathogenesis of the anaemia of chronic disease (ACD). The aim of this study was to assess the relationship between anaemia and inflammatory activity in patients with solid tumours. Patients were classified as having iron deficiency anaemia (IDA) (hypoferremia and hypoferretinemia), ACD (hypoferremia, normal or increased serum ferritin) and anaemia related to cancer (ARC) (no abnormalities in iron status). Serum pro-hepcidin, IL-6, C-reactive protein (CRP) and iron status parameters were measured using commercial kits. CRP and IL-6 levels were significantly higher in patients with ACD when compared to IDA, ARC and non anaemic patients (P < 0.005). Serum pro-hepcidin levels were not different among all studied groups (P = 0.138). A negative correlation was observed between haemoglobin and serum ferritin, CRP and IL-6 levels only in group of ACD. Serum pro-hepcidin concentrations were not correlated with degree of anaemia or iron metabolism parameters. According to our results the inflammatory activity represented by high levels of IL-6 and CRP are involved in the pathogenesis of ACD, probably due to the action of inflammation on iron metabolism, but not in ARC. It was not possible to demonstrate a significant effect of pro-hepcidin on the anaemia in cancer patients.

Serum interleukin-18 and soluble tumour necrosis factor receptor 2 are associated with disease severity in patients with paracoccidioidomycosis.

Interleukin (IL)-18 is a proinflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response. The aim of this study was to determine serum levels of IL-18 and other inflammatory mediators [IL-12, soluble intercellular adhesion molecule 1 (sICAM-1), soluble tumour necrosis factor receptor 1 (TNF-RI), sTNF-RII, CXC chemokine ligand 9 (CXCL9), CXCL10] at baseline and after anti-fungal therapy in serum from patients with juvenile (JF) and adult (AF) forms of paracoccidioidomycosis (PCM), as well as in healthy controls (C), and to assess their possible relationships to the severity of disease. IL-18 and sTNF-RII levels in patients with the JF of PCM were significantly higher than those in the AF and controls. In relation to sICAM-1, no difference was observed between JF and AF patients but both presented higher levels than controls. sTNF-RI levels were higher in patients with PCM than in controls, and significantly higher concentrations were detected in AF patients compared to JF patients. Moreover, IL-12 and chemokines CXCL9 and CXCL10 were also higher in patients than in controls. In JF patients IL-18 levels correlated significantly with sICAM-1 (r=0 x 62, P<0 x 0001), sTNF-RI (r=0 x 63, P<0 x 0001), sTNF-RII (r=0 x 51, P=0 x 02), as well as with clinical severity. The results suggest the value of serum IL-18 and sTNF-Rs levels as a parameter of PCM severity and may support a possible role for them in the pathogenesis of the disease.

Evaluation of bronchoalveolar cells in pulmonary paracoccidioidomycosis.

To investigate the local immune response, the cellular infiltrate and cytokine levels were analysed in bronchoalveolar lavage (BAL) from patients with pulmonary paracoccidioidomycosis. The group consisted of 19 patients aged 34-65 yrs. The diagnosis was confirmed by demonstration of the fungus in the sputum or BAL fluid and by serological tests. Cytospin preparations showed an increased number of lymphocytes and neutrophils in BAL. A higher number of CD8+ lymphocytes were observed in BAL compared with peripheral blood. Alveolar macrophages (AM) expressed approximately three-fold more major histocompatibility class II, intercellular adhesion molecule-1 and B7-2 molecules on their surfaces than their circulating counterparts, indicating that they had differentiated into activated macrophages inside the lungs. Cultured AM produced higher levels of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-1alpha than peripheral blood monocytes. BAL fluid contained low but detectable amounts of IL-6, TNF-alpha and MIP-1alpha, and specific antibodies to Paracoccidioides brasiliensis, mainly of the immunoglobulin G2 isotype. As macrophage inflammatory protein-1alpha was shown to selectively attract CD8+ T-cells and this population was elevated in bronchoalveolar lavage, the data suggest that, besides macrophages, CD8+ T-cells may have an important role in the pathogenesis of pulmonary paracoccidioidomycosis.

Immunocytochemical localization of cytokines and inducible nitric oxide synthase (iNOS) in oral mucosa and lymph nodes of patients with paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is a deep mycosis caused by Paracoccidioides brasiliensis, with high incidence in Brazil. In order to examine the immune response in lesional tissue from patients with PCM, we analyzed cytokines as well as the phenotype of the cell infiltrate. Paraffin-embedded tissue from the oral mucosa of eight patients with the localized adult form (AF) of PCM and from the lymph nodes of 10 patients with the juvenile form (JF) of PCM was analyzed by immunohistochemistry to detect tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10). Most of the inflammatory cells in the lymph nodes were CD68+ (macrophages, epithelioid and giant cells), while a mixed infiltrate with macrophages, plasma cells and neutrophils was detected in the oral mucosa. TNF-alpha as well as iNOS expression was similar in lymph nodes and oral mucosa, whereas TGF-beta and IL-10 were observed in a larger number of macrophages, epithelioid and giant cells in the lymph nodes, where numerous yeast cells were visualized. The higher expression of anti-inflammatory cytokines (IL-10 and TGF-beta) in lesions of patients with the JF of PCM (lymph nodes) may represent a mechanism by which the fungus evades the host immune response, contributing to a more severe and disseminated form of the disease.

Enhanced production of specific IgG4, IgE, IgA and TGF-beta in sera from patients with the juvenile form of paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) occurs in two distinct forms, the acute or juvenile form (JF), and the chronic or adult form (AF). To clarify the basis of this dichotomy, specific IgG subclasses, IgA and IgE anti-gp43 were measured by enzyme-linked immunosorbent assay, in patients with different forms of PCM. Serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, macrophage inflammatory protein (MIP)-1alpha and transforming growth factor (TGF)-beta were also quantified. We show here that JF patients have significantly higher titers of IgE antibodies against gp43, an immunodominant antigen specific for Paracoccidioides brasiliensis, than do patients with the unifocal adult form (UF-AF, isolated lesions). Patients with the multifocal adult form (MF-AF, lesions in more than one organ) also produced elevated levels of anti-P. brasiliensis IgE. Furthermore, specific IgE levels were correlated with IgG4, IgA and eosinophilia. Patients with JF showed eosinophilia and increased levels of TGF-beta, a switching factor for IgA. These results indicate a T helper (Th)-2 pattern of cytokine expression in both the JF and the MF-AF of PCM. On the other hand, patients with UF-AF had a significantly lower production of specific IgE, IgG4 and IgA than was seen in the other patient groups.

Capture enzyme-linked immunosorbent assay to detect specific immunoglobulin E in sera of patients with paracoccidioidomycosis.

Paracoccidioidomycosis (PCM) is the most frequent systemic mycosis in South America. The disease is characterized by a polyclonal activation of B cells, resulting in hyperimmunoglobulinemia. The production of immunoglobulin (Ig) E in deep mycosis has been related to the severity of the disease. However, the detection of specific IgE in sera of patients is difficult because of the competition with the IgG. We compared a capture and an indirect enzyme-linked immunosorbent assay (ELISA) technique to detect Paracoccidioides brasiliensis IgE. We found that the capture ELISA presented higher performance and lower background values than the indirect assay, resulting in a significant quantitative discrimination between sera from patients with the 2 major clinical forms of PCM. Patients with the juvenile form presented significantly higher levels of P. brasiliensis IgE, as compared with patients with the adult form. The capture ELISA was used in the follow-up of patients receiving treatment, showing that the levels of specific IgE decreased as the patient's clinical conditions improved.

Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases in the southeast region.

This paper describes the clinical-seroepidemiologic characteristics of patients with paracoccidioidomycosis (PCM) who visited the University Hospital at the State University of Campinas (Campinas, Sao Paulo, Brazil). The study group consisted of 584 individuals (492 males and 92 females) with ages ranging from 5 to 87 years. The highest incidence of the disease occurred between the ages of 41 and 50 years for men and between 11 and 40 years for women. Rural activities were the principal occupation of 46% of the patients. The diagnosis was confirmed by histopathologic examination and demonstration of fungus in scrapings, secretions, or in the sputum. Serologic test results for PCM were positive in 80% of the 584 patients studied. The significant number of patients, including 33 children less than 14 years old, indicates the presence of the fungus in the area and that this region is an important endemic area for PCM.