Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy / Infecção sistêmica e localizada por Candida spp. em pacientes reumatológicos em terapia anti-TNF

ABSTRACT Objective: To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Methods: Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints; specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. Results: 194 patients [67 with rheumatoid arthritis (RA), 47 with ankylosing spondylitis (AS), 36 with juvenile idiopathic arthritis (JIA), 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42 ± 16 years, with 68 (35%) male and mean disease duration of 15 ± 10 years. Sixty-four (33%) patients were receiving adalimumab, 59 (30%) etanercept and 71 (36%) infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressant drugs. At the time of the study, only one (0.5%) patient had localized fungal infection (vaginal candidiasis). None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. Conclusions: This was the first study to assess the prevalence of invasive and localized fungal disease by Candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use.

RESUMO Objetivo: Avaliar a prevalência de infecção sistêmica e localizada por Candida spp. e sua possível associação com dados demográficos, manifestações clínicas e laboratoriais e terapêutica em pacientes com doenças reumatológicas em uso de anti-TNF. Métodos: Foram incluídos pacientes consecutivos com doenças reumatológicas em uso de agentes anti-TNF. Foram analisados os seguintes fatores de risco até quatro semanas antes do estudo: uso de antibioticoterapia, imunossupressores, hospitalização e procedimentos invasivos. Todos foram avaliados para queixas clinicas, coletaram hemocultura específica para fungos e amostras de sangue para pesquisa de Candida spp. por reação em cadeia de polimerase. Resultados: Foram incluídos 194 pacientes [67 com artrite reumatoide (AR), 47 espondilite anquilosante (EA), 36 artrite idiopática juvenil (AIJ), 28 artrite psoriásica e 16 outros]. A média de idade era de 42 ± 16 anos, com 68 (35%) do sexo masculino e média de duração de doença de 15 ± 10 anos; 64 (33%) pacientes usavam adalimumabe, 59 (36%) etanercepte e 71 (36%) infliximabe; 81% faziam uso concomitante de imunossupressores. No momento do estudo, apenas um (0,5%) paciente apresentou infecção fúngica localizada (candidíase vaginal). Nenhum dos pacientes incluídos apresentou candidíase sistêmica com hemocultura positiva para fungos ou PCR positiva para Candida spp. em amostra de sangue periférico. Conclusões: Este foi o primeiro estudo que avaliou prevalência de doença fúngica invasiva e localizada por Candida em um expressivo número de pacientes reumatológicos em terapia anti-TNF e demonstrou baixo risco de candidíase, apesar da alta prevalência de uso de imunossupressores.

Influência da condição de hipoinsulinemia-hiperglicemia na candidíase experimental sistêmica: avalição da atividade macrofágica e da distribuição das subpopulações de monócitos sanguíneos / Influence the condition of hypoinsulinemia - hyperglycemic in experimental systemic candidiasis: evalution of macrophage activity and distribution of subpopulations of monocytes blood

Diabetes mellitus (DM) é um importante fator de predisposição para o desenvolvimento de infecções, incluindo a candidíase. Embora a incidência e a gravidade das doenças infecciosas em pacientes diabéticos estejam com frequência relacionadas a disfunções da resposta imune, seus mecanismos ainda não foram bem esclarecidos. No presente estudo avaliou-se a influência da condição de hipoinsulinemia-hiperglicemia (HH) na evolução da candidíase experimental sistêmica. Parâmetros histológicos, microbiológicos e imunológicos envolvendo medula óssea, cérebro, baço e fígado, níveis plasmáticos de quimiocina e de citocinas, atividade macrofágica e distribuição de granulócitos e subpopulações de monócitos do sangue periférico foram avaliados. Para tanto, camundongos suiços, HH-induzidos ou não pela aloxana, foram inoculados com Candida albicans pela veia da cauda e avaliados 12, 24 e 96 horas e 7 dias após infecção. A presença de fungos foi avaliada em: sangue, medula óssea, rins, fígado, cérebro e baço. A atividade macrofágica foi estudada pela resposta de fagócitos peritoneais cultivados ou não com C. albicans mortas pelo calor, avaliando-se a produção de peróxido de hidrogénio e de óxido nítrico e os níveis de TNF-α, IL-6, IL-10, IFN-γ, IL-12p70 e CCL2 em sobrenadande de cultura. Os níveis plasmáticos destas citocinas também foram determinados. A distribuição de granulócitos e das subpopulações de monócitos circulantes foi determinada por citometria de fluxo. Os resultados mostraram aumento da mortalidade em camundongos HH; apesar da ausência de diferenças de resposta tecidual entre os grupos infectados; notamos diferenças importantes na carga fúngica presente nos diversos tecidos examinados...

Diabetis mellitus (DM) is an important predisposing factor for the development of infections, including candidiasis. Although the incidence and severity of infectious diseases in diabetic patients are related to dysfunction in the immune function, the mechanisms involved in the high susceptibility to this fungal infection are not clear. In the present study, we evaluated the influence of hypoinsulinemia-hyperglycemia (HH) on plasma levels of chemokine/cytokines, macrophage activity and distribution of peripheral blood granulocytes and monocytes subsets in a murine model of systemic candidiasis. C. albicans was intravenously inoculated in alloxan-induced HH mice, which were evaluated 12, 24 and 96 hours, and 7 days after infection. Colony-forming unit analysis and/or histopathological examination were performed on blood, bone-marrow, kidney, brain, liver and spleen. Peritoneal phagocytes were cultured with or without heat-killed C. albicans, and the production of hydrogen peroxide and nitric oxide were determined. The levels of TNF-α, IL-6, IL-10, IFN-γ, IL-12p70 and CCL2 were measured in the culture supernatants and also in the plasma of the mice. The distribution of peripheral blood granulocytes and monocytes subsets were performed by flow cytometry. Our findings showed an increased mortality in the infected HH mice, but they showed no significant differences in fungal recovery. Upon histopathological examination, no differences were observed between both infected groups, but strong discrepancies in fungal load were found among the tissues examined. High plasma levels of IL-6 and TNF-α as well as an excessive TNF-α-mediated macrophage response were also observed in the infected HH-induced mice. Soon after the fungal challenge, increased percentage of granulocytes and inflammatory monocytes was observed...

Infecções oportunistas por leveduras e perfil enzimático dos agentes etiológicos / Opportunistic yeast infections and enzymatic profile of the etiological agents

Infecções por leveduras são freqüentes em imunocomprometidos, contudo espécies emergentes têm alterado o perfil epidemiológico. A habilidade de secretar proteases tem sido associada à patogenicidade do gênero Candida. Esta pesquisa teve como objetivos diagnosticar leveduroses em pacientes imunocomprometidos e avaliar a virulência dos agentes etiológicos baseado em teste de secreção de protease utilizando soro de albumina bovina como substrato. Do total de 104 pacientes estudados, 19 apresentaram episódios de leveduroses. O trato respiratório (63,2 por cento), seguido pelo trato urinário (10,5 por cento) foram os locais mais comuns de infecção. Candida albicans, Candida parapsilosis, Candida tropicalis e espécies emergentes como Candida krusei e Candida guilliermondii foram isoladas. Cinco isolados de Candida parapsilosis e um de Candida albicans e Candida guilliermondii exibiram alta atividade enzimática. Concluímos que a caracterização enzimática de isolados de Candida pode ser um útil marcador prognóstico, especialmente em imunocomprometidos, uma vez que leveduroses nestes pacientes são geralmente graves.

Yeast infections are common in immunocompromised patients, although emerging species have been changing the epidemiological profile. The ability to secrete proteinases has been associated with pathogenicity within the genus Candida. This study had the aims of diagnosing yeast infections in immunocompromised patients and evaluating the virulence of the etiological agents, based on a proteinase secretion assay using bovine serum albumin as a substrate. Out of a total of 104 patients studied, 19 presented episodes of yeast infection. The respiratory tract (63.2 percent), followed by the urinary tract (10.5 percent), were the most common sites of infection. Candida albicans, Candida parapsilosis, Candida tropicalis and emerging species such as Candida krusei and Candida guilliermondii were isolated. Five isolates of Candida parapsilosis and one of Candida albicans and Candida guilliermondii exhibited high enzymatic activity. We conclude that enzymatic characterization of Candida isolates may be a useful prognostic marker, especially among immunocompromised individuals, since yeast infections in such patients are generally serious.

Recurring Candida albicans esophagitis in a HIV-infected patient undergoing long-Term antiretroviral therapy, and with absent-negligible immunodeficiency

A patient with HIV infection developed the first episode of AIDS-defining opportunism (severe Candida albicans esophagitis) with an underlying CD4+ lymphocyte count of 1,025 cells/µL. After treatment with a highly active antiretroviral therapy (HAART), taken with insufficient compliance and leaving a residual viral load, our patient suffered from two relapses of esophageal candidiasis, which occurred three months and seven years later, when his CD4+ lymphocyte count was 930 and 439 cells/µL, respectively, and a viral load slightly above 10(4) copies/mL was still present. Also in the HAART era, Candida esophagitis remains one of the most common AIDS-defining diseases, but a presentation with a concurrent CD4+ count above 1,000 cells/µL remains a rare exception, as well as the two isolated, subsequent relapses, occurred with a CD4+ count ranging from 439 to 930 cells/µL, and a residual HIV viremia due to insufficient adherence to the prescribed HAART regimens. Our case report represents the opportunity to revisit the epidemiology and, especially, the pathogenesis of this opportunistic fungal complication in HIV-infected patients and in other subjects at risk, on the ground of an extensive literature review, and to explore possible alternative supporting factors other than the crude absolute CD4+ lymphocyte count, with emphasis on the possible role of a persisting HIV viremia, and other potential contributing factors. Clinicians engaged with immunocompromised patients and subjects with HIV disease, should be aware that a Candida esophagitis may occur and relapse also when the cell-mediated immunity, as measured by a simple CD4+ cell count, do not show relevant abnormalities.

Candidiasis esofágica en pacientes inmunocompetentes: estudio clínico e inmunológico / Clinical and immunological study of 10 immunocompetent patients with esophageal candidiasis

Background: Esophageal candidiasis is associated with conditions that cause an immune depression. It is a defining disease for AIDS, is observed in poorly controlled diabetics, in patients with renal or hepatic failure, in patients with cancer and in subjects using medications causing immunosuppression or broad spectrum antimicrobials. Aim: To report the features of 10 immunocompetent patients with esophageal candidiasis. Patients and methods: Six males and four females aged between 48 and 82 years, without conditions associated with immunosuppression, in whom an esophageal candidiasis was found on an upper gastrointestinal endoscopy. Delayed skin hypersensitivity to eight antigens, Iymphocyte subpopulations, yeast phagocytosis and neutrophil chemotaxis were measured. Results: Six patients had a low CD4 Iymphocyte count and seven had a low CD8 count. Seven patients were anergic on skin hypersensitivity challenge. Yeast phagocytosis was abnormal in one patient and neutrophil chemotaxis was abnormal in two. Humoral immunity was normal in all subjects. All patients were treated with oral fluconazole in doses of 150 mg/day for 14 days, with complete resolution of candidiasis in all. Conclusions: Patients with esophageal candidiasis, have frequent alterations of cellular immunity, that must be diagnosed and treated.

Human, monoclonal and recombinant candidacidal, pneumocysticidal and mycobactericidal antibodies.

Antiidiotypic antibodies (antiIds) representing the internal image of some antigenic deteminants have been proposed as surrogate vaccines or, conjugated with toxins, in the immunotherapy of cancer. Experimental studies on antiidiotypic vaccination against fungal infections have been lacking. A conceptually new model of idiotypic vaccination against fungal infection has been recently developed. The vaccine used is monoclonal antibody that in vitro neutralizes the activity of killer toxin from the yeast, Pichia anomala (KT). This is effective against a wide range of fungal pathogens including Candida albicans and Pneumocystis carinii, and is also active against Mycobacterium tuberculosis. In an experimental mouse model, this vaccination was found to confer significant protection against systemic and mucosal infection with C. albicans. Human recombinant killer toxin antibodies and its synthetic derivatives hold promise of a potentially powerful tool against fungal and mycobacterial infections.

In vitro immunity of rat peritoneal macrophages to Candida albicans.

Phagocytic, germ tube inducing and candidacidal activities were investigated in monolayers of peritoneal macrophages of rats. The phagocytic activities observed in macrophages of the healthy rats in the presence of normal serum, those in the presence of immune serum and of immunized rats in the presence of normal serum were 40%, 45.3% and 44.8% respectively. The percent of macrophages in which intracellular Candida formed germ tubes in the above three situations were 10, 9.59 and 10.19, respectively and the percent of intracellular Candida that formed germ tubes were 6.6, 3.7 and 4.1, respectively. The candidacidal activity observed in the above three sets of macrophages were 5.33%, 22.66% and 19.88%, respectively. Induction of germ tube in C. albicans in supplemented tissue culture medium containing normal serum was 15 per cent. These observations indicate that immunisation/sensitisation of individuals with C. albicans organisms does provide some degree of cell mediated immunity by activating macrophages. This may partly be due to the appearance of specific antibodies. It is likely that this type of immunity can be produced by subclinical infections during invasion by the commensal organism thus preventing further invasion establishment of infection and keeping the organism (C. albicans) in a state of commensalism. However, the degree of immunity so produced is so low that predisposing factors suppress it and allow establishment of infection.

Relationship between clinical conditions and CD4 counts in HIV-infected persons in Pune, Maharashtra, India.

BACKGROUND: A decade after the detection of human immunodeficiency virus (HIV) infection in India, a steady increase in the number of patients with acquired immunodeficiency syndrome (AIDS) has been observed. The therapeutic options for patients with AIDS in developing countries include chemoprophylaxis and identifying and treating opportunistic infections. CD4 counts help in clinical monitoring and making decisions about initiating antiretroviral therapy or chemoprophylaxis. Flowcytometry is expensive and available only at specialized laboratories. Therefore, the possibility of using clinical indicators to predict low CD4 counts and disease progression needs to be explored. METHODS: This cross-sectional study was conducted among 137 HIV-infected persons investigated at an HIV reference centre in Pune. The study methods comprised pre-test counselling, informed consent, blood withdrawal and clinical evaluation. Serum samples were tested for HIV and CD4 counts were estimated on FACSort. RESULTS: Study participants commonly reported with oral candidiasis, herpes zoster, pulmonary tuberculosis, lymphadenopathy, weight loss, rash, diarrhoea and fever. CD4 counts were significantly lower among men, symptomatic patients and those with oral candidiasis, weight loss and multiple clinical conditions. The sensitivity of most of the clinical conditions was low, the specificity was high and the positive predictive value of oral candidiasis and weight loss for low CD4 counts was > 75%. CONCLUSION: The presence of oral candidiasis and weight loss were highly predictive of low CD4 counts and these can be considered as markers of HIV disease progression. Absence of clinical conditions was found to be a good predictor of high CD4 counts. Larger systematic natural history studies may help in identifying clinical conditions that could have a prognostic significance among HIV-infected people.

Fungal infections in the immunocompromised host

In recent years many remarkable changes occurred in our way of life, producing opportunities for microbes. All these changes are related to the recent emergence of previously unrecognized diseases, or the resurgence of diseases that, at least in developed countries, were thought to be under control. This concept is reviewed regarding fungal infections and their agents in the immunocompromised host. The changing pattern of these infections, the portals of entry of fungi into the human host, fungal pathogenicity and the main predisposing factors are analyzed. Opportunistic fungal infections in cancer, organ transplant and acquired immunodeficiency syndrome patients are reviewed, specially candidiasis and aspergillosis

Imunologia na candidíase / Immunology in candidiasis

Os autores realizam um trabalho de revisão, atualizando os conceitos modernos dos mecanismos imunológicos presentes na candidíase (local e sistêmica). O papel dos linfócitos T, anticorpos, fatores neuroendócrinos e citocininas é discutido. São propostos tratamentos imunomoduladores futuros para esta infecção

Aspectos básicos de la neuroendocrinoinmunología (NEI) / Basic aspects of the neuroendocrinoimmunology

En este artículo se discuten los aspectos básicos de la interacción entre los sistemas neuroendócrino e inmune. Existen dos vías principales de comunicación ente el cerebro y el sistema inmune: el sistema nervioso autónomo y la rama neuroendócrina a través de los productos que libera la pituitaria. La pincipal influencia del cerebro sobre la función inmune es ejercida a través del eje hipotálamo-pituitaria adrenal (HPA). Ciertos neurotransmisores, neuropéptidos y neurohormonas afectan la función inmune tanto in vivo como in vitro. Además, las células inmunes expresan en sua membranas receptores para esas moléculas. Una característica de esta comunicación es su bidireccionalidad ya que las citoquinas que se producen y liberan durante la respuesta inmune pueden a su vez, afectar al eje HPA. En este contexto, describimos parte de nuestro trabajo experimental desarrolado en ratas infectadas com Candida albicans y expuestas a un esquema de estrés crónico y variado.

Candidiasis esofágica en un paciente inmunocompetente / Esophageal candidiasis in a immunocompetent patient

La candidiasis esofágica es una infección micótica del esófago que en la actualidad se asocia con inmunodeficiencias. Sin embargo, existen otros factores de riesgo que favorecen la aparición de dicha afección aún en pacientes inmunocompetentes. La incidencia de candidiasis esofágica en este último grupo, se calcula como inferior al 5 por ciento. Presentamos un paciente de sexo masculino, de 36 años de edad, portador de una esofagitis por reflujo, que consultó por odinofagia. El examen físico, los análisis de laboratorio, la radiología torácica y la ecografía abdominal, fueron normales. Las serologías para HIV, CMV y hepatitis, resultaron negativas. La fibrogastroscopía permitió el diagnóstico de candidiasis esofágica, siendo medicado con fluconazol, omeprazol y sucralfato, con rápida desaparición de la sintomatología. Una fibrogastroscopía de control a los 4 meses, no detectó signos de candidiasis. Se concluye afirmando la necesidad de realizar fibrogastroscopía a todo paciente con odinodisfagia, dado que este síntoma es el más sugerente de candidiasis esofágica

Inmuniead y Caldida albicans: un estudio de poblaciones y subpoblaciones linfocitarias / Inmmunity and Candida albicans: a study of lymphocytari popolations and subpopulations

En este trabajo se presentan los resultados de un estudio inmunológico, realizado en 13 pacientes con síndrome de hipersensibilidad a la Candida. Los estudios micológicos confirmaron los hallazgos clínicos de candidiasis. En cada uno de los casos, se realizó cultivo, tipificación y recuente de colonias, que fluctuaron entre 9 800 y 90 000 unidades formadores de colonias de C. albicans/g de materia fecal peso húmedad. Las pruebas de hipersensibilidad cutánea fueron realizadas con 4 antígenos. Todos los pacientes mostraron positividad en la lectura precoz y negatividad en la tardía, a excepción de 4 de ellos. La inmunogluvina E fue cuantificada por ELISA y se encontraron valores por encima de lo normal en 84%de los casos. Los valores hallados fluctuaron entre 31 y 1 000 Ul/ml. La cantidad de LB fue normal en todos los casos, mientras que el de Lt fue normal en 46%y disminuido en 54%de los pacientes. En ambas determinaciones se usó el método de las rosetas. En subpoblaciones de LT se determinaron por técnica de inmunofluorescencia indirecta, con anticuerpos monoclonales. Los CD4+ (cooperadores/inductores) se encontraron disminuidos en 77%de los casos mientras que los CDB+ (citotómicos/supresores) estuvieron normales en la mayoría de ellos (84%). De acuerdo con estos resultados se puede deducir que existe una estrecha relación entre candidiasis, IgE aumentada e inmunodeficiencia fundamentalmente de la inmunidad mediada por células y en especial de las subpoblaciones CD4+. Se propone que en el momento de programar el esquema terapéutico, se incluya un tratamiento inmunomodelador, si fuera necesario, con la finalidad de lograr mayor eficacia terapéutica.

Patologías médicas en la adicción a la heroína / Medical pathologies in heroin addiction

Se presenta un análisis de las patologías médicas motivo de hospitalización de los heroinómanos de la Provincia de Vizcaya, País Vasco, España, en el lapso 1982 a 1987, y su posible asociación a la infección por el virus de la inmunodeficiencia humana, VIH. Se observó que existe un franco incremento en los ingresos hospitalarios desde 1982, y que las patologías infecciosas constituyen la principal entidad nosológica en este grupo de sujetos. La infección VIH se encontró en un porcentaje superior al 90% de los individuos estudiados y con patologías infecciosas. Es de particular significación el aumento de casos de tuberculosis y de candidiasis. Se discute la posible asociación y repercusión del aumento en la susceptiblidad a infecciones no oportunistas y su asociación a la infección VIH