Sepse é um importante problema de saúde pública, uma vez que seu tratamento gera altos custos a um sistema de saúde já sobrecarregado. É uma síndrome de alta mortalidade e morbidade que afeta, em geral, pacientes jovens com plena capacidade produtiva. A identificação e o tratamento precoce desta síndrome reduzem a morbimortalidade, assim como o custo. A proteína C reativa (PCR) e a procalcitonina (PCT) são bem estudadas como ferramentas para diagnóstico de infecção bacteriana em imunocompetentes, mas seu uso como ferramenta diagnóstica ainda não está estabelecido em pacientes imunossuprimidos. Portanto, a proposta deste estudo é avaliar a acurácia diagnóstica destes biomarcadores, em pacientes críticos imunossuprimidos (vírus da imunodeficiência adquirida  HIV positivos, portadores de tuberculose (TBC), cirróticos e transplantados). Como o uso da proteína C ainda não está estabelecido, a primeira questão de pesquisa investigou seu potencial diagnóstico quando comparado ao teste padrão (cultural). O segundo artigo comparou a PCR com a PCT. Para isto foram realizados dois artigos de revisão sistemática com metanálise. O primeiro artigo comparou a acurácia em determinar infecção bacteriana em imunossuprimidos da PCR ao teste padrão-ouro (as culturas). A primeira revisão incluiu 1.418 pacientes e demonstrou uma boa acurácia da PCR como biomarcador no diagnóstico de infecção bacteriana, apresentando sensibilidade de 69% e especificidade de 76% com uma área sob a curva (AUC) de 0,77. Os resultados encontrados são similares aos da literatura para imunocompetentes,(3) sensibilidade de 75%, especificidade de 67% e Área Sob a Curva Receiver Operating Characteristic (AUROC) de 0,92. Quando a PCT foi comparada com a PCR, ambos os biomarcadores mostraram acurácia moderada na utilização como ferrramenta de diagnóstico de infecção bacteriana, com um diagnóstico da razão de chances (DOR) de 7,24 (95% CI (2,83-14,60) para PCT e de 5,56 (95% CI (5,21-10,30) para PCR. A PCT e a PCR apresentaram sensibilidade de 69% e 68% e uma especificidade de 75% e 71%, respectivamente. Ambas mostraram resultados semelhantes, podendo ser utilizadas no diagnóstico de sepse em imunossupressos. / Sepsis is a major public health problem, since its treatment generates high costs, a health system already overburdened. A high mortality and morbidity syndrome affects, in general, young patients with full production capacity. The identification and early treatment of this syndrome reduce morbidity and mortality as well as the cost. C-reactive protein (CRP) and procalcitonin (PCT) are well studied as tools for diagnosis of bacterial infection in immunocompetent patients, but its use as a diagnostic tool is not yet established in immunocompromised patients. Therefore, the purpose of this study is to evaluate the diagnostic accuracy of these biomarkers in immunosuppresses critical patients (human immunodeficiency virus, cirrhotic and transplant). As the use of the c protein is not yet established, the first research question investigated their diagnostic potential when compared to the pattern (cultural). The second article compared to CRP and PCT. For this, there were two articles of a systematic review and meta-analysis. The first article compared the accuracy in determining bacterial infection in immunosuppresses of CRP to the gold standard (cultures). Our first review included 1,418 patients and showed good accuracy of CRP as a biomarker for the diagnosis of bacterial infection presenting a sensibility of 69% and 76% specificity with an area under the curve (AUC) 0.77. The results are similar to those found in the literature for immunocompetent,(3) sensitivity 75%, specificity of 67% and Area Under the Receiver Operating Characteristic Curve (AUROC): 0.92. When the PCT was compared with PCR, both biomarkers showed a moderately accurate for use as tool diagnostic bacterial infection with a Odds ratio diagnostic (DOR) 7.24 (95% CI (2.83-14.60) and PCT to 5:56 (95% CI (5.21-10.30) for CRP. the PCT and CRP had a sensitivity of 69% and 68% and a specificity of 75% and 71%, respectively. Both showed similar results may be used in the diagnosis of sepsis in immunosuppression.

Cryprosporidium parvum is a coccidian protozoan that colonizes epithelial cells lining respiratory and digestive tracts of animals and humans. Cryptosporidiosis is a well-recognized zoonotic disease infecting primarily neonates and immunocompromised hosts, including human immunodeficiency virus-infected patients. Clinical disease is manifested as a chronic diarrheal illness that is self-limiting in immunocompetent hosts and prolonged and often life-threatening in hosts with compromised immune systems.The lack of a suitable small animal model for screening anti-cryptosporidial drugs and for examining the pathogenicity and immunobiology of chronic cryptosporidiosis was the impetus for this research effort. The objectives of the present study were three-fold: to characterize chronic Cryptosporidium parvum infections in dexamethasone-immunosuppressed mice; evaluate the effects of Cryprosporidium parvum and dexamethasone on B and T lymphocyte proliferation; and determine the effects of the immunomodulator dehydroepiandrosterone on oocyst shedding intensities of mice infected with Cryptosporidium parvum. Adult C57BL/6N mice were immunosuppressed with the synthetic glucocorticoid dexamethasone, then infected with Cryprosporidium parvum (106 oocysts/mouse) investigated for their ability to sustain a four-month chronic infection. Dexamethasone was administered intraperitoneally (125 Jlg/mouse/day) or orally (8 Jlg/ml) in the drinking water ad libitum. Infection chronicity was characterized by evaluating mouse monality, oocyst excretion in the feces, tissue distribution of the parasite, and parasite-induced pathology. A progressive infection with Cryptosporidium parvum occurred in mice immunosuppressed intraperitoneally and orally as long as dexameth sone was administered. Mice receiving dexamethasone given intraperitoneally had a shoner prepatent period and a more consistent, although cyclic, oocyst shedding pattern when compared with mice given dexamethasone orally. Mice given dexamethasone orally exhibited a delayed prepatent period, with a steady increase in oocyst shedding. All mice receiving dexamethasone orally died within three months following oocyst inoculation. Clinical signs included dehydration, icterus, and reduction in spleen and body weights. Clinical signs were more abrupt in mice receiving oral dexamethasone. Parasite colonization involved the entire intestinal tract, including the pyloric ring and Peyer's patches, but was the heaviest in the terminal ileum. Parasites were present in the lungs, gallbladder, and pancreatic ducts. Pathologic abnormalities were isolated to the terminal small intestine and included blunting and fusion of intestinal villi and crypt hyperplasia. Cryptosporidium parvum and dexamethasone administered in vivo reduced B and T lymphocyte responses to the mitogens lipopolysaccharide and concanavalin A. Dehydroepiandrosterone and dehydroepiandrosterone-sulfate resulted in no significant reductions in cryptosporidial activity as determined by oocyst shedding in the feces.

Sepse é um importante problema de saúde pública, uma vez que seu tratamento gera altos custos a um sistema de saúde já sobrecarregado. É uma síndrome de alta mortalidade e morbidade que afeta, em geral, pacientes jovens com plena capacidade produtiva. A identificação e o tratamento precoce desta síndrome reduzem a morbimortalidade, assim como o custo. A proteína C reativa (PCR) e a procalcitonina (PCT) são bem estudadas como ferramentas para diagnóstico de infecção bacteriana em imunocompetentes, mas seu uso como ferramenta diagnóstica ainda não está estabelecido em pacientes imunossuprimidos. Portanto, a proposta deste estudo é avaliar a acurácia diagnóstica destes biomarcadores, em pacientes críticos imunossuprimidos (vírus da imunodeficiência adquirida  HIV positivos, portadores de tuberculose (TBC), cirróticos e transplantados). Como o uso da proteína C ainda não está estabelecido, a primeira questão de pesquisa investigou seu potencial diagnóstico quando comparado ao teste padrão (cultural). O segundo artigo comparou a PCR com a PCT. Para isto foram realizados dois artigos de revisão sistemática com metanálise. O primeiro artigo comparou a acurácia em determinar infecção bacteriana em imunossuprimidos da PCR ao teste padrão-ouro (as culturas). A primeira revisão incluiu 1.418 pacientes e demonstrou uma boa acurácia da PCR como biomarcador no diagnóstico de infecção bacteriana, apresentando sensibilidade de 69% e especificidade de 76% com uma área sob a curva (AUC) de 0,77. Os resultados encontrados são similares aos da literatura para imunocompetentes,(3) sensibilidade de 75%, especificidade de 67% e Área Sob a Curva Receiver Operating Characteristic (AUROC) de 0,92. Quando a PCT foi comparada com a PCR, ambos os biomarcadores mostraram acurácia moderada na utilização como ferrramenta de diagnóstico de infecção bacteriana, com um diagnóstico da razão de chances (DOR) de 7,24 (95% CI (2,83-14,60) para PCT e de 5,56 (95% CI (5,21-10,30) para PCR. A PCT e a PCR apresentaram sensibilidade de 69% e 68% e uma especificidade de 75% e 71%, respectivamente. Ambas mostraram resultados semelhantes, podendo ser utilizadas no diagnóstico de sepse em imunossupressos. / Sepsis is a major public health problem, since its treatment generates high costs, a health system already overburdened. A high mortality and morbidity syndrome affects, in general, young patients with full production capacity. The identification and early treatment of this syndrome reduce morbidity and mortality as well as the cost. C-reactive protein (CRP) and procalcitonin (PCT) are well studied as tools for diagnosis of bacterial infection in immunocompetent patients, but its use as a diagnostic tool is not yet established in immunocompromised patients. Therefore, the purpose of this study is to evaluate the diagnostic accuracy of these biomarkers in immunosuppresses critical patients (human immunodeficiency virus, cirrhotic and transplant). As the use of the c protein is not yet established, the first research question investigated their diagnostic potential when compared to the pattern (cultural). The second article compared to CRP and PCT. For this, there were two articles of a systematic review and meta-analysis. The first article compared the accuracy in determining bacterial infection in immunosuppresses of CRP to the gold standard (cultures). Our first review included 1,418 patients and showed good accuracy of CRP as a biomarker for the diagnosis of bacterial infection presenting a sensibility of 69% and 76% specificity with an area under the curve (AUC) 0.77. The results are similar to those found in the literature for immunocompetent,(3) sensitivity 75%, specificity of 67% and Area Under the Receiver Operating Characteristic Curve (AUROC): 0.92. When the PCT was compared with PCR, both biomarkers showed a moderately accurate for use as tool diagnostic bacterial infection with a Odds ratio diagnostic (DOR) 7.24 (95% CI (2.83-14.60) and PCT to 5:56 (95% CI (5.21-10.30) for CRP. the PCT and CRP had a sensitivity of 69% and 68% and a specificity of 75% and 71%, respectively. Both showed similar results may be used in the diagnosis of sepsis in immunosuppression.

Sepse é um importante problema de saúde pública, uma vez que seu tratamento gera altos custos a um sistema de saúde já sobrecarregado. É uma síndrome de alta mortalidade e morbidade que afeta, em geral, pacientes jovens com plena capacidade produtiva. A identificação e o tratamento precoce desta síndrome reduzem a morbimortalidade, assim como o custo. A proteína C reativa (PCR) e a procalcitonina (PCT) são bem estudadas como ferramentas para diagnóstico de infecção bacteriana em imunocompetentes, mas seu uso como ferramenta diagnóstica ainda não está estabelecido em pacientes imunossuprimidos. Portanto, a proposta deste estudo é avaliar a acurácia diagnóstica destes biomarcadores, em pacientes críticos imunossuprimidos (vírus da imunodeficiência adquirida  HIV positivos, portadores de tuberculose (TBC), cirróticos e transplantados). Como o uso da proteína C ainda não está estabelecido, a primeira questão de pesquisa investigou seu potencial diagnóstico quando comparado ao teste padrão (cultural). O segundo artigo comparou a PCR com a PCT. Para isto foram realizados dois artigos de revisão sistemática com metanálise. O primeiro artigo comparou a acurácia em determinar infecção bacteriana em imunossuprimidos da PCR ao teste padrão-ouro (as culturas). A primeira revisão incluiu 1.418 pacientes e demonstrou uma boa acurácia da PCR como biomarcador no diagnóstico de infecção bacteriana, apresentando sensibilidade de 69% e especificidade de 76% com uma área sob a curva (AUC) de 0,77. Os resultados encontrados são similares aos da literatura para imunocompetentes,(3) sensibilidade de 75%, especificidade de 67% e Área Sob a Curva Receiver Operating Characteristic (AUROC) de 0,92. Quando a PCT foi comparada com a PCR, ambos os biomarcadores mostraram acurácia moderada na utilização como ferrramenta de diagnóstico de infecção bacteriana, com um diagnóstico da razão de chances (DOR) de 7,24 (95% CI (2,83-14,60) para PCT e de 5,56 (95% CI (5,21-10,30) para PCR. A PCT e a PCR apresentaram sensibilidade de 69% e 68% e uma especificidade de 75% e 71%, respectivamente. Ambas mostraram resultados semelhantes, podendo ser utilizadas no diagnóstico de sepse em imunossupressos. / Sepsis is a major public health problem, since its treatment generates high costs, a health system already overburdened. A high mortality and morbidity syndrome affects, in general, young patients with full production capacity. The identification and early treatment of this syndrome reduce morbidity and mortality as well as the cost. C-reactive protein (CRP) and procalcitonin (PCT) are well studied as tools for diagnosis of bacterial infection in immunocompetent patients, but its use as a diagnostic tool is not yet established in immunocompromised patients. Therefore, the purpose of this study is to evaluate the diagnostic accuracy of these biomarkers in immunosuppresses critical patients (human immunodeficiency virus, cirrhotic and transplant). As the use of the c protein is not yet established, the first research question investigated their diagnostic potential when compared to the pattern (cultural). The second article compared to CRP and PCT. For this, there were two articles of a systematic review and meta-analysis. The first article compared the accuracy in determining bacterial infection in immunosuppresses of CRP to the gold standard (cultures). Our first review included 1,418 patients and showed good accuracy of CRP as a biomarker for the diagnosis of bacterial infection presenting a sensibility of 69% and 76% specificity with an area under the curve (AUC) 0.77. The results are similar to those found in the literature for immunocompetent,(3) sensitivity 75%, specificity of 67% and Area Under the Receiver Operating Characteristic Curve (AUROC): 0.92. When the PCT was compared with PCR, both biomarkers showed a moderately accurate for use as tool diagnostic bacterial infection with a Odds ratio diagnostic (DOR) 7.24 (95% CI (2.83-14.60) and PCT to 5:56 (95% CI (5.21-10.30) for CRP. the PCT and CRP had a sensitivity of 69% and 68% and a specificity of 75% and 71%, respectively. Both showed similar results may be used in the diagnosis of sepsis in immunosuppression.

Cryptosporidium parvum is a coccidian protozoan that colonizes epithelial cells lining respiratory and digestive tracts of animals and humans. Cryptosporidiosis is a well-recognized zoonotic disease infecting primarily neonates and immunocompromised hosts, including human immunodeficiency virus-infected patients. Clinical disease is manifested as a chronic diarrheal illness that is self-limiting in immunocompetent hosts and prolonged and often life-threatening in hosts with compromised immune systems. The lack of a suitable small animal model for screening anti-cryptosporidial drugs and for examining the pathogenicity and immunobiology of chronic cryptosporidosis was the impetus for this research effort. The objectives of the present study were three-fold: to characterize chronic Cryptosporidium parvum infections in dexamethasone-immunosuppressed mice; evaluate the effects of Cryptosporidium parvum and dexamethasone on B and T lymphocyte proliferation; and determine the effects of the immunomodulator dehydroepiandrosterone on oocyst shedding intensities of mice infected with Cryptosporidium parvum Adult C57BL/6N mice were immunosuppressed with the synthetic glucocorticoid dexamethasone, then infected with Cryptosporidium parvum (106 oocysts/mouse) and investigated for their ability to sustain a four-month chronic infection. Dexamethasone was administered intraperitoneally (125μ/mouse/day) or orally (8μ/ml) in the drinking water ad libitum. Infection chronicity was characterized by evaluating mouse mortality, oocyst excretion in the feces, tissue distribution of the parasite, and the parasite-induced pathology. A progressive infection with Cryptosporidium parvum occurred in mice immunosuppressed intraperitoneally and orally as long as dexamethsone was administered. Mice receiving dexamethasone given intraperitoneally had a shorter prepatent period and a more consistent, although cyclic, oocyst shedding pattern when compared with mice given dexamethasone orally. Mice given dexamethasone orally exhibited a delayed prepatent period, with a steady increase in oocyst shedding. All mice receiving dexamethasone orally died within three months following oocyst inoculation. Clinical signs included dehydration, icterus, and reduction in spleen and body weights. Clinical signs were more abrupt in mice receiving oral dexamethasone. Parasite colonization involved the entire intestinal tract, including the pyloric ring and Peyer's patches, but was the heaviest in the terminal ileum. Parasites were present in the lungs, gallbladder, and pancreatic ducts. Pathologic abnormalities were isolated to the terminal small intestine and included blunting and fusion of intestinal villi and crypt hyperplasia. Cryptosporidium parvum and dexamethasone administered in vivo reduced B and T lymphocyte responses to the mitogens lipopolysaccharide and concanavalin A. Dehydroepiandrosterone and dehydroepiandrosterone-sulfate resulted in no significant reductions in cryptosporidial activity as determined by oocyst shedding in the feces.

<p>Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants.</p><p>In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values.</p><p>Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation.</p><p>Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.</p>

Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants. In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values. Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation. Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.