Diagnostic-driven antifungal therapy in neutropenic patients using the D-index and serial serum galactomannan testing

Abstract Introduction Invasive mold disease is an important complication of patients with hematologic malignancies, and is associated with high mortality. A diagnostic-driven approach has been an alternative to the classical empiric antifungal therapy. In the present study we tested an algorithm that incorporated risk stratification using the D-index, serial serum galactomannan and computed tomographic-scan to guide the decision to start antifungal therapy in neutropenic patients. Patients and methods Between May 2010 and August 2012, patients with acute leukemia in induction remission were prospectively monitored from day 1 of chemotherapy until discharge or death with the D-index and galactomannan. Patients were stratified in low, intermediate and high risk according to the D-index and an extensive workup for invasive mold disease was performed in case of positive galactomannan (≥0.5), persistent fever, or the appearance of clinical manifestations suggestive of invasive mold disease. Results Among 29 patients, 6 (21%), 11 (38%), and 12 (41%) were classified as high, intermediate, and low risk, respectively. Workup for invasive mold disease was undertaken in 67%, 73% and 58% (p = 0.77) of patients in each risk category, respectively, and antifungal therapy was given to 67%, 54.5%, and 17% (p = 0.07). Proven or probable invasive mold disease was diagnosed in 67%, 45.5%, and in none (p = 0.007) of high, intermediate, and low risk patients, respectively. All patients survived. Conclusion A risk stratification using D-index was a useful instrument to be incorporated in invasive mold disease diagnostic approach, resulting in a more comprehensive antifungal treatment strategy, and to guide an earlier start of treatment in afebrile patients under very high risk.

Patogenia de las citopenias autoinmunes primarias / Primary autoimmune cytopenias

Las enfermedades autoinmunes son trastornos secundarios a una des regulación del sistema inmune; éste pierde la capacidad de autotolerancia, y produce un daño crónico, continuo y progresivo. Son patologías muy diversas y pueden llegar a afectar hasta el 5 por ciento de la población. Pueden ser clasificadas en sistémicas u órgano-especificas, dependiendo si el antígeno reconocido es exclusivo del tejido target. A este grupo de enfermedades corresponden las citopenias autoinmunes, condiciones que se caracterizan por disminución del recuento de glóbulos rojos, plaquetas, leucocitos o la mezcla de ellos. Si bien los mecanismos patogénicos que participan en producción de cada una de ellas son similares, cada la tiene características que la hacen particularmente interesante. De esta manera tenemos que la anemia hemolítica autoinmune (AHAI) en un síndrome clínico que se produce debido a la disminución de glóbulos rojos secundaria a una destrucción exagerada de ellos, mediada por la alteración de la respuesta inmune, en la que los antígenos de la membrana de estas células son reconocidos como extraños por nuestro sistema inmune. La clasificación de la AHA/ está dada por la temperatura óptima de unión entre el anticuerpo y la membrana del glóbulo rojo; de esta forma, tenemos tres grandes grupos: por Anticuerpos calientes (WAHA), por Anticuerpos fríos (CAHA) y Mixtas (mediadas por anticuerpos calientes y frios). El diagnóstico de AHAl se confirma con la demostración de anticuerpos y/o proteínas del complemento en la superficie de los eritrocitos; entre ellos encontramos: Coombs directo y Coombs indirecto, test de Coombs recto anti-lgM , búsqueda de C3b en la membrana del glóbulo rojo y finalmente la prueba cualitativa de Donath-Landsteine Las trombopenias autoinmunes corresponden a un grupo de desórdenes que se caracterizan por tener un recuento plaquetario bajo 150.000, mediado por una alteración del sistema inmune. (3.14) La trombocitopenia autoinmune puede ser...

Autoimmune diseases are disorders secondary to a deregulation of the immune system, which loses the capacity for self-tolerance, resulting in chronic, continuous and progressive damage. These pathologies are very diverse and affect up to 5 percent of the population. They can be classified into systemic or organ-specific, depending on whether the recognized antigen is unique to the target tissue. Autoimmune cytopenias belong to this group of diseases and are characterized by a decreased count of red blood cells, platelets, leukocytes, or a mix of these. While the pathogenic mechanisms involved in the production of each are similar, each has features that make it particularly interesting. We have autoimmune hemolytic anemia (AlHA), which is a clinical syndrome that occurs due to a decreased number of red blood cells secondary to an exaggerated destruction of the same, mediated by an alteration of the immune response, in which the membrane antigens of these cells are recognized as foreign by our immune system. The classification of AIHA is given by the optimum bond temperature between the antibody and red blood cell membrane. There are 3 main groups: warm antibodies(WAHA), Cold antibodies (CAHA) and mixed (mediated by hot and cold antibodies). AIHA diagnosis is confirmed with the demonstration of antibodies and/or complement proteins on the surface of red blood cells, among these are the direct and indirect Coombs test, direct anti-IgM Coombs test, the search for C3b in the membrane of the red cell and, finally, the qualitative Donath-Landsteiner test. Autoimmune thrombocytopenia isassociated with a group of disorders characterized by a platelet count under 150,000, mediated by an alteration of the immune system.(3-14) Autoimmune thrombocytopenia can be classified as primary or secondary, and these, in turn, into acute and chronic, depending on whether they last 6 months or more, respectively. Antibodies that react against the glycoproteins of the plate...

Epidemiologia e perfil de sensibilidade dos germes isolados de hemoculturas de pacientes hematológicos com neutropenia febril / Epidemiology and sensitivity profile of germs isolated in blood cultures of hematological patients with febrile neutropenia

A neutropenia febril(NF) é uma complicação muito freqüente nos pacientes com neoplasias hematológicas submetidos à quimioterapia. Determinar a prevalência e a sensibilidade aos antimicrobianos dos germes isolados de hemoculturas(HMC) de pacientes hematológicos com NF internados no HCPA. Foram analisadas, retrospectivamente, todas as HMC solicitadas para pacientes com NF(contagem total de neutrófilos<500/uL) internados na Unidade de Hematologia do HCPA entre fev/2003 e fev/2005. Considerou-se febre uma temperatura axilar>38,5oC ou duas medidas>38oC em 24 horas. Comparou-se o perfil de sensibilidade das infecções em pacientes com NF em relação às demais unidades de internação clínica do hospital. Foram solicitadas no período em estudo 2389 hemoculturas para 178 pacientes. Destas, 719 (30,1 por cento) foram positivas sendo que este percentual subiu para 38,7 por cento quando consideradas apenas as hemoculturas coletas sem a vigência de antibiótico. A análise dos germes isolados revelou que a maioria das infecções foi causada por Bacilos Gram-negativos(53,8 por cento) seguido pelos Cocos Gram-positivos(31,2 por cento). Os microrganismos isolados com maior freqüência foram: E. coli(14,6 por cento), S. aureus(13,8 por cento), K. pneumoniae(12,2 por cento), Streptococcus sp.(8,5 por cento), Pseudomonas sp. (7,9 por cento), Staphylococcus coagulase-negativo (7,3 por cento). A sensibilidade dos Bacilos Gram-negativos aos diferentes antimicrobianos foi: Cefepime(63 por cento), Amicacina(65 por cento), Ciprofloxacin(63 por cento), Piperacilina/Tazobactam(71 por cento), Ceftazidima(63 por cento), Meropenem(97 por cento). A sensibilidade dos Cocos Gram-positivos foi: Oxacilina(30 por cento), Levofloxacin(38 por cento), Vancomicina(100 por cento). Comparativamente ao perfil de sensibilidade das unidades de internação clínica adulta não-hematológicas constatou-se diferença estatisticamente significante(p<0,05) entre a sensibilidade dos Bacilos Gram-negativos ao Cefepime...

Neutropenia inmune - aloinmune neonatal IgG serica reactiva y fenotipo especifico de los neutrofilos evaluados por citometria de flujo / Autoimmune-alloimmune neonatal neutropenia. Serum reactive IgG and neutrophil-specific

La neutropenia inmune se diagnostica por la presencia de auto o aloanticuerpos reactivos con losneutrófilos. La neutropenia aloinmune neonatal es consecuencia de la sensibilización materna alos antígenos específicos de los neutrófilos paternos que afectan al neonato al atravesar la barrera placentaria. Se presentan 4 casos de niños, 2 de ellos hermanos consanguíneos con doble vínculo. Se estudiaron los sueros de los pacientes y sus padres. Por citometría de flujo se establecen los valores de referencia de la IgG sérica reactiva con los neutrófilos en voluntarios sanos, para 3 diluciones (1/2, 1/5 y 1/20) en reacción autóloga(suero y células de un mismo individuo) y heteróloga (suero y células de diferentes individuos). Los resultadosse expresan por un índice definido como el cociente entre la mediana de la intensidad de fluorescencia media del suero incógnita y la de un suero utilizado como referencia. Por leucoaglutinación se evaluó la dilucióndel suero 1/20. Se determinó el nivel de complejos inmunes circulantes. Se determinó el fenotipo, para los epitopes HNA-1a, HNA-1b y HNA-2a. En los 4 niños se encontró IgG reactiva y/o factores aglutinantes; 2/3 sueros maternos fueron reactivos con los neutrófilos del cónyuge y de los hijos. Los complejos inmunes circulantes fueron positivos en 2/4 sueros negativos en 3/3 sueros maternos. Se encontró incompatibilidad materno-infantil en los 4 casos. Las 3 madres tenían igual fenotipo: homocigotos NA1/NA1, NB1+. En síntesis, se presenta el hallazgo de 4 casos con neutropenia inmune: 3/4 auto-inmune, 1/3 se asocia a complejos inmunes circulantes y 1/4 con neutropenia neonatal aloinmune

Auto or alloantibodies reactive with neutrophils define immune neutropenia. Alloimmune neonatal neutropenia is caused by maternal sensitization to paternal neutrophil antigens, resulting in IgG antibodies that are transferred to the fetus through the placenta. We present the studies in 4 children from 3 families with neutropenia of unknown origin (two of them were brothers). Theywere evaluated by flow cytometry in parallel with leukoagglutination. Reference values were established forserum reactive IgG in healthy volunteers for three dilutions (1/2, 1/5 and 1/20), both for the autologous reaction (serum and cells of the same individual) and for the heterologous reaction (serum and cells of differentindividuals). Results were expressed by an index defined by the quotient of the mean fluorescence intensityof the patient’s serum divided by that of the reference serum. Serum reactive/agglutinant factors and circulating immune complexes were evaluated in patients and parents serum. Neutrophil specific phenotypes weredetermined for HNA-1a, HNA-1b and HNA-2a. Reactive IgG/agglutinant factors were found in 4 children. Twomaternal sera were reactive against paternal and/or children neutrophils. Circulating immune complexes weredetected in 2/4 children sera and were negative in 3/3 maternal sera. Maternal/children incompatibility wasdetected in the four cases. The three mothers had the same phenotype: homozygous NA1/NA1, NB1+

Alloimmune cytopenia: part II ; alloimmune thrombocytopenia, and neutropenia alloimmune thrombocytopenia

Feto-maternal alloinmmune thrombocytopenia and neutropenia occurs when the mother produces antibodies against a platelet or a neutrophil alloantigen that the fetus has inherited from the father. As a result, there is destruction of the fetal platelets or the neutrophil according to the condition and result in a reduction in their numbers. Reduction in the platelets can cause intrauterine fetal bleeding or bleeding after birth. In severe cases, this bleeding may lead to long lasting disabilities. In the case of neonatal neutropenia the reduction of the neutrophils will increase the susceptibility to serious infectious. Current advances in management attempts at the prevention of thrombocytopenia and neutropenia in the fetus. This includes administration of intravenous immunoglobulin corticosteroids, or intrauterine transfusion of antigen-compatible platelets or neutrophils to the fetus. The management is costly and requires specialized labs and skilled perinatal and neonatal care

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

Neutropenia autoinmune infantil / Autoimmune neutropenia in children

Se describen 15 lactantes que sufrieron neutropenia crónica, con recuentos absolutos de neutrófilos menores a 1 000/µl de sangre al ingreso. En todos los pacientes se efectuaron recuentos de leucocitos y fórmula leucocitaria repetidamente durante la enfermedad, estudio de médula ósea y mediciones de anticuerpos antineutrófilos por inmunofluorescencia indirecta. La mediana de la edad al diagnóstico era 8 meses, márgenes 5 a 18 meses. La enfermedad fue comprobada en todos los pacientes por anticuerpos antineutrófilos circulantes en el suero a titulos entre 1/20 y 1/80. Todos los casos se recuperaron expontáneamente, sin mediar tratamientos "específicos" para la neutropenia, al cabo de 4 a 63 meses, mediana de 15 meses, desde la detección del trastorno. 6 pacientes sufrieron episodios reiteradosde infección durante el curso de la neutropenia, 3 uno sólo. Todos los casos respondieron a los tratamientos convencionales con antibióticos. 6 pacientes fueron asintomáticos. La neutropenia autoinmune es probablemente la causa más frecuente de neutropenia crónica del lactante. Evoluciona en plazos variables a la mejoría espontánea, requiriendo de tratamiento conservador

Neutropenia in an infant: possible autoimmune etiology

The present study was undertaken to determine if the serum of a child with severe neutropenia contained antibodies against parental neutrophils. The presence of IgG antibodies to granulocytes from both parents was demonstrated using the indirect immunofluorecence technique. These data suggest an auatoimmune etiology for the neutropenia of this patient

A rare case of variable immune deficiency with type II dysgammaglobulinaemia, light chain defect, gut associated IgA deficiency and progressive neutropenia.

This report describes in detail an unusual variant of a common variable immunodeficiency disease in a seven-year-old boy. The unique features were progressive neutropenia due to defective myelopoiesis, serum IgG and IgA deficiencies, defective immunoglobulin light-chain synthesis, absence of secretory IgA and IgM gammopathy. He had been born healthy, but following a thermal injury at the age of 1 1/2 years, he suffered recurrent attacks of sinopulmonary and urinary tract infections, enteritis due to enteropathogenic E. coli, Giardia lamblia and E. histolytica, developed pulmonary tuberculosis and died of deep mycotic infection of the oral cavity and obstruction of the bronchial tree. The cause of the defective myelopoiesis could not be determined, but it might have been due to prolonged sulphomamide therapy administered for controlling his persistent urinary tract infection due to paraphymosis.