Fernando Laguna

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Tuberculous meningitis in patients infected with the human immunodeficiency virus.

BACKGROUND AND METHODS Tuberculosis is a frequent complication of human immunodeficiency virus (HIV) infection. We describe the clinical manifestations and outcomes of tuberculous meningitis in patients with HIV infection, and compare them with those in non-HIV-infected patients. We reviewed the records from 1985 through 1990 at two large referral hospitals in Madrid for patients who had Mycobacterium tuberculosis isolated from cerebrospinal fluid. RESULTS Of 2205 patients with tuberculosis, 455 (21 percent) also had HIV infection, of whom 45 had M. tuberculosis isolated from the cerebrospinal fluid. Of the 37 HIV-infected patients with tuberculous meningitis for whom records were available, 24 (65 percent) had clinical or radiologic evidence of extrameningeal tuberculosis at the time of admission. In 18 of 26 patients (69 percent), a CT scan of the head was abnormal. In most patients, analysis of cerebrospinal fluid showed pleocytosis (median white-cell count, 0.234 x 10(9) per liter) and hypoglycorrhachia (median glucose level, 1.3 mmol per liter), but in 43 percent (15 of 35), the level of protein in cerebrospinal fluid was normal. In four patients with HIV infection, tuberculosis was only discovered after their deaths. Of the 33 patients who received antituberculous treatment, 7 died (in-hospital mortality, 21 percent). Illness lasting more than 14 days before admission and a CD4+ cell count of less than 0.2 x 10(9) per liter (200 per cubic millimeter) were associated with a poor prognosis. Comparison with tuberculous meningitis in patients without HIV infection showed that the presentation, clinical manifestations, cerebrospinal fluid findings, and mortality were generally similar in the two groups. However, of the 1750 patients without HIV infection, only 2 percent (38 patients) had tuberculous meningitis, as compared with 10 percent of the HIV-infected patients (P less than 0.001). CONCLUSIONS HIV-infected patients with tuberculosis are at increased risk for meningitis, but infection with HIV does not appear to change the clinical manifestations or the outcome of tuberculous meningitis.

Visceral leishmaniasis in patients infected with human immunodeficiency virus

We describe 40 HIV-seropositive patients who developed visceral leishmaniasis. All the patients lived in areas endemic for visceral leishmaniasis and belonged to groups at risk for AIDS. Twenty-three patients (57.2%) had definitive AIDS before or after diagnosis of leishmaniasis and 77.5% were classified as belonging to CDC group IV. Fever was present in 95% patients and enlargement of the liver and/or spleen in 92.5%. Lymphopenia was found in 78.3%, depression of the absolute number of CD4 lymphocytes in 90% and depression of the CD4 to CD8 ratio in all evaluated cases but leishmania antibodies were found in only 35.2%. Parasites were demonstrated in the bone marrow or liver in every case. Thirty patients (75%) showed an initial good response to antimonial drugs, although the leishmaniasis followed a chronic or relapsing course in 17 (42.5%). HIV-related mortality was 40%. A significant correlation was found only between the relapsing course of the disease and mortality. In a multivariate linear regression model, the relapsing course was the only variable that influenced mortality. Visceral leishmaniasis is an opportunistic disease that should be suspected in HIV-infected patients. We suggest that it should be included in the CDC group IV C-1 and considered as a disease indicative of AIDS.

A nested polymerase chain reaction (Ln-PCR) for diagnosing and monitoring Leishmania infantum infection in patients co-infected with human immunodeficiency virus

We investigated a Leishmania-specific nested polymerase chain reaction (Ln-PCR) for the diagnosis and treatment monitoring of L. infantum infections in patients co-infected with human immunodeficiency virus (HIV). Peripheral blood and bone marrow samples from 89 HIV patients in Spain suspected of having leishmaniasis were examined by different diagnostic techniques (Ln-PCR, microscopy, NNN culture and indirect fluorescent antibody test). The sensitivity of Ln-PCR compared with microscopy and culture of bone marrow was 95.45% using blood and 100% when using bone marrow. 38 of these patients with confirmed leishmaniasis were entered in a chemotherapy trial (reported elsewhere), and samples from them were collected before treatment, one month after treatment ended and during follow-up (1-20 months), and examined similarly. Ln-PCR was shown to be a good method for testing efficacy of treatment and for predicting relapses after treatment (relapses were predicted on average 5 months earlier than when using classical diagnostic techniques). We suggest that Ln-PCR (especially using peripheral blood) should be the technique of choice for diagnosis, monitoring the success of treatment, and predicting relapses in patients with HIV and suspected or confirmed L. infantum infection.

Clinical Course and Prognostic Factors of Progressive Multifocal Leukoencephalopathy in Patients Treated with Highly Active Antiretroviral Therapy

We analyzed survival rates, neurologic function, and prognostic factors for 118 consecutive patients with acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) in 11 hospitals throughout Spain. Seventy-five patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML. Neurologic function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. The baseline CD4+ cell count was the only variable found with prognostic significance. The odds ratio of death was 2.71 (95% confidence interval, 1.19-6.15) for patients with CD4+ cell counts of <100 cells/microL, compared with patients who had CD4+ cell counts of > or =100 cells/microL. One-third of patients with PML died despite receipt of HAART; neurologic function improved in approximately one-half of the survivors. A CD4+ cell count of <100 cells/microL was associated with higher mortality.

Correlation of the MIC and Dose/MIC Ratio of Fluconazole to the Therapeutic Response of Patients with Mucosal Candidiasis and Candidemia

ABSTRACT We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 episodes caused by an isolate with a fluconazole MIC ≤2 mg/liter, 93.7% (136 of 145) responded to fluconazole treatment. The response for those infected with a strain with a MIC of 4 mg/liter was 66% but reached 100% when the dose was greater than 100 mg/day, whereas the response for those infected with strains with MICs ≥8 mg/liter was only 12%. Hence, a MIC of 2 mg/liter or 4 mg/liter was able to predict successful treatment. A cure rate of 93.9% (140 of 149) was achieved when the dose/MIC ratio was ≥100 but fell to 14.6% (16 of 109) when the ratio was less. The dose/MIC required to achieve a response rate of 50% (the 50% effective concentration) was 43.7 for the cohort of patients with oropharyngeal candidiasis. Classification and regression analysis indicated that a dose/MIC of 35.5 was the threshold for the prediction of cure or failure. However, an increase in exposure above this threshold further increased the probability of cure, and all patients were cured when the dose/MIC exceeded 100. Monte Carlo simulations showed a probability of target attainment of 99% at MICs ≤2 mg/liter and a pharmacodynamic target of a dose/MIC ratio of 100, which was equivalent to an unbound fraction of the fluconazole area under the curve versus the MIC of 79.

La aplicación de las tablas del SCORE a varones de edad avanzada triplica el número de sujetos clasificados de alto riesgo en comparación con la función de Framingham

Fundamento y objetivo La funcion de Framingham, recomendada por el National Cholesterol Education Program en su documento Adult Treatment Panel III (ATP-III) y las tablas de riesgo del Systematic Coronary Risk Evaluation (SCORE) son las funciones mas utilizadas para la estratificacion del riesgo cardiovascular, y ambas recomiendan intensificar las medidas higienicas y terapeuticas en las personas que presenten un riesgo alto. El objetivo del presente estudio fue comparar la estratificacion del riesgo obtenida con ambas clasificaciones en una poblacion de sujetos mayores de 60 anos. Sujetos y metodo Se incluyo en el estudio a 1.001 personas no diabeticas de entre de 60 y 79 anos (media de 69 anos, un 67%, mujeres) sin evidencia de enfermedad vascular. Se clasifico a los participantes segun su riesgo fuera bajo, medio o alto de acuerdo con el ATP-III ( 20% de riesgo a los 10 anos, respectivamente) y el SCORE ( Resultados Un 11,7% de la poblacion se considero de riesgo alto segun la ecuacion de Framingham, frente a un 17,6% segun el SCORE. Unicamente un 5% de las mujeres fueron clasificadas de riesgo alto con cualquiera de las funciones, frente a un 16,7 y un 44,4% de los varones segun las tablas de Framingham y de SCORE, respectivamente. Los resultados fueron similares al dividir por grupos de edad. De acuerdo con las guias del SCORE, un 39% de los varones y un 20% de las mujeres eran candidatos a recibir tratamiento hipolipemiante. Conclusiones En comparacion con la funcion de Framingham, la aplicacion del SCORE en varones mayores de 60 anos triplica el numero de sujetos de alto riesgo candidatos a medidas de prevencion energicas.

Relapses versus Reinfections in Patients Coinfected with Leishmania infantum and Human Immunodeficiency Virus Type 1

In the Mediterranean basin, Leishmania infantum is a major opportunistic parasite in people with acquired immunodeficiency syndrome (AIDS), and up to 9% of the patients with AIDS suffer from newly acquired or reactivated visceral leishmaniasis. Distinguishing between reinfections and relapses in these patients is important because some apparent treatment failures occur in patients with new rather than reactivated infections. Isoenzyme characterization is limited for use in determining relapsed versus newly acquired leishmaniasis in human immunodeficiency virus (HIV)-infected patients because of the variability of L. infantum and the predominance of the MON-1 zymodeme in people coinfected with HIV. A seminested polymerase chain reaction (PCR) was used to amplify L. infantum minicircle kinetoplast DNA, and, after digestion, the restriction fragment-length polymorphism (RFLP) profiles showed that 3 (7.5%) of 40 patients coinfected with L. infantum and HIV had a new infection, whereas isoenzyme characterization indicated that all 40 patients had infection relapses. These results suggest the utility of this PCR-RFLP analysis in detecting leishmaniasis reinfection in HIV-positive patients.

Prevalencia de un índice tobillo-brazo patológico según el riesgo cardiovascular calculado mediante la función de Framingham

Fundamento y objetivo La medicion del indice tobillo-brazo (ITB) es un metodo sencillo para detectar la presencia de arteriosclerosis en miembros inferiores. Un valor inferior a 0,9 o superior a 1,4 se asocia con un riesgo elevado de enfermedad cardiovascular, cerebrovascular y/o muerte por cualquier causa. A pesar de ello, su implantacion en la practica clinica es escasa. El objetivo del presente estudio fue determinar la prevalencia de un ITB patologico en una poblacion en prevencion primaria clasificada segun su riesgo vascular calculado por la funcion de Framingham recomendada por el National Cholesterol Education Program en su documento Adult Treatment Panel III. Pacientes y metodo Participaron en el estudio 1.001 sujetos sin enfermedad vascular conocida atendidos en atencion primaria. A todos ellos se les estimo el riesgo vascular y se les midio el ITB. Resultados El ITB fue bajo (menor de 0,9) en un 3,8% de los participantes (un 3,9% de las mujeres y un 3,6% de los varones). Se considero patologico (inferior a 0,9 o mayor de 1,4) en un 6,4% (un 5,2% de las mujeres y un 8,8% de los varones). En el analisis multivariante los factores que se asociaron con un ITB patologico fueron la edad odds ratio (OR) = 1,09 por cada ano de edad; intervalo de confianza (IC) del 95%, 1,03-1,15), el tabaquismo (OR = 2,96; IC del 95%, 1,51-5,80), la concentracion de colesterol unido a lipoproteinas de alta densidad (OR = 0,98 por cada mg/dl; IC del 95%, 0,95-0,99) y la presencia de hipertension arterial (OR = 1,80; IC del 95%, 1,05-3,06). Al ser clasificados segun su riesgo vascular, el porcentaje de sujetos de riesgo bajo, intermedio y alto con un ITB patologico fue del 2,6, el 8,7 y el 14,9%, respectivamente. Conclusiones En prevencion primaria, uno de cada 10 sujetos con riesgo intermedio y uno de cada 6 con riesgo elevado presentan un ITB patologico. En estos sujetos estan indicadas las medidas preventivas energicas y la antiagregacion.

Recomendaciones de GESIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en pacientes adultos infectados por el virus de la inmunodeficiencia humana en el año 2002

Objetivo Efectuar una puesta al dia de las recomendaciones sobre el tratamiento antirretroviral (TAR) para los adultos infectados por el virus de la inmunodeficiencia humana (VIH). Metodos Estas recomendaciones se han consensuado por un comite del Grupo de Estudio de Sida (GESIDA) y del Plan Nacional sobre el Sida (PNS). Para ello, se han revisado los avances en la fisiopatologia del VIH, los resultados de eficacia y seguridad de ensayos clinicos, estudios de cohortes y de farmacocinetica, publicados en revistas biomedicas o presentados en congresos en los ultimos anos. Se han definido tres niveles de evidencia segun la procedencia de los datos: estudios aleatorizados (nivel A), de cohortes o de caso-control (nivel B) u opinion de expertos (nivel C). En cada una de las situaciones se ha establecido recomendar, considerar o no recomendar el TAR. Resultados En el momento actual, el TAR con combinaciones de al menos 3 farmacos constituye el tratamiento de eleccion de la infeccion cronica por el VIH. En los pacientes con una infeccion por VIH sintomatica se recomienda iniciar el TAR. En los pacientes asintomaticos el inicio de TAR se basara en la cifra de linfocitos CD4+/μl y en la carga viral plasmatica (CVP): a) en pacientes con linfocitos CD4+ 350 cel./μl se puede diferir el inicio del TAR. El objetivo del TAR es lograr una CVP indetectable. La adherencia al TAR tiene un papel en la durabilidad de la respuesta antiviral. Las opciones terapeuticas en los fracasos del TAR son limitadas por la aparicion de resistencias cruzadas. Los estudios genotipicos en estos casos son de utilidad. La toxicidad es un factor limitante del TAR. Tambien se discuten los criterios de TAR de la infeccion aguda, embarazo y profilaxis postexposicion, y el manejo de la coinfeccion por el VIH y los virus de las hepatitis B y C (VHC y VHB). Conclusiones En la actualidad existe una actitud mas conservadora para iniciar el TAR que en recomendaciones previas. La cifra de linfocitos CD4+ es el factor de referencia mas importante para iniciar el TAR en pacientes asintomaticos. Por otra parte, el numero considerable de farmacos disponibles, los metodos de monitorizacion mas sensibles (CVP) y la posibilidad de determinar las resistencias hacen que las estrategias terapeuticas sean mucho mas individualizadas.