RESUMEN
OBJECTIVES: Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival. METHODS: We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post-enrolment. RESULTS: The median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7-13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence interval (CI) -4.6 to -3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin ≥ 8.5 g/dL. The median haemoglobin concentration was 8.1 g/dL (IQR 6.5-9.5 g/dL) at 2 weeks, increasing to 9.4 g/dL (IQR 8.2-10.9 g/dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio (HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks (HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin ≥ 8.5 g/dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality (HR 2.0; 95% CI 0.5-9.1; P = 0.4). CONCLUSIONS: Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment.
Asunto(s)
Anfotericina B/uso terapéutico , Anemia/patología , Antifúngicos/uso terapéutico , Hemoglobinas/análisis , Meningitis Criptocócica/complicaciones , Meningitis Criptocócica/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sudáfrica , Análisis de Supervivencia , Resultado del Tratamiento , Uganda , Adulto JovenAsunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Antibióticos Antituberculosos/administración & dosificación , Antifúngicos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Micosis/tratamiento farmacológico , Tuberculosis/tratamiento farmacológico , Antibióticos Antituberculosos/farmacocinética , Antifúngicos/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fluconazol/administración & dosificación , Fluconazol/farmacocinética , Humanos , Rifampin/administración & dosificación , Rifampin/farmacocinética , Sertralina/administración & dosificación , Sertralina/farmacocinéticaAsunto(s)
Cryptococcus/inmunología , Infecciones por VIH , Antígenos Fúngicos , VIH , Humanos , Prevalencia , Sudáfrica/epidemiologíaRESUMEN
The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae, Nocardia brasiliensis, measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings.
Asunto(s)
Meningitis , Mycobacterium tuberculosis , Tuberculosis Meníngea , Sistema Nervioso Central , Humanos , Meningitis/microbiología , Metagenómica , Mycobacterium tuberculosis/genética , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/genéticaRESUMEN
BACKGROUND: TB meningitis (TBM) diagnosis is difficult and novel diagnostic methods are needed. The World Health Organization recommends Xpert(®) MTB/RIF as the initial TBM diagnostic test based on two studies reporting suboptimal sensitivity (~50-60%). OBJECTIVE: To study the effect of cerebrospinal fluid (CSF) centrifugation on Xpert performance for TBM detection. DESIGN: A total of 107 predominantly human immunodeficiency virus (HIV) infected adults with presumed meningitis were screened prospectively in Kampala, Uganda. CSF was tested using 1) microscopy for acid-fast bacilli; 2) MGIT™ culture; 3) Xpert of 2 ml of unprocessed CSF; and 4) Xpert of centrifuged CSF. Diagnostic performance was measured against an a priori composite reference standard of any positive CSF tuberculosis test. RESULTS: Of 107 participants, 18 (17%) had definite TBM. When CSF was centrifuged, Xpert had better sensitivity (13/18, 72%) than when using 2 ml of unprocessed CSF (5/18, 28%; P = 0.008). The median centrifuged CSF volume was 6 ml (IQR 4-10). Mycobacterial culture yielded 71% (12/17) sensitivity at a median delay of 27 days. Only 39% were positive by both culture and centrifuged Xpert, with additional cases detected by Xpert and culture. CONCLUSIONS: CSF centrifugation optimizes the diagnostic performance of Xpert in the detection of TBM. A combination of culture and Xpert detected the largest number of cases.
Asunto(s)
Infecciones por VIH/epidemiología , Técnicas de Diagnóstico Molecular/métodos , Tuberculosis Meníngea/diagnóstico , Adulto , Centrifugación/métodos , Estudios de Cohortes , Femenino , Humanos , Masculino , Microscopía/métodos , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/microbiología , Uganda/epidemiologíaRESUMEN
Tuberculosis (TB) continues to kill more than 2 million people globally each year. Annual TB case notification rates have risen up to fourfold since the mid-1980s, with the highest rate of 1000/100,000 around Cape Town, South Africa. There is an urgent need for novel diagnostic methods and preventive vaccines to control this epidemic. The rising incidence of TB has been attributed to HIV co-infection especially in developing countries. The threat of drug resistance arising from ineffective TB treatment programmes is looming and could potentially lead to loss of any gains made in controlling the disease globally.