RESUMO
Advancements in allogeneic haematopoietic stem cell transplant (alloHSCT) procedures have improved patient outcomes over the last two decades, though invasive fungal infections (IFIs) remain a significant risk. The incidence of IFIs in alloHSCT recipients is estimated at 6%, with a mortality rate of 13%, and Aspergillus species are the most common pathogens involved. Posaconazole is effective in preventing IFIs post-transplant and is standard care during neutropenia or when managing graft-versus-host disease (GvHD) with high-dose steroids. However, azole prophylaxis may cause resistant Aspergillus species like A. calidoustus, which are difficult to treat. We report a case from our institution where a patient developed a dual infection with Aspergillus calidoustus and Talaromyces columbinus after alloHSCT and posaconazole prophylaxis. While A. calidoustus is known to cause IFIs in HSCT recipients, T. columbinus represents a previously unreported occurrence in medical literature. This case underscores the importance of a multifaceted diagnostic strategy, integrating BAL diagnosis, mycological cultures, direct microscopy, fungal speciation, susceptibility testing, and biomarkers. These comprehensive approaches are indispensable for accurate pathogen identification and effective management of IFIs with appropriate antifungal agents.
RESUMO
Triazole antifungal drugs are widely used for the prophylaxis and treatment of invasive fungal disease (IFD). Efficacy may depend on attaining minimum effective plasma concentrations. The aim of this study was to ascertain the proportion of samples in which the recommended concentrations were achieved in patients given these drugs in relation to outcome. In-patients prescribed standard doses of fluconazole, itraconazole solution, posaconazole suspension, or oral voriconazole for at least one week were studied. Pre-dose serum triazole concentrations were measured using validated methods. There were 359 samples from 90 patients. The median (range) number of samples per patient was 3 (1-13), and the median (range) fluconazole, itraconazole, posaconazole (prophylaxis), posaconazole (treatment), and voriconazole serum concentrations were 5.64 (0.11-18), 0.57 (0-5.3), 0.31 (0.02-2.5), 0.65 (0.02-2.5), and 0.95 (0.10-5.4) mg/l, respectively. The number of samples in which the recommended pre-dose concentrations were achieved was 98 (54%), 9 (20%), 2 (18%), and 29 (49%) for itraconazole, posaconazole (>0.7 mg/l prophylaxis), posaconazole (treatment), and voriconazole, respectively. No significant differences were detected in the median triazole trough concentrations between patients with proven/probable IFD compared to those with no evidence of IFD. However, itraconazole was not detected in 10 samples (7 patients). The small number of patients who achieved the recommended trough posaconazole concentrations may explain the high rate of break-through IFD observed in patients prescribed this drug. Except for fluconazole, the number of patients prescribed standard doses of triazoles who achieved recommended trough triazole concentrations was low. The prospective use of serum triazole measurements assay may have improved outcomes with itraconazole, posaconazole, and with voriconazole.
Assuntos
Quimioprevenção/métodos , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Soro/química , Triazóis/administração & dosagem , Triazóis/farmacocinética , Adulto , Idoso , Monitoramento de Medicamentos , Feminino , Neoplasias Hematológicas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Invasive fungal disease (IFD) is difficult to diagnose. We investigated the incidence of IFD and risk factors using the revised European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) definitions. Patients (N = 203) undergoing intensive therapy with expected neutropenia ≥10 d were recruited prospectively and followed for a median (range) of 556 (12-730) d. Baseline chest computerized tomography (CT) was performed pre-therapy. Twice-weekly surveillance with galactomannan (GM) was combined with targeted ß-d-glucan (BDG) testing on patients with possible IFD or who were GM-positive. Tissue diagnosis was obtained whenever possible. The cumulative incidence of proven/probable IFD among the 202 evaluable cases after 2 years follow-up was 21%, including 14 proven and 30 probable IFDs. Using either GM or BDG as the sole biomarker (plus host and clinical evidence) the apparent overall incidence of proven/probable IFD was 11% and 16%, respectively. Combined GM/BDG detected all biopsy-proven mould IFD. Baseline CT abnormalities were found in 76/202 (38%) patients. Baseline CT abnormalities and Karnofsky score <90, monocytopenia >10 d and bacteraemia were independent risk factors associated with greater than twofold increased IFD risk. This combined diagnostic approach identified a high incidence of IFD and important risk factors in this cohort.
Assuntos
Glucanos/análise , Doenças Hematológicas/microbiologia , Mananas/análise , Micoses/diagnóstico , Adulto , Idoso , Biópsia , Feminino , Galactose/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Fatores de Risco , Tomografia Computadorizada por Raios X/métodos , Adulto JovemAssuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus , Neoplasias Hematológicas , Pandemias , Pneumonia Viral , RNA Viral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , SARS-CoV-2 , Taxa de Sobrevida , Fatores de TempoRESUMO
OBJECTIVES: The direct cost of invasive fungal disease (IFD) includes antifungal drugs as well as diagnostic tests. The aim of this study was to determine these costs. METHODS: A total of 203 haematology patients were enrolled into the study and followed for a median of 556 days. Data were prospectively collected on antifungal drugs, diagnostic tests, length of stay and antibiotic usage. RESULTS: The overall mean (IQR) cost of care per patient (using UK-based reference costs) was £88â911 (45â339-121â594), £61â509 (39â748-78â383), £50â332 (23â037-72â057) and £34â075 (19â928-43â900) for proven/probable IFD, possible IFD, not classified and no evidence of IFD, respectively (P<0.001). The attributable cost of IFD was £54â836. Inpatient hospital stay accounted for nearly 74% of costs. In proven/probable IFD inpatient care, antifungals, antibiotics and IFD status accounted for 68%, 25%, 5% and 2%, respectively, compared with 85%, 11%, 2% and 2%, respectively, for no IFD (P<0.001). Among the allogeneic transplant patients, £36â914 (60%) of the total cost (£60â917) was used during the first 100 days. CONCLUSIONS: IFD was associated with longer length of stay and higher total overall cost of care, with attributable costs greater than £50â000 per case of IFD. Costs for inpatient stay far outstrip the cost of antifungal agents.
Assuntos
Antifúngicos/economia , Testes Diagnósticos de Rotina/economia , Custos de Cuidados de Saúde , Neoplasias Hematológicas/complicações , Micoses/diagnóstico , Micoses/tratamento farmacológico , Adulto , Idoso , Antifúngicos/uso terapêutico , Testes Diagnósticos de Rotina/métodos , Uso de Medicamentos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reino Unido , Adulto JovemAssuntos
Bradicardia , Doença de Erdheim-Chester , Tomografia Computadorizada por Raios X , Idoso de 80 Anos ou mais , Bradicardia/diagnóstico por imagem , Bradicardia/metabolismo , Bradicardia/patologia , Doença de Erdheim-Chester/diagnóstico por imagem , Doença de Erdheim-Chester/metabolismo , Doença de Erdheim-Chester/patologia , Humanos , MasculinoAssuntos
Neoplasias Hematológicas/complicações , Aspergilose Pulmonar Invasiva/diagnóstico , Medição de Risco , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Neoplasias Hematológicas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/normasAssuntos
Criptococose/etiologia , Mieloma Múltiplo/complicações , Idoso , Feminino , Humanos , Masculino , Mieloma Múltiplo/patologiaRESUMO
BACKGROUND: Itraconazole and posaconazole are used in the prevention and treatment of invasive fungal infections. However, the oral bioavailability of both compounds varies widely, and dose-serum concentration relationships are poorly defined for these analytes. The aim of this work was to develop and validate a simple assay that could be implemented in most laboratories for the purpose of therapeutic drug monitoring. METHODS: Calibrators (n = 7) and internal quality control solutions (n = 3) were prepared in pooled human serum. Sample (100 µL), internal standard solution (25 µL), Tris solution (2 mol/L; pH 10.6), and extraction solvent (methyl tert-butyl ether, 600 µL) were vortex mixed and centrifuged. The solvent layer was removed and evaporated to dryness and the residue reconstituted in water:methanol (1 + 3, 50 µL). A portion (5 µL) of the reconstituted extract was analyzed using a 3-µm Gemini C6 phenyl column with fluorescence detection (excitation 260 nm, emission 350 nm). The method was used to measure itraconazole and hydroxyitraconazole, or posaconazole, in serum samples taken 1-2 hours before the next dose, from patients forming part of a study into management and diagnostic strategies for invasive aspergillosis. RESULTS: Response was linear over the calibration ranges. Accuracy and imprecision were 92-111.4% and 3.2-13.4% (relative standard deviation), respectively. No interferences were noted. There was a good agreement with nominal values of each analyte in an external quality assessment scheme. In patients prescribed either 400 mg/d of itraconazole (n = 46) or 600-800 mg/d of posaconazole (n = 28) only 24% and 7% of samples, respectively, had serum itraconazole or posaconazole concentrations above the target threshold suggested in published guidelines. CONCLUSIONS: A simple, sensitive high-performance liquid chromatographic method has been developed for the analysis of itraconazole, hydroxyitraconazole, and posaconazole in serum/plasma. Few of the samples measured from patients participating in the clinical study attained concentrations of the drug/metabolite in serum that have been recommended for effective antifungal therapy.
Assuntos
Antifúngicos/sangue , Itraconazol/análogos & derivados , Itraconazol/sangue , Triazóis/sangue , Adulto , Idoso , Antifúngicos/administração & dosagem , Calibragem , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Aspergilose Pulmonar Invasiva/sangue , Aspergilose Pulmonar Invasiva/complicações , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Itraconazol/administração & dosagem , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Neutropenia/complicações , Reprodutibilidade dos Testes , Espectrometria de Fluorescência , Triazóis/administração & dosagem , Adulto JovemRESUMO
Intractable pruritus without visible primary skin lesions and refractory to antihistamines as a primary presentation of chronic myelomonocytic leukaemia (CMML) and myelodysplastic syndrome (MDS) is not well recognised. We present two cases of CMML and two cases of MDS with this challenging symptom. In two of them, the pruritus preceded the diagnosis of MDS/CMML by months. Various chemotherapeutic and immunosuppressive options were used with variable success. In one of the cases, the pruritus persisted despite achieving morphological remission of CMML with azacitidine but had a remarkable complete response to cladribine. The pathogenesis of intractable itching in CMML and MDS remains unclear but seems to be linked to the biology of these diseases and could precede definitive diagnostic features. Earlier diagnosis of these myeloid disorders may therefore be aided by increasing awareness among clinicians of the association with pruritus.
Assuntos
Leucemia Mielomonocítica Crônica/complicações , Síndromes Mielodisplásicas/complicações , Prurido/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Masculino , Síndromes Mielodisplásicas/tratamento farmacológico , Prurido/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
AIMS: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical utility of a composite biomarker panel to help identify individuals at risk of developing aGVHD, and to help predict and differentiate between severity of aGVHD following T-cell-depleted allogeneic HSCT. METHODS: We retrospectively analysed our cohort of biopsy confirmed patients with aGVHD, who underwent T-cell-depleted HSCT and matched them with negative controls without any evidence of aGVHD. Post-transplant serum samples on days 0 and 7 and at onset of aGVHD were analysed for elafin, regenerating islet-derived 3-α, soluble tumour necrosis factor receptor-1, soluble interleukin-2 receptor-α and hepatocyte growth factor. Biomarker data were combined as composite panels A-F (table 2) using logistic regression analysis. Receiver operating characteristic analysis was performed to study sensitivity and specificity of the composite panels. RESULTS: Our composite biomarker panels significantly differentiated between aGVHD and no GVHD patients at time of onset (panel E) and reliably predicted severity of GVHD grades at days 0 and 7 post-transplant (panels B and D). The area under the curve for the composite panel at time of onset was 0.65 with specificity, sensitivity, positive and negative predictive values of 100%, 55.6%, 100% and 78.9%, respectively (p=0.03). CONCLUSIONS: This pilot data support the usefulness of these composite biomarker panels in the prediction of severity and diagnosis of aGVHD in patients undergoing T-cell-depleted reduced intensity allogeneic HSCT.
Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Área Sob a Curva , Ensaio de Imunoadsorção Enzimática , Feminino , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Linfócitos T/imunologia , Transplante HomólogoRESUMO
BACKGROUND: Invasive fungal disease (IFD) is a disease of immunocompromised hosts. Cytokines are important mediators of innate and adaptive immune system. The aim of this study was to identify cytokine profiles that correlate with increased risk of IFD. METHODS: We prospectively enrolled 172 adult haematology patients undergoing intensive chemotherapy, immunosuppressive therapy, and haematopoietic stem cell transplantation. Pro-inflammatory cytokine profiling using 30-plex Luminex assay was performed at baseline and during treatment. Nine single nucleotide polymorphisms (TLR1, TLR2, TLR3, TLR4.1, TLR4.2, TLR6, CLEC7A, CARD9, and INFG) were investigated among transplant recipients and donors. FINDINGS: The incidence of IFD in this cohort was 16.9% (29/172). Median baseline serum concentrations of IL-15, IL-2R, CCL2, and MIP-1α were significantly higher whilst IL-4 was lower in patients with proven/probable IFD compared to those with no evidence of IFD. Baseline high IL-2R and CCL2 were associated with increased risk of IFD in the multivariate analysis (adjusted hazard ratio 2.3 [95% CI 1.1-5.1; P = 0.037], and hazard ratio 2.7 [95% CI 1.2-6.1; P = 0.016], respectively). However, these differences were not significant in follow up measurements. Similarly, no significant independent prognostic value was associated with baseline cytokine profile. INTERPRETATION: High baseline IL-2R and CCL2 concentrations were independent indicators of the risk of developing IFD and could be used to identify patients for enhanced prophylaxis and early antifungal therapy.
Assuntos
Aspergilose/imunologia , Citocinas/imunologia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/imunologia , Linfoma/terapia , Adulto , Idoso , Antifúngicos/uso terapêutico , Aspergilose/complicações , Aspergilose/microbiologia , Quimiocina CCL2/imunologia , Citocinas/genética , Feminino , Doenças Hematológicas/complicações , Doenças Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro Imunocomprometido , Subunidade alfa de Receptor de Interleucina-2/imunologia , Infecções Fúngicas Invasivas/complicações , Infecções Fúngicas Invasivas/tratamento farmacológico , Linfoma/complicações , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Transplantados , Adulto JovemRESUMO
Adult T-cell leukaemia lymphoma (ATLL) is an aggressive T-cell malignancy caused by the human T-lymphotropic virus type-1 (HTLV-1) and is associated with a very poor prognosis. Combination chemotherapy has had little impact on the long term survival of these patients. ATLL cells are characterised by the expression of CD25 (IL-2Rα), which is not expressed in normal resting T-cells. Daclizumab (Zenapax(®)) is a humanised murine anti-CD25 monoclonal antibody, which contains 10% murine CDR sequences. In this prospective trial 15 patients with aggressive ATLL were treated with CHOP-Zenapax (CHOP-Z) to determine the tolerability and feasibility of this novel regimen as well as evaluate its efficacy. Eleven patients had acute ATLL and four had the lymphoma subtype. The main presenting features were elevated LDH (100%), lymphocytosis (73%), lymphadenopathy (67%), skin lesions (40%), hypercalcaemia (53%), and hepato-splenomegaly (27%). Ten (67%) patients received the six scheduled cycles. Complete response (CR) lasting for two months or more was seen in 5 (33%), partial response in 3 (20%), minor response in 1 (7%), and no response in 6 (40%) patients. The median overall survival was 10 months (95% CI: 0.05-20.88) but this was significantly longer among responders (18 months) compared to non responders (3 months) (P = 0.019). For patients who achieved CR the disease free survival (DFS) was 15 months while the event-free survival (EFS) was 5 months. In conclusion CHOP-Z is safe and in those who achieve a complete response it was associated with prolonged overall survival.