High loading dose AmBisome is efficacious and well tolerated in the management of invasive fungal infection in hematology patients.

Despite improved supportive care, and the introduction of less toxic lipid-formulations of amphotericin B deoxycholate and other new antifungal agents the mortality from invasive fungal infection (IFI) in hematology patients remains high. New management strategies are therefore required to improve outcome.

Erythroblast iron metabolism in sideroblastic and sideropenic states.

Iron appears to exert self-regulatory control over erythroblast iron uptake, iron storage and its incorporation into haem. It does this via iron regulatory proteins (IRPs) which bind reversibly to the iron responsive elements (IREs) on the mRNA of transferrin receptor (TfR), erythroid 5-aminolaevulinic acid synthase (ALA-S2) and ferritin. Iron deficiency leads to the binding of IRP to IRE. This binding inhibits the translation of mRNA for ALA-S2 and ferritin but stabilizes mRNA for TfR expression. Sideroblastic erythropoiesis is highly ineffective and characterized by mitochondrial iron loading. The study of X-linked sideroblastic anaemia has shown that the entry of iron into the mitochondria is poorly controlled and able to occur when protoporphyrin production is reduced, as is seen with the ALA-S2 mutations, or when it is increased as has been seen with ABC7 transporter mutations. Sideropenia characterises both iron deficiency anaemia (IDA) and the anaemia of chronic disease (ACD). Erythroblasts in ACD seem doubly equipped to protect their iron supply with their ability to increase the efficiency of transferrin-iron uptake as well as to activate the IRP/IRE system to increase surface TfR production. This increase in efficiency restricts the need to increase surface TfR production and maintains serum soluble TfR (sTfR) values within the normal range in iron replete ACD. The coexistence of iron deficiency with chronic disease, however, is associated with an increase in both the efficiency and number and a highly significant rise in sTfR values.

Impact of diagnostic markers on early antifungal therapy.

PURPOSE OF REVIEW: The early treatment of invasive fungal infection is critical but is hampered by the non-specific nature of clinical and radiological signs and the insensitivity of current laboratory diagnostic methods. If mortality due to invasive fungal infection is to be reduced, new, preemptive therapeutic strategies, targeting those patients at highest risk, are required and these will depend on the development of rapid, sensitive diagnostic methods. Such methods have become available in the form of high-resolution computed tomography scanning and serological and molecular techniques and in this review the authors describe recent studies assessing the utility of these methods and consider their role in management strategies. RECENT FINDINGS: Sensitive assays for the detection of fungal DNA and antigens such as galactomannan and glucan have been prospectively evaluated in the clinical setting and enable identification of patients at an earlier stage of infection. However, the sensitivity and specificity of the assays vary considerably in different studies, depending on several factors including patient selection and clinical application of the test, and issues regarding the release and circulation of galactomannan and fungal DNA remain to be clarified. SUMMARY: Rapid serological and molecular diagnostic methods facilitate the early diagnosis of invasive fungal infection and would appear to be most useful when used prospectively to screen high-risk patients. However, in order to determine the optimal approach to treatment it is essential that these tests are incorporated into management strategies and their impact on incidence of invasive fungal infection and clinical outcome evaluated in further clinical trials.

Advances in the molecular and serological diagnosis of invasive fungal infection in haemato-oncology patients.

Current laboratory diagnostic methods for invasive fungal infection (IFI) in haemato-oncology patients are insensitive, resulting in late diagnosis and contributing to high mortality. In recent years, progress has been made in the development and evaluation of sensitive sero-diagnostic assays, including detection of genomic DNA sequences and fungal antigens, which aid in a rapid, early diagnosis of IFI. The sensitivity and specificity of the assays vary considerably between studies, highlighting the need to correlate serological results with conventional laboratory tests and clinical or radiological findings. As part of management protocols, these assays may help to confirm the diagnosis of suspected IFI; however, the impact on mortality from IFI may be greatest when they are used to screen high-risk patients. Persistently positive screening results could direct early aggressive antifungal therapy, guided further by radiological and microbiological findings combined with regular clinical review, while the excellent negative predictive value may allow treatment to be withheld in patients with antibiotic resistant neutropenic fever but no other signs of IFI. However, this pre-emptive approach requires evaluation in prospective randomized trials.