Early diagnosis of invasive pulmonary aspergillosis in hematologic patients: an opportunity to improve the outcome.

Invasive pulmonary aspergillosis (IPA) is the leading invasive fungal disease in high-risk hematologic patients, including those with acute myeloid leukemia (AML) receiving chemotherapy for induction of remission, and allogeneic hematopoietic cell transplant (HCT) recipients. Studies conducted in the 1990s and early 2000s reported crude mortality rates of 60-80%. However, recent data suggest that the mortality rate of IPA has decreased. Although the exact reasons for the improvement in the outcome are not clear, it is possible that this is partly due to the fact that IPA has been diagnosed at an earlier disease stage, after the introduction of routine chest computed tomography (CT) scans, and the use of serum biomarkers, such as galactomannan (GMI). The concept of early diagnosis and improved outcomes is very familiar to hematologists since the outcome of hematologic malignancies is usually influenced by the tumor burden when treatment is started. For example, high white blood cell count at diagnosis of acute leukemia is associated with poor outcome, disease stage strongly influences the outcome in Hodgkin’s lymphoma, and high tumor burden is associated with poor prognosis in multiple myeloma. Therefore, it is tempting to speculate that fungal burden may influence the outcome of IPA, with poorer responses to treatment as long as the fungal burden increases. The halo sign is the radiological representation of lung infarction that follows angioinvasion by hyphae. The nodule represents the coagulation necrosis, and the halo is the edema and hemorrhage that surrounds the zone of infarction. Although not specific, its presence in persistently febrile neutropenic patients must be interpreted as suggestive of an invasive mold disease. An important contribution to the management of IPA was made by studies showing the importance of the halo sign as the earliest detectable sign of disease. Caillot et al. analyzed the diagnosis of IPA in two periods. In the first, high-resolution chest computed tomography (CT) was obtained at the discretion of clinicians, based on clinical signs of infection, whereas in the second period CT scans were systematically performed, regardless of clinical signs. When CT scans were obtained upon clinical suspicion of IPA, the halo sign was detected in 13% of patients, compared with 92% when CT scans were systematically performed. This resulted in a reduction in the time to diagnosis, from seven to 1.9 days, and a marked improvement in the outcome. More recently, the importance of the halo sign as an early sign of IPA was demonstrated in a study in which base-line chest CT scans of 235 patients who participated in a randomized clinical trial were reviewed. The halo sign was observed in 61% of cases, and patients with the halo sign had significantly better responses to treatment and greater survival than did patients with other images. A similar finding was also observed in a smaller number of patients. In these studies, the most reasonable explanation for the improved outcome was that the halo sign represented an earlier stage of IPA, allowing the initiation of antifungal therapy with a lower fungal burden. Although the outcome of IPA has improved, the prognosis is still poor, particularly in some groups of patients, such as allogeneic HCT recipients. Therefore, attempts to further improve the outcome are needed. In order to do this, clinicians should be able to recognize IPA before the appearance of the halo sign. A detailed description of the events that occur early in the