Discussion
In this work, we showed that host factors, particularly neutropenia and
hematologic malignancies, are determinant in the survival times of
children affected with IFD. The accelerated failure time models estimate
the effects of the variables on acceleration or deceleration on the
survival times: so, we demonstrated that the children with leukemia,
besides having multiplied the hazard for death due to IFD by 2.5, also
could have their survival time shortened by a factor of 0.006. Among the
several reasons why patients with leukemia are at risk of dying from
IFD, one of the most important is neutropenia, which was prolonged in
this cohort, and was a determinant factor for shortening survival in our
analysis. Many patients with leukemia have severe, prolonged neutropenia
caused by the disease itself or chemotherapy, and mucosal lesions that
can predispose to infection.6 We analyzed few cases of
lymphoma, but this diagnosis was also a factor to shorten survival in
patients with IFD.
The overall mortality reported here, around 28%, is identical to that
reported by Castagnola et al, in 2006.7 After 14
years, we are using the same therapeutic options, and little progress
has been made in the development of new antifungal
agents.8 Another point of similarity with the study of
Castagnola et al. was the lower mortality in patients with fungemia,
compared to other IFD.7 The high mortality observed in
pulmonary infections can be explained by several factors: as noted,
pulmonary involvement was correlated with the conditions that most
favored mortality from IFD, such as the diagnosis of leukemia, cancer
recurrences and neutropenia. The most life-threatening form of
aspergillus infection, pulmonary angioinvasive aspergillosis, occurs in
immunosuppressed or neutropenic patients: the lung shows a necrotizing
pneumonia with areas of hemorrhage and acute and granulomatous
inflammation.9 Over the last years, there has been a
reduction of mortality due to invasive aspergillosis in those patients
with myeloid leukemia, in whom remission of malignancy and effective
antifungal treatments can be attained, but mortality can grew up to 54%
in relapsed/refractory disease, reflecting the compromised immune status
of these patients.10 Pulmonary zygomycoses andFusarium spp. pneumonia also have high fatality
rates.11,12
The use of empirical antifungal drugs at the time of diagnosis of IFD
affected the survival negatively, but the prophylaxis with fluconazole
did not. This finding probably means that the children who received
empirical treatment were at higher risk of severe infections, or
presented a clinical deterioration, requiring the coverage with
antifungals. The risk of death was also 3.8-fold higher in patients
already receiving antifungals at the time of diagnosis of IFD in the
study of Castagnola et al., but these authors analyzed prophylaxis and
empiric use as a single variable.7
Candidemia is now a frequent cause of bloodstream infection, due to the
widespread use of central venous catheters, parenteral nutrition,
broad-spectrum antibiotics, and immunosuppressive therapy. Rare
opportunistic yeasts are emerging as cause of IFD.13We observed 16 episodes of fungemia caused by these rare yeasts, but
mortality was similar to observed in candidemia.
Allogeneic unrelated HSCT or mismatched donor HSCT put the patient in
the highest risk group for IFD.14 Compared with
allogeneic HSCT, autologous HSCT is associated with a lower risk of
invasive aspergillosis because the period of pre-engraftment neutropenia
is shorter and the possibility of graft-versus-host disease is
absent.15 Although the mortality of our HSCT patients
with IFD was still high (25.8%), and the fact that most were
allogeneic, the transplantation was not a factor for shortening
survival. One explanation is that HSCT is the best chance of cure for
diseases like myeloid leukemia,16 and most of the
patients will recover from neutropenia.
The most obvious weakness of this study, common to several others of its
kind, is the absence of sensitivity tests to antifungals, not routinely
performed in our institution. The results are also limited to patients
treated in a single center, and may not reflect practices from other
parts of our country or the world.