DISCUSSION
In this study we analyzed the diagnostic and management patterns of children with AIFR over the past 15 years and their implications on outcomes. While still considered an extremely aggressive disease with dismal prognosis, the results of this study showed a significant increase in patients’ survival in the past decade compared to earlier years. AIFR had historically been associated with high mortality rates of 50%–90%16. Recently published data indicated better prognosis with mortality rates of 30-50% which was attributed mainly to early detection of AIFR17 and aggressive surgical management18. In the present study, the overall mortality rate was 38%, and the disease-specific mortality rate was 26%. Nonetheless, no patient has died of AIFR since 2012.
The status of the underlying disease was previously shown to be among the leading prognostic factors4,19. Hematologic malignancies, most notably ALL and AML, were reported to be the leading causes of immunosuppression3,4. The decrease in overall mortality rate in our study may reflect better control of the underlying disease, which may have contributed to the change in AIFR-specific survival. The majority of patients (68%) developed AIFR during disease remission, and as expected, had better overall survival outcomes compared to patients with non-complete remission. These data highlight the importance of better control of the immunosuppressive state to improve the prognosis of patients with AIFR.
Early diagnosis and aggressive surgical treatment of AIFR have been proven to be critical in improving patients’ outcomes20. In the present study a low threshold for diagnosis led to early investigation and surgical intervention within a median of 4 days from the onset of fever. In 71% of our patients, multiple surgical procedures were performed, and debridement was repeated until no further disease progression was observed. Moreover, along with the improvement in technology and experience, a more aggressive surgical approach was adopted in our institution in the latter years of the study including pterygopalatine fossa, infratemporal fossa and skull base debridement as needed, which may have been associated with the improved survival, observed in recent years.
Novel detection methods and newer systemic antifungal therapies may also have contributed to improved patient survival. Culture studies had long been considered the gold standard for identification of the culprit subspecies in AIFR, but their reported sensitivity was low (30-54%), and their diagnostic value was further limited by the slow growth rate of fungal pathogens, leading to delays in appropriate antifungal therapy20,21. Since PCR first came into use in our practice in 2011, it has become a leading detection method, and was used in >90% of cases. Although recognized as an augmenting tool to improve diagnosis of AIFR, PCR was not included in the revised definitions of invasive fungal disease published in 2008, because the technique had not yet been clinically validated22. More recent data, however, have shown that with the advantage of rapid detection of mixed infection in a single specimen, panfungal PCR is more sensitive and specific than cultures and direct sequencing in patients with fungal rhinosinusitis8. In our practice, we found panfungal PCR to be superior to fungal cultures in the detection of pathogens and to be associated with a change of treatment in nearly one-fifth of cases.
Historically, AmB has been considered the drug of choice for treatment of invasive fungal infections, and it remains the agent with the broadest antifungal spectrum23. However, its use has become limited due to high incidence of adverse effects and substantial risk of nephrotoxicity which led to adaptations of therapy23,24. With improved safety profile and greater efficacy, novel agents such as liposomal AmB, triazoles and echinocandins have gradually become the drugs of choice for invasive fungal infections10,22,24,25. In the current study, since 2011 AmB, which was associated with decreased survival, has been replaced as the treatment of choice by liposomal AmB, and novel triazoles and echinocandins. We believe that this may have contributed to the improved survival in recent years.
The main limitations of this study include its retrospective design and small cohort size. Nonetheless, the study’s duration period enabled us to view with perspective the trends in management and survival of children with AIFR.