The Probability of Invasive Fungal Infection Among Children with Persistent Febrile Neutropenia and Respiratory Viral Infection

Febrile neutropenia (FN) is a common complication among children undergoing chemotherapy for hematologic malignancies. A microbial agent is identified in 15–30% of these episodes. Recently, several studies reported a high incidence (25% -60%) of respiratory viral infections (RVI) in children with FN, using RT- PCR analysis. Implementation of routine RVI workup in children with FN was suggested, in order to minimize the overuse of antibiotics.

However, data on the incidence of RVI in children with persistent FN (PFN) is meager. In the setting of PFN, invasive fungal infection (IFI) is a major concern.

The incidence of IFI among children with hematologic malignancies varies with clinical settings, although most children who present with PFN do not have IFI eventually. Yet, most international guidelines indicate empiric initiation of antifungal therapy after 4-7 days of FN. Alternatively, a “preemptive” approach using currently available diagnostic modalities (CT and serum specific biomarkers) was suggested in adult patients.

In children with PFN, however, this workup resulted only in a modest decline in the antifungal treatment rate.

Therefore, there is a growing need to enhance diagnostic resolution, in order to stratify pediatric patients according to their risk for IFI, and minimize the overuse of antifungal drugs, imaging, and invasive procedures.

To the best of our knowledge, there are no studies comparing the incidence of RVI to that of IFI in the setting of PFN.

Based on previous published data, we hypothesized that RV infection is a significant cause of PFN in children with hematologic malignancies, and that IFI is the cause in a minority of cases.

We further aimed to investigate whether detection of RVI, as the cause of PFN in these children, would affect their risk of IFI.

For that purpose, we analyzed the clinical charts of children (<21 years) with hematologic malignancies who presented to our department during 2007-2013 with PFN (>38^oc, for >96 hours and ≤500ANC/µl) and documented PCR results of RV.

Patients were considered positive for IFI if they had ‘possible’, ‘probable’ or ‘proven’ infection according to the revised EORTC definition (2008).

RVI were detected in nasopharyngeal aspirates using RT-PCR and included: RSV, Influenza A/B, H1N1, Parainfluenza 1/2/3, HMPV, Adenovirus and HHV-6.

Additional data included age and gender, specific hematologic malignancy, total number of neutropenia (<500 ANC/µl) days per episode, total number of antibiotic therapy days per episode, bacterial co-infection, anti-fungal prophylaxis, imaging results, BAL/biopsy results and serum biomarkers.

A total number of 75 PFN episodes were evaluable, representing 54 patients with ALL (HR n=18; SR n=23), AML (n=6), NHL (n=5) or Hodgkin’s (n=2). Of these, there were 31 episodes with RV-positive infections (41.3%). The most prevalent virus was RSV (29%), followed by Parainfluenza (26%) and Adenovirus (19%).There were 16 possible (21%), 2 probable (2.6%), and 2 proven (2.6%) episodes of IFI. Only in 3 episodes we detected co-infection of IFI (2 possible and 1 probable) and RVI.

Multivariate analysis revealed that the total days of neutropenia and antibiotic therapy were independent risk-factors for IFI (p<0.0109; P< 0.0034 respectively). RVI was independently associated with a significant reduced risk for IFI, with an odds ratio of 7.47 (p<0.0082, 95% CI -1.6-50.4). Age, specific hematologic malignancy, bacterial co-infection, and antifungal prophylaxis did not reach significance.

Children with PFN and RVI have a significantly lower risk for IFI. This observation may reduce unnecessary imaging and invasive procedures, antifungal treatment, and hospital expanses. Further studies are needed in order to establish whether RV-status can be implemented in the routine workup algorithm of PFN in children with hematologic malignancies.