Discussion:
These cases highlight the intricacies of the management of m-HLH in pediatric patients with the spectrum of disease severity and complex diagnostic evaluations one must consider at presentation. Careful consideration must be taken with suspicion of HLH to carry out a thorough workup that will prevent delays in diagnosis for possible underlying malignancy.
The treatment of m-HLH is a delicate balance due to the myriad toxicities that arise from HLH and malignancy protocols. Although they are the backbone of HLH treatment, dexamethasone and etoposide may be inappropriate for some of the most unstable patients. This also highlights the importance of recognizing a lack of response to standard treatment to explore the use of investigational therapeutics for refractory cases in a timely manner. There is much to explore and learn from the use of novel therapeutics as with our patients who received emapalumab for their refractory HLH. Although they both demonstrated response to the addition of emapalumab, one of our patients may have succumbed to fulminant candidiasis as result of emapalumab. We theorize that as emapalumab blocks IFNγ, subsequently blocking neutrophil activation and IL-6 modulation, it led to our patient being more susceptible to systemic candidiasis, resulting in fungal emboli that led to her intraparenchymal hemorrhage. [8]
Due to the toxicity of treatment options required for concurrent processes of malignancy, infection, and HLH, novel therapeutics such as emapalumab and ruxolitinib are required and should be evaluated in larger studies. Considerations for the diagnostic approach of m-HLH should account for significant correlations like those seen in lymphoma-associated HLH and the sIL-2 to ferritin ratio. [9] Furthermore, guidelines for the management of pediatric m-HLH are required with inclusion of adjustments to standard therapy based on toxicity, inciting factors, concurrent infections, and the incorporation of novel therapeutics to lead to improved outcomes.
Conflict of interest statement:We have no conflicts of interests to disclose.