As mentioned before, HLH is diagnosed through clear clinical criteria. Despite awareness of the diagnostic criteria, HLH diagnosis can be challenging because of the variability in presentation. Symptoms, especially if infection associated, may spontaneously remit [3] . Individual diagnostic criteria can be observed at distinct points in the disease course and can also remit and recur. Moreover, many of the criteria are non-specific for HLH, making it a diagnosis of exclusion in many cases. Finally, criteria such as NK cell function and genetic testing can take weeks to be finalized. Given all these challenges, it is important to consider HLH as a diagnosis both at onset and in the early stages of the disease process. In a review of familial and acquired HLH, key laboratory findings in establishing a diagnosis were identified as negative or decreased NK function as well as elevated soluble CD25 levels in all patients [16] , suggesting these studies must be evaluated early on in the clinical course. In some centers, CD107a upregulation, a marker of NK cell degranulation is used as a surrogate for NK cell cytotoxicity [17] . However, as depressed NK cell cytotoxicity is seen in many conditions secondary to inflammation or immunosuppressive factors, other symptoms must be considered. Fever and splenomegaly occur in approximately 70% of HLH patients [16] . Fevers may be protracted, variable and may even resolve spontaneously. About 50% of patients initially present with elevated triglycerides, high ferritin, high LDH and/or a combination of anemia, neutropenia and thrombocytopenia [8, 16] . Of note, ferritin is rarely > 200 μg/L in pediatric patients with infections outside of the context of HLH [16] and levels higher than this should raise suspicion for HLH. Lastly, hemophagocytosis is seen in less than 40% of patients at onset but is present in >80% of patients at time of diagnosis [16] .