An Evidence-Based Guideline Improves Outcomes for Patients With Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome

Abstract

Objective: To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG).

Methods: A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts.

Results: After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH-related biomarkers in the patients post-EBG.

Conclusion: While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.

Keywords: hemophagocytic lymphohistiocytosis; macrophage activation syndrome.

Figure 1.. Inclusion & Exclusion of Patients Identified in the EMR Search Algorithm

EMR, electronic medical record; EBG, evidence-based guideline; rheum, rheumatology; once, oncology; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome

Figure 2.. First-line Immunomodulatory Treatment for HLH and MAS

The bar graph depicts the proportion of patients in the pre- and post-EBG cohorts treated with the given medications. EBG, evidence-based guideline; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; IVIG, intravenous immunoglobulin

Figure 3.. Clinical Outcomes in the Pre- and Post-EBG Cohorts.

Kaplan-Meier estimates of the cumulative probability of A) remaining without a diagnosis of HLH/MAS over days since hospital admission stratified by pre- (n=8) and post-EBG (n=17) cohorts, or B) remaining without HLH/MAS directed immunomodulatory therapy over days since hospital admission, stratified by pre- (n=7) and post-EBG (n=15) cohorts. C) Median number of febrile days with interquartile range (IQR) in the pre- and post-EBG patients. D) Median length of hospital admission with IQR in the pre- and post-EBG patients. E) Cumulative probability of not yet achieving 50% reduction in ferritin over days since peak ferritin level, by pre- (n=9) and post-EBG (n=16) cohorts. F) Cumulative probability of not yet achieving 50% reduction in CRP over days since peak CRP level, by pre- (n=7) and post-EBG (n=13) cohorts. The p-values represent log-rank tests comparing survival curves. EBG, evidence-based guideline; HLH, hemophagocytic lymphohistiocytosis; MAS, macrophage activation syndrome; HR, hazard ratio; CI, confidence interval; CRP, C-reactive protein