. 2022 Sep;49(9):1042-1051.

doi: 10.3899/jrheum.211219. Epub 2022 Jul 15.

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

Maria L Taylor¹, Kacie J Hoyt², Joseph Han³, Leslie Benson⁴, Siobhan Case⁵, Mia T Chandler¹, Margaret H Chang⁵, Craig Platt¹, Ezra M Cohen¹, Megan Day-Lewis¹, Fatma Dedeoglu¹, Mark Gorman⁴, Jonathan S Hausmann⁶, Erin Janssen¹, Pui Y Lee¹, Jeffrey Lo¹, Gregory P Priebe⁷, Mindy S Lo¹, Esra Meidan¹, Peter A Nigrovic⁵, Jordan E Roberts¹, Mary Beth F Son¹, Robert P Sundel¹, Maria Alfieri⁸, Jenny Chan Yeun⁸, Damilola M Shobiye⁸, Barbara Degar⁹, Joyce C Chang¹, Olha Halyabar¹, Melissa M Hazen¹, Lauren A Henderson¹⁰

Affiliations

¹ M.L. Taylor, BS, M.T. Chandler, MD, C. Platt, MD, PhD, E.M. Cohen, MD, M. Day-Lewis, RN, MSN, CPNP, F. Dedeoglu, MD, E. Janssen, MD, PhD, P.Y. Lee, MD, PhD, J. Lo, MD, M.S. Lo, MD, PhD, E. Meidan, MD, J.E. Roberts, MD, M.B.F. Son, MD, R.P. Sundel, MD, J.C. Chang, MD, MSCE, O. Halyabar, MD, M.M. Hazen, MD, L.A. Henderson, MD, MMSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts.
² K.J. Hoyt, MSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, and Virginia Tech Carilion School of Medicine, Roanoke, Virginia.
³ J. Han, BS, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ L. Benson, MD, M. Gorman, MD, Division of Neurology, Boston Children's Hospital, Boston, Massachusetts.
⁵ S. Case, MD, M.H. Chang, MD, PhD, P.A. Nigrovic, MD, Division of Immunology, Boston Children's Hospital, and Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts.
⁶ J.S. Hausmann, MD, Division of Immunology, Boston Children's Hospital, and Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
⁷ G.P. Priebe, MD, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts.
⁸ M. Alfieri, MPH, J. Chan Yeun, MSPH, D.M. Shobiye, MPH, Department of Pediatric Quality Program, Boston Children's Hospital, Boston, Massachusetts.
⁹ B. Degar, MD, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁰ M.L. Taylor, BS, M.T. Chandler, MD, C. Platt, MD, PhD, E.M. Cohen, MD, M. Day-Lewis, RN, MSN, CPNP, F. Dedeoglu, MD, E. Janssen, MD, PhD, P.Y. Lee, MD, PhD, J. Lo, MD, M.S. Lo, MD, PhD, E. Meidan, MD, J.E. Roberts, MD, M.B.F. Son, MD, R.P. Sundel, MD, J.C. Chang, MD, MSCE, O. Halyabar, MD, M.M. Hazen, MD, L.A. Henderson, MD, MMSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts; Lauren.Henderson@childrens.harvard.edu.

PMID: 35840156
PMCID: PMC9588491
DOI: 10.3899/jrheum.211219

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

Maria L Taylor et al. J Rheumatol. 2022 Sep.

. 2022 Sep;49(9):1042-1051.

doi: 10.3899/jrheum.211219. Epub 2022 Jul 15.

Authors

Affiliations

¹ M.L. Taylor, BS, M.T. Chandler, MD, C. Platt, MD, PhD, E.M. Cohen, MD, M. Day-Lewis, RN, MSN, CPNP, F. Dedeoglu, MD, E. Janssen, MD, PhD, P.Y. Lee, MD, PhD, J. Lo, MD, M.S. Lo, MD, PhD, E. Meidan, MD, J.E. Roberts, MD, M.B.F. Son, MD, R.P. Sundel, MD, J.C. Chang, MD, MSCE, O. Halyabar, MD, M.M. Hazen, MD, L.A. Henderson, MD, MMSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts.
² K.J. Hoyt, MSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, and Virginia Tech Carilion School of Medicine, Roanoke, Virginia.
³ J. Han, BS, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ L. Benson, MD, M. Gorman, MD, Division of Neurology, Boston Children's Hospital, Boston, Massachusetts.
⁵ S. Case, MD, M.H. Chang, MD, PhD, P.A. Nigrovic, MD, Division of Immunology, Boston Children's Hospital, and Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts.
⁶ J.S. Hausmann, MD, Division of Immunology, Boston Children's Hospital, and Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
⁷ G.P. Priebe, MD, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts.
⁸ M. Alfieri, MPH, J. Chan Yeun, MSPH, D.M. Shobiye, MPH, Department of Pediatric Quality Program, Boston Children's Hospital, Boston, Massachusetts.
⁹ B. Degar, MD, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁰ M.L. Taylor, BS, M.T. Chandler, MD, C. Platt, MD, PhD, E.M. Cohen, MD, M. Day-Lewis, RN, MSN, CPNP, F. Dedeoglu, MD, E. Janssen, MD, PhD, P.Y. Lee, MD, PhD, J. Lo, MD, M.S. Lo, MD, PhD, E. Meidan, MD, J.E. Roberts, MD, M.B.F. Son, MD, R.P. Sundel, MD, J.C. Chang, MD, MSCE, O. Halyabar, MD, M.M. Hazen, MD, L.A. Henderson, MD, MMSc, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts; Lauren.Henderson@childrens.harvard.edu.

PMID: 35840156
PMCID: PMC9588491
DOI: 10.3899/jrheum.211219

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.

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Conflict of interest statement

COI: LAH had received salary support from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and consulting fees from Sobi, Pfizer, and Adaptive Biotechnologies. FD received consulting fees from Novartis and royalties from UpToDate. PAN has received investigator-initiated research grants from Bristol Myers Squibb (BMS), Pfizer, and Sobi; consulting fees from BMS, Exo Therapeutics, Novartis, Pfizer, and Sobi; royalties from UpToDate Inc. and the American Academy of Pediatrics; and salary support from CARRA. None of the funding sources played a role in the design, collection, analysis, or interpretation of data presented in this manuscript.

Figures

**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

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Comment in

Improving Outcomes for Patients With Hemophagocytic Lymphohistiocytosis.
Rousset M, Ray A. Rousset M, et al. J Rheumatol. 2023 Jul;50(7):967. doi: 10.3899/jrheum.221010. Epub 2022 Nov 15. J Rheumatol. 2023. PMID: 36379564 No abstract available.

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

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

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