Guideline sources The following summarized guidelines for the evaluation and management of hemophagocytic lymphohistiocytosis (HLH) are prepared by our editorial team based on guidelines from the Histiocyte Society (HS 2019). 1 1 3 4 5 5 Definition HLH is a severe hyperinflammatory syndrome caused by aberrant activation of macrophages and cytotoxic T cells. 1 Epidemiology Primary HLH is due to genetic abnormalities (including perforin and syntaxin mutations), while secondary HLH is due to underlying conditions such as infections (notably, EBV, CMV, parvovirus B19, human immunodeficiency virus, and HHV-6), autoimmune/rheumatologic disease, malignancy, or metabolic conditions. Secondary HLH caused by rheumatologic disease is often termed "macrophage activating syndrome," and has been reported in association with adult-onset Still's disease, polyarteritis nodosa, mixed connective tissue disease, pulmonary sarcoidosis, systemic sclerosis, Sj gren's syndrome, and SLE. 4 Pathophysiology The incidence of HLH is estimated at 0.1 cases per 100,000 person-years. 3 https://web.pathway.md/diseases/reclLNJCDurXzGWE8 1/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Disease course Key clinical manigestations include fever, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias. In addition, elevated liver enzymes, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen. 5 Prognosis and risk of recurrence Mortality has been reported to vary from 8-22% in rheumatologic HLH to 18-24% in EBV associated HLH. 5 Calculator Diagnostic criteria for hemopha Guidelines 1. Screening and diagnosis Indications for testing: test for HLH in critically ill patients with persistent fever, cytopenias, and organomegaly, particularly in confirmed or presumed cases of sepsis, sepsis-like syndromes, and/or evolving multiorgan failure. E Diagnostic criteria: as per HS 2019 guidelines, use the HLH-2004 diagnostic criteria in conjunction with clinical judgment and the patient's history in order to establish a diagnosis of HLH in adults. E 2. Classification and risk stratification Classification: As per HS 2019 guidelines: Recognize that primary and secondary hemophagocytic syndromes, including macrophage activating syndrome, are hyperferritinemic, hyperinflammatory syndromes with a common terminal pathway but with different pathogenetic roots. E Recognize that malignancy-associated HLH may present as one of two distinct entities: malignancy-triggered HLH, as a presenting feature of the malignancy at diagnosis or at relapse HLH during chemotherapy, in most cases induced by infections. E 3. Diagnostic investigations https://web.pathway.md/diseases/reclLNJCDurXzGWE8 2/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Evaluation for etiology: conduct a meticulous search for an underlying trigger in patients with HLH, including occult malignancies, despite ongoing HLH treatment. E Show 3 more Genetic testing: consider obtaining functional assessment of lymphocyte cytotoxicity and guided genetic testing, while not delaying the clinical decision to initiate treatmen, to detect potential genetic predisposition to HLH in patients with HLHt. E 4. Medical management General principles: As per HS 2019 guidelines: Recognize that the variable severity of HLH, including macrophage activating syndrome, demands graded intensity and length of treatment. Tailor treatment to control hyperinflammation and treat identified disease triggers. E Recognize that treatment of macrophage activating syndrome is different from that recommended for HLH, as a result of partial pathogenetic diversity. E HLH-94 regimen: recognize that HLH-94 treatment components (consisting of corticosteroids, typically dexamethasone, cyclosporine A, intrathecal therapy, and etoposide) are highly effective in treating hyperinflammation in adult patients with HLH, However, do not use a "1-size-fits-all protocol because o, the heterogeneity of adult HLH. E Management of HLH due to intracellular infections: as per HS 2019 guidelines, initiate specific antimicrobial treatment for HLH induced by intracellular infections, such as tuberculosis, leishmaniasis, or rickettsial disease. Avoid using HLH-94-like treatment. E Management of refractory/relapsing HLH: Recognize that secondary infections are a major cause of fatality and may erroneously be diagnosed as disease relapse. E Administer combined chemotherapy and consolidation with allo-SCT for salvage treatment of eligible adult patients with refractory/relapsing HLH. E Likelihood Ratios Pertinent positives The following findings increase the probability of hemophagocytic lymphohistiocytosis in adults. 1 5 Finding LR+ Value Increased serum soluble IL-2 receptor (> 10,000 u/ml) 6.0 (1.9-18.7) Decreased serum glycosylated ferritin fraction (< 25%) 3.6 (1.2-12.3) Increased serum soluble IL-2 receptor (> 2,400 u/ml) 2.7 (1.8-4.0) https://web.pathway.md/diseases/reclLNJCDurXzGWE8 3/4 6/24/23, 12:31 PM Hemophagocytic lymphohistiocytosis Pathway Increased serum ferritin (> 10,000 g/L) 2.6 (1.6-4.4) Show 1 more Pertinent negatives The following findings decrease the probability of hemophagocytic lymphohistiocytosis in adults. 1 5 Finding LR- Value serum ferritin not increased ( 500 g/L) 0.01 (0.0-0.01) serum soluble IL-2 receptor not increased ( 2,400 u/ml) 0.01 (0.0-0.01) serum glycosylated ferritin fraction not decreased ( 25%) 0.2 (0.1-0.8) serum ferritin not increased ( 10,000 g/L) 0.3 (0.2-0.6) Show 1 more References 1. La Ros e P, Horne A, Hines M et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019 Jun 6;133 23 2465 2477. Open 2. Kai Lehmberg, Kim E Nichols, Jan-Inge Henter et al. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015 Aug;100 8 997 1004. Open 3. Delaney A, Mai C, Smoots A et al. Population-Based Surveillance of Birth Defects Potentially Related to Zika Virus Infection 15 States and U.S. Territories, 2016. MMWR Morb Mortal Wkly Rep. 2018 Jan 26;67 3 91 96. Open 4. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014 Jun 12;5 69 86. Open 5. Kleynberg RL, Schiller GJ. Secondary hemophagocytic lymphohistiocytosis in adults: an update on diagnosis and therapy. Clin Adv Hematol Oncol. 2012 Nov;10 11 726 32. Open 6. Hayden A, Lin M, Park S et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv. 2017 Dec 6;1 26 2529 2534. Open https://web.pathway.md/diseases/reclLNJCDurXzGWE8 4/4