Insights into the Natural History and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis (INTO-HLH) Patient Registry: Study Design and Clinical Characteristics
Authors: Zoref-Lorenz Adi , Fajgenbaum David C. , Korn Shanna , Kaufmann Tayloranne , Anderson Brady , Oladapo Abiola , Saltonstall Laura , Fournier Deanna , Behrens Edward , Allen Carl E , Jordan Michael B. 
Published: December 2024

Purpose
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation and dysregulation. HLH's diverse etiologies, including genetic mutations, infections, and malignancies, lead to varied clinical presentations and outcomes. The Insights into the Natural History and Treatment Outcomes of Hemophagocytic Lymphohistiocytosis (INTO-HLH), a disease registry, aims to advance understanding and improve outcomes for HLH patients through a patient-centric approach and comprehensive data collection.
Methods
This is a retrospective/prospective registry led by the INTO-HLH Registry Team (IHRT) at Cincinnati Children's Hospital Medical Center. It employs patient self-consent through the INTO-HLH website (https://hlhregistry.org/) for the patient-powered arm and traditional patient consent for the physician-powered arm. Centralized data abstraction is used to compile detailed patient information from medical records. This registry uniquely relies on patient empowerment, with individuals agreeing to contribute extensive source data documents.
The Registry's data of interest include demographic information, clinical presentations, laboratory values, genetic testing results, treatments, and treatment outcomes. The date of initial presentation is defined as the day of the appearance of fever or neurologic symptoms that are later accompanied by one other HLH-defining laboratory abnormality. The date of HLH diagnosis is recorded from the patient's medical chart, while the IHRT diagnosis date is when the patient met the relevant HLH diagnostic criteria (HLH-2004 or disease specific) as assessed retrospectively by the IHRT. The time to each of these dates was analyzed. Data on patients in the registry with detailed abstracted data are presented.
Results
As of July 21st, 2024, the INTO-HLH Registry contains 93 enrolled patients. Among the 60 patients with detailed data abstracted, the median age was 1.45 years (IQR 0.24-12.83). The cohort comprised 57.5% males, 78.8% white, 7.6% Asian, 4.6% black, and 9% from other racial/ethnic groups. Their underlying disease triggers included familial HLH (61.7%), macrophage activation syndrome (MAS, 20%), malignancy-associated HLH (1.6%), and other types of secondary HLH (16.7%). Notably, two of the twelve MAS patients had positive HLH genetic abnormalities. Among the 37 patients with proven genetic abnormalities, the identified mutations were UNC13D in 54.1%, PRF1 in 27%, STXBP2 and XIAP in 5.41% each, and AP3B1, BIRC4, and RAB27A in 2.7% each.
Among the 11 patients with recorded infections at diagnosis, 5 (45.4%) had viral infections, and 4 (36.4%) had bacterial infections. Regarding immunizations within two months before the onset of HLH, 25 patients (42%) received immunizations, including one adult and 24 pediatric patients.
Of the clinical diagnostic features, 78.3% of the patients had fever, and only 17% had splenomegaly at the initial presentation. However, the frequency of many clinical symptoms increased from the initial presentation to the diagnosis of HLH: splenomegaly from 7% to 42%, arthralgia from 5% to 13%, vomiting from 23% to 30%, diarrhea from 17% to 27%, tachypnea from 15% to 43%, hepatomegaly from 12% to 42%, lymphadenopathy from 7% to 28%, tachycardia from 23% to 62%, hypoxemia from 13% to 25%, and neurologic symptoms from 33% to 38%. According to medical charts, the median time to HLH diagnosis from the onset of symptoms was 13 (IQR 5-24) days, while the median time to IHRT assessed HLH diagnosis was 9 (IQR 4-16.5) days.
At IHRT HLH diagnosis, median laboratory values were: neutrophils 0.7 K/mL, platelets 55 K/mL, hemoglobin 8.6 g/dL, triglycerides 355 mg/dL, fibrinogen 102 mg/dL, ferritin 2,423 ng/mL, and soluble interleukin 2 receptor (sCD25) 8,597 U/mL. Notably, 34% had respiratory failure, 31% had liver failure, and 28% had kidney failure. Of 60 patients, 13 were deceased at enrollment, and one died during follow-up. The 5-year survival probability was 76% (95% CI 62%-85%).
Conclusion
This initial report from the INTO-HLH Registry describes patient presentations and highlights gaps between physician-assessed diagnosis and expert review. It also highlights unique clinical features that evolve between presentation and diagnosis, underscoring the potential for improved diagnosis of HLH through a deeper understanding of its natural history.