Diagnosing Hemophagocytic Lymphohistiocytosis with Machine Learning: A Proof of Concept.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome characterized by uncontrolled activation of immune cells and mediators. Two diagnostic tools are widely used in clinical practice: the HLH-2004 criteria and the Hscore. Despite their good diagnostic performance, these scores were constructed after a selection of variables based on expert consensus. We propose here a machine learning approach to build a classification model for HLH in a cohort of patients selected by glycosylated ferritin dosage in our tertiary center in Lyon, France. On a dataset of 207 adult patients with 26 variables, our model showed good overall diagnostic performances with a sensitivity of 71.4% and high specificity, and positive and negative predictive values which were 100%, 100%, and 96.9%, respectively. Although generalization is difficult on a selected population, this is the first study to date to provide a machine-learning model for HLH detection. Further studies will be required to improve the machine learning model performances with a large number of HLH cases and with appropriate controls.

Evaluation of Glycosylated Ferritin in Adult-Onset Still's Disease and Differential Diagnoses.

Glycosylated ferritin (GF) has been reported as a good diagnostic biomarker for adult-onset Still's disease (AOSD), but only a few studies have validated its performance. We performed a retrospective study of all adult patients with at least one GF measurement over a 2-year period in one hospital laboratory. The diagnosis of AOSD was based on the expert opinion of the treating physician and validated by two independent investigators. Patients' characteristics, disease activity, and outcome were recorded and compared. Twenty-eight AOSD and 203 controls were identified. Compared to controls, the mean GF was significantly lower (22.3% vs. 39.3, p < 0.001) in AOSD patients. GF had a high diagnostic accuracy for AOSD, independent of disease activity or total serum ferritin (AUC: 0.674 to 0.915). The GF optimal cut-off value for AOSD diagnosis was 16%, yielding a specificity of 89% and a sensitivity of 63%. We propose a modified diagnostic score for AOSD, based on Fautrel's criteria but with a GF threshold of 16% that provides greater specificity and increases the positive predictive value by nearly 5 points. GF is useful for ruling out differential diagnoses and as an appropriate classification criterion for use in AOSD clinical trials.

Extreme Hyperferritinemia: Causes and Prognosis.

The significance of extreme hyperferritinemia and its association with certain diagnoses and prognoses are not well characterized. We performed a retrospective analysis of adult patients with at least one total serum ferritin (TSF) measurement ≥ 5000 µg/L over 2 years, in three university hospitals. Conditions associated with hyperferritinemia were collected, and patients were classified into 10 etiological groups. Intensive care unit (ICU) transfer and mortality rates were recorded. A total of 495 patients were identified, of which 56% had a TSF level between 5000 and 10,000 µg/L. There were multiple underlying causes in 81% of the patients. The most common causes were infections (38%), hemophagocytic lymphohistiocytosis (HLH, 18%), and acute hepatitis (14%). For TSF levels > 10,000 µg/L, there were no solid cancer or hematological malignancy without another cause of hyperferritinemia. Isolated iron-overload syndromes never exceeded TSF levels > 15,000 µg/L. Extreme hyperferritinemia (TSF levels > 25,000 µg/L) was associated with only four causes: HLH, infections, acute hepatitis and cytokine release syndromes. A total of 32% of patients were transferred to an ICU, and 28% died. Both ICU transfer rate and mortality were statistically associated with ferritin levels. An optimized threshold of 13,405 µg/L was the best predictor for the diagnosis of HLH, with a sensitivity of 76.4% and a specificity of 79.3%. Hyperferritinemia reflects a variety of conditions, but only four causes are associated with extreme hyperferritinemia, in which HLH and acute hepatitis are the most common. Extreme hyperferritinemia has a poor prognosis with increased mortality.

Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with Bilateral Adrenal Hemorrhage in Two Caucasian Patients.

BACKGROUND Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome is a variant of idiopathic multicentric Castleman disease. Adrenal hemorrhage has rarely been reported in TAFRO syndrome, and previous cases have mainly been Asian patients. This report is of two Caucasian patients with TAFRO syndrome presenting with acute adrenal insufficiency due to bilateral adrenal hemorrhage. CASE REPORT Case 1 was a 19-year-old Caucasian man with no significant past medical history who was admitted with acute abdominal pain, vomiting, anorexia, and moderate weight loss. Case 2 was a 31-year-old Caucasian woman with no past medical history who was admitted to hospital with fever, dyspnea, thoracic and abdominal pain, polyarthralgia, and hypotension. Both patients had splenomegaly, mild lymphadenopathy, thrombocytopenia, acute kidney injury, and myelofibrosis. In both cases, lymph node biopsy histology showed mixed-type idiopathic multicentric Castleman disease. In both patients, a diagnosis of TAFRO was made, and they developed bilateral adrenal hemorrhage with adrenal insufficiency. Case 1 was treated with high-dose steroids, followed by tocilizumab infusion. Due to persistent thrombocytopenia, second-line treatment commenced with rituximab, but the patient relapsed two months later. Tocilizumab treatment was recommenced, which was followed by an immuno-allergic adverse event. He then had a good response to sirolimus. Case 2 died nine months after diagnosis due to acute respiratory distress. CONCLUSIONS Two cases of TAFRO syndrome presented with acute adrenal insufficiency due to bilateral adrenal hemorrhage. The symptoms were only partially controlled with tocilizumab, rituximab, and tacrolimus. Adrenal hemorrhage may be a specific manifestation of TAFRO syndrome.