Abstract
The difficulties and challenges of applying the HLH-2004 diagnostic criteria to early identification and diagnosis of haemophagocytic lymphohistiocytosis have been fully addressed in previous studies. However, the distribution of the diagnostic time lag of haemophagocytic lymphohistiocytosis and related patient characteristics remain unclear. This study investigated the time lags between symptom onset and diagnosis and between hospital admission and diagnosis among pediatric patients with haemophagocytic lymphohistiocytosis, and identified factors that associated with a shorter or longer diagnostic time lag. The cohort of patients with haemophagocytic lymphohistiocytosis was drawn from a tertiary children's hospital and consisted of 122 pediatric patients. The distributions of symptom-to-diagnosis and admission-to-diagnosis time lags were assessed. Clinical characteristics within 48 h of admission and the fulfillment of HLH-2004 diagnostic criteria were compared among admission-to-diagnosis time lag categories. Logistic regression analyses were conducted to identify factors associated with an admission-to-diagnosis time lag >3 days. The median interval from first symptom onset to HLH diagnosis was 12 days (range 4–71 days) and the median interval from hospital admission to HLH diagnosis was 2 days (range 0–23 days). The following factors were negatively associated with admission-to-diagnosis > 3 days: Epstein–Barr virus infection; admission through pediatric intensive care unit; diagnosis established without NK-cell activity and soluble CD25 tests; the performance of all readily available diagnostic tests for HLH (within 48 and 72 h); concurrent fever, splenomegaly, and cytopenias within 48 h; hemophagocytosis, hypertriglyceridemia and/or hypofibrinogenemia within 48 h; and elevated ferritin, total bilirubin, alanine aminotransferase, and prothrombin time within 48 h. Our findings suggest that performance of adequate diagnostic tests for HLH is essential for early diagnosis of HLH. Once suspected, immediate and adequate diagnostic tests for HLH should be arranged for PICU patients. Improvements in diagnostic procedures and monitoring plans are needed to promote early diagnosis of HLH.
Highlights
Haemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by extreme immune activation, which results in hypercytokinaemia and immune-mediated injuries to multiple organ systems [1,2,3]
23 patients were excluded from this study, either because they had been diagnosed with HLH prior to the indicated hospital admission date or because essential information was missing, leaving 122 patients for the analysis (Figure 1)
More patients in the ≤3 days admission-to-diagnosis time group could have an HLH diagnosis established without natural killer cell (NK-cell) activity and soluble CD25 (sCD25) tests, compared with the corresponding number of patients in the >3 days group (91.5% and 77.5%, p = 0.0320)
Summary
Haemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by extreme immune activation, which results in hypercytokinaemia and immune-mediated injuries to multiple organ systems [1,2,3]. Secondary HLH occurs in patients without a family history or a genetic cause, and these patients typically have an underlying disease that triggers the HLH, such as infection, malignancy, and/or an autoimmune disorder. Patients with HLH who have a genetic cause but lack adequate genetic tests might be clinically classified as a secondary HLH. Both primary and secondary types of HLH are life-threatening [1]. For pediatric patients with either primary or secondary HLH, delayed initiation of HLH treatment is a risk factor for early death, timely diagnosis and treatment are essential for survival [3, 12, 13]
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