Hemophagocytic Lymphohistiocytosis and Other Cytokine Storm Syndromes in Adults
Bibliographic record
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and highly fatal syndrome of pathological immune activation leading to excessive inflammation, hypercytokinemia, and multi-organ failure. HLH is broadly divided into primary HLH, driven mainly by genetic defects in cytotoxicity and secondary HLH, a heterogeneous group of disorders with similar clinical and laboratory features to primary HLH, but characterized by hyperinflammation rather than defective cytotoxicity. Primary HLH occurs nearly exclusively in children. Most adult HLH is secondary, often in the context of immunomodulatory therapy, infection, malignancy, autoimmune/autoinflammatory diseases, or immunodeficiency. HLH falls under the umbrella concept of cytokine storm syndrome (CSS). In 2020, the coronavirus disease 2019 (COVID-19) pandemic greatly amplified clinical interest and research in CSS, and specifically the concept of a maladaptive immune response to infection. Early on, COVID-19-CSS was compared to HLH. However, HLH is mainly driven by the interferon-γ (IFN-γ)-chemokine ligand 9 (CXCL-9) axis, resulting in profound T cell and macrophage activation, and is characterized by very high ferritin and soluble CD25 (sCD25, synonymous with the alpha chain of the soluble interleukin (IL)-2 receptor), often with only modestly elevated C-reactive protein (CRP). In contrast, COVID-19-CSS is characterized by defective type I/type III interferon responses leading to excessive IL-6 signaling and very high CRP, which can be ameliorated by IL-6 inhibition. The increased interest in CSS spurred by COVID-19 has coincided with significant recent advances in our understanding of other CSS, such as thrombocytopenia, anasarca, fever/(reticulin) fibrosis, organomegaly, renal dysfunction (TAFRO) syndrome (typically associated with idiopathic multicentric Castleman disease, iMCD-TAFRO) and severe or catastrophic Still’s disease. This review will provide practical guidance for clinicians in diagnosing adult HLH, differentiating it from TAFRO syndrome and Still’s disease. Specifically, in section 3 and Table 2, we propose a heuristic (problem-solving strategy or shortcut) to decrease cognitive load when faced with an acutely ill patient with evolving CSS, with a focus on simple and readily available inflammatory markers (CRP, ferritin, sCD25). This heuristic can help clinicians make diagnostic and therapeutic decisions in real time.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".