January 2026 Research Update

Across these reports (each describing one patient), secondary hemophagocytic lymphohistiocytosis (HLH) was most often described after an infection, but it was also reported with an inflammatory bowel disease flare and after a targeted cancer medicine. Several reports highlighted how secondary HLH can look like severe infection (including septic shock), and how identifying the underlying trigger can be difficult. Outcomes varied widely, from full recovery to death, and some patients had complications involving the brain, eyes, liver, or blood clotting. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Multiple viral triggers were described, including Epstein-Barr virus, influenza B, West Nile virus, varicella-zoster virus (chickenpox virus), and congenital cytomegalovirus. In these cases, HLH sometimes overlapped with shock, brain inflammation (meningoencephalitis), or eye inflammation, and not every patient had hemophagocytosis seen on bone marrow testing. [1] [2] [5] [7] [11]

Less common infectious triggers in this set included murine typhus (Rickettsia typhi), leptospirosis, and a rare organism (Spiroplasma ixodetis) detected after death in a kidney transplant recipient with fulminant hepatitis and macrophage activation syndrome (a closely related hyperinflammatory condition). Two reports emphasized advanced sequencing tests (metagenomic next-generation sequencing or shotgun metagenomics) as a way to uncover an unexpected germ when routine tests are unrevealing. [3] [4] [8]

Non-infectious situations were also described: one child was ultimately diagnosed with Crohn disease after presenting with HLH-like inflammation, and one adult with chronic lymphocytic leukemia developed HLH after starting ibrutinib, with the authors raising immune disruption as a possible explanation. These examples underline that secondary HLH can be reported in the setting of immune disease or immune-altering medicines, not only classic infections. [9] [10]

For patients and caregivers, this group of papers mainly adds background about the wide range of situations that have been reported around secondary HLH, especially infections, but also immune disease and certain immune-targeting drugs. Because all papers are single-patient case reports, they can suggest possibilities but cannot show how often a trigger occurs or what will happen for another person. What remains uncertain is which triggers are most common in the broader HLH community and how much outcomes depend on the trigger versus a persons overall health (for example, transplant status) or complications such as liver failure, clotting problems, or brain involvement. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Across this group of studies, hemophagocytic lymphohistiocytosis (HLH) was described as a severe inflammatory reaction that can occur alongside blood cancers, sometimes revealing the cancer for the first time. In a larger adult study, early survival differed depending on which treatment was used first, while pediatric data suggested worse survival when HLH occurred together with a blood cancer. Several single-patient reports highlighted that HLH linked to cancer can come with unexpected organ problems, including nerve system and eye complications. [12] [13] [14] [15]

In a multicenter retrospective study of 136 adults with HLH tied to natural killer (NK) cell cancers (extranodal NK/T-cell lymphoma or aggressive NK-cell leukemia), starting with an etoposide-containing HLH regimen improved survival at 60 days but did not improve overall survival. In treatment-naive patients, asparaginase-containing cancer regimens improved both 60-day survival and overall survival, and higher Epstein-Barr virus (EBV) blood levels plus lower albumin and platelets were linked to worse short-term outcomes. [12]

In a single-center cohort of 67 children with HLH, those who also had an underlying blood cancer had lower 1- and 2-year overall survival than children with HLH but no blood cancer, even though baseline blood counts were not meaningfully different between groups. This supports the idea that the underlying cancer can strongly shape outlook in HLH, at least in this pediatric cohort. [13]

Case reports showed how HLH can appear with unusual complications and may require care across multiple specialties, but these individual stories may not apply to most patients. One 74-year-old man developed HLH along with lactic acidosis, low blood sugar, and Guillain-Barre syndrome, and later testing found diffuse large B-cell lymphoma in the bone marrow; after steroids and lymphoma chemotherapy, he had a good clinical and scan response. [14]

Another case described HLH occurring with two coexisting blood cancers (multiple myeloma and B-cell lymphoma), where the patient did not improve with steroids, anakinra, or initial cancer chemotherapy but improved rapidly after tocilizumab, then continued cancer treatment. A separate case in a 26-year-old man with NK/T-cell lymphoma-associated HLH described a spontaneous corneal perforation that was repaired surgically, with vision improving over 3 months. [16] [15]

One report of a 31-year-old man with histiocytic sarcoma and HLH described remission after chemotherapy followed by a matched unrelated donor stem cell transplant, with long-term remission reported beyond 5 years and full functional recovery. The same report also noted that a later suspected relapse turned out to be a benign lesion, illustrating how follow-up testing can sometimes clarify unclear findings after intensive treatment. [17]

For patients and caregivers, these studies reinforce that when HLH is triggered by a cancer, the course can depend heavily on the specific cancer type and which treatments are used, with some research focusing on very early survival (first 2 months). The stronger evidence here comes from the adult multicenter study and the pediatric cohort, while the case reports mainly add background about possible, uncommon complications (such as nerve problems or eye injury) and how complex diagnosis can be when HLH is the first sign of an underlying cancer. Many uncertainties remain because several papers describe only one patient, and even the larger studies were not randomized and reflect real-world differences in care across centers. [12] [13] [14] [15] [17] [16]

Across these papers, the main pattern is that inherited (genetic) forms of hemophagocytic lymphohistiocytosis (HLH) can start very early in life and can be hard to recognize quickly because symptoms may resemble severe infection. The reports also show that genetic testing can confirm the exact cause, but access and turnaround time can be major barriers in real-world settings. [18] [19] [20]

In two brothers with neonatal HLH, genetic testing identified a biallelic (two-copy) STEAP3 variant, broadening what has been reported for STEAP3-related disease to include low blood counts and HLH in the newborn period. The authors described a combined clinical and molecular workup to help consider this diagnosis when a newborn has HLH without a clear explanation. [18]

A separate report described one full-term newborn girl with fulminant neonatal-onset familial HLH type 2 caused by biallelic PRF1 variants that were only identified after death using whole-exome sequencing. The baby had a sepsis-like course with negative infection testing, and the authors highlighted that the very short clinical window made rapid genetic testing difficult to complete in time. [19]

In a resource-limited setting, one 1-year-old boy was diagnosed clinically with Griscelli syndrome type 2 (a genetic condition linked to HLH risk) because genetic testing was not available. Hair shaft microscopy and typical clinical features supported the diagnosis, and over 2 months the child had partial improvement and more stable blood counts with supportive care, while transplant planning could not move forward due to resource constraints. [20]

For families, these reports mainly add background on why genetic confirmation matters in HLH: different gene causes can lead to similar early symptoms, including illness that resembles severe infection, and some cases progress too quickly for standard testing timelines. They also show that when genetic testing is not available, clinicians may rely on clinical patterns and specialized non-genetic tests (such as hair microscopy) to narrow the likely diagnosis, but certainty and long-term planning can remain limited. [18] [19] [20]

This study focused on a faster way to support diagnosis of XIAP deficiency (an inherited immune disorder that can be linked with HLH) using a functional blood test rather than DNA sequencing alone. Overall, the test showed a clear difference between XIAP-deficient patients and healthy controls, and it also appeared useful for tracking recovery of immune function after hematopoietic cell transplantation (HCT) in a small number of patients. [21]

Using a flow cytometry assay that measures how much CD62L decreases on immune cells after muramyl dipeptide stimulation, XIAP-deficient patients had very low inhibition levels compared with healthy controls (around 6% vs about 85%). With a 35% cutoff, the authors reported 100% sensitivity and 100% specificity in their cohort, while noting the need for larger validation. [21]

The authors also reported that, in monitored patients after HCT, the functional readout improved in line with donor chimerism (the proportion of donor blood cells), suggesting the assay may help follow immune pathway recovery after transplant. Results also correlated with another functional readout (MDP-flow tumor necrosis factor-alpha), supporting that the test reflects XIAP pathway activity. [21]

For patients and caregivers, this research is most relevant as a diagnostic and monitoring tool: it describes a practical lab test that may help confirm XIAP deficiency and help follow immune function after transplant, at least in the study setting. Important uncertainties include the small number of XIAP-deficient patients studied, the need for multicenter confirmation, and real-world issues like sample handling and situations where normal CD62L changes may make the test harder to interpret. [21]

Across these studies, researchers looked for blood-based ways to support or speed up diagnosis when hemophagocytic lymphohistiocytosis (HLH) is suspected. The overall direction was that immune cell activation patterns and common lab results can help distinguish HLH from look-alike conditions, but accuracy varied and most approaches were tested in single-center, retrospective or exploratory datasets. [22] [23] [24] [25]

One pediatric study tested a flow cytometry marker of T-cell activation (HLA-DR on CD8+ T cells) as a practical substitute for a less available activation blood test. Using a specific threshold, it showed mid-range sensitivity and specificity for identifying children who met multiple standard HLH features, and it correctly flagged most (but not all) primary HLH cases, meaning some children with primary HLH could still be missed by this marker alone. [22]

In children hospitalized with Epstein-Barr virus (EBV) infection, a separate study built a prediction model using four routine measurements (hemoglobin, ferritin, fibrinogen, and CD3+CD4+ T cells) to distinguish EBV-related HLH from uncomplicated infectious mononucleosis. The model performed extremely well inside the same center that created it, but the authors noted limitations around generalizing it to other settings without stronger external validation. [23]

Another childhood HLH study reported that about one in five patients had unusual (aberrant) T-cell patterns on immune testing at diagnosis, and these patterns were more common in EBV-associated HLH and linked with higher interferon-gamma levels. However, these immune patterns did not clearly predict early treatment response or longer-term outcomes in this cohort, so their main value may be in understanding or characterizing disease rather than forecasting what happens next. [24]

A small transcriptome study compared blood immune cells from people with HLH versus healthy controls and identified five iron-metabolism related genes with potential diagnostic value, with expression trends confirmed in a very small follow-up group. Because this was exploratory and involved small numbers, it suggests possible future blood markers but does not yet show they work reliably in day-to-day clinical diagnosis. [25]

For patients and caregivers, these papers mainly describe research on test development rather than changes to current care. Some tests use technology already common in many hospitals (routine blood tests and immune-cell testing by flow cytometry), which could make them practical if they are confirmed in larger, multi-center studies; for now, their accuracy and how well they transfer between hospitals remains uncertain. The gene-expression markers are earlier-stage work that may help explain biology and guide future diagnostic tests, but they are not yet established tools for routine diagnosis.

Across these retrospective hospital-based studies, higher risk in hemophagocytic lymphohistiocytosis (HLH) was consistently tied to two patterns: signs of severe inflammation with organ stress, and abnormal blood clotting that could progress to disseminated intravascular coagulation (DIC). Several groups built prediction tools using routine blood tests (and a few immune markers) to estimate short-term outcomes, but these tools still need confirmation in other settings. [26] [27] [28] [29] [30]

In 209 children with secondary HLH, DIC and central nervous system (CNS) involvement were each independent predictors of death, and infection-related HLH had more severe clotting abnormalities than autoimmune-related HLH. Tracking clotting tests over time suggested prothrombin time, fibrinogen, and D-dimer changed in ways that separated DIC from non-DIC and reflected recovery trends. [26]

A separate pediatric study built a three-factor model to predict DIC using C-reactive protein (CRP), prothrombin time, and interferon-gamma, with strong performance in an external validation group. This points to the idea that a small set of blood tests may help flag which children are more likely to develop DIC during HLH. [27]

In 64 children with HLH, those who died within two months had multiple abnormal routine lab results, and low albumin was the strongest single predictor of early death in their analyses. Younger age (under two years) and involvement of multiple organs also tracked with higher death risk in this study. [28]

In 117 people with Epstein-Barr virus (EBV)-associated HLH, a 0 to 5 point score using urea, direct bilirubin, high-sensitivity cardiac troponin I, ferritin, and prothrombin time separated groups with very different 28-day outcomes. The included tests reflect kidney stress, liver stress, heart injury marker levels, inflammation, and clotting function, suggesting that short-term risk may be better estimated when several organ-related markers are considered together. [29]

In 130 adults with secondary HLH, CNS involvement independently predicted higher death risk, and it was linked to signs of strong inflammation in spinal fluid and frequent brain scan abnormalities. This work adds to pediatric data suggesting that brain involvement is an important risk signal across ages, although the study was from a single center and the CNS group was relatively small. [30]

For patients and caregivers, this set of studies reinforces that clinicians often rely on patterns in standard hospital blood tests to estimate how severe HLH is and how closely complications like DIC or brain involvement may need to be watched. Some papers proposed simple scoring tools (including one specific to EBV-HLH and one focused on predicting DIC in children), but these are not yet universal standards and may not work the same way in every hospital or patient group. The main uncertainties are how well these models perform outside the original study centers, and whether using them changes outcomes compared with usual care.

The papers this month described several approaches used or tested when hemophagocytic lymphohistiocytosis (HLH) occurs together with severe infection, pregnancy, or multi-organ failure: standard immune-suppressing chemotherapy and steroids, blood-filtering devices aimed at lowering inflammatory proteins, and a lab-based drug strategy that blocks inflammatory cell death. Overall, the human evidence was limited to one small pregnancy cohort, one small pediatric case series, and two single-patient reports, so it is not yet clear which patients are most likely to benefit or what the risks are in different situations. [31] [32] [33] [34] [35]

In a laboratory and mouse study, disulfiram reduced an inflammatory form of immune cell death (called PANoptosis) by limiting injury to mitochondria (the cell's energy centers) and blocking key steps needed for this cell-death process. In a mouse HLH model triggered by immune stimulation, disulfiram increased survival and reduced inflammation and damage in the liver, kidney, and lung, but this was not a human study and dosing and effects in people are unknown. [35]

Two reports looked at blood purification methods used during severe, ICU-level illness, aiming to remove inflammatory proteins (including cytokines). One single-patient report described a woman with HIV and disseminated tuberculosis who developed severe secondary HLH with shock; after hemoadsorption was added to continuous kidney support, her blood pressure support and breathing support were able to be reduced, alongside a rapid drop in an inflammatory blood marker (IL-6). [33]

In a five-patient pediatric case series of dengue shock syndrome with infection-associated hemophagocytic syndrome and multiple organ dysfunction, early hemoperfusion using a hemoadsorption cartridge was given along with other treatments (such as intravenous immune globulin, steroids, plasma exchange, and organ support). The authors reported decreases in ferritin and IL-6 and improvements in organ dysfunction and shock-support scores, and they did not observe procedure-related adverse events, but the study could not separate the cartridge effect from the other treatments. [32]

In a small retrospective cohort of nine pregnant patients with HLH, high-dose steroids were commonly used, and responses were mixed, with some complete responses and many deaths during follow-up. The report also described varied pregnancy outcomes (including terminations and fetal losses), highlighting how HLH in pregnancy can be life-threatening and management decisions can be complex. [31]

A separate single-patient report highlighted the difficulty of treating adult secondary HLH even when standard HLH-directed chemotherapy and steroids lead to initial improvement. The patient improved on etoposide plus dexamethasone, later relapsed with sepsis and serious complications (including infections and kidney injury), had to stop etoposide because of toxicity, and had little benefit from a later trial of anakinra before transitioning to comfort care. [34]

For patients and caregivers, these studies mainly add context about how HLH care may look in very high-risk situations (ICU shock, severe infections like tuberculosis or dengue, and pregnancy), where teams may combine HLH-directed medicines with intensive supportive care and sometimes blood-filtering technologies. The device-based reports and case series suggest inflammatory blood markers can drop alongside clinical stabilization in some individuals, but the evidence is too limited to know how often this helps, which patients it helps most, or how it compares with other supportive measures. The disulfiram work is background research that may help explain future drug directions, but it does not show that disulfiram is effective or safe for HLH in people. [33] [32] [35]

Across two case reports, patients had symptoms and lab results that raised the question of hemophagocytic lymphohistiocytosis (HLH), but their final explanations were autoimmune conditions. The overall message is that fever, swollen lymph nodes, very high inflammation markers, and sometimes low blood counts can occur in more than one illness, and the most accurate diagnosis may only become clear after targeted immune testing and biopsy results. [36] [37]

In one report, a 24-year-old woman had adult-onset Still's disease that also had lymph node inflammation described as Kikuchi-Fujimoto disease-like lymphadenitis, which can resemble severe inflammatory syndromes. Her ferritin level was very high at 6500 microg/L, but an H-score calculation was very low (5), supporting Still's disease rather than HLH or macrophage activation syndrome, and her fever improved within 48 hours after high-dose steroids. [36]

In another report, a Hispanic woman in her 50s had fever, pancytopenia (low blood counts), and widespread enlarged lymph nodes, initially raising concern for HLH in the setting of Epstein-Barr virus (EBV) infection. Although her HLH score was high (203), later testing supported systemic lupus erythematosus (SLE) with lupus nephritis, including positive anti-dsDNA antibodies and low complement (C3/C4), with the kidney diagnosis confirmed by biopsy; she improved after high-dose steroids and continued on lupus-directed medicines. [37]

For patients and caregivers, these reports are mainly background information showing why HLH can be hard to separate from other inflammatory illnesses early on, especially autoimmune diseases and viral infections that can cause overlapping symptoms and lab changes. Because each paper describes one person, it is not possible to know how often these patterns occur or which tests will be most helpful in every situation. The key uncertainty is that similar early signs can still lead to different final diagnoses, sometimes only after additional blood tests and tissue biopsies are completed. [36] [37]