February 2026 Research Update

Across this months papers, hemophagocytic lymphohistiocytosis (HLH) was described after several different infections, often in people with other risk factors such as immune-suppressing medicines, HIV, or an underlying immune-system gene change. These were mostly single-patient reports (and a few two-patient series), so they show what can happen but cannot tell how common any trigger is or which approach works best. A repeated pattern was very high inflammation and blood-count problems, with some patients improving once the infection was identified and treated, while others worsened to severe organ failure despite intensive care. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Several reports involved tuberculosis or related mycobacteria, and these cases showed how difficult diagnosis and management can be when HLH and widespread infection overlap. One older adult on immune-suppressing therapy had miliary tuberculosis plus an iliopsoas abscess and developed HLH, but died from multi-organ failure despite standard tuberculosis medicines and HLH-94 protocol therapy. [1]

In another tuberculosis-related case, an HIV-positive transgender woman developed HLH triggered by extrapulmonary tuberculosis; diagnosis relied on bone marrow biopsy and a positive urine test (LF-LAM), yet she still progressed to kidney injury, severe hepatitis, shock, and death despite combined tuberculosis treatment and HLH-directed immune-modulating medicines. These cases highlight that severe organ complications can occur even when treatment is started. [6]

A separate mycobacterial report described HLH linked to disseminated Bacillus Calmette-Guerin (BCG) infection after bladder-cancer therapy; the patient improved with antimycobacterial therapy plus immune-modulating treatments including intravenous immunoglobulin (IVIG), corticosteroids, and anakinra. Another case involved a bronchial infection with Mycobacterium marseillense in a teenager with a GATA2 gene variant; she improved with antimycobacterial therapy and prednisone, although some low blood counts persisted at follow-up. [5] [7]

Visceral leishmaniasis was also repeatedly linked with HLH, with diagnosis made by seeing the parasite in bone marrow in these reports. Two adults in Greece improved on liposomal amphotericin B, with one also receiving IVIG because of multi-organ dysfunction, while an 11-month-old with refractory disease improved after miltefosine was added and liposomal amphotericin B was repeated, with blood counts and ferritin returning to normal during follow-up. [3] [4]

Bacterial infections beyond mycobacteria were described as triggers, with different outcomes. A typhoid-triggered HLH case presented with black stools (melena) and low blood counts and improved after high-dose methylprednisolone alongside antibiotics and supportive care. In contrast, two adult cases of murine typhus-triggered HLH were fatal; autopsies confirmed typhus-group rickettsiae in tissues along with hemophagocytosis, even though classic severe rickettsial blood-vessel changes were not seen. [2] [10]

Epstein-Barr virus (EBV) was discussed in severe liver inflammation (hepatitis) cases and in a child with drug reaction. In a two-patient series of acute EBV hepatitis, one patient had fulminant disease and was treated for suspected EBV-related HLH (his bone marrow showed hemophagocytosis); he died, and testing after death found an underlying immune disorder (X-linked lymphoproliferative disease). A second patient, with cytopenias and an enlarged liver and spleen, did not meet HLH criteria and improved with dexamethasone, rituximab, and supportive care. Separately, a 12-year-old boy had phenytoin-related DRESS (a severe drug reaction) followed by HLH linked to EBV reactivation; he improved after dexamethasone and etoposide with normal labs at follow-up. [8] [9]

One report highlighted an invasive fungal infection as the likely trigger in the setting of a genetic immune problem. A 28-year-old HIV-negative man with a STAT1 gain-of-function mutation developed disseminated Talaromyces marneffei infection with HLH, and his HLH resolved as the fungal infection improved on liposomal amphotericin B followed by voriconazole. [11]

For patients and caregivers, these papers mainly serve as background about the wide range of infections that have been reported alongside HLH, and how outcomes can differ substantially from one person to another. They also underline that clinicians sometimes look for underlying immune vulnerabilities (such as HIV or inherited immune-system variants) when HLH occurs with unusual, severe, or hard-to-treat infections, but the reports do not prove how often this is the reason. Because nearly all evidence here comes from individual cases, it remains uncertain which infection-HLH patterns are most likely to respond to specific immune-modulating approaches versus improving primarily as the infection is controlled. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Across these papers, hemophagocytic lymphohistiocytosis (HLH) in people with cancer most often showed up in two situations: as a reaction during immune-based cancer treatment, or as a complication triggered by an underlying lymphoma (sometimes not yet diagnosed). The overall evidence is limited because most papers were single-patient case reports, but they consistently describe severe inflammation with changes in blood counts and inflammation markers. [12] [13] [14] [15] [16]

Two case reports described HLH after immune checkpoint inhibitors (drugs that release brakes on the immune system), including in breast cancer and kidney cancer. In the breast cancer case, HLH included multi-organ problems and required intensive care, and the patient improved after immunosuppression with steroids and anakinra. [14] [12]

In the kidney cancer case, HLH developed after a combination of tislelizumab (a PD-1 blocker) and bevacizumab, and it was unusual in that fever was not present and a blood immune marker (sCD25) was relatively low for HLH; bone marrow testing supported the diagnosis. The person improved rapidly after high-dose prednisone, with short-term scans showing no major tumor growth during HLH recovery. [12]

Another case report described Epstein-Barr virus (EBV)-associated HLH in cholangiocarcinoma after sequential treatment with durvalumab (an immune checkpoint inhibitor) followed by BRAF and MEK targeted therapies (dabrafenib and trametinib). The patient needed intensive care support but improved quickly after high-dose steroids, stopped the suspected triggering cancer therapies, and later had a complete response to subsequent chemotherapy. [15]

Two reports emphasized that HLH can be driven by an underlying blood cancer even when a person already has a different cancer diagnosis. One patient with metastatic breast cancer had sepsis-like episodes and was found to have a new mantle cell lymphoma as the likely HLH trigger, and the authors highlighted the risk of confusing malignancy-associated HLH with infection in emergency settings. [13]

In a separate patient who developed HLH after COVID-19, a bone marrow biopsy revealed EBV-positive large B-cell lymphoma as an underlying trigger; the person improved quickly on dexamethasone before planned lymphoma-directed care. This report underscored how more than one trigger (infection plus cancer) may combine to push the immune system into HLH. [16]

A retrospective study in extranodal NK/T-cell lymphoma (a rare lymphoma type) focused on HLH with liver involvement. It proposed a liver injury index (based on three routine lab tests) that separated higher-risk from lower-risk patients, and it also reported that higher interferon-gamma levels tracked with worse liver injury. Two severe liver injury cases improved rapidly after emapalumab, but this was only two patients within a larger retrospective study. [17]

Finally, a tissue-mapping study comparing two EBV-positive T/NK-cell lymphoma subtypes found that HLH occurred more often in EBV-positive nodal T/NK-cell lymphoma (14 patients) than in extranodal NK/T-cell lymphoma. People with the nodal subtype also had shorter survival, and uncontrolled HLH accounted for most of the deaths in that small group. The biology differed between subtypes, including differences in immune cell patterns and PD-1/PD-L1 signals, which may help explain why immune-related complications vary across lymphomas, but the main tissue analysis was based on very small numbers. [18]

For patients and caregivers, these studies mainly provide background on when HLH has been reported in cancer settings: during immune-based therapies, during combinations or sequences of immune and targeted drugs, and when an underlying lymphoma (sometimes EBV-related) is the real driver. They also highlight that HLH symptoms can overlap with severe infection and that liver injury can be an important part of HLH in some lymphoma types. What remains uncertain is how often these situations occur and which patients are most at risk, because most evidence here comes from single-patient reports and small, retrospective datasets.

Across these papers, the shared message is that inherited changes in immune-related genes can sit in the background until an infection or other stress unmasks hemophagocytic lymphohistiocytosis (HLH), and the first signs may involve organs outside the bone marrow and spleen. Evidence ranged from a national pediatric registry (stronger, real-world picture) to individual case reports and a mouse study (early-stage biology), so certainty varies by finding. Together, they underline that gene results can help explain why HLH looks different from person to person, but many gene-variant effects still need functional confirmation. [19] [20] [21] [22] [23] [24] [25]

Several reports centered on PRF1, a gene involved in how immune cells kill infected or abnormal cells, and showed that PRF1-related HLH can present in unexpected ways. One adult with PRF1 mutations had prominent nervous system symptoms and unusual lung involvement; fever and neurologic symptoms improved quickly after HLH-94 treatment, while lung scans and lung biopsy remained hard to interpret. [20]

In a separate case, an 11-year-old girl developed HLH after SARS-CoV-2 infection (with additional viral coinfections reported), and genetic testing identified a new homozygous PRF1 variant that fit an autosomal recessive inheritance pattern in her family. Despite immunosuppressive therapy, she developed seizures and intracranial hemorrhage and died, showing how severe the course can be in some genetically susceptible situations. [22]

Inherited HLH risk was also described beyond PRF1, including possible "modifier" genetics that may complicate prediction. A 2-year-old girl with HLH had a homozygous pathogenic ERCC6L2 variant and a heterozygous ADA2 variant; despite HLH-directed therapy and immunomodulation, she developed progressive multiorgan failure and died, and the authors noted that functional studies were not performed so the role of each variant remains uncertain. [21]

A national registry from Kuwait showed that in pediatric primary immune regulatory disorders, familial HLH was the most common category, and genetic testing provided a molecular diagnosis in 84.9% of tested children (45 of 53). The registry also reported substantial mortality overall (35.6%, 21 of 59), with sepsis as the most common cause of death (14 cases), highlighting infection risk in this broader population. [19]

For XIAP deficiency (an inherited immune disorder that can include HLH and bowel inflammation), two brothers with the same XIAP variant showed different clinical paths, illustrating how variable inherited conditions can be even within one family. In the linked literature review (64 patients), common features included enlarged spleen (53.1%, 34 of 64), HLH (42.2%, 27 of 64), and inflammatory bowel disease or colitis (31.8%, 20 of 64), and among 13 patients who had a stem cell transplant, survival was 61.5% (8 of 13). [23]

Two infants with familial HLH type 2 (PRF1 mutations) were reported to be alive and disease-free after reduced-intensity conditioning cord blood transplantation, with long follow-up in one child (10 years). One infant had transplant complications (grade II acute graft-versus-host disease and sinusoidal obstruction syndrome) that were managed, while the other had no graft-versus-host disease reported. [24]

A mouse study added background biology on ZNFX1 deficiency: after viral infection, Znfx1 knockout mice developed temporary HLH-like inflammation (including enlarged spleen, anemia, high ferritin, and liver injury markers) along with strong T-cell activation and increased inflammatory macrophages in the liver. The mice still cleared the virus normally, suggesting that in this model, inflammation and viral control can be disconnected. [25]

For patients and caregivers, this set of studies mainly adds context about why HLH can look different across people and why infections may coincide with the first major flare in someone with an inherited risk. The registry data suggest genetic diagnoses are often achievable in pediatric immune-regulation disorders and that serious infections are a major contributor to outcomes, while the case reports show that lungs, brain, and gut can be involved in inherited conditions, sometimes with severe consequences. What remains uncertain is how to predict severity from many individual variants (especially newly reported ones without functional testing) and how well early-stage animal results map onto human disease. [19] [20] [21] [22] [23] [24] [25]

Across these studies, involvement of the brain, spinal fluid, or eyes often signaled a more severe form of hemophagocytic lymphohistiocytosis (HLH). In pediatric HLH, abnormal brain scans and spinal-fluid inflammation were frequent, and early deaths were more common when the central nervous system was involved. In a separate HLH cohort, retinal (eye) hemorrhage was also linked to worse survival, suggesting that eye and brain findings can carry prognostic information. [26] [27]

In a small, single-center review of 22 children with HLH, central nervous system involvement was reported in 17 of 22 children. Brain MRI abnormalities were very common, including patchy areas of change on MRI in 17 of 20 imaged children and diffuse brain shrinkage in 8 of 20. Spinal fluid testing showed higher white blood cell counts in genetically driven (primary) HLH than in secondary HLH, suggesting more spinal-fluid inflammation in that subgroup. [26]

In a retrospective cohort of children with Epstein-Barr virus (EBV)-associated HLH, children with EBV detected in spinal fluid had higher EBV levels in blood and a lower CD4/CD8 ratio than those without EBV detected in spinal fluid. EBV in the central nervous system was an independent risk factor for worse overall survival, and spinal-fluid EBV levels strongly tracked with spinal-fluid cell counts (a marker of inflammation). Injections into the spinal fluid using methotrexate plus dexamethasone lowered EBV levels and cell counts in spinal fluid, but overall survival was not clearly improved in this analysis. [28]

An eye-focused case-control study of 104 people with HLH (52 with retinal hemorrhage matched to 52 without) found that retinal hemorrhage was linked to shorter survival. The retinal hemorrhage group also had more intracranial lesions and lower hemoglobin, platelets, and fibrinogen, alongside higher ferritin and soluble interleukin-2 receptor (sIL-2R). Different patterns of retinal bleeding (petechial versus scattered) showed different survival times, with scattered hemorrhage having shorter median survival (55 days) than petechial hemorrhage (476 days). [27]

Two pediatric case reports highlighted that severe brain inflammation can look like an antibody-associated demyelinating disorder while also fitting a broader hyperinflammatory syndrome such as HLH. These cases emphasize that a positive antibody test does not rule out another or coexisting diagnosis when systemic and brain inflammation occur together, which can complicate timely recognition. Because this evidence comes from two individual patients, it may not apply to most people with HLH. [29]

For patients and caregivers, these studies add context that HLH can involve the brain and eyes, and when it does, outcomes may be worse in some groups, especially early in the illness. Spinal-fluid testing for EBV may help identify a higher-risk subset within EBV-related HLH, and eye exams that identify retinal hemorrhage may provide additional information about severity, but how best to use these results in day-to-day care is still uncertain. Most data here are retrospective (chart-based) and from single centers, so the exact rates and predictions may differ across hospitals and patient populations. [26] [28] [27] [29]

Across these papers, the overall pattern is that several lab approaches are being refined to better measure immune over-activation that can appear in hemophagocytic lymphohistiocytosis (HLH) and related syndromes such as macrophage activation syndrome (MAS). Two studies focused on tests that could support earlier recognition or clearer tracking of immune pathway activity, while one study focused on making a commonly used immune marker easier to measure reliably in children, with age-appropriate reference values. [30] [31] [32]

One clinical validation study described a flow cytometry test that reads out interferon pathway activity using two markers on monocytes: CD169 for type I interferon activity and CD274 (also called PD-L1) for interferon-gamma activity. The authors reported that this test could be used across several inflammatory diseases, including MAS and HLH, to screen for interferon pathway dysregulation and to monitor how interferon-targeted treatments are affecting these pathways over time. [30]

In a single-center prospective study of 50 people with active systemic lupus erythematosus (SLE), 28% developed MAS, and the researchers identified three blood RNA transcripts (KLRG1, KLRC3, ULK2) that predicted MAS, with KLRG1 performing best (area under the curve 0.927). The paper also reported that SLE patients who developed MAS more often had features such as fever and low blood counts, along with abnormal HLH-related lab tests, suggesting that this RNA-based signal may add information beyond traditional blood markers in that specific setting. [31]

A separate method validation study evaluated an automated fluorescence immunoassay to measure soluble interleukin-2 receptor alpha (sIL-2R alpha), a marker often used when HLH is being considered. The test showed strong agreement with a chemiluminescent reference method (correlation R = 0.99) and established that sIL-2R alpha levels were higher in younger children, providing age-specific reference intervals from birth through 19 years. [32]

For patients and caregivers, these studies are mainly about improving how clinicians can measure immune activation and follow changes over time, rather than about new treatments. The interferon activity assay and the RNA predictors in lupus-related MAS suggest ways future testing could better separate different immune pathways or identify higher-risk situations, but one is a validation study across diseases and the other is an exploratory single-center study in active lupus, so broader confirmation and real-world use are still uncertain. The pediatric sIL-2R alpha validation is more immediately practical background, because it supports reliable testing and reminds families that normal ranges for some immune markers can differ by age. [30] [31] [32]

Across this month's papers, most evidence came from single-patient case reports, so results may not apply to everyone. A consistent pattern was rapid improvement in fever and blood inflammation markers after immune-suppressing treatment (most often corticosteroids), sometimes combined with other therapies depending on the trigger (infection, drug reaction, autoimmune disease, or post-transplant setting). [33] [34] [35] [36] [37] [38]

In one pediatric post liver re-transplant case with Epstein-Barr virus (EBV) associated HLH and severe liver dysfunction, the team avoided etoposide due to liver impairment and used emapalumab (interferon-gamma blocking antibody) with steroids and immune globulin. Ferritin fell quickly, liver injury reversed, and the child recovered with normal liver function and sustained EBV negativity reported over 2 years. [33]

Several adult case reports described improvement after corticosteroids, sometimes alongside immune globulin or etoposide, when HLH appeared in different contexts such as Kikuchi-Fujimoto disease, cytomegalovirus infection, severe drug reaction with eosinophilia and systemic symptoms (DRESS), or after a tumor necrosis factor (TNF) blocking drug exposure. These reports also noted that bone marrow testing may not show hemophagocytosis even when HLH is present, and that complications like nervous system symptoms or serious infections can occur alongside HLH. [35] [36] [37] [38]

One adult case described secondary HLH developing after a blood transfusion without another identified trigger, with rapid clinical and lab improvement after dexamethasone plus etoposide. The authors used this case to emphasize that HLH can sometimes present even when a clear trigger is not found right away. [34]

For patients and caregivers, this set of papers mainly provides background about how varied secondary HLH can be and how treatments are often selected based on the suspected trigger and a person s overall condition (for example, severe liver dysfunction after transplant). Because most reports describe single individuals, they cannot predict which treatment will work best for a new patient, and they do not establish safety across larger groups; they do, however, document real-world situations clinicians may face, including overlapping infections, medication reactions, and autoimmune disease. [33] [34] [35] [36] [37] [38]

Two papers focused on HLH-like inflammation in the setting of chimeric antigen receptor (CAR) T-cell therapy. Together they suggest HLH-like syndrome can occur as a treatment-related complication, and that measuring specific blood cytokines may help describe or track severity, although how best to use these markers in care was not established here. [39] [40]

In a multicenter, single-arm phase 2 trial of an autologous CD19 CAR T-cell product (var-cel) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia, HLH-like syndrome occurred in 2 of 33 patients in the safety group. The trial also reported common treatment-emergent side effects overall, and one death linked to a protocol violation during uncontrolled sepsis. [40]

A separate report comparing different CAR T targets stated that an IEC-HS-like syndrome occurred more often with CD22- or BCMA-targeted constructs than with CD19-targeted constructs. It also described a three-cytokine pattern (interferon-gamma, interleukin-10, and interleukin-1 receptor antagonist) that correlated most strongly with syndrome severity. [39]

One lab and animal study explored a different potential future direction: blocking a form of inflammatory cell death (PANoptosis) by targeting a protein called XIAP. In a mouse model designed to mimic HLH, the plant-derived compound luteolin disrupted PANoptosome assembly, reduced inflammation, protected organs, and improved survival, but this was not a human study. [41]

This theme matters most for people receiving or considering CAR T-cell therapy, because it highlights that HLH-like inflammation is a recognized complication in that setting and was seen in a clinical trial. The cytokine pattern and the XIAP targeted lab approach are best viewed as research tools right now: they may help scientists understand and monitor immune overactivation, but these papers do not show that any specific test or lab-discovered compound improves outcomes in people with HLH. [39] [40] [41]