June 2026 Research Update

Across these studies, a consistent message was that hemophagocytic lymphohistiocytosis (HLH) can look like severe infection or cancer, so researchers are testing add-on ways to improve early recognition and to sort out the underlying trigger. Several teams used computer models based on early hospital data, while others looked at CT scan patterns, specialized immune blood tests, and the limits of bone marrow findings. Overall, performance looked strong in some pediatric Epstein-Barr virus (EBV) focused models, while other approaches were more exploratory or context-specific. [1] [2] [3] [4] [5] [6] [7] [8] [9]

In two large pediatric studies focused on acute EBV infection, machine learning models used early, commonly collected information to help distinguish EBV-associated HLH from EBV infectious mononucleosis. One model built from routine complete blood count results (plus lactate) had very high accuracy in both internal and external testing, and key drivers included white blood cell count, platelet count, lactate, and hemoglobin. [1]

A second pediatric EBV study also reported very high accuracy using a different machine learning approach, with the most influential inputs including D-dimer, swollen neck lymph nodes, and several blood tests reflecting liver stress or inflammation, plus a type of immune cell measurement. This study noted that it still needs outside confirmation in other hospitals, which matters because performance can drop when a tool is moved to new settings. [2]

For children who were suspected of having HLH for various reasons (not limited to EBV), a smaller single-center study found that longer fever duration and changes in several standard lab tests (including ferritin, triglycerides, fibrinogen, and D-dimer) helped separate those who did versus did not end up meeting HLH criteria, but the combined model had only moderate accuracy. This suggests that broader suspected-HLH populations may be harder to classify than narrowly defined EBV infection groups. [4]

Imaging and tissue sampling studies highlighted how clinicians may look for the underlying cause, especially cancer-related HLH. In a pediatric CT study of children with low blood counts, certain chest and belly CT patterns differed between malignancy-associated HLH, acute leukemia, and EBV-associated HLH, but the authors cautioned that the cutoffs may be specific to their dataset and should be used only as supportive clues. [3]

In adults, one cohort study from France suggested that a set of inflammatory blood signals (cytokines) and age could help predict whether HLH was linked to an underlying cancer, and the IL-10/IL-6 ratio alone also separated groups reasonably well in the subgroup with those tests available. Because these are specialized tests that may not be routinely available everywhere, the practical impact may depend on local access and standardization. [6]

Two studies focused on the role and limits of bone marrow-related clues. In children being evaluated for septic shock, soluble CD25 was much higher in the HLH group than in the septic shock or infection groups overall, but there was overlap, including a septic shock subset with very high levels and severe outcomes. In adults with blood cancers and COVID-19, hemophagocytosis in the bone marrow was common but did not by itself support an HLH diagnosis, highlighting that this marrow finding can appear in other intense inflammatory states. [5] [7]

A European workshop report emphasized that bone marrow appearances can be shaped by infections, autoimmune disease, cancers, or treatment effects, sometimes resembling other blood disorders and potentially leading to misinterpretation without full clinical context. Separately, a two-patient case report described HLH triggered by B-cell lymphoma where ultrasound-guided spleen biopsy provided the key diagnosis when other tests were not definitive, and the procedure did not cause major bleeding in these cases. [8] [9]

For patients and caregivers, this set of papers mainly adds background on why HLH can be difficult to recognize and why doctors may combine different kinds of information (routine labs, specialized immune tests, scans, and sometimes biopsies) to narrow down the cause. Some EBV-focused pediatric prediction tools looked very accurate, but they were developed for a specific situation (children with EBV infection) and may not apply to other HLH triggers. Several other approaches were early-stage or limited to single centers, so it remains uncertain how well they work across different hospitals, age groups, and causes of HLH.

Across these studies, short-term outcomes in hemophagocytic lymphohistiocytosis (HLH) were linked to how severe the illness looked at the start, especially blood test signs of inflammation, problems with clotting, and signs that the body was under heavy stress. Several teams also explored ways to combine multiple measurements into risk groups or calculators, but these tools still need testing in new patient groups before they can be considered reliable everywhere. [10] [11] [12] [13]

In a 79-person adult HLH study focused on death within 40 days, early death was common and was independently linked to older age, low platelet counts, and higher lactate dehydrogenase (a blood marker that can rise with tissue damage). In this study, the underlying trigger for HLH appeared to have little effect on early death compared with these clinical and lab signals. [12]

In a 35-child single-center HLH study, overall mortality was 11%, and the children who died had lower fibrinogen (a clotting-related blood protein) and higher triglycerides (a blood fat). Many children had no identified trigger, and the study did not include some specialized immune tests, which limited how fully risk could be characterized. [10]

One 133-child study used a data-driven approach to sort children into two baseline risk classes with very different 30-day survival, with the high-risk class having a 7.42-fold higher risk of dying within 30 days. The strongest contributors to the high-risk pattern included a clotting test (activated partial thromboplastin time), nervous system involvement, an inflammation marker (C-reactive protein), and an enlarged liver; the authors also noted that treatment choices (such as cyclosporine use) could affect the model. [11]

A 167-adult multicenter study developed a machine-learning risk calculator for secondary HLH to predict early severity and death at several time points, using eight clinical and lab features. Soluble interleukin-2 receptor (a blood marker of immune activation), albumin, and platelet counts were among the most important inputs, but the authors emphasized that external validation is still needed and the calculator is for research use only. [13]

In 23 children with cancer-associated HLH, achieving remission of HLH was strongly linked to longer survival, with a reported 90% reduction in the risk of death among those who reached remission. Because this was a small retrospective study, it cannot prove which treatment approach caused remission, but it highlights that controlling HLH activity is closely tied to outcomes in this setting. [14]

In a 43-person study of subcutaneous panniculitis-like T-cell lymphoma (a rare lymphoma that can be complicated by HLH), more extensive skin involvement was linked to a higher likelihood of developing HLH. In this lymphoma group, having HLH independently predicted worse overall survival, and both extensive skin stage (T3) and HLH predicted shorter time without relapse. [15]

For patients and caregivers, this set of studies mainly reinforces that HLH outcomes are often tied to measurable signs of how strongly the immune system and organs are being affected early on, rather than to any single symptom. Several groups are building multi-factor risk tools (including machine-learning models), but these are not yet validated broadly and are best viewed as background research that may shape future research and monitoring practices. Uncertainty remains because most studies were retrospective, often single-center, and used different available blood tests and definitions across hospitals. [10] [11] [12] [13] [14] [15]

Across these papers, the overall pattern was that controlling the immune over-activation in hemophagocytic lymphohistiocytosis (HLH) often went along with quick improvements in symptoms (like fever) and lab signs of inflammation (like ferritin). Evidence this month was mostly exploratory, coming from one small prospective trial and several individual case reports, so results may not apply to everyone. [16] [17] [18] [19] [20] [21] [22] [23] [24]

In a prospective pediatric trial, a ruxolitinib-containing regimen was reported as well tolerated, with rapid early stabilization and improved ferritin in the first week. All newly diagnosed children in this study reached complete response by 8 weeks, while outcomes were worse in some relapsed or refractory primary HLH cases. [16]

Several case-based reports described ruxolitinib use in specific HLH-like situations: adults whose HLH looked like severe drug-related liver injury, and children with macrophage activation syndrome linked to systemic juvenile idiopathic arthritis, where many cases reported fever and lab improvements and sometimes steroid tapering. These reports also noted that other treatments (such as steroids, other immune medicines, plasma exchange, or supportive care) were often given at the same time, making it hard to separate the effect of one drug. [17] [18]

Other single-patient reports highlighted that treatment choice often depended on the trigger: a child with scrub typhus-associated HLH improved after antibiotic treatment alongside ruxolitinib, and an infant whose test results suggested visceral leishmaniasis with secondary HLH improved after continuing the needed anti-parasite drug using a desensitization approach after anaphylaxis. These examples emphasize that treating the underlying infection can be central, sometimes together with medicines aimed at calming immune inflammation. [21] [24]

Multiple reports described improvement with anti-inflammatory medicines without ruxolitinib, including corticosteroids alone for HLH linked to an immune checkpoint inhibitor in an older adult with cancer, canakinumab for refractory macrophage activation syndrome in pediatric lupus, and anakinra plus corticosteroids in parvovirus-related HLH during a high-risk pregnancy. One adult case also described improvement after dexamethasone and intravenous immunoglobulin (IVIG), with etoposide added when blood counts worsened again. [23] [19] [20] [22]

For patients and caregivers, these studies mainly add background on the range of treatments doctors have reported using to control HLH, especially medicines that reduce immune-driven inflammation and, when relevant, treatments that target an infection or a drug-related trigger. What remains uncertain is which approaches work best for which HLH causes, how safe each option is across larger groups, and how well these results hold up outside of small trials and case reports. [16] [17] [18] [19] [20] [21] [22] [23] [24]

Across these June 2026 papers, infections were described as triggers for hemophagocytic lymphohistiocytosis (HLH) in very different settings, including autoimmune disease, travel-related viral illness, organ transplant, stem cell transplant, inherited muscle disease, and an adult immune deficiency. Because all reports were single-patient cases, they highlight possible patterns and warning situations but cannot predict what will happen for any one person. Overall, some patients improved when both the infection and the overactive immune response were addressed, while others worsened quickly with liver, kidney, lung, or whole-body failure. [25] [26] [27] [28] [29] [30] [31]

Several reports emphasized that HLH can look like other illnesses at first, and the trigger infection may not be obvious immediately. One patient had dengue fever where an early dengue PCR test was negative, but later blood tests supported dengue, and she recovered with supportive care while also having gallbladder inflammation without stones (acute acalculous cholecystitis). [26] Another report described HLH from Ehrlichia chaffeensis that mimicked a lupus flare, creating diagnostic confusion. [30]

When people already had major immune system stress, the infection-triggered HLH described in these cases could be severe and sometimes fatal. A kidney transplant recipient developed disseminated Toxoplasma gondii infection with HLH, improved at first, then later had evidence of persistent infection requiring ongoing management. [27] A stem cell transplant recipient developed HLH triggered by disseminated Mycobacterium immunogenum and died after progressing to liver and kidney failure despite treatment. [28]

Two other reports highlighted very rapid decline in settings of serious immune vulnerability. A 4-year-old boy with late-onset Pompe disease developed disseminated human adenovirus infection with an HLH-like illness and multiorgan failure leading to death; sequencing showed small differences in the virus across different body sites, showing how complex these infections can be inside the body. [29] A 42-year-old man with adult-onset severe combined immunodeficiency (SCID) developed cryptococcosis and deteriorated quickly despite antifungal treatment, with HLH confirmed after death. [31]

Not all infection-triggered HLH cases had poor outcomes. A 33-year-old woman had cytomegalovirus (CMV) reactivation triggering secondary HLH around the time she was diagnosed with systemic lupus erythematosus (SLE), and she improved quickly after combined antiviral and immune-suppressing therapy, with remission reported at 6 months. [25]

For patients and caregivers, these reports mainly serve as background that HLH can be set off by many kinds of infections, and that the same overall syndrome can appear in very different medical situations (autoimmune disease, travel-related infection, transplant, or immune deficiency). They also show that the course can vary widely, from improvement with supportive care or targeted therapy to rapid worsening with organ failure. What remains uncertain is how often each trigger occurs and which factors best predict recovery versus deterioration, because each paper describes only one person.

Across these reports, hemophagocytic lymphohistiocytosis (HLH) was closely tied to an underlying cancer or blood cancer, and in several patients it was the first clue that a malignancy was present. A repeated challenge was that HLH symptoms overlapped with infection, inflammation, or post-surgery problems, which delayed recognizing what was driving the immune overreaction. The evidence here is limited to individual case reports, so the patterns may not apply to everyone. [32] [33] [34] [35] [36] [37] [38] [39] [40]

Two reports described severe HLH occurring alongside a solid tumor, one as the initial presentation and one after cancer surgery. A 38-year-old man was found to have diffuse gastric signet ring cell adenocarcinoma after presenting with HLH, but severe thrombocytopenia and rapid multi-organ failure led to death within 28 days despite anakinra. An 83-year-old woman developed HLH after colon cancer surgery, did not respond to corticosteroids, and died shortly afterward, underscoring how hard HLH can be to recognize early around the time of cancer care and postoperative complications. [33] [32]

Several cases involved cancers linked to Epstein-Barr virus (EBV), where HLH flared alongside high EBV levels or EBV-positive tumor cells. This included gastrointestinal extranodal NK/T-cell lymphoma with later EBV-related HLH and acute liver failure, and a case where HLH revealed nasal-type extranodal NK/T-cell lymphoma treated with etoposide and pembrolizumab-based immunochemotherapy. Another patient had HLH as the first sign of newly diagnosed multiple myeloma with high EBV load, later developing an aggressive B-cell lymphoma after multiple HLH relapses, with only temporary control before death from septic complications. [35] [36] [34]

HLH also appeared in settings of immune dysregulation and immunosuppression, where infection, inflammation, and cancer were difficult to separate. One kidney transplant recipient developed late-onset EBV-positive hairy cell leukemia concurrently with HLH, and the authors noted HLH can look like sepsis in transplant patients. In a young woman with systemic lupus erythematosus on chronic immunosuppression, EBV-positive diffuse large B-cell lymphoma presented as diffuse lung nodules that initially resembled lupus pneumonitis; diagnosis required surgical lung biopsy, and she later developed HLH and respiratory failure requiring ECMO during treatment. [40] [39]

A few reports emphasized that careful tissue and bone marrow evaluation can be central to identifying the cancer driving HLH, and that some patients can have meaningful clinical improvement when the cancer is addressed. In one case, HLH was linked to splenic Hodgkin lymphoma, confirmed after imaging and splenectomy; HLH was brought under control before chemotherapy, and later salvage chemotherapy with nivolumab led to improvement with the patient asymptomatic at follow-up. Another report described a woman with severe Crohn's disease who developed acute myeloid leukemia and HLH after infliximab induction, where early marrow changes were difficult to interpret in a hyperinflammatory state and later evolved into clear leukemia with a complex karyotype. [37] [38]

For patients and caregivers, these cases reinforce that HLH linked to cancer can look different from person to person and may appear before the cancer is clearly diagnosed, including in solid tumors, lymphomas, and leukemias. In the near term, this set of reports mainly serves as background on why clinicians may pursue broad testing (including biopsies) when HLH is suspected, especially when symptoms overlap with infection, autoimmune disease, transplant-related complications, or postoperative recovery. What remains uncertain is how often each cancer type triggers HLH, which tests best speed diagnosis in real-world care, and which approaches reliably control HLH without causing serious complications, since the evidence here comes from single-patient experiences.

Across these papers, HLH (or HLH-like hyperinflammation) was described as a possible complication of several underlying genetic conditions, including immune signaling changes, immune cell function problems, glycosylation disorders, and an inborn error of metabolism. The overall evidence is mostly from individual case reports and one small cross-sectional study and case series, so the frequency and predictability of HLH in these conditions remains uncertain. A repeated pattern was that infections or other stressors could coincide with the inflammatory episode, and organ involvement could include liver, kidneys, brain, and the nervous system. [41] [42] [43] [44] [45] [46] [47]

One report described a child with NBAS variants and severe multisystem disease who developed HLH that did not respond to treatment and later died; lab work suggested the variants lowered NBAS protein and disrupted cell transport pathways. The authors also reviewed 322 previously reported people with NBAS deficiency and noted that HLH has been described in several cases, positioning HLH as a potential severe inflammatory complication in this genetic spectrum. [41]

A separate report described an 18-year-old with a cytomegalovirus infection and an HLH-like illness who carried a STING1 gain-of-function variant that was inherited from an unaffected father, suggesting that carrying the variant alone may not always lead to disease. The patient improved with antiviral treatment and corticosteroids, and the authors noted that the full HLH criteria were not met in this case. [42]

Another child had a newly identified STAT1 gain-of-function variant along with severe infection (disseminated tuberculosis), early-onset systemic lupus erythematosus, and later development of HLH; immune testing showed a marked reduction in IL-17 producing T cells, consistent with the reported syndrome. The child had partial improvement with ruxolitinib as bridging therapy, and hematopoietic stem cell transplantation was planned, but the report could not confirm the STAT1 mechanism with direct functional testing. [43]

In a case series of three people with COG6 or COG7 deficiency, recurrent febrile episodes repeatedly came with lab features suggestive of HLH, and in two patients these episodes were followed by neurological decline and the onset of epilepsy. The authors also reviewed prior reports and estimated that recurrent, poorly tolerated fevers occur in about 40% of published COG deficiency cases, but fully documented HLH was rarely reported, raising concern that partial HLH features may be missed or inconsistently labeled. [44]

A cross-sectional study of 24 children in Iran with HLH diagnosed by HLH-2004 criteria found two patients with missense PRF1 variants that the authors linked to familial HLH type 2, and many patients carried a separate synonymous PRF1 change. The authors emphasized that larger studies with functional testing are needed to confirm which variants truly change perforin function and how genotype relates to clinical course in that population. [45]

Two additional case reports highlighted non-classic settings where HLH can overlap with other immune problems. One 18-month-old with genetically confirmed isovaleric acidemia met 7 of 8 HLH-2004 criteria during a crisis with viral infections and anti-NMDA receptor autoimmune encephalitis, and he stabilized after intensive care and combined management targeting multiple causes. [46] Another report described an 8-year-old with overlapping neuromyelitis optica spectrum disorder (AQP4 antibody positive) and anti-MDA5 positive dermatomyositis who developed secondary HLH and later fully recovered after intensive immunotherapy, with improvement in antibody levels over follow-up. [47]

For patients and caregivers, this set of studies reinforces that HLH can be the visible end-result of different underlying causes, including inherited immune conditions, metabolic disorders, and autoimmune overlap syndromes, and that infections may be part of the trigger in some situations. Most evidence here is early-stage (single-patient reports, small series, and one small genetic screening study), so it mainly serves as background research about why HLH happens and why the same label can describe different pathways. Key uncertainties include how often HLH occurs in each genetic condition, why some family members with the same variant may stay well, and which lab changes best predict risk or severity across different genetic backgrounds.

Across this month's transplant-focused papers, the clearest pattern was that outcomes after donor stem cell transplant for hemophagocytic lymphohistiocytosis (HLH) looked better when inflammation was controlled before transplant, and that pre-transplant organ function and virus activity may help predict risk. The evidence here comes from retrospective studies, so results can vary across hospitals and patient groups. [48] [49]

In a retrospective study of 35 adolescents and adults with HLH who received myeloablative conditioning allogeneic hematopoietic stem cell transplantation (donor stem cell transplant), engraftment occurred in 34 of 35 patients. Survival at 1 year and 2 years was 78.2% and 74.1%, and relapse-free survival at 1 year and 2 years was 73.0% and 69.0%. Better relapse-free survival was reported when HLH was in inactive remission before transplant compared with active disease, and higher pre-transplant creatinine (a blood marker related to kidney function) predicted worse survival. [48]

In a separate small retrospective study of 20 adults with chronic active Epstein-Barr virus disease (a condition that can overlap with HLH), adding post-transplant cyclophosphamide to ATG (two medicines used to prevent graft-versus-host disease) lowered both acute and chronic graft-versus-host disease and led to faster clearing of Epstein-Barr virus DNA in blood, with less early virus reactivation. However, 5-year overall survival was not clearly different between the two prevention approaches, and patients who had HLH before transplant or higher virus levels before transplant had worse overall survival. [49]

For patients and caregivers, these studies mainly add context about what transplant teams watch closely around the time of donor stem cell transplant: whether HLH is active or quiet, kidney-related lab values, and blood measures of Epstein-Barr virus when that virus is part of the illness. The transplant results summarized here come from retrospective reports (not randomized trials), and the virus-focused study was small, so it cannot prove one graft-versus-host disease prevention approach is best for everyone. Questions that remain include how well these patterns apply across different ages, causes of HLH, and transplant centers, and how bridging or monitoring strategies discussed in the studies affect outcomes in broader practice. [48] [49]

Across several reports, HLH or HLH-like inflammation appeared as a severe complication in different settings: after solid-organ transplant with Epstein-Barr virus (EBV)-driven disease, after CAR-T cell therapy, and during serious infection. These papers were mostly single-patient case reports or retrospective cohorts, which can describe what happened but cannot estimate how often it occurs or who is most at risk. [50] [51] [52]

One pediatric kidney transplant recipient with EBV-positive post-transplant lymphoproliferative disorder and secondary HLH received EBV-specific T-cell therapy (tabelecleucel) after prior virus-specific T-cell exposure, and then developed cytokine release syndrome and immune effector cell-associated neurotoxicity with multiorgan failure and death. The report highlights that cellular immunotherapy given during very active HLH can be accompanied by dangerous immune over-activation, and it also noted possible underlying genetic vulnerability based on variants of uncertain significance. This is a single case and may not reflect typical outcomes. [50]

A separate case report described a 71-year-old woman who developed immune effector cell-associated hemophagocytic syndrome six months after CAR-T therapy for diffuse large B-cell lymphoma, and she died. The authors suggested that long-lasting CAR-T cells might contribute to continued immune dysregulation, but this remains uncertain because the report describes only one person. [51]

In a single-center pediatric cohort of 16 children with secondary HLH, infections were the most common trigger and overall survival was 87.5%, with deaths occurring in higher-risk noninfectious causes (Wolman disease and Langerhans cell histiocytosis-associated HLH). The pattern described was faster improvement more often in infection-triggered HLH and poorer or delayed response in some noninfectious triggers, but treatment was not standardized and testing was incomplete, which limits firm comparisons. [53]

A retrospective neonatal intensive care unit series of 15 infants treated off-label with anakinra for severe inflammatory and respiratory conditions reported less need for invasive breathing support over 60 days and all infants survived, with mostly transient lab abnormalities reported. This study did not focus on HLH specifically and had no control group, so it cannot show whether anakinra would have the same effects in HLH or in other hospitals. [54]

In a study of 149 people with murine typhus, 119 adults were hospitalized and 28% of them required intensive care; two died in intensive care, one of them from multiorgan failure with HLH that was confirmed by bone marrow biopsy. This supports that HLH can occur as part of severe infection, but the study was not designed to detail HLH treatment or to track HLH outcomes beyond that complication. [52]

For patients, this theme is most relevant as background on where HLH can show up in real-world care: as a complication of certain infections, in people with EBV-related disease after organ transplant, and as a rare but severe immune toxicity reported after some cell therapies. The case reports highlight that HLH-like immune over-activation can be life-threatening, including late after CAR-T therapy and during EBV-driven illness, but they cannot tell how common these outcomes are. The pediatric cohort adds that the underlying trigger matters for outcomes in secondary HLH, while the neonatal anakinra series is early, indirect evidence about controlling inflammation in very sick infants rather than proof for HLH. [50] [51] [53] [54] [52]