May 2026 Research Update

Across these papers, earlier recognition of hemophagocytic lymphohistiocytosis (HLH) was most difficult when another illness was also active, such as autoimmune inflammation, lymphoma, or severe infection. The overall pattern was that no single test solved the problem; diagnosis became clearer when clinicians combined blood marker patterns with the right place and timing of tissue sampling, and when biopsy results were interpreted in the full clinical context. Evidence here is mainly from case reports, with two moderate-strength cohort studies that focused on blood markers and cytokines. [1] [2] [3] [4] [5] [6]

In one patient with adult-onset Still's disease, lymph node tissue initially looked like a benign reaction and later looked like T-cell lymphoma, but expert re-review plus immunohistochemistry supported inflammation with hemophagocytosis rather than cancer. This report highlights that lymph node patterns can shift and may be misleading if read without the broader picture, which can delay recognition of HLH. The authors emphasized integrating symptoms, blood tests (including very high ferritin), imaging, and tissue staining patterns to reduce misdiagnosis. [1]

Two case reports focused on malignancy-related HLH where finding the cancer early was central to clarifying the diagnosis. In suspected intravascular large B-cell lymphoma, a pattern of very high ferritin, high lactate dehydrogenase (LDH), and high interleukin-10 (IL-10) helped raise suspicion, and a subtle PET-CT signal guided a targeted lung biopsy that confirmed the lymphoma. In another patient with pneumonia-like lung disease, flow testing on lung wash fluid (bronchoalveolar lavage) showed an abnormal T-cell population earlier than bone marrow testing did, pointing to lymphoma involvement that was later confirmed on lymph node biopsy. [2] [3]

Specialized blood marker work also aimed to separate overlapping inflammatory illnesses that can lead to HLH-like complications. In a 47-person study of untreated adult-onset Still's disease, the active form of interleukin-18 (IL-18) was much higher than in rheumatoid arthritis, tracked with disease activity, and dropped after immunosuppressive therapy, suggesting it may help clarify Still's disease activity when symptoms overlap with other conditions. In children with Epstein-Barr virus (EBV)-associated HLH, early changes in EBV viral load tracked with changes in IL-10 and interferon-gamma (IFN-gamma) during initial chemotherapy, showing how repeated marker measurements can reflect how the disease is moving over time, even though the best way to use these patterns to forecast short-term response remained mixed. [5] [6]

One case report highlighted the diagnostic challenge of HLH occurring alongside severe, hard-to-define infection in an immunocompromised person. Metagenomic next-generation sequencing (mNGS) performed on lymph node, blood, and serum detected multiple microbes that standard testing had not clearly identified, suggesting it can add information when routine cultures are confusing or negative. However, the results came too late to guide decisions in this case, underlining turnaround time and interpretation as key limits for earlier diagnosis. [4]

For patients and caregivers, these studies mainly explain why HLH can be recognized late when it is triggered by another illness and why teams may need multiple types of tests to understand the cause. Right now, the strongest takeaways are about process: combining blood markers with targeted sampling (for example, PET-CT-guided biopsy or lung fluid testing) and careful pathology review can help clarify what is driving HLH in some complex situations. What remains uncertain is how well newer marker ideas (such as active IL-18 in Still's disease or combined marker patterns in EBV-HLH) will generalize across hospitals and patient groups, and how quickly newer infection tests like mNGS can return results in real-world care. [1] [2] [3] [4] [5] [6]

Across these papers, hemophagocytic lymphohistiocytosis (HLH) was described after many different infections, not just one type. The reports included viral infections (several different viruses) and bacterial infections (including throat and lung infections), with outcomes ranging from recovery to death. Overall, this evidence is mostly from individual case reports and small series, so it shows what can happen but cannot estimate how common each trigger is. [7] [8] [9] [10] [11] [12] [13] [14] [15]

Several different viruses were reported as triggers, identified with different testing approaches. These included chikungunya in an elderly man who recovered with supportive care, human herpesvirus-6B detected in blood and liver tissue in a middle-aged woman who entered remission after antiviral and immune-suppressing medicines, and severe fever with thrombocytopenia syndrome virus (SFTSV) in a man who developed multi-organ failure and died. [12] [14] [13]

Bacterial infections were also described as triggers, including common and less common bacteria. One immunocompetent adult developed HLH after streptococcal pharyngitis and presented with shock and multi-organ failure but improved after steroid therapy. Another report described HLH in a young man with an underlying immune disorder, triggered during pneumonia where Legionella pneumophila and SARS-CoV-2 were identified. [8] [15]

Tick-borne and related infections appeared repeatedly in pediatric reports, especially scrub typhus. A 14-year-old boy from an endemic region met HLH criteria and recovered after doxycycline plus immune-modulating medicines, and a larger pediatric synthesis suggested infants had higher death rates, less visible skin signs, and more frequent brain or nervous system involvement than older children. Another child was ultimately considered to have infection-associated HLH with Epstein-Barr virus exposure and Ehrlichia serology after initially being treated for MIS-C-like illness, with heart ultrasound changes later normalizing. [9] [10] [7]

Mycobacterial infection was also reported in a high-risk setting: one patient had disseminated tuberculosis along with previously undiagnosed HIV and HLH, presenting with bowel perforation and eventually recovering after prolonged, staged care. [11]

For patients and caregivers, these reports reinforce that HLH can follow many kinds of infections, and the same overall HLH syndrome can occur in very different situations: otherwise healthy adults, children in areas where certain infections are common, and people with weakened immune systems from HIV or inherited immune problems. Most of the evidence here is case-based, so it is strongest for documenting possible triggers and symptom patterns (for example, higher nervous system involvement in infants with scrub typhus) rather than predicting an individual persons risk or expected outcome. What remains uncertain is how often each infection leads to HLH and which patient factors most strongly influence severity, because larger, systematic studies were not part of this set of papers. [7] [8] [9] [10] [11] [12] [13] [14] [15]

Across this group of papers, hemophagocytic lymphohistiocytosis (HLH) linked to cancer showed very different paths depending on the underlying cancer and the situation. A pediatric hospital series suggested that some children respond to treatment and can live years after diagnosis, while several adult case reports involving rare T/NK-cell and natural killer cell blood cancers had very poor outcomes. One case report also highlighted that HLH-like inflammation can sometimes occur during targeted cancer therapy, and careful adjustment of cancer treatment alongside anti-inflammation treatment may allow continued cancer control. [16] [17] [18] [19]

In a single-center retrospective study of 44 children with malignancy-associated HLH, about two-thirds had a response by follow-up, and overall survival was 67% at 2 years. Worse survival was linked to ferritin above 5000 ng/mL, age over 10 years, and lactate dehydrogenase (LDH) above 500 U/L, while not reaching complete remission by the end of follow-up was an independent risk factor for poorer outcomes. The study also reported differences depending on whether HLH happened at cancer diagnosis or after chemotherapy. [16]

Several case reports describe HLH occurring together with aggressive blood cancers where the overall course was rapid and severe. A 73-year-old man with aggressive natural killer cell leukemia (ANKL) and HLH worsened despite treatment and died from multiple organ failure. A 58-year-old man with Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma presenting with HLH died within 2 months, and the authors emphasized that this rare condition can be misdiagnosed and lacks an established standard treatment. [17] [18]

Not all cancer-linked HLH-like inflammation occurred in the same way, including cases tied to cancer treatment itself. An 89-year-old man with BRAF V600E-mutated metastatic lung adenocarcinoma developed an HLH-like hyperinflammatory syndrome after starting dabrafenib and trametinib; after adding ruxolitinib along with corticosteroids and dose-modified targeted therapy, inflammatory markers decreased and no further flares were reported while he continued cancer treatment. This was a single patient, so it cannot show how often this approach works for others. [19]

One additional case illustrates that HLH can overlap with lymphoma and, in some people, with inherited immune system changes. A 20-year-old man had HLH and classical Hodgkin lymphoma along with a germline STXBP2 mutation; he improved after HLH-directed therapy and lymphoma treatment, later relapsed with HLH, and then underwent an allogeneic stem cell transplant with full donor chimerism reported, alongside infection complications. As a single case, it mainly shows the complexity that can arise when HLH, cancer, and genetics intersect. [20]

For patients and caregivers, this month’s papers reinforce that “HLH linked to cancer” is not one uniform situation: outcomes ranged from meaningful survival in a pediatric series to very rapid decline in rare adult T/NK-cell and natural killer cell cancers, and to a treatment-triggered HLH-like syndrome that was controlled while continuing targeted therapy in one person. Most of the evidence here comes from single-patient reports, so it mainly adds background on possible scenarios rather than giving clear, widely applicable expectations. What remains uncertain is how best to predict who will improve versus worsen across different cancer types, and which inflammation-lowering strategies can be safely paired with specific cancer treatments beyond individual cases. [16] [17] [18] [19] [20]

Across studies, outcomes looked better when treatment went beyond infection treatment and general supportive care, especially when regimens combined therapies that calm the immune system (such as intravenous immune globulin) with steroids or chemotherapy. Evidence was strongest in two retrospective hospital cohorts, while individual case reports showed that some people with autoimmune-related HLH improved with immune-targeted approaches but others did not. [21] [22] [23] [24] [25] [26]

In a multicenter study of 162 people with HLH, combination regimens had higher response rates than anti-infective and supportive treatment alone, and use of intravenous immune globulin or chemotherapy was linked with survival. For example, chemotherapy plus intravenous immune globulin had a complete response rate of 44.44%, while anti-infective and supportive care had a complete response rate of 8.16%. The study also reported that delays to starting treatment and markers of severe illness were tied to worse outcomes. [21]

In a single-center pediatric study of 110 children with secondary HLH, most cases were infection-associated and Epstein-Barr virus was the most common trigger. Children with Epstein-Barr virus related HLH who received HLH-94/04 style chemotherapy had a reported remission rate of 91.9%, and overall in-hospital mortality was 13.6%, with most deaths due to multiple organ dysfunction. In the same report, children with macrophage activation syndrome (HLH related to rheumatic disease) often reached remission with high-dose steroids and cyclosporine, highlighting that treatment choices differed by the underlying trigger. [22]

Three case reports focused on HLH tied to systemic lupus erythematosus (an autoimmune disease) and showed very different courses. One patient improved rapidly after treatment with high-dose steroids and anakinra (an immune-targeting medicine), alongside lupus treatment. [26] Another patient had severe brain involvement with seizures and only partial recovery after escalation from steroids and plasma exchange to HLH-94 style chemotherapy, with treatment pauses due to low blood counts. [25] A third patient had refractory disease despite many immune-targeting medicines and chemotherapy, and a stem cell transplant was considered but not possible due to multiple organ failure. [23]

One additional case report described a woman with severe HLH/macrophage activation syndrome and painful skin inflammation (panniculitis) in a resource-limited setting. She improved after a non-chemotherapy rescue approach using therapeutic plasma exchange, then intravenous immune globulin and cyclosporine, with remission reported for 6 to 8 months. Because this is one person and the diagnosis overlapped with lymphoma-like features that could not be fully tested, it is not clear how often similar results would occur. [24]

For patients and caregivers, these papers add context that HLH outcomes in hospitals have been better in groups where treatment included immune-calming medicines and/or chemotherapy rather than supportive care alone, particularly for Epstein-Barr virus related HLH in children. At the same time, the autoimmune-related case reports show that responses can range from rapid improvement to ongoing, hard-to-control disease, including when the brain is involved. What remains uncertain is which specific combinations work best for each HLH trigger and which people are most likely to benefit, because much of the evidence here comes from retrospective studies and single-patient reports rather than head-to-head trials.

Across a meta-analysis and two single-center reports, hemophagocytic lymphohistiocytosis (HLH) after CAR T-cell therapy was reported as uncommon overall, but outcomes varied widely from study to study. The larger pooled data suggested low overall HLH-related death rates, while one center reported very high death rates among people who developed this complication. A small pediatric and young adult report described quick improvement when a targeted immune-blocking medicine was used in two cases, but this evidence is still early. [27] [28] [29]

In a systematic review and meta-analysis (19 studies; 2,780 patients), the pooled HLH rate after CAR T-cell therapy was 1.6%, and HLH-related deaths were 0.7%. Rates were higher in B-cell acute lymphoblastic leukemia (6.9%), and differences were also reported by CAR T product, including higher rates with tisagenlecleucel and with ciltacabtagene autoleucel compared with some other products. Higher-grade cytokine release syndrome (a separate inflammatory side effect) tracked with more HLH events in some groups, especially multiple myeloma. [27]

In a single-center adult retrospective study (301 treated; 14 HLH cases), the center reported a 4.7% HLH rate, usually starting around 10 days after infusion, with very high inflammation markers and frequent low blood counts and liver problems. Infections were common (11 of 14), and 11 of 14 patients died despite use of immune-suppressing treatments such as steroids and anakinra, with worse 1-year overall survival than the full CAR T group. This highlights that, in some real-world settings, HLH after CAR T can be hard to control and can overlap with serious infections and organ stress. [28]

In a small pediatric and young adult cohort treated with tisagenlecleucel for relapsed or refractory B-cell acute lymphoblastic leukemia (12 patients), two developed HLH after cytokine release syndrome had improved. Both were treated with emapalumab (an interferon-gamma blocking antibody), and the authors reported rapid improvement in symptoms and blood markers, supporting the idea that interferon-gamma may be an important driver in at least some cases. Because this report involved only two patients, it cannot show how often this approach works or how it compares with other treatments. [29]

For patients and caregivers, these studies reinforce that HLH after CAR T therapy is not common, but when it happens it can be very serious and may occur alongside other inflammatory side effects and infections. The most reliable information about how often it occurs comes from pooled data across many studies, while the very high death rate reported by one center shows that outcomes may differ by patient population and care setting. Targeted immune-blocking treatment aimed at interferon-gamma is still supported by very limited data (two patients), so its role remains uncertain and mainly background research at this time. [27] [28] [29]

Across this group of studies, a common message was that pinpointing the genetic cause of hemophagocytic lymphohistiocytosis (HLH) or related immune disorders can change how teams think about timing and goals of care, including whether a stem cell transplant is pursued as a cure. The evidence ranges from small patient reports to retrospective cohorts, so many conclusions are still uncertain, but the direction consistently supports combining genetics with immune function testing when the presentation is atypical. [30] [31] [32] [33]

In a small retrospective cohort of seven children with genetically confirmed primary HLH, treatment with emapalumab (a medicine that blocks interferon-gamma) was linked to rapid control of HLH activity and allowed most children to proceed to hematopoietic stem cell transplantation (HSCT). A higher starting dose strategy reached inactive disease faster than a lower starting dose strategy in this single-center experience, and the study reported no treatment-related safety concerns during emapalumab use. [34]

Several case-based reports showed how genetics and lab-based functional testing can explain unusual HLH presentations and reduce confusion when symptoms do not fit classic patterns. Two children with Griscelli syndrome type 2 had normal-looking pigmentation but severely reduced immune cell degranulation, explained by specific RAB27A variants that preserved pigment cell transport while impairing immune granule release; one child died shortly after transplant. A separate single-child report found a STX11 variant that produced an unstable protein with partial remaining function, matching a more gradual, self-limited inflammatory phase before full HLH developed. [30] [31]

Transplant as a potential cure was also described in rare, HLH-adjacent genetic immune disorders and in Epstein-Barr virus (EBV)-driven conditions. In HEM1 deficiency (NCKAP1L-related disease), one transplanted sibling achieved full donor blood system replacement and was doing well four years later, although she had a serious liver blood-flow complication after transplant that required treatment; the younger sibling had not been transplanted at follow-up. In CD137 deficiency (TNFRSF9), a case series plus literature review reported frequent EBV viremia, HLH or overgrowth of immune cells, and lymphoma; transplanted patients were alive at last follow-up, while deaths occurred among non-transplanted patients in reported cases. [35] [33]

Two studies added context for EBV-triggered inflammation and how it can overlap with inherited HLH. One adult case report showed that UNC13D gene mutations can underlie adult-onset primary HLH even when EBV infection is present, and the care plan included chemotherapy for HLH and planning for a family donor transplant. In a retrospective cohort of 75 people with chronic active EBV infection, allogeneic HSCT had better response and survival outcomes than non-transplant approaches overall; a PD-1 blocking medicine had similar outcomes to HSCT in a subset, and having HLH was an independent risk factor for worse survival. [32] [36]

Finally, one mouse study explored gene editing as a future route toward cure for familial HLH type 3 (UNC13D-related disease). Using cytosine base editing to correct a harmful splice signal restored immune cell killing function and, after transplanting edited blood stem cells, protected mice from virus-triggered HLH; however, the study also found off-target DNA changes and chromosomal rearrangements that differed by editing platform and cell type, underlining safety questions that still need careful study before human use. [37]

For patients and caregivers, this set of papers mainly reinforces that HLH can have different genetic causes, and that some gene changes can lead to unusual or delayed features, including cases where skin or hair changes are absent or where inflammation builds over time. Right now, the most immediately relevant information is from the clinical cohorts and case series showing how immune control treatments may help patients reach transplant, and how transplant outcomes can differ depending on the underlying condition and whether HLH is present (for example in chronic active EBV infection). The gene-editing work is early, animal-based research that helps scientists understand what might be possible in the future, but it also highlights unresolved safety issues such as off-target edits and DNA rearrangements. [34] [36] [37]

Across these reports, higher risk in hemophagocytic lymphohistiocytosis (HLH) was tied to how sick someone is early on and to measurable blood markers of inflammation and organ stress. Several papers also showed that HLH can be mistaken for sepsis or start with brain symptoms, which can delay diagnosis and may worsen outcomes. Overall, the evidence is mostly retrospective and exploratory, meaning it can describe patterns but cannot prove cause and effect. [38] [39] [40] [41]

In a retrospective study of 204 people aged 65 years and older with HLH, five factors were linked to higher 30-day death risk: older age, lower platelet count, higher liver enzyme (ALT), higher urea (a kidney-related blood test), and higher ferritin (an inflammation-related blood marker). The authors built a prediction tool using these factors that separated people into higher vs lower short-term risk groups in the same dataset. [39]

A systematic review focused on HLH with persistent high lactate (a blood marker often checked in very ill patients) described a high-mortality pattern, with many patients initially treated as having sepsis. Survival tracked more strongly with whether lactate fell within 72 hours after HLH treatment started than with the highest lactate level reached, and longer time from symptom onset to diagnosis was reported in those who did not survive. [38]

In a small single-center pediatric cohort (20 children) with HLH affecting the central nervous system, seizures were common and brain imaging was abnormal in nearly all imaged patients; spinal fluid abnormalities were also frequent. Many children were first evaluated for other conditions, suggesting that early HLH can be harder to recognize when brain symptoms come first or overshadow other signs; in the available follow-up, fewer than half survived. [40]

One case report described a 24-year-old man with a sepsis-HLH overlap picture who developed life-threatening bleeding problems, including spontaneous spleen rupture and bleeding in the brain, and required a long intensive care unit stay and rehabilitation. This single-patient experience illustrates how severe HLH-related inflammation and clotting problems can become when the trigger is unclear and illness is critical, but it cannot be used to estimate risk for others. [41]

One additional study in this set was in a different histiocytic disorder (Langerhans cell histiocytosis, not HLH) and reported that fever at the first visit identified children who had much poorer response to first treatment and shorter time without worsening, although later-line or targeted treatments narrowed this gap. While not directly about HLH, it supports the broader idea that early fever and stronger inflammation signals can mark more aggressive disease biology in related immune disorders. [42]

For patients and caregivers, these papers mainly add context about who tends to have a harder early course with HLH: older adults with certain abnormal blood tests, people who present with very high lactate that does not quickly improve after HLH treatment begins, and children whose first major symptoms are seizures or other brain problems. They also underline an ongoing uncertainty: many reported risks may partly reflect delays in recognizing HLH because it can look like severe infection, and most data come from retrospective reports rather than planned studies.