August 2026 Research Update

Across these studies, the main pattern was that combining a small number of early, routinely available clinical signs and blood tests into a risk score or calculator separated higher-risk from lower-risk groups better than relying on any one feature alone. These tools were built and tested within the same hospital datasets, so it remains unclear how well they work in different centers, countries, or patient groups.

In 190 adults hospitalized for adult-onset Still's disease, a five-item risk score (fever level, platelet count, D-dimer, a systemic disease activity score, and early response to glucocorticoids) showed good ability to identify who developed hemophagocytic lymphohistiocytosis or macrophage activation syndrome during the hospital stay. The study reported an overall accuracy pattern that looked solid on internal checks, but it was based on one center and needs outside validation. [1]

In 106 hospitalized children, a five-variable model aimed to distinguish Epstein-Barr virus (EBV)-related HLH from macrophage activation syndrome within the first 48 hours of admission, using rash, enlarged liver/spleen, bone marrow hemophagocytosis, fibrinogen, and neutrophil percentage. The model showed strong separation between the two groups in internal validation, and the authors provided a nomogram and online calculator, but it was still single-center and retrospective. [2]

For patients and caregivers, this body of work mainly matters as background on how hospitals may try to recognize HLH sooner in specific settings (such as adult-onset Still's disease in adults, or EBV-related illness in children). Because these tools were developed in single centers and have not been validated broadly, it is still uncertain how reliably they apply to other hospitals, ages, and underlying causes of HLH.

These papers together suggest that earlier diagnosis may come from two complementary approaches: (1) using certain blood markers to help distinguish HLH from other severe illnesses, and (2) using targeted tissue sampling when HLH may be driven by an underlying cancer. The evidence is mostly from small or single-center studies, so the accuracy and practical value of each approach outside those settings is still uncertain.

In a prospective study of 75 critically ill children with very high ferritin, ferritin levels separated adjudicated HLH from non-HLH conditions better than soluble interleukin-2 receptor alpha (sIL-2Ra), and ferritin also predicted pediatric ICU mortality better than sIL-2Ra. Adding sIL-2Ra did not meaningfully improve how well ferritin performed in this dataset, and the authors noted limits such as single-center design and lab assay differences. [3]

In 60 children with EBV-associated HLH receiving first-line etoposide-based treatment, changes over the first 2 weeks in plasma EBV-DNA, ferritin, and interferon-gamma (IFN-gamma) helped identify who was more likely to have worse outcomes. The study created a prognostic nomogram that performed better than using week-2 EBV-DNA alone, but it was retrospective and needs external validation. [4]

In a case series of three adults with HLH, liver lesions, and severe low platelets that did not respond to transfusions, a transjugular liver biopsy identified aggressive B-cell lymphoma as the underlying cause in all three patients. The authors reported no major biopsy-related bleeding, and in two patients platelet counts and HLH inflammation improved after lymphoma-directed therapy, while the third had a complicated course with infection. Because this describes only three people, the results may not apply to others. [5]

Right now, these studies add context for why certain blood tests may be tracked closely when HLH is being considered, and why doctors sometimes pursue tissue sampling to look for an underlying trigger like lymphoma when the liver is involved. What remains uncertain is how well specific marker cutoffs or combined marker approaches perform across different hospitals and lab platforms, and when invasive testing changes outcomes in larger, more varied groups.

These reports show that many different infections can trigger hemophagocytic lymphohistiocytosis (HLH), including common viruses and less common fungal, parasitic, and mycobacterial infections. A repeated pattern was very high inflammation and low blood counts, but the course varied widely: some people improved quickly once the specific infection was identified and treated, while others became critically ill or died despite intensive care. Several cases also highlight that risk and severity may be influenced by the immune system being weakened (from medicines or cancer therapies) or by overlapping triggers such as coinfections.

Viral triggers ranged from influenza A(H1N1) in an infant to herpesviruses in adults with immune suppression. An 8-month-old with influenza A(H1N1) developed severe HLH with very high inflammatory blood markers and died from progressive heart-lung failure despite multiple HLH-focused therapies; genetic testing found uncertain variants that raised the possibility of an underlying immune vulnerability. [6]

In another viral case, a 27-year-old with Crohn's disease and psoriasis developed HSV-1 (herpes simplex virus type 1) related HLH after long-term sequential immune-suppressing treatments that included a JAK inhibitor (upadacitinib). HSV-1 was detected using metagenomic sequencing, and the patient improved after antiviral and immune-modulating medicines were started and the JAK inhibitor was stopped. [7]

HHV-6 (human herpesvirus 6) was reported as a late trigger after cancer cell therapy: a 76-year-old man developed HHV-6 encephalitis with secondary HLH 14 months after CAR-T therapy and died from a bacterial infection despite antiviral and HLH-directed treatment. This case underlines that infection-triggered HLH can appear long after major immune-altering therapies, and can involve the brain and spinal fluid. [8]

Several cases involved infections that are often harder to recognize because they can mimic other illnesses. Two separate reports described disseminated histoplasmosis (a fungal infection) causing HLH: one in a 72-year-old woman with rheumatoid arthritis on immune-suppressing medicines, and one in an immunocompetent 73-year-old man whose earlier diagnosis of sarcoidosis was revised. Both were treated with antifungal therapy plus a short steroid course or taper; the first report described rapid improvement, while the second report's summary did not describe the outcome. [9] [10]

Parasitic infections were also reported as triggers, sometimes requiring advanced testing to identify the cause. In two adults with visceral leishmaniasis related HLH, standard smears were negative, but metagenomic sequencing identified the parasite and targeted anti-parasitic treatment was followed by rapid clinical and lab recovery. [11]

A separate leishmaniasis case in an immunocompetent 68-year-old man used a combination of scoring tools and bone marrow molecular testing to confirm infection, and markers such as ferritin and soluble CD25 fell as the patient improved after anti-parasitic therapy and steroids. [12]

Some reports suggested a "double trigger" or overlap between infections. A 63-year-old woman with mixed malaria (two Plasmodium species) plus SARS-CoV-2 met multiple HLH criteria and improved rapidly after antimalarial therapy with short-term steroids, with parasite clearance reported by day 3. [13]

Liver infections were described as another possible trigger on the HLH spectrum. A 30-year-old man with hepatitis A and hepatitis E coinfection met several HLH criteria (including very high ferritin and bone marrow hemophagocytosis) but recovered with supportive care alone, showing that infection-driven hyperinflammation can sometimes resolve without HLH-directed immune suppression in selected situations. [14]

Bacterial-like triggers and exposures also appeared, including mycobacterial disease after bladder cancer therapy. A 50-year-old man developed HLH after intravesical Bacillus Calmette-Guerin (BCG) treatment, had Mycobacterium bovis detected in urine by PCR, improved briefly with steroids, and then died despite escalation to etoposide, highlighting how HLH can resemble severe infection (sepsis) with multiorgan problems. [15]

Finally, severe fever with thrombocytopenia syndrome (SFTS), a viral illness, was linked to HLH-like tissue damage in the lungs. In an autopsy-proven fatal case in a 79-year-old man with underlying lung disease, chest scans progressed to widespread lung consolidation, and autopsy showed diffuse lung bleeding and hemophagocytosis with many virus-infected cells in lung tissue. [16]

For patients and caregivers, this set of papers mainly serves as background on how wide the range of infectious triggers can be, and why clinicians often keep searching for a specific infection even when early tests are negative. It also shows that the same overall syndrome can have very different paths, from recovery after treating the underlying infection (including fungal or parasitic infections that may be missed at first) to life-threatening organ failure, sometimes shaped by immune suppression, coinfections, or possible underlying immune vulnerabilities. Because these are mostly single-patient reports (and one two-patient series), it is still uncertain how often each trigger occurs or which factors most strongly predict who will recover versus become critically ill.

Across these papers, hemophagocytic lymphohistiocytosis (HLH) was described as a serious complication that can occur alongside several blood cancers, especially lymphomas, and sometimes during cancer treatment. The overall direction of the evidence suggests HLH can signal a more severe course or higher risk situation, but most details come from individual case reports, so it is hard to know how often each pattern occurs. The strongest evidence in this set came from one larger pediatric lymphoma study showing that HLH present at diagnosis was linked to worse outcomes.

In a multicenter review of 294 children newly diagnosed with non-Hodgkin lymphoma, survival improved in later years overall, but having HLH at the time of lymphoma diagnosis was an independent risk factor for both event-free survival and overall survival. [17] This means that, in children with lymphoma, HLH at diagnosis marked a higher-risk group even as overall care outcomes improved over time. [17]

Several case reports showed that HLH can be the first clue of an underlying lymphoma and may involve major organ inflammation. One 24-year-old man presented with severe acute hepatitis and was ultimately diagnosed with diffuse large B-cell lymphoma, with rapid clinical deterioration despite initial immune-suppressing treatment. [18] Another report described intravascular large B-cell lymphoma diagnosed through a skin biopsy after HLH features, with later clinical and scan improvement during lymphoma-directed therapy, although a fever during low white blood cell counts occurred. [19]

EBV (Epstein-Barr virus)-related immune activation was a recurring thread in lymphoma-linked HLH in two single-patient reports. An older man with EBV-positive classic Hodgkin lymphoma had persistent fever and HLH that improved quickly after rituximab was added, with blood markers dropping within a week and EBV DNA becoming undetectable, followed by a complete response to lymphoma therapy. [20] In a separate elderly patient previously treated with rituximab for follicular lymphoma, an EBV-positive T-cell lymphoproliferative disorder developed with HLH, and evaluation included bone marrow examination and EBV viral load. [21]

Two other case reports emphasized that HLH may coincide with very aggressive disease behavior in different cancer settings. A 37-year-old man with a HAVCR2-mutated subcutaneous panniculitis-like T-cell lymphoma developed rapidly progressive HLH with liver failure and fatal brain bleeding, and autopsy showed widespread tumor involvement in fat tissue and bone marrow. [22] In a 76-year-old man with multiple myeloma, HLH occurred during daratumumab-based therapy and came before a rapid relapse; autopsy showed widespread cancer outside the bone marrow with only minimal visible hemophagocytosis. [23]

For patients and caregivers, these papers mainly add context about how HLH can appear in real-world cancer situations: as a severe inflammatory state that may show up with fever, hepatitis (liver inflammation), low blood counts, or enlarged liver and spleen, and sometimes around changes in the cancer itself. The pediatric study suggests HLH at the time of lymphoma diagnosis can identify children with higher risk, but the adult evidence here is largely from single-patient stories that cannot predict what will happen to others. Important uncertainties remain, including how often HLH occurs in each cancer type and which lab or biopsy patterns best reflect what is happening in the body in different settings.

In August 2026 papers on hemophagocytic lymphohistiocytosis (HLH), the treatments tried were mostly reported in single patients or very small series, so the evidence is early and cannot show which approach is best overall. The overall pattern was to combine steroids with therapies aimed at the suspected driver of inflammation: cancer therapy, infection treatment, or targeted immune-blocking medicines. Several reports described quick drops in fever and inflammation blood markers after targeted immune therapies, but results were not consistent across situations. [24] [25] [26] [9] [27] [28] [29] [30]

When HLH happened alongside blood cancer, one report described combining an HLH-94-based regimen with venetoclax (a leukemia medicine). In that one 27-year-old patient with CD56-positive acute myeloid leukemia and HLH, fever resolved, HLH lab markers improved, bone marrow blasts dropped to 3% after two weeks, and complete remission was reported later, while the authors noted long-term durability is unknown. [24]

Several papers focused on targeted immune-suppressing medicines added to steroids, especially when HLH was linked to immune therapies or severe inflammation after transplant. A 3-patient series of immune checkpoint inhibitor-related HLH used dexamethasone plus one of anakinra, ruxolitinib, or tocilizumab, with variable responses between patients. In two post-transplant cases with early hyperinflammatory toxicities, one patient meeting clinical features of secondary HLH improved rapidly after a single dose of emapalumab, and another with a cytokine-related neurologic syndrome improved within 24 hours after tocilizumab. [25] [26]

In HLH-like syndromes tied to autoimmune disease, case reports described steroid-centered combinations with other immune suppressants. A 14-month-old with Kawasaki disease-associated macrophage activation syndrome (a related hyperinflammatory condition) improved quickly on ruxolitinib plus corticosteroids after failing standard Kawasaki disease therapy, with normal labs reported at 1 month. A 15-year-old with systemic lupus erythematosus-related macrophage activation syndrome and Epstein-Barr virus-related Evans syndrome improved after methylprednisolone, cyclosporine A, and high-dose intravenous immunoglobulin, along with supportive antibiotics and antivirals, and was discharged after 20 days. [27] [28]

When a treatable infection appeared to be the trigger, one report emphasized antifungal therapy alongside a short steroid course rather than intensive HLH chemotherapy. A 72-year-old woman with rheumatoid arthritis on immune-suppressing drugs developed disseminated histoplasmosis with secondary HLH and improved rapidly with liposomal amphotericin B followed by itraconazole plus short-course dexamethasone, with imaging showing resolution of splenic lesions at 12 months and no need for etoposide-based HLH therapy. [9]

A few reports explored less common or less well-described options as possible "bridge" treatments toward stem cell transplant in refractory, Epstein-Barr virus (EBV)-associated settings. One case report described Tripterygium glycosides in secondary HLH with aggressive natural killer cell leukemia and EBV infection, with clinical and lab improvement within 3 weeks and lab-based testing suggesting the drug component triptolide could kill the patient's cells outside the body. Another paper mentioned golidocitinib used as salvage therapy before allogeneic stem cell transplant in refractory EBV-associated HLH, but details and outcomes were not available from the provided text. [29] [30]

For patients and caregivers, these papers mainly show the range of treatments clinicians may consider depending on what is driving HLH (for example, cancer, infection, immune therapy side effects, autoimmune disease, or post-transplant inflammation). Most of the evidence here comes from single-patient reports or very small series, so it is most useful as background on what has been tried, not proof that any one approach works broadly. What remains uncertain is how well these approaches compare across different HLH triggers, how durable responses are, and which patients benefit most from targeted immune-blocking drugs versus treating the underlying trigger alone. [24] [25] [26] [9] [27] [28] [29] [30]

Across these papers, transplant was described as a key part of long-term management for some people with hemophagocytic lymphohistiocytosis (HLH), but long-term outcomes were strongly influenced by nervous system involvement and by transplant-related risks. Larger cohort data in children clarified that neurological problems can persist or appear years after transplant, while smaller reports showed that transplant can lead to long remissions even when HLH mainly affects the nervous system. [31] [32] [33]

In a prospective multinational pediatric cohort (365 children), having both neurological symptoms and abnormal spinal fluid at diagnosis predicted worse survival. Among long-term survivors who had a transplant, nearly one-third still had neurological symptoms at last follow-up, including movement and development delays, seizures, and later diagnoses of attention or autism-related conditions, sometimes identified several years after transplant. [31]

Two small reports highlighted that HLH can sometimes show up first as nervous system disease and that outcomes can differ depending on whether transplant can be completed. One 13-year-old with familial HLH type 3 and isolated brain involvement had neurological remission after donor stem cell transplant and remained without relapse at 679 days, with minimal toxicity reported. [32]

In a report of two adults with UNC13D deficiency, both initially had autoimmune-type neuropathy before later progressing to familial HLH; one improved neurologically and clinically 1 year after transplant, while the other died after disease progression when a suitable donor could not be found. This suggests donor availability and timing may be important contributors to long-term outcome in some genetic forms that involve the nerves. [33]

Separate from HLH-specific outcomes, a small prospective cohort of 20 children with genetic rare diseases described a transplant preparation approach that used close drug-level monitoring for one chemotherapy medicine to guide dosing. The study reported reliable engraftment (no graft failure) and long follow-up survival results, while also noting that graft-versus-host disease still occurred in a subset. [34]

For patients and caregivers, these studies mainly add context about what long-term life after transplant can look like, especially when HLH affects the brain, spinal cord, or peripheral nerves. The strongest evidence here comes from a large pediatric cohort showing that early nervous system involvement can signal higher risk and that neurological or developmental challenges may continue or appear years later, even in survivors; the case reports show what is possible for individual patients but cannot predict typical outcomes. What remains uncertain is how often specific long-term neurological issues occur across different HLH subtypes and how much outcomes vary by transplant approach, donor factors, and pre-transplant nervous system disease.

Across these studies, survival risk in hemophagocytic lymphohistiocytosis (HLH) appeared to vary with the underlying trigger (especially cancer-related HLH), signs of more severe inflammation or organ stress in blood tests, and abnormalities in blood clotting. Several reports suggested that single lab tests do not perform the same way in every setting, with ferritin showing mixed value depending on whether patients had HLH itself or severe infection where HLH may develop. Overall, the evidence comes mainly from observational studies, so results can be influenced by differences in patient mix and care. [35] [36] [37] [38]

In a systematic review of 18 adult observational cohorts (3,570 people), overall mortality was about 49.5%, and HLH linked to cancer had higher mortality than non-cancer triggers. Older age, higher ferritin, and higher lactate dehydrogenase (a blood marker that can rise with tissue stress) each added independent information about death risk, while low platelets and a prolonged clotting test trend were harmful but less certain. The authors noted substantial differences between studies and possible confounding, limiting precision. [35]

In a retrospective study of 90 people with secondary HLH, remission status strongly separated outcomes: most patients who did not reach remission died in the hospital. Lower absolute neutrophil count (a measure of infection-fighting white blood cells) at diagnosis and a lower lowest neutrophil count during hospitalization were linked to higher mortality, while ferritin was not a helpful predictor in this group. Treatment with dexamethasone was associated with better outcomes in this dataset. [36]

In a retrospective cohort of 75 children with HLH, younger age, a more prolonged activated partial thromboplastin time (a blood clotting test), and lower fibrinogen (a clotting protein) independently predicted worse outcomes. A combined model using these three factors showed good accuracy for distinguishing higher- and lower-risk patients in this single-center dataset (AUC 0.88). This points to clotting-system disruption as an important risk signal in pediatric HLH. [37]

In a prospective study of 123 children with severe sepsis or septic shock (not all with HLH), higher ferritin was linked to septic shock and to higher mortality. The study also reported that a higher ferritin threshold identified children thought to have secondary HLH with high sensitivity and specificity in that sepsis population. This supports ferritin as a marker of severe inflammation in infection, but it does not prove ferritin predicts outcomes the same way once HLH is confirmed or across different HLH triggers. [38]

For patients and caregivers, these papers add detail about which clinical features tended to travel with higher risk of death in different HLH settings: cancer-related HLH in adults, very low neutrophil counts in secondary HLH, and clotting abnormalities (prolonged clotting times and low fibrinogen) in children. They also show that ferritin can mean different things depending on the situation: it was useful for risk and possible secondary HLH in severe infection, but not prognostic in one confirmed secondary HLH cohort, and it had mixed but sometimes independent prognostic value in adult pooled data. What remains uncertain is how well any single marker predicts an individual person outcome across hospitals and HLH subtypes, since most evidence here is observational and affected by differences in triggers, timing, and treatments. [35]

Across these papers, a clearer picture emerges that hemophagocytic lymphohistiocytosis (HLH) can involve multiple immune system problems happening at the same time, rather than a single "overactive" cell type. Detailed blood-cell profiling in Epstein-Barr virus (EBV)-related HLH points to a tug-of-war between inflammatory signals and immune-suppressing signals, alongside signs that key virus-fighting T cells may become less effective. [39]

In one exploratory study of six people with EBV-HLH, researchers found EBV-transcript positive NK/NKT-like cells that showed clonal expansion and strong cytokine signaling, including interferon-gamma (IFN-gamma) and IL-10 pathways. They also reported monocytes shifting toward an immune-suppressing pattern marked by TGFB1, and signs of CD8 T-cell exhaustion, which in plain language suggests some immune cells may be "revved up" while others are less able to clear the virus. These patterns were supported using flow cytometry and blood-protein tests in a separate group of 37 people with secondary HLH. [39]

The same work also reported reduced diversity in T-cell receptor patterns in HLH blood samples, which can reflect a narrowed immune response. It also suggested that NK/NKT-like cells may communicate with other immune cells through specific receptor-ligand pathways (NECTIN2-CD226 and NECTIN2-TIGIT), although this type of signaling is predicted from data and not yet proven to cause disease changes. [39]

For patients and caregivers, this research mainly matters as background science that may help explain why EBV-linked HLH can be difficult for the immune system to control: the studies point to both inflammation and immune "brakes" operating together, plus signs of T cells becoming less functional. The evidence here is early and based on small numbers, so it cannot yet say which immune changes matter most in each person or how best to use these signals for day-to-day care. [39]

These results suggest that when HLH occurs in the setting of inborn errors of immunity (genetic immune system conditions), it may be part of a broader pattern of immune imbalance that can also include autoimmune blood problems and lymph tissue overgrowth. In a real-world cohort, outcomes differed across patients and treatment approaches, and the study emphasized that incomplete molecular diagnoses can limit how precisely care can be tailored to the underlying immune mechanism. [40]

In a multicenter Italian retrospective study of 116 patients with inborn errors of immunity and blood-related immune dysregulation, targeted therapies overall had higher response rates than non-targeted regimens, though the group included several conditions beyond HLH. For the subset treated with HLH-specific regimens, complete response was 20%, partial response was 40%, and no response was 40%, with HLH-related mortality reported as 27.3%. The authors noted heterogeneity, referral bias, and limited genetic confirmation as important limits on what can be concluded. [40]

For families affected by HLH alongside a known or suspected inherited immune condition, this study reinforces that HLH can appear within a wider immune dysregulation picture and that outcomes can vary. Because the evidence is retrospective and includes diverse diagnoses and treatment choices, it mainly helps describe real-world complexity rather than giving clear, one-size conclusions about HLH mechanisms or which approach fits an individual patient. [40]