September 2026 Research Update

Across these studies, researchers focused on tests done on blood to help (1) recognize hemophagocytic lymphohistiocytosis (HLH) earlier, (2) tell HLH apart from other severe illnesses such as sepsis or uncomplicated Epstein-Barr virus (EBV) infection, and (3) estimate how severe HLH may be. Overall, the papers pointed toward using combinations of results (cytokines, routine labs, immune cell measurements, virus levels, and genetics) rather than relying on a single number, but most approaches were developed in single countries or single centers and need broader confirmation. [1] [2] [3] [4] [5] [6]

In a prospective single-center study of 180 children with different HLH causes, cytokine patterns and lymphocyte (a type of white blood cell) subsets differed by cause, and a combined model using cause plus a 15-marker cytokine panel plus lymphocyte measurements separated higher-risk from lower-risk children. The study also reported that a change in interferon-gamma over the first week helped stratify death risk within each cause group, suggesting repeat testing may add information beyond the first-day results. [1]

Two studies focused on EBV-related situations in children. In Japan, baseline EBV DNA in plasma was higher in children who later had refractory or recurrent EBV-HLH than in those who went into remission, but the ability to separate these groups was only modest and the authors stated plasma EBV DNA should not be used alone; EBV DNA in blood cells did not differ between groups. In China, a machine-learning tool using five routine admission markers (triglycerides, interferon-gamma, ferritin, platelet count, and the CD4/CD8 ratio) showed strong internal performance for distinguishing EBV-HLH from uncomplicated EBV infection, but it still lacks external multicenter validation. [4] [2]

For situations where HLH can resemble other critical illnesses, a cross-sectional adult study suggested that certain activated CD8 T-cell subsets measured by flow cytometry (CD38 and HLA-DR markers) differed between sepsis and HLH, with proposed cutoffs showing high sensitivity and specificity in that dataset. Because this was a single study without reported sample size and was cross-sectional, the authors called for larger validation before these markers can be considered reliable in broader practice. [3]

Two papers looked beyond standard blood tests to identify triggers or inherited contributions. In a study of 19 children with suspected or confirmed HLH, researchers sequenced genetic material (RNA) in blood plasma to look for viruses. Two children already known to have EBV- or CMV-associated HLH were included to check the method. Among the other 17 children, sequencing detected genetic material from HHV-6B, HHV-7, and a little-known virus called HRLV 14 in one child each. The study also found differences in host gene activity between virus-positive and virus-negative groups. Some findings were checked using PCR, but HRLV 14 could not be confirmed. The study was small and did not establish whether the detected viruses caused HLH. In a large Chinese multicenter genetic study of 1224 people with confirmed or suspected HLH, about 29% carried variants in a 12-gene panel and 108 had a definite genetic diagnosis, showing that genetic testing can identify inherited forms in a subset and that the most common genes in this population were UNC13D, LYST, and PRF1. [5] [6]

For patients and caregivers, these studies help explain why HLH evaluation often involves multiple blood tests and sometimes specialized immune testing or genetic testing: different tests answer different questions (possible trigger, immune activation pattern, inherited risk, and illness severity). Most of the tools described here are early-stage or location-specific and still need confirmation in other hospitals and patient groups, so it remains uncertain how widely they will be used and how well they will perform in everyday care.

Across these papers, the main direction was toward clearer, more consistent language for diagnosing and describing hemophagocytic lymphohistiocytosis (HLH) and related severe inflammation. The goal is to reduce variation between hospitals and regions by using shared criteria, shared grading definitions, and structured checklists for evaluation. The papers do not present new patient outcome data; they focus on standardization and practical guidance. [7] [8] [9]

A Gulf Cooperation Council (GCC) expert panel produced 40 consensus statements for adults and children, with agreement reached in the first voting round. The recommendations highlighted early recognition and using established tools (HLH-2004 criteria and the HScore) as supportive ways to organize suspected HLH evaluation. They also emphasized looking for possible triggers in parallel (such as infections, cancers, rheumatologic disease, or genetic causes) and noted the need for rapid escalation to intensive care and transplant-capable centers when illness is severe. [7]

The 2026 Chinese HLH guidelines summarized 16 recommendations across 11 domains, spanning classification, diagnostic criteria, lab testing, treatment strategies, and how response is evaluated. This type of document is intended to make care more consistent within a health system by setting shared expectations for what should be assessed and how HLH is categorized. The summary provided did not include details of the individual recommendations. [8]

Separately, an updated consensus document from the American Society for Transplantation and Cellular Therapy (ASTCT) focused on standard definitions and grading for immune effector cell therapy toxicities, including an HLH-like syndrome linked to these therapies. The stated purpose was to make toxicity reporting more comparable across clinical trials and real-world care, and to help clinicians describe severity in a consistent way that can connect to management guidance. This is relevant to HLH because some therapy-related toxicities can resemble HLH or share overlapping features of uncontrolled inflammation. [9]

For patients and caregivers, these publications mainly matter as background work that can improve consistency: when teams use shared criteria, shared scoring tools, and shared grading language, communication between hospitals and across studies can be clearer. They do not change what any one person is experiencing day to day, and they do not provide new evidence that a specific approach leads to better outcomes. Uncertainty remains because guidelines can differ by region and are influenced by local resources, and because standardized definitions still need validation through real-world data collection and research comparisons.

Across these retrospective studies, several routine lab tests and imaging findings at diagnosis or hospital admission lined up with differences in survival in hemophagocytic lymphohistiocytosis (HLH). The overall pattern was that signs of stronger inflammation (such as very high ferritin), signs of liver/bile stress (higher bilirubin), changes in blood counts and clotting markers, and fluid buildup in the abdomen were linked to worse outcomes, although these studies cannot prove cause and effect. [10] [11] [12] [13]

In a small pediatric series of secondary HLH/macrophage activation syndrome (MAS), survival differed alongside ferritin and fibrinogen levels, with ferritin highlighted as a useful marker for prognosis. This study included 26 children and reported 65% survival and 35% deaths, with rheumatologic triggers most common. [10]

In adults with secondary HLH, fluid in the belly (peritoneal effusion) at diagnosis was linked to much shorter survival and remained a predictor of worse overall survival even after accounting for other factors. People with peritoneal effusion also tended to have lower blood cell counts, higher direct bilirubin, and an immune-cell pattern that included lower CD4 T cells and higher natural killer (NK) cell percentages in the subset with available data. [11]

Two adult studies pointed to bilirubin as a warning sign for short-term outcomes. In a 269-person secondary HLH cohort, higher total bilirubin and higher alkaline phosphatase on admission were independently linked to higher in-hospital death at 7 and/or 28 days, while the more common liver enzymes (ALT and AST) were not after adjustment. [12]

In a 251-person lymphoma-associated HLH cohort, elevated total bilirubin tracked with other signs of more severe illness, including higher soluble CD25, higher ALT and AST, and lower platelets and fibrinogen. In the subgroup with HLH triggered by T/NK-cell non-Hodgkin lymphoma, higher bilirubin was linked to worse 60-day survival and shorter overall survival. [13]

For the sickest children needing extracorporeal membrane oxygenation (ECMO), outcomes were guarded but not uniformly poor. In a 30-patient multicenter study, 63% survived to coming off ECMO and 37% survived to hospital discharge, and half of ECMO deaths occurred within the first 10 days; survivors often had functional limitations and major multi-organ problems. Survival to coming off ECMO was higher when HLH was diagnosed while already on ECMO than when HLH was diagnosed before ECMO. [14]

These studies suggest that everyday information available early in care, such as bilirubin and other liver-related blood tests, ferritin and fibrinogen, blood counts, and whether fluid is seen in the abdomen on imaging, can help describe risk in secondary HLH and lymphoma-associated HLH. Most results matter now as context for how clinicians talk about severity and short-term risk, but they are not definitive because the evidence comes from retrospective, single-center (or limited-center) datasets and may not apply the same way to every HLH trigger or age group. What remains uncertain is how well any single marker predicts an individual person's outcome, and whether changing these markers directly would change survival.

Across these papers (mostly single-patient reports and one three-patient series), a consistent pattern was that an infection can trigger secondary hemophagocytic lymphohistiocytosis (HLH), sometimes even when the infection is not obvious at first. Several reports described organ involvement such as enlarged liver and spleen, lung changes on scans, pancreatitis, or clotting problems, alongside high inflammation blood markers and low blood counts. Overall, patients improved when both the infection and the overactive immune response were addressed, but outcomes varied in severe multi-organ illness.

In one patient with multiple sclerosis taking ocrelizumab (a B-cell depleting medicine), Babesia infection triggered HLH even though the parasite level in blood was extremely low on the smear. Microbial cell-free DNA next-generation sequencing helped point to Babesia, which was then confirmed by blood testing, and the patient improved after anti-parasite treatment plus corticosteroids. [15]

Two reports showed HIV-related situations where HLH was part of the first presentation or a complication of severe infection. A 19-year-old man had HLH as the initial manifestation of acute HIV-1 infection and improved quickly after starting antiretroviral therapy and corticosteroids, with no relapse reported at 8 months. [16]

In a small case series of three adults with HIV/AIDS, disseminated Talaromyces marneffei fungal infection was complicated by HLH; two people recovered and one died in the setting of poor baseline condition and multi-organ failure. The report described combined antifungal therapy along with corticosteroids for HLH, and it noted no major drug reactions during treatment in these three patients. [17]

Two malaria cases highlighted that HLH can appear during severe malaria, with different complication patterns and different levels of added immune-suppressing treatment. A 70-year-old traveler with severe Plasmodium falciparum malaria developed secondary HLH and required intensive care support, transfusions, and immune-targeting medicines in addition to antimalarial therapy, then improved enough to go home on steroid treatment, with near-complete settling of inflammation on blood tests at later follow-up visits. [18]

A separate report described a 19-year-old woman with severe Plasmodium vivax malaria who developed HLH along with disseminated intravascular coagulation and acute pancreatitis, and she improved with intravenous artesunate and supportive care without HLH-directed immunosuppression. The authors noted important uncertainties about confirming the exact malaria species and fully excluding other infections, reflecting real-world diagnostic limits in some settings. [19]

One neonatal case showed that HLH-like immune overactivation can also appear alongside severe metabolic illness, although how metabolic disorders lead to HLH is unclear. A newborn with classical galactosemia developed liver failure with prolonged clotting times and a transient low factor V level, and secondary HLH was diagnosed; the low factor V level resolved after treating the underlying galactosemia (the study summary does not say how the HLH itself responded). [20]

For patients and caregivers, these papers mainly add background on how widely different infections (and infection-like triggers during serious illness) can set off secondary HLH, including situations where the germ level is very low or hard to confirm with routine tests. The evidence here is limited because most reports involve one person (or three people), so it cannot predict what will happen for others, but it does show the range of organs that can be affected (blood counts, liver and spleen enlargement, lungs, clotting, pancreas) and the importance of identifying the specific trigger when possible. Uncertainties remain about why some people improve with infection treatment alone while others also receive immune-calming medicines, and which diagnostic tests are most useful when standard tests are negative.

Across these papers, hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS, a form of HLH linked to rheumatic/immune diseases) appeared as a severe "immune overreaction" that can mimic infection and involve different organs depending on the underlying immune condition. A recurring message was that blood tests and scoring tools may support the diagnosis, but they do not look identical across diseases, and bone marrow results can be absent or variable. Evidence here is mostly from case reports/series plus one moderate-sized retrospective adult study, so patterns are useful but not definitive. [21] [22] [23] [24] [25] [26]

In the multicenter adult comparison, MAS linked to systemic lupus erythematosus more often involved the central nervous system and showed stronger blood cell abnormalities, including frequent signals of autoimmune hemolysis, while MAS linked to Still's disease more often showed enlarged organs and more liver injury. People with lupus-MAS also tended to have lower ferritin and lower C-reactive protein than those with Still's disease-MAS, meaning "classic" inflammation markers may be less striking in some lupus cases. The same report noted that an interleukin-1 blocker (anakinra) was used more often in Still's disease-MAS and seemed less clearly effective in lupus-MAS in this retrospective dataset. [22]

A small cytokine study in lupus-MAS suggested that not all lupus-MAS inflammation looks the same: some patients had a pattern with higher interferon-alpha that tended to occur with low white blood cell counts and lupus kidney involvement, while another pattern with higher CXCL9 tracked with higher lactate dehydrogenase and higher HScore values. The authors emphasized these were descriptive, hypothesis-generating patterns rather than validated subtypes that can be used to choose treatment. [23]

Several individual patient reports illustrated how MAS/HLH can be difficult to confirm with a single test and can overlap with other severe immune complications. One infant with systemic juvenile idiopathic arthritis had MAS that looked like sepsis, with very high ferritin and abnormal clotting tests, but no hemophagocytosis seen in bone marrow; he improved rapidly after high-dose steroid treatment and had no relapse reported at 3 months. Another report described a woman with longstanding lupus and antiphospholipid syndrome who developed catastrophic clotting problems after heart valve surgery with suspected HLH overlap and recurrent lupus heart inflammation, progressing to multi-organ failure despite multiple immune therapies, complicated by infections, and she died about four months after surgery. [21] [24]

Rare or newly recognized immune conditions were also linked to MAS/HLH in these reports. In three older men with VEXAS syndrome, MAS was supported by very high HScore estimates and bone marrow showing activated macrophages or hemophagocytosis; all had rapid initial improvement with high-dose steroids, with additional medicines used in some cases, and one relapse occurred after exposure to a white blood cell growth factor (G-CSF). In a teenager with recurrent panniculitis (painful skin nodules) and a genital ulcer, MAS occurred in the setting of genetic variants including a newly described homozygous HAVCR2 change; she achieved sustained remission on steroids and tacrolimus in that single case. [26] [25]

For patients and caregivers, these studies reinforce that HLH/MAS linked to immune diseases is not one uniform illness: it may show up with different organ problems (for example brain symptoms in some lupus cases, liver injury in some Still's disease cases, or severe clotting problems in complex lupus-related overlap). They also show why clinicians may use multiple pieces of information (symptoms, blood markers, imaging, scoring tools, and sometimes bone marrow) rather than relying on one test, since bone marrow changes can be absent and inflammation markers can vary by underlying disease. Much of the evidence in this month is from small or retrospective reports, so it mainly helps explain why care teams may describe uncertainty and why outcomes can range from rapid improvement in some situations to severe, complicated courses in others.

Across these papers, hemophagocytic lymphohistiocytosis (HLH) was described as an intense inflammatory reaction that sometimes appeared after cancer treatments, including immune checkpoint inhibitors, tumor-infiltrating lymphocyte therapy, and adjuvant chemotherapy. Most evidence here is exploratory, largely based on case reports plus one systematic review of published cases, so results may not represent all patients. Overall, many patients improved with anti-inflammatory treatment, but serious complications and death were also reported, and the best way to confirm the diagnosis and track recovery varied across reports. [27] [28] [29]

In the systematic review of 96 published cases of immune checkpoint inhibitor-associated HLH, the most common cancers were melanoma and lung cancer, and symptoms often began early after starting treatment (median 2 cycles and 30 days). Fever and low blood counts were very common, ferritin levels were typically very high, and about 83% had a complete or partial HLH response after treatment, while about 25% died. All reported patients received corticosteroids, and some also received additional immune-targeting medicines or etoposide, reflecting that care approaches differed from case to case in the literature. [27]

One case report described HLH developing during tumor-infiltrating lymphocyte (TIL) therapy for metastatic melanoma, where disseminated toxoplasmosis was identified in the bone marrow and the brain. Despite targeted anti-toxoplasma treatment, the patient worsened and died, highlighting that infections during profound immune suppression can overlap with HLH and may be hard to control. The authors also noted gaps in prevention options when standard preventive antibiotics cannot be used due to intolerance. [28]

Another case report described a woman who developed secondary HLH during adjuvant chemotherapy for HER2-positive breast cancer and improved quickly after dexamethasone-based HLH treatment. She fully recovered her blood counts and later resumed parts of her cancer treatment plan, with no HLH recurrence reported over four years of follow-up in that single patient. This illustrates that some treatment-related HLH episodes may be reversible when recognized and treated. [29]

For patients and caregivers, these papers reinforce that HLH can sometimes be a rare but serious complication of certain cancer treatments, and it can also overlap with severe infections in people whose immune systems are suppressed. The strongest information here comes from a collection of published checkpoint inhibitor cases, but it still relies on reported cases rather than controlled trials, so estimates like death rates and response rates may not apply to every setting. What remains uncertain is which patients are most at risk, how best to standardize diagnosis across hospitals, and when (or whether) restarting an immune therapy after HLH is safe, since rechallenge experiences were limited and sometimes led to recurrence. [27]

These case reports describe HLH occurring as part of lymphoma, including situations where the lymphoma was not obvious at first. The shared pattern is that searching for an underlying cancer cause mattered, and tissue-based testing (such as bone marrow examination) played a central role when imaging or early evaluations did not fully explain the HLH. Because these are single-patient reports, they illustrate possibilities rather than giving general rates or predictions. [30]

In one 76-year-old man, secondary HLH was the initial presentation of an otherwise occult high-grade diffuse large B-cell lymphoma. After initial HLH-directed therapy, he improved rapidly once he started lymphoma-directed chemotherapy (R-mini-CHOP), and an interim PET-CT after two cycles showed a complete metabolic response; his day-to-day function improved from bedbound to walking independently. The authors emphasized that early bone marrow examination and multidisciplinary evaluation can be important when adult HLH has no clear trigger on initial testing. [30]

In a 28-year-old woman with relapsed extranodal NK/T-cell lymphoma, HLH occurred alongside oral mucosal involvement, described as recurrent oral ulcers. The report highlighted oral lesions as a potential early clue to lymphoma relapse with lymphoma-associated HLH, alongside systemic treatment for HLH and the lymphoma and supportive mouth care for symptoms. This single case suggests that mouth symptoms can be part of how lymphoma-associated HLH shows up, but it does not establish how common this is. [31]

For patients, this theme is mainly background information about why doctors may look for an underlying lymphoma when HLH occurs in adults, even if early scans do not show a clear cancer. These reports also show that symptoms affecting daily life, such as profound weakness or painful mouth ulcers, can occur in lymphoma-associated HLH, but they do not prove that these symptoms always indicate lymphoma or HLH. Uncertainty remains because single cases cannot tell how often HLH is the first sign of lymphoma, which tests are best for every person, or how quickly improvement should be expected in different lymphoma types. [30]

Across these reports, hemophagocytic lymphohistiocytosis (HLH) was described after medication reactions (including severe drug rashes) or a suspected toxin exposure, and it sometimes came with serious organ problems such as severe liver injury, kidney injury, or heart dysfunction. The evidence here is mainly from single-patient case reports (and one two-patient letter), so it shows what can happen but cannot predict how often it happens or which approach is best. A repeated theme was that clinicians had to sort out overlapping problems like infection, drug allergy, or other inflammatory complications while tracking inflammation blood markers over time. [32] [33] [34] [35] [36] [37]

In one adult with rheumatoid arthritis, leflunomide was linked to a severe drug reaction with rash and acute liver injury (including early confusion from liver dysfunction) along with secondary HLH, and the patient improved after drug removal steps plus immune-suppressing treatment. This case highlights that HLH can appear as part of a broader drug reaction affecting the skin and liver, with very high inflammation markers and low blood counts. [32]

In a child who developed a severe drug reaction after phenobarbital, HLH occurred along with a temporary episode of DAT-positive hemolysis (an immune test on red blood cells) during high-dose intravenous immunoglobulin (IVIG). The report emphasized that DAT positivity in this setting can be hard to interpret because it might reflect the illness itself or antibodies that came from IVIG, and the timing of tests mattered in their interpretation. [33]

Another report linked propylthiouracil (used for Graves' disease) to HLH with severe complications including shock, clotting problems, and multiorgan failure, followed by improvement after immune-suppressing medicines. After recovery, the patient ultimately had thyroid surgery, with allergy testing used to help manage multiple medication allergies around the operation. [34]

A separate adult case described HLH after suspected spider envenomation, with very high inflammation markers and temporary kidney failure needing dialysis, and improvement after a combination of immune-modulating medicines without using etoposide. The authors highlighted certain immune pathway markers (including CXCL9 and soluble CD25) to support that the illness involved strong immune activation. [35]

Two post-transplant cases showed that after allogeneic stem cell transplant, HLH-like inflammation can be difficult to separate from other transplant complications such as graft-versus-host disease or infection, and clinicians used serial inflammation markers while giving immune-modulating treatments that included ruxolitinib in both cases. The letter underlined that there are not yet standardized criteria or clear guidelines for HLH in this post-transplant setting. [36]

One additional case report described heart involvement during HLH, where reduced heart pumping function and a serious heart rhythm problem improved completely by day 10 after HLH-directed immune-suppressing therapy. This supports that some heart complications in HLH may be driven by inflammation and can reverse when the overall immune storm calms down. [37]

For patients and caregivers, this set of papers mainly adds real-world examples of situations where HLH appeared after medicines (including severe drug rashes) or a suspected toxin exposure, and the kinds of organ problems that can occur at the same time (liver, kidneys, and sometimes the heart). Because most reports are single cases, they are best viewed as background information rather than proof that one treatment strategy is better than another. The biggest uncertainty that remains is how to quickly and reliably tell HLH apart from look-alike problems (drug allergy, infection, transplant-related inflammation) and how to choose among different immune-suppressing options in those complex settings. [32] [33] [34] [35] [36] [37]

One multicenter retrospective study in adults with HLH evaluated whether combining two inflammation blood markers could help flag cases where an underlying lymphoma might be present. Overall, the soluble CD25 to ferritin ratio was higher in lymphoma-related HLH than in HLH from other causes, but the separation was not perfect. [38]

Among 126 patients, soluble CD25 levels were higher in lymphoma-associated HLH, while ferritin levels were not clearly different between groups, making the ratio informative mainly because of the soluble CD25 difference. Using a cutoff above 1.02, the ratio had 73% sensitivity and 73% specificity, which the authors described as moderate discrimination rather than a definitive answer. [38]

The study emphasized that this ratio is best used to enrich risk for an occult (hidden) lymphoma, not to confirm it. The authors explicitly noted it cannot replace a tissue diagnosis, meaning it cannot stand in for biopsy-based confirmation when lymphoma is suspected. [38]

This research matters now mainly as context for why clinicians may order multiple inflammation blood tests when looking for the trigger of HLH, especially when lymphoma is one possibility. The ratio described here may help estimate likelihood, but because it is only moderately accurate, it cannot by itself explain the cause of HLH or rule lymphoma in or out. What remains uncertain is how well this ratio performs in different hospitals and patient subgroups, and how it should be combined with imaging and tissue testing in real-world care. [38]