July 2026 Research Update

Across these papers, a clear pattern is that hemophagocytic lymphohistiocytosis (HLH) can be missed during a hospital stay, and other illnesses can look similar at first. The studies describe underrecognition in routine care and show how targeted tests (including biopsies and infection testing) sometimes clarified the true diagnosis. [1] [2] [3] [4]

In one urban hospital cohort of 25 adults who met HLH criteria, 8 were only identified after the fact rather than during the hospitalization. Mortality was higher in the retrospectively recognized group than in the group diagnosed during the admission, and hematology consultation was less frequent in the missed group. [1]

One case report showed that HLH-like lab and bone marrow features do not always mean HLH. A 23-year-old man had high ferritin and hemophagocytosis in the bone marrow, but a lymph node biopsy ultimately supported Kikuchi-Fujimoto disease instead of HLH, and he improved after a short course of corticosteroids. [2]

One report described two adults with visceral leishmaniasis who were first thought to have an autoimmune disease. In one, a repeat bone marrow test and polymerase chain reaction (PCR) testing confirmed the infection; the other tested positive for Leishmania during treatment and was also diagnosed with hemophagocytic syndrome (another name for HLH). [3]

In another single-patient report, a man with Crohn's disease on anti-TNF therapy developed leishmaniasis-associated HLH, with PET/CT showing spleen and bone marrow activity and bone marrow confirming both hemophagocytosis and Leishmania. After leishmaniasis treatment, fever improved within 48 hours and blood tests normalized over about 2 months, supporting the idea that finding a specific trigger can change the course. [4]

For patients and caregivers, these papers mainly provide background on why HLH may not be recognized right away and why doctors may broaden testing when HLH is suspected. They also show that an inflammatory condition can mimic HLH and that a hidden infection can trigger it, so confirming the underlying cause can matter as much as recognizing the HLH pattern. What remains uncertain is how well these observations apply across different hospitals and populations, since several reports were small and included single patients.

These studies focused on tools that might help clinicians recognize HLH earlier in specific situations: leishmaniasis patients being screened for HLH risk, patients being evaluated for inherited (familial) HLH, and children with suspected HLH affecting the brain and spinal cord. Overall, the evidence is early and based on small cohorts or case reports, so the tools described still need confirmation in larger groups. [5] [6] [7]

In a small single-center study of 21 adults with visceral leishmaniasis, people with leishmaniasis-associated HLH had higher C-reactive protein (CRP) and larger spleen thickness than those with leishmaniasis alone. The authors proposed a simple 0 to 2 point score using CRP and spleen thickness that separated leishmaniasis-only from leishmaniasis-associated HLH with high accuracy in their dataset, and PET/CT scans (available in a subset) commonly highlighted the spleen and bone marrow. [5]

A multicenter study from Mexico described how combining an immune-function test (natural killer cell degranulation) with genetic testing expanded the range of detectable inherited HLH causes. Variants were reported across multiple HLH-related genes, including several novel variants, and the authors noted that some disease-causing changes may be outside standard coding regions and affect protein expression (such as Rab27A). [6]

A two-patient pediatric case series suggested that neopterin in spinal fluid may reflect inflammation in the central nervous system (brain and spinal cord) when HLH affects those areas. Both children had genetically confirmed primary HLH and nervous system involvement, and the report linked elevated neopterin with this complication, while emphasizing the seriousness of central nervous system disease. [7]

For patients, this theme is mostly about the types of testing that may be discussed when HLH is suspected in certain settings (for example, known leishmaniasis, concern for an inherited immune problem, or neurologic symptoms). These studies do not establish one standard approach, but they illustrate how adding imaging, infection-focused testing, immune-function assays, or genetic testing can sometimes clarify the diagnosis and organ involvement. What remains uncertain is how these tools perform across larger and more diverse groups, because the studies were small and some were based on only a few patients.

This months papers highlight that hemophagocytic lymphohistiocytosis (HLH) and HLH-like inflammation can appear in several different inherited immune conditions, sometimes after a trigger such as infection or a live vaccine. The reports also show that genetic results often need additional supporting evidence (for example, RNA or immune function tests) to understand how a variant might relate to symptoms. Overall, the evidence is exploratory because most reports describe one person or a few patients. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Several papers focused on classic familial HLH (an inherited tendency toward HLH) and showed how immune-function testing can help confirm the genetic diagnosis. One teenager with a homozygous PRF1 variant had absent perforin in natural killer cells and later underwent stem cell transplantation with long-term donor chimerism reported. [9]

Adult-onset familial HLH was also described, including a 30-year-old woman with a homozygous UNC13D variant and a degranulation defect on immune testing, in the setting of T-cell large granular lymphocytic leukemia. Despite multiple therapies and transplant being considered, she died from severe fungal infection and other infectious complications, underscoring how complex these cases can be when HLH overlaps with other blood disorders. [15]

Other reports broadened the list of genetic conditions that can look like, trigger, or overlap with HLH. A 4-month-old with a homozygous IFNGR2 mutation (a condition that increases risk from mycobacterial infections) had lymph node testing that showed both acid-fast bacilli and hemophagocytosis, prompting concern for evolving secondary HLH. [13]

One series described autosomal recessive STAT2 deficiency due to novel variants, with laboratory evidence of failed interferon signaling, and one child developed HLH after measles-mumps-rubella vaccination and was treated with immune globulin, steroids, and ruxolitinib (later stopped because of infection risk). This connects certain immune signaling defects to severe inflammatory reactions, while still leaving uncertainty about how often HLH occurs in this condition. [16]

Multiple reports emphasized that HLH risk may be part of broader syndromes affecting other organs. A man with STXBP2-related familial HLH type 5 had severe lifelong diarrhea and was later diagnosed with microvillus inclusion disease years after transplant, along with Fanconi syndrome and growth and hormone-related problems that improved after nutritional changes. [12]

Skin and hair clues were highlighted in conditions related to HLH risk. Three patients with Chediak-Higashi syndrome had partial albinism with characteristic findings on blood smear and hair microscopy, and two previously unreported LYST splice-site variants were identified, which the authors suggested could help with earlier diagnosis. [10]

Two additional single-patient reports described HLH-like inflammation connected to interferon pathway biology. A preterm newborn with DNASE2 deficiency and two novel variants had pancytopenia, enlarged liver and spleen, and cholestatic jaundice; treatment with ruxolitinib was followed by clinical and laboratory improvement in this one case. [14]

A separate infant with an HLH-like syndrome had a heterozygous IFIH1 splice-site variant with RNA testing confirming exon skipping, but the authors stressed that a single case cannot prove the gene change caused the illness. This report mainly adds to background knowledge about possible genetic contributors to extreme inflammation. [8]

Finally, one toddler was reported with genetically confirmed Griscelli syndrome type 2 alongside systemic juvenile idiopathic arthritis, improved with corticosteroids, and did not meet HLH criteria during that episode. Another case report noted familial HLH initially presenting like autoimmune lymphoproliferative syndrome, reminding clinicians that early symptoms can resemble other immune disorders. [11] [17]

For patients and caregivers, this group of papers mainly provides context: HLH can be part of different inherited immune syndromes, and those syndromes may also involve the gut (severe diarrhea), liver (jaundice), bone or nerve issues, or visible hair/skin changes. Because most reports describe only one person (or a few), they cannot tell how common any feature is or predict what will happen for an individual patient. The clearest near-term impact is on understanding why genetic confirmation often includes immune function tests or RNA studies, while treatment-related details (including use of ruxolitinib in rare interferon-related conditions) remain uncertain beyond these individual cases. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]

Across these papers, treatments used for hemophagocytic lymphohistiocytosis (HLH) ranged from established approaches (steroids and etoposide-type medicines) to newer immune-targeting therapies (interferon-gamma blockade, JAK inhibitors, and PD-1 inhibitors). Most evidence here came from single-patient case reports and one small retrospective pediatric study, so it remains uncertain which options work best for which causes of HLH.

Interferon-gamma blocking treatment with emapalumab was described in multiple settings: a small pediatric cohort where 5 of 10 children reached remission when emapalumab was added to conventional therapy, and case reports in transplant-related reactivation and autoimmune-related HLH. In the pediatric cohort, adding ruxolitinib did not show a clear added benefit in subgroup comparisons, including in Epstein-Barr virus (EBV) related HLH and in relapsed or refractory disease. [18] [19] [20] [21]

Several case reports highlighted multi-drug treatment combinations for HLH linked to autoimmune disease or complex immune illness, often alongside infection monitoring and supportive care. Examples included emapalumab combined with teniposide and dexamethasone plus additional therapies for central nervous system involvement, and ruxolitinib used after initial etoposide and steroids in macrophage activation syndrome (a form of HLH) occurring with Sjogren's syndrome. [21] [22]

JAK inhibitors were used in case reports as part of treatment for macrophage activation syndrome (closely related to secondary HLH), including baricitinib added with glucocorticoids and tacrolimus in adult-onset Still's disease, and ruxolitinib in Sjogren's syndrome-associated macrophage activation syndrome. These reports described clinical improvement and longer-term remission in the individual patients, but they cannot show how often this would happen in others. [23] [22]

Chemotherapy-type and steroid-only approaches were also described. One young adult with HLH after COVID-19 improved gradually after etoposide treatment, while another case of infection-triggered secondary HLH improved rapidly on dexamethasone alone without cytotoxic chemotherapy. Because these are single-patient reports, it is unclear how broadly the results apply, especially across different HLH triggers. [24] [25]

A literature synthesis focused on PD-1 inhibitors (such as sintilimab and nivolumab) mainly for EBV-associated HLH, including use as salvage therapy and as a bridge to donor stem cell transplant. It also emphasized safety concerns, particularly graft-versus-host disease when PD-1 blockade was given after transplant, and noted that key practical questions like timing still need more research. [26]

Other immune-targeting medicines mentioned included anakinra in a child with acute lymphoblastic leukemia and cytomegalovirus infection who developed HLH, described in a single case report. The paper mainly documented the clinical course and use of anakinra in that situation rather than providing comparative effectiveness data. [27]

For patients and caregivers, this set of papers mainly shows the range of treatments that clinicians have used for HLH in different causes (viral-associated, autoimmune-related, infection-triggered, and around transplant), rather than proving one best option. Much of the information is from small numbers of patients, so uncertainty remains about who benefits most and what the main risks are in each situation; transplant timing and infection-related safety were recurring concerns in these reports. [26]

Across this group of papers, hemophagocytic lymphohistiocytosis (HLH) appeared as an intense, body-wide inflammation that can be triggered by many infections (viral, bacterial, and parasitic). Some patients recovered, especially when the infection and the inflammation were both addressed, but several reports described rapid worsening with bleeding, organ failure, or death, showing that infection-triggered HLH can look very different from one person to the next. [28] [29] [30] [31] [32] [33]

In viral illnesses, several reports described HLH happening alongside strong liver and blood abnormalities, sometimes with brain or lung involvement. In hepatitis A with atypical manifestations, HLH was reported in 12.8% of patients and the atypical group had higher multiorgan involvement and an 11.7% mortality, with a very high-performing 90-day mortality model based on baseline ammonia, total white blood cell count, and INR (a clotting test). [34]

Dengue-related hyperinflammation showed two different paths in two single-patient reports: one patient met multiple HLH measures and improved rapidly after intravenous dexamethasone, while another patient who also met multiple HLH measures recovered fully with supportive care alone and showed early fever resolution plus a rapid rebound in blood counts over time. Together, these cases highlight that dengue can sometimes resemble HLH on lab tests, yet the clinical course may differ. [35] [36]

HLH triggered by viruses beyond dengue was also described in individual patients, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV). A previously healthy woman with CMV-triggered HLH improved quickly after ganciclovir plus immune-modulating therapy, with the CMV blood test becoming undetectable. [29]

In advanced HIV, another case described CMV infection in the central nervous system that became apparent after starting antiretroviral therapy, complicated by HLH and kidney and liver problems; CMV was detected in spinal fluid despite non-diagnostic brain MRI. The patient recovered after valganciclovir plus a short course of dexamethasone, including full neurologic recovery. [33]

A pediatric EBV-HLH case reported a rare blood-smear change called green neutrophilic inclusions appearing during hospitalization, followed by rapid decline and death from multiorgan dysfunction despite intensive supportive care. Because this is a single case, it cannot prove the blood-smear finding predicts outcomes, but it raises a question about whether it could be a warning sign in very severe pediatric EBV-HLH. [30]

Bacterial and parasitic triggers were also described, including Escherichia coli sepsis and babesiosis. In a woman on low-dose methotrexate, HLH occurred during resistant E. coli sepsis and she died of multiorgan failure; the bone marrow showed both hemophagocytosis and bacteria inside cells. [31]

In contrast, an immunocompetent man with babesiosis developed HLH even though the parasite level in blood was very low, and he improved rapidly after pulse-dose methylprednisolone added to standard antimicrobial therapy. This case suggests that, in some infections, the intensity of inflammation may not match how much organism is seen in the bloodstream. [28]

Several papers focused on tuberculosis (TB) and fungal infections as HLH triggers, with mixed outcomes. One TB-HLH case improved after early anti-tubercular therapy plus corticosteroids, and a small four-patient TB-HLH series reported three favorable outcomes with anti-tubercular therapy and steroids (with IVIG used in one critically ill patient). [37] [38]

For disseminated fungal infections, an immunocompetent patient with Histoplasma capsulatum-associated HLH improved after amphotericin B along with immune-modulating medicines, and diagnosis was supported by bone marrow microscopy plus metagenomic sequencing. Another report described a man with Talaromyces marneffei infection complicated by HLH and repeated relapses over three years, with later short-term remission after a different antifungal plan and three months of follow-up without recurrence. [39] [40]

Two larger studies added context on how often HLH can appear during specific infections and what tracks with severity. In a 22-child cohort with Crimean-Congo hemorrhagic fever, secondary HLH was common (18 of 22) and all children recovered; platelet counts improved by around day 7 while ferritin stayed elevated longer. [32]

In 135 hospitalized adults with scrub typhus, a three-variable admission model (hemoglobin, creatinine, and fibrinogen) predicted severe disease, and HLH was uncommon but serious: among severe cases, HLH occurred in 5 patients and mortality was higher in the HLH subgroup (40%) than in severe cases without HLH (2.6%). [41]

Finally, one two-patient report linked parvovirus B19 to bone-marrow and blood problems, including a 2-year-old with an HLH-like picture who improved with immune-modulating therapy and intravenous immunoglobulin. This reinforces that careful bone marrow and blood testing can be important in sorting out infection-related causes of HLH-like inflammation. [42]

Not every infection-related paper in this group focused specifically on HLH, but they still help show how broad and organ-specific severe infection complications can be. A 12-patient malaria series described rare organ complications (mostly in Plasmodium vivax) with most patients recovering and one poor outcome in Plasmodium falciparum with a brain bleeding event. [43]

For patients and caregivers, these studies mainly serve as background on how HLH can be a reaction to many different infections and why the course can be unpredictable: some people improve quickly, while others develop bleeding and multiple organ failure. The strongest evidence here comes from a few moderate-sized hospital studies (hepatitis A, scrub typhus, and Crimean-Congo hemorrhagic fever), while most other information comes from single-patient reports that may not apply broadly. What remains uncertain is how to reliably tell, early on, which infection-triggered HLH cases will be self-limited versus rapidly progressive across different infections and age groups.

Taken together, these papers show that hemophagocytic lymphohistiocytosis (HLH) triggered by cancers, especially lymphomas, can become severe quickly and may still have poor outcomes even when initial control is achieved. Across studies, outcomes appeared to depend on both the underlying cancer situation (newly recognized versus previously known) and the bodywide immune over-activation that can persist during care. [44] [45]

In a 49-person retrospective study of malignancy-associated HLH, lymphoma was the most common trigger (34/49). Overall survival was short (median 56 days), and people whose cancer was newly recognized at the time HLH appeared had lower mortality than those with a previously known cancer (23.5% vs 78.1%). [44]

That same cohort also showed two practical patterns: people who received cancer-directed chemotherapy (often alongside HLH-directed treatment) had lower mortality than those who received HLH-directed therapy alone, and infections could be devastating. All 6 people with invasive mold infection died. [44]

In a larger multicenter study of 277 adults with lymphoma-associated HLH, very low baseline HDL-cholesterol (a type of cholesterol often called "good cholesterol") was linked to worse overall and 60-day survival (baseline <0.48 mmol/L). In addition, less HDL-cholesterol recovery after treatment (post-treatment/baseline ratio <1.71) identified a higher-risk group with poorer survival. [46]

For patients and caregivers, this group of studies mainly adds context about why cancer-associated HLH can be hard to control: it is often tied to aggressive lymphomas, can be complicated by serious infections, and may have measurable blood marker patterns that track with higher risk. The cholesterol-related results are from retrospective data and need confirmation, but they suggest that routinely collected lab values might help researchers understand risk differences within lymphoma-associated HLH. [44] [46]

Across these case reports, HLH appeared as a severe complication of different blood cancers, most often lymphomas, and it sometimes emerged before the cancer was fully proven by biopsy. Several reports emphasized that clinicians needed multiple tests (bone marrow review, blood cell studies, genetics, and scans) to connect HLH to an underlying cancer and to guide treatment decisions. [47] [48]

One 73-year-old woman with a diffuse large B-cell lymphoma (DLBCL) pattern involving bone marrow, liver, and spleen presented with multiorgan failure and features suggestive of secondary HLH, and improved rapidly after prompt R-CHOP chemotherapy selected based on bone marrow smear results, with prolonged survival reported. This is a single-patient experience and may not apply to others. [49]

A 71-year-old man with quiescent adult-onset Still's disease developed HLH after a mild SARS-CoV-2 infection, and workup supported probable lymphoma-associated HLH with clinically diagnosed stage IVB DLBCL, including a small clonal B-cell population and lymphoma-related mutations found in blood and marrow. He had transient improvement after HLH-directed therapy followed by rituximab-based chemotherapy, but later died from viral encephalitis and fungal pneumonia. [48]

A 59-year-old woman with extranodal NK/T-cell lymphoma had complete metabolic response on PET/CT after HLH-directed and lymphoma-directed therapy, but later developed worsening HLH without clear tumor regrowth on imaging, alongside rising HLH activity markers (such as ferritin and triglycerides). The authors described this as a possible "tumor-immune dissociation," where HLH activity and tumor burden do not move together. [45]

Other rare cancer links were also described: an adult with ALK-positive anaplastic large cell lymphoma presenting in a leukemic phase with HLH, where extensive additional testing was needed to confirm the diagnosis and blood involvement. In a separate report, a 15-year-old boy with a rare syncytial variant of classical Hodgkin's lymphoma had secondary HLH and achieved partial remission at 6 months after ABVD chemotherapy. [47] [50]

One case report focused on a rare adult erythroblastic sarcoma complicated by secondary HLH, where detailed genetic testing found a PCM1::JAK2 fusion plus a novel NOP10::NUTM1 fusion and other changes. The patient initially gained disease control with HLH-directed therapy and then ruxolitinib, but died from progressive disease at 7 months. [51]

For patients and caregivers, these reports highlight that when HLH is linked to cancer, the underlying cancer type can vary and may be difficult to confirm immediately, so care teams may use several kinds of tests to clarify what is driving the inflammation. They also show that improvement can occur after lymphoma-directed treatment in some situations, but relapse of HLH activity or severe infections can still occur, even when scans show the cancer shrinking. Because these are individual cases, they mainly serve as background examples of how complex and variable cancer-associated HLH can be. [49] [48] [45] [50] [47] [51]

Across two real-world studies in people receiving CD19 CAR T-cell therapy, hemophagocytic lymphohistiocytosis (HLH)-like syndromes were uncommon but severe when they occurred, often involving very high inflammation markers, long-lasting low blood counts, frequent infections, and a high need for intensive care. Overall, the direction of results was consistent: patients who developed an HLH-like syndrome had worse outcomes than those who did not, although uncertainty remains because these were retrospective analyses with no randomized comparisons. [52] [53]

In a multicenter registry analysis of 42 cases after standard-of-care CD19 CAR T-cell therapy, the syndrome typically began early (median 9 days) and more than half were severe, with intensive care admission in many patients and infections in most. Mortality was high, and prolonged low blood counts were a major ongoing issue reported in this group. [52]

That registry study also described a range of medicines used to try to control inflammation, including corticosteroids, etoposide, anakinra, and tocilizumab, with responses reported across approaches in this real-world setting. It also highlighted how hard it can be to predict who will worsen and to separate this syndrome from overlapping problems after CAR T, such as infection or other inflammatory complications. [52]

In a separate multicenter cohort of 154 children and young adults with B-cell acute lymphoblastic leukemia treated with tisagenlecleucel, any HLH-like syndrome (using several published definitions) was linked to shorter overall and event-free survival and higher non-relapse mortality by 1 year compared with patients without HLH-like syndrome. In patients with high leukemia burden, HLH-like syndrome was also tied to much higher rates of CD19-negative relapse, and this relationship persisted after adjusting for disease burden. [53]

For patients and caregivers, these studies frame HLH-like syndromes after CAR T as a serious complication that can involve infection risk, long periods of low blood counts, and sometimes intensive care, and may also go along with worse cancer outcomes in some settings. This is most relevant now for people currently considering or receiving CAR T, but the evidence is still evolving because the studies were retrospective and used different ways to define HLH-like syndromes. What remains uncertain is how best to predict risk early and which management strategies lead to better outcomes across different centers and CAR T products. [52] [53]

Across several single-patient reports, HLH (or HLH-like inflammation) occurred after different immune-changing situations: immune checkpoint inhibitors for cancer, teplizumab for early type 1 diabetes, and liver transplantation with immune suppression. The overall pattern was that people could look acutely ill with a sepsis-like picture and multiple organ problems, while lab tests showed very high inflammation markers such as ferritin; outcomes ranged from recovery to death, emphasizing uncertainty and wide variation between individuals. [54] [55] [56] [57] [58]

Two cancer case reports described HLH or HLH-like features after immune checkpoint inhibitors. One woman with inflammatory triple-negative breast cancer developed HLH after pembrolizumab-containing chemoimmunotherapy and improved after high-dose corticosteroids once infection testing did not find a cause, with pembrolizumab stopped. [55]

Another report in metastatic melanoma described HLH occurring during sequential treatment (checkpoint blockade followed by targeted therapy), alongside posterior reversible encephalopathy syndrome with temporary visual symptoms that resolved within 2 days as inflammation and organ function improved with supportive and immunosuppressive therapy. The report also noted Epstein-Barr virus (EBV) reactivation and marked T-cell activation, suggesting immune overactivation as part of the picture. [56]

A separate melanoma case report described cytokine release syndrome after nivolumab plus ipilimumab that showed HLH-like features, with liver problems, blood clotting changes, and marked hyperferritinemia; the authors suggested tocilizumab could help quickly control inflammation while limiting steroid exposure. Because this is one person, it cannot show how often this happens or what approach works best in general. [54]

Outside of cancer, a man with trisomy 21 receiving teplizumab for stage 2 type 1 diabetes developed EBV reactivation followed by secondary HLH with respiratory, liver, and kidney failure, and EBV-related lymph node overgrowth; he recovered after dexamethasone and rituximab and was reported to be insulin-free at 12 months. This report could not prove teplizumab caused the EBV reactivation because EBV testing before treatment was not available. [57]

After liver transplantation, one woman developed secondary HLH diagnosed by multiple HLH-2004 criteria and a high H-score, was treated with HLH-directed therapy and antiviral therapy for cytomegalovirus, and then developed invasive mucormycosis that was fatal despite antifungal treatment and surgery. The report highlighted the added challenge after transplant of balancing immune suppression, infection risk, and HLH treatment side effects like low blood counts. [58]

For patients, these reports mainly serve as background information showing that HLH or HLH-like inflammation can be triggered in very different settings where the immune system is strongly altered (certain cancer immunotherapies, a diabetes immune therapy, or after transplant). They also show that symptoms can involve multiple organs, including possible brain and vision effects in rare situations, and that severe infections can occur alongside HLH, especially in transplant settings. Because these are individual cases, it remains uncertain how common these events are, who is most at risk, and which approaches work best across larger groups. [54] [55] [56] [57] [58]

Across these retrospective studies, worse outcomes in hemophagocytic lymphohistiocytosis (HLH) and closely related hyperinflammatory syndromes tended to cluster with early signs of severe illness and organ failure in the intensive care unit. Several papers highlighted that patterns over time, such as ferritin staying very high rather than falling, may be more informative than a single lab value. A few groups also tested simple risk tools using routine blood counts or bedside intensive care scores, but these need external validation before they can be considered reliable in different hospitals. [59] [60] [61] [62] [63]

In one pediatric intensive care unit (PICU) study of 48 children with HLH, overall PICU mortality was 33.3%, and death was more common in primary HLH (60%) than in secondary HLH (35.1%), while no deaths were reported in macrophage activation syndrome (MAS) in this cohort. On admission, enlarged spleen and low white blood cell counts were more common in children who died, and during the PICU stay, multiple organ failure and acute kidney failure were also more frequent in non-survivors. Ferritin stayed elevated throughout the PICU stay in non-survivors, and platelet counts were lower later in the PICU course. [59]

A separate study in 120 children with MAS (a condition that can overlap with HLH) also connected higher ferritin levels with worse outcomes. Higher peak ferritin predicted mortality (odds ratio 2.01) and was linked to a lower chance of being in remission off therapy (odds ratio 0.70), while MAS caused by systemic juvenile idiopathic arthritis had lower mortality than other causes (odds ratio 0.21) but higher recurrence. In the subgroup who had genetic testing, HLH-related variants were found in 22.4% and were linked to younger onset and more acute organ dysfunction and recurrence, along with higher ferritin. [63]

Two studies explored prediction using information available very early in care. In 133 children with HLH, a model combining two red blood cell measures (mean corpuscular hemoglobin and hematocrit) had an area under the curve of 0.728 for predicting 30-day mortality, suggesting modest ability to sort higher vs lower risk in that single-center dataset. In another PICU cohort of 40 children with systemic rheumatologic or autoinflammatory diseases, an exploratory bedside score that included a high illness-severity score at 24 hours, having HLH/MAS, and needing two or more blood pressure-supporting medicines showed an apparent area under the curve of 0.91 in the derivation sample, but it was based on only 6 deaths and needs confirmation elsewhere. [60] [61]

In a tertiary-center cohort of 87 critically ill children co-managed by pediatric rheumatology and the PICU, secondary HLH was the most common diagnosis among those without a prior rheumatologic condition, and mortality in secondary HLH was 28.3%. Across the full cohort, children who died more often needed mechanical ventilation within the first 24 hours, pointing to early respiratory failure as one marker of higher risk in these hospitalized patients. [62]

For patients and caregivers, this set of studies mainly helps explain what clinicians mean by "higher risk" HLH during hospitalization: organ failure, need for intensive supports (like ventilation or blood pressure medicines), and ferritin that stays very high over time were repeatedly linked with worse outcomes in these cohorts. Some proposed prediction tools use routine blood tests or bedside ICU information, but they were developed in single centers and may not perform the same way in other settings, so their role is still uncertain. Results also varied by the underlying trigger or subtype (for example, different patterns in primary HLH, secondary HLH, and MAS), which is a reminder that outcome estimates from one group may not fit everyone.

These individual case reports highlight that HLH can appear in very different clinical contexts and can bring unexpected complications, especially involving the liver, blood clotting system, and kidneys. Because each report describes only one person, the details may not apply to most patients, but they show the kinds of problems teams may look for when HLH is suspected or when a hospitalized patient worsens. Several reports also emphasized monitoring a specific marker tied to the trigger (for example, virus levels in blood) or investigating unusual lab abnormalities to better understand what is happening. [64] [65] [66] [67] [68]

One report described a 23-year-old woman with Epstein-Barr virus (EBV)-associated HLH who presented with disseminated intravascular coagulation (a severe clotting and bleeding disorder) and marked liver dysfunction. Her care team followed EBV-DNA in plasma over time, and the virus level became undetectable by day 15, with clinical recovery and no relapse reported at 6 months. This case suggests that, at least for some EBV-driven HLH, serial viral levels in blood may reflect disease activity during treatment, although this needs study in larger groups. [64]

Another case involved a patient with acute lymphoblastic leukemia who developed HLH and severe low phosphate levels due to the kidneys losing phosphate. The workup showed very high fibroblast growth factor 23 (FGF23) without known causes of abnormal FGF23 breakdown, raising the possibility that HLH-related inflammation contributed to this hormone change. The report highlights renal phosphate wasting and FGF23 as potential explanations when low phosphate is persistent and severe in an HLH setting. [65]

Two adult case reports linked secondary HLH to adult-onset Still's disease, including one where HLH appeared after percutaneous kidney stone surgery, and another where symptoms were initially treated as tuberculosis. Both patients improved after intensive immunomodulatory care, but one report also noted later complications during the illness course, such as serious infection and thrombosis. These cases underscore how trigger identification and diagnostic uncertainty can shape the early course of care in secondary HLH. [66] [67]

One report described a woman with lysinuric protein intolerance and established immune dysregulation including HLH and systemic lupus erythematosus who had an unplanned pregnancy. With multidisciplinary metabolic, obstetric, and immune-focused management, she delivered a live infant at 35 weeks with favorable maternal and neonatal outcomes, although complications such as episodes of high ammonia and steroid-related problems were reported. This case mainly serves as background about the complexity of pregnancy in rare metabolic disease with HLH history, rather than a predictor model. [68]

For patients, these reports are most useful as examples of the range of complications that can occur alongside HLH and the kinds of lab signals clinicians may track when a specific trigger is suspected (like EBV) or when an unusual problem appears (like kidney-driven phosphate loss). Because each report is a single person, it is not possible to estimate how common these situations are or to predict outcomes for others from them. Their main value is helping clinicians and researchers recognize less typical presentations and consider targeted monitoring questions for future studies.