HHV‐8‐Associated Hemophagocytic Lymphohistiocytosis in a HIV‐Negative and Nontransplant Man: A Case Report and Literature Review

Cytomegalovirus pneumonitis-induced secondary hemophagocytic lymphohistiocytosis and SIADH in an immunocompetent elderly male literature review

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by cytokine storms leading to multi-organ dysfunction and is a highly fatal disease. Infectious diseases are the most common cause of secondary HLH. A wide variety of infections can lead to secondary HLH. In this case series, we report five cases of HLH which had different therapeutic approaches and varied clinical courses, with one of them diagnosed as a rare entity of coronavirus disease 2019 (COVID-19)-associated HLH of multisystem inflammatory syndrome in children (MISC) spectrum, one case each of idiopathic HLH, staphylococcal infection-associated secondary HLH, leptospirosis with secondary HLH and dengue-associated HLH. The case of idiopathic HLH required initiation of immunosuppressive therapy but had a fatal outcome while others were treated successfully with antibiotics, steroids, intravenous immunoglobulin and supportive therapy.Our case series highlights the importance of evaluating for all possible infective causes thoroughly in HLH. Most patients can be managed without chemotherapy by treating the secondary causes of HLH, including common tropical infections and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Hemophagocytic lymphohistiocytosis (HLH) is not one condition but descriptive of a life-threatening, hyper-inflammatory syndrome with multiorgan involvement with a variety of triggers, both genetic and environmental. It is described as primary HLH (familial HLH) and secondary HLH (acquired following malignancy, rheumatologic disorders, primary immune deficiencies or infection alone). Infections commonly precipitate HLH in those with primary HLH, in combination with an underlying disease (malignancy, rheumatologic or primary immune deficiency) or may be the sole trigger.1 Many people with “secondary” HLH may also have potentially pathogenic polymorphisms in an HLH- associated gene.2 Rapid diagnosis of HLH and initiation of appropriate treatment is essential to reduce mortality from this condition. PATHOGENESIS Across the spectrum of HLH, impaired natural killer (NK) and cytotoxic T lymphocytes (CTL) function has been a consistent finding. These cytotoxic deficiencies lead to loss of feedback inhibition on activated macrophages resulting in a “cytokine storm,” causing multiorgan tissue damage. The excessive activated macrophages engulf host blood cells (hemophagocytosis), which may be seen in biopsies from the bone marrow, lymph nodes, liver and spleen.1,3 Around 25% of all HLH presentations are thought to be autosomal recessive primary HLH and these commonly present in early life, although may develop at any age. Genes identified as causing monogenic HLH include: PRF1, UNC13D, STX11, STXBP2. Other genetic causes of HLH include primary immunodeficiency syndromes including Griscelli syndrome (RAB27A), Chediak-Higashi syndrome (LYST), Hermansky-Pudlak 2 (Ap3B1) and X-linked lymphoproliferative disease 1 and 2 (SH2D1A, XIAP).2 Viral infections are a common precipitant in primary HLH, malignancy and in those without known underlying disease. Epstein-Barr virus (EBV) is a well-described trigger and X-linked lymphoproliferative disease is almost exclusively associated with EBV.4,5 Other common viruses found in association with HLH include cytomegalovirus (CMV), parvovirus, herpes simplex virus (HSV) (particularly neonates), varicella-zoster virus (VZV), measles, human herpes virus (HHV)-6, HHV-8, H1N1 influenza virus, parechovirus, parvovirus, Dengue virus and HIV. Bacteria causing HLH are far less common, but Gram-negative bacterial infections, Brucellosis and Mycobacterium tuberculosis associated HLH have been described. HLH has also been described in fungal infections such as Histoplasma capsulatum and in parasitic infections such as Leishmania and malaria.6 Malignancy is a common cause of HLH, especially lymphoid malignancies with acute B-lymphoblastic leukemia being the commonest. Cytokines produced by malignant cells activate CTLs, NK cells and macrophages. HLH also can occur during hematopoietic stem cell transplantation, especially in the early phase.6 Rheumatologic conditions, especially systemic-onset juvenile idiopathic arthritis and less commonly polyarticular juvenile idiopathic arthritis, systemic lupus erythematous and Kawasaki disease can present with HLH at diagnosis, during treatment or any time in response to infection; therapeutic drugs themselves may trigger HLH. In the context of a rheumatologic condition, HLH is referred to as macrophage activating syndrome.6 Any of the primary immune deficiency disorders will increase the risk of HLH as a result of the immune dysregulation. In combined immune deficiencies, viral infections are commonly associated with HLH, especially EBV and CMV, and in chronic granulomatous disease patients, common infectious precipitants were Burkholderia cepacia, Leishmania and fungi. The development of HLH in patients with absence of T and NK cells indicates excess macrophage activation may occur independently of lymphocytes.7 CLINICAL PRESENTATION AND INVESTIGATION OF HLH Regardless of the underlying cause, HLH is a clinical diagnosis with supporting laboratory criteria. Typically, patients are febrile, acutely unwell with multiorgan involvement; therefore, the initial differential diagnosis includes liver disease, encephalitis, malignancy, autoimmune, rheumatologic diseases and general sepsis. A family history of immunodeficiency, consanguinity or autoimmunity may be relevant. Key clinical features identified in the HLH-94 study were hepatosplenomegaly (95%), fever (93%), lymphadenopathy (33%), neurologic symptoms (33%) and rash (31%).8 Other features include bleeding (epistaxis, hematemesis, rectal bleeding, petechiae and purpura), liver dysfunction and respiratory insufficiency. Specific features (such as albinism) may point towards syndromes predisposing to HLH (eg, Chediak-Higashi syndrome, Griscelli syndrome type 2 and Hermansky-Pudlak syndrome type 2). In the neonate, HLH may present with isolated central nervous system disease or fulminant liver failure.6 Figure 1 outlines suggested investigations and management. Early laboratory parameters in a septic child which indicate the development of HLH are a climbing ferritin >500 μg/L (ferritin >10 000 μg/L in children was found to be 90% sensitive and 96% specific for HLH9 however, diagnosis and treatment should not be delayed until ferritin reaches this threshold); evolving cytopenias which are transfusion dependent, (anemia and thrombocytopenia present in over 80% patients on presentation9); and multiple organ involvement (renal, liver, neurologic). High triglycerides and low fibrinogen further support the diagnosis of HLH. A rising C-reactive protein occurs, while erythrocyte sedimentation rate may fall due to reduced fibrinogen from liver consumption.6 Low immunoglobulins or lymphocyte subsets point towards an underlying immunodeficiency although commonly deranged by severe illness.FIGURE 1.: Investigation and management of HLH. CRP indicates C-reactive protein; ESR, erythrocyte sedimentation rate; HLA, human leukocyte antigen; IV, intravenous; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Full blood count (FBC), Chest radiograph (CXR), haematopoietic stem cell transplant (HSCT).Bone marrow biopsy, where possible, is useful to provide evidence of hemophagocytosis and to look for any underlying malignancy. It should also be sent for microscopy, culture and viral and Leishmania polymerase chain reactions (in endemic areas). Hemophagocytosis is not always visualized in the bone marrow during HLH; it may also be present in lymph nodes, liver and spleen and is not specific for HLH. If lymphadenopathy is present, node biopsy should be taken as lymphoma is frequently the underlying condition. Cerebrospinal fluid shows a pleocytosis in 50% of cases and a high protein. DIAGNOSIS The HLH-2004 protocol uses the presence of 5/8 criteria to diagnose HLH: (1) fever, (2) splenomegaly, (3) bicytopenia, (4) hypertriglyceridemia and or hypofibrinogenemia, (5) hemophagocytosis, (6) low/absent NK cell activity, (7) hyperferritinemia (>500) and (8) high soluble interleukin-2 receptor levels.10 However, probable HLH should be considered and treated well before the presence of 5/8 criteria, as several of the tests are only done in reference laboratories and if treatment is delayed for these results, it may be too late to reverse the process. Other common features aiding diagnosis include liver enzyme derangement and neurologic abnormalities. All cases of HLH should be investigated for primary immunodeficiency syndromes, and underlying genetic causes as clinical presentation cannot distinguish between primary and secondary HLH. Soluble interleukin-2 receptor alpha is a useful marker of disease activity but is not available in most centers. Protein expression studies and genetic panels are helpful in diagnosing primary HLH conditions which will need HSCT for definitive cure. MANAGEMENT Patients with HLH commonly require pediatric intensive care support to maximize chances of survival. Replacement blood products are necessary to maintain hemoglobin, platelet levels and normal coagulation. Induction of amenorrhea is advised in menstruating girls. Whilst supportive therapy is given, the priorities for initial management are identifying and treating the trigger, exclusion of malignancy (as this diagnosis is difficult once immunosuppression has been given) and early immune modulation.11 These patients may deteriorate quickly and should be treated in centers with facilities for bone marrow transplantation and intensive care. Prompt aggressive therapy may be necessary even when infection is present. It may be possible to tailor therapy according to the severity of the condition and the rapidity of response. In some cases, where early intervention produces a rapid response then induction chemotherapy may be avoided or weaned with close monitoring. However, if the condition does not respond to initial management, then early recourse to more aggressive treatment will be necessary; in primary, persistent or recurring HLH, chemotherapy should be continued to HSCT.12 Opportunistic infection during therapy may confound the picture and careful surveillance is necessary particularly where symptoms recur after an apparent initial response. Key markers of response to treatment are resolution of fever, reducing ferritin (although it can be slow to decline and levels fluctuate with blood transfusions), reducing transfusion requirements, improved coagulation parameters and resolving organ dysfunction. Neurologic involvement should be monitored with serial cerebrospinal fluid analysis with each intrathecal therapy and neuroimaging. Weekly monitoring of soluble interleukin-2 receptor alpha or soluble CD163 may be helpful to guide reduction or increase in therapy. Markers of infection should be monitored for response to treatment.12 When induction therapy is being planned, HLA tissue typing should be sent to allow for rescue HSCT without delay if this becomes necessary. The HLH-1994 protocol8 recommends combination chemotherapy [etoposide, ciclosporin A, corticosteroids and intrathecal methotrexate if (central nervous system) involvement] followed by HSCT for persistent, recurring or primary HLH. The HLH-2004 protocol modified this with early cyclosporin, but survival was not significantly improved.10 An alternate regimen using steroids and anti-thymocyte globulin (ATG) was similarly effective.13 Survival is dramatically improved with these protocols compared with survival without treatment with an overall survival at 3 years of 55% (51% in the familial cases) and 3-year probability of survival 3 years after HSCT of 62%.8 Trials comparing a combination of the two main regimes (the Hybrid Immunotherapy trial and the European cooperative pilot study for testing Hydbrid ImmunoTherapy for Hemophagocytic LymphoHistiocytosis (Euro-HIT-HLH) trial) have finished recruiting, and results are awaited. Other studies of alternate or combination approaches have also been initiated with agents such as alemtuzumab, ruxolitinib and anti-interferon gamma monoclonal antibody. Alemtuzumab (monoclonal antibody to CD52 protein expressed on surface of mature T cells and NK cells) may be a useful salvage agent for refractory HLH enabling survival to HSCT.12 CONCLUSIONS HLH is a life-threatening hyperinflammatory condition that needs to be considered early in any patient with fever, multiorgan failure and cytopenias. Infection plays a key role as a trigger but also causes concern for clinicians when delivering the necessary immunosuppression to terminate the cytokine storm. Immunomodulatory treatment should be started if high clinical suspicion, and not wait for specific immunology and genetic testing. Early recourse to chemotherapy and planning for HSCT if HLH is recurrent or refractory to initial treatment. Survival has improved with this treatment, however, mortality remains very high.

Ruxolitinib combined with dexamethasone in adult patients with newly diagnosed Hemophagocytic lymphohistiocytosis: A single-center pilot trial.

Modern management of children with haemophagocytic lymphohistiocytosis.

The complex dance of immunity: A review of secondary HLH in HIV (2000-2025)

Secondary hemophagocytic lymphohistiocytosis (HLH) is a group of diseases characterized by fever, splenohepatomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, decreased natural killer cell activity, high ferritin value, high soluble interleukin-2 receptor value, and hemophagocytosis, which are induced or associated by infections, malignant tumors, or autoimmune diseases. In Eastern Asia, primary Epstein–Barr virus (EBV) infection is the most common cause of secondary HLH. Other common causes of secondary HLH are non-EBV viral infections (cytomegalovirus, adenovirus, herpes simplex virus, varicella–zoster virus, parvovirus B19, parainfluenza virus, influenza virus, etc.), malignant lymphoma, and juvenile idiopathic arthritis. Secondary HLH can develop in a wide range of age groups starting from children to seniors. Autoimmune diseases and infection-related HLH are common in children, whereas lymphoma-related HLH is common in seniors. Although EBV-HLH is a heterogeneous disorder with various symptoms ranging from mild to severe, early initiation of immunochemotherapy consisting of dexamethasone, cyclosporin A, and etoposide has been recommended for patients with moderate to severe EBV-HLH.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by immune system dysregulation of natural killer cells, cytotoxic CD8+ T-cells, and macrophages, resulting in malignant inflammation and multi-organ failure. Secondary HLH, often triggered by malignancies, infections, and/or autoimmune disease, typically affects adults. This systematic review investigated the characteristics and prognostic factors associated with secondary HLH. Methods: A systematic review was conducted in adherence to the PRISMA guidelines. A literature search was performed utilizing Medline, Embase, Scopus, Cochrane, and Clinicaltrials.gov databases without restricting to a starting date. Inclusion criteria encompassed retrospective or prospective, randomized, or non-randomized controlled studies published in English, focusing on adult patients over the age of 18 with secondary/acquired HLH. The primary outcomes of interest were overall survival (OS) and HLH-free/relapsed-free survival. Results: The systematic review yielded 23 eligible studies, including 2833 patients with a median age of 48.3 years and 1482 (52%) males. Most studies originated from China (48%), followed by Korea (13%) and the USA (13%). Malignancies, particularly lymphomas, and infections, notably Epstein-Barr virus (EBV), were identified as the most common underlying causes of secondary HLH. Two studies involved ICU-related secondary HLH diagnoses, whereby sepsis-associated HLH with gram-negative bacteremia, particularly E. coli (30%), was most implicated. OS was a ubiquitously reported outcome, with only two studies (9%) including HLH-free survival/HLH-relapse-free survival. Most frequently reported statistically significant worse prognostic factors in terms of OS included older age in 8 (35%), low platelets <100 in 7 (30%), and malignancy-associated HLH in 7 (30%) studies. Two studies demonstrated worse prognosis in terms of HLH-free survival. Other poor OS prognostic factors included EBV-associated HLH in 6 (26%), low fibrinogen in 5 (22%), elevated AST in 5 (22%), elevated LDH >400 in 4 (17%), high bilirubin in 4 (17%), albumin <2.8 g/dL in 4 (17%), male sex in 3 (13%), ferritin >2000 in 3 (13%), low hemoglobin in 3 (13%), prolonged APTT in 3 (13%), prolonged PT in 3 (13%), elevated creatinine in 2 (9%), elevated sCD25 in 2 (9%) and elevated IL-10 in 2 (9%). Least frequently reported were prolonged INR, fever, low total T3, and elevated beta-2-microglobulin. One study demonstrated that germline HAVCR2 mutation had a better prognosis. Conclusion: Older age, thrombocytopenia, and malignancy were the most common poor prognostic indicators for secondary HLH when indexed to outcomes of OS. This review also highlights a potential gap in the global understanding and documentation of secondary HLH, given the notable scarcity of studies from countries outside of China. Citation Format: Maha Hameed, Gustavo Garcia, Kevin C. Zhen, Brooke A. Hartenstein, Laura D. Herrera, Utkarsh Acharya, Kai He, Karen Hamad, Wilhelmine Wiese-Rometsch. Secondary hemophagocytic lymphohistiocytosis: A systematic review of incidence and prognostic outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5856.

Clinical Features and Outcomes of Hemophagocytic Lymphohistiocytosis Secondary to Lymphoma: Insights from a Tertiary Center in Saudi Arabia

Salivary Lactoferrin Is Recognized by the Human Herpesvirus-8

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Group G streptococcal endocarditis-associated hemophagocytic syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a rare, but fatal syndrome characterized by an excessive inflammatory response, leading to hemophagocytosis, cytopenias, and multi-organ failure. Primary HLH commonly presents in infancy, and is associated with various germline mutations that affect NK or T cell activity or immunoregulation.1 Secondary HLH primarily affects adolescents and adults, and is typically triggered by infection, autoimmune disease, or malignancy. Secondary HLH treatment protocols have been derived from pediatric protocols in primary HLH, utilizing etoposide, cyclosporine, dexamethasone, and intrathecal methotrexate for central nervous system involvement, and potentially followed by hematopoietic stem cell transplant (HLA-94 and HLA-2004).2 Mortality in adults is greater than 40%, and 30% of patients have refractor disease that requires additional therapy to attempt to achieve remission.2 Several reports suggest that a cytokine-targeted approach may be effective for secondary HLH as adjunctive in relapsed/refractory disease. In particular, ruxolitinib demonstrated efficacy in preclinical murine models of primary HLH by blunting cytokine release via inhibition of Janus kinase (JAK) 1/2, resulting in decreased interferon γ (IFN-γ), interleukin-6 (IL-6), and interleukin 12 (IL-12) signaling.2-5 Moreover, ruxolitinib was recently used to treat an adult patient with refractory secondary HLH, and a phase I clinical trial (NCT02400463) using ruxolitinib to treat secondary HLH is actively recruiting patients.2, 6 Herein, we present the first case of ruxolitinib as a first line agent to treat secondary HLH in a critically ill patient with disseminated histoplasmosis. A 71-year-old woman with rheumatoid arthritis, on methotrexate and hydroxychloroquine, and coronary artery disease was admitted to the hospital for 2 weeks of diarrhea, fevers, and malaise. On admission, she had thrombocytopenia, anemia, and transaminitis. A peripheral blood smear and ADAMTS-13 assay were obtained, which showed no schistocytes and mildly reduced ADAMTS13 activity at 57%, making thrombotic thrombocytopenic purpura less likely. Given the clinical stability of her rheumatoid arthritis, autoimmune associated illness was thought to be unlikely. Infectious disease workup was initiated, and included a negative tick borne panel, HIV, EBV, CMV, and hepatitis B and C. Serum and urine histoplasma antigen were positive. On hospital day 5, the patient was diagnosed with disseminated histoplasmosis involving the liver and gastrointestinal tract, and treatment with amphotericin was started. Given the cyotpenias, fevers, high ferritin, and low fibrinogen, there was concern for HLH, and a bone marrow biopsy was performed on hospital day 7. This demonstrated increased macrophages and histiocytes with morphologic features of hemophagocytosis without any morphologic features of malignant lymphoma, plasma cell proliferative disorder, or other malignant processes. Bone marrow fungal stains were negative. She met 5 out of 8 criteria for HLH, including elevated ferritin (13 850 mcg/L), bilineage cytopenia, fever, bone marrow findings, and hypofibrinogenemia (116 mg/dL). She had normal triglycerides (126 mg/dL). Soluble CD25 and NK cell activity were not analyzed given high clinical suspicion of secondary HLH with other supportive laboratory diagnostics. Despite supportive therapy, she developed distributive shock, worsening cytopenias, renal and hepatic failure, altered mental status, and hypoxic respiratory failure on hospital day 8. Broad spectrum antibiotics and stress-dose corticosteroids were initiated to cover septic shock and adrenal insufficiency secondary to disseminated histoplasmosis, respectively. Given the patient's critical illness, multiorgan failure, and age, conventional cytotoxic chemotherapy was likely to be poorly tolerated. As an alternative, ruxolitinib was initiated on day 8 of hospitalization after detailed discussion with the patient and family. Ruxolitinib 10 mg p.o. twice daily was started with a dose reduction due to renal failure and severe thrombocytopenia (standard therapy 15–20 mg twice daily). Daily ferritin, fibrinogen, CRP, liver function tests, and CBC were monitored (Figure 1A,B). There were no immediate adverse effects, and her shock, mental status, and respiratory failure improved within two days of initiating therapy. The antibiotics were rapidly de-escalated as no additional infectious agent was identified, and her steroids were tapered without incident. Her abnormal liver and renal function was thought to be a combination of medication effects, disseminated histoplasmosis, and HLH. Therefore, the patient was carefully monitored without stopping treatment. On hospital day 12, her liver abnormalities peaked to total bilirubin 10.1, AST 424, and AST 324 before downtrending, and her cytopenias gradually improved thereafter (Figure 1A,B). Given clinical and laboratory improvement on hospital day 15, ruxolitinib was slowly tapered over 3 weeks given the risk of hepatotoxicity. Itraconazole was started on hospital day 18, and amphotericin was discontinued once itraconazole levels were therapeutic. A, Normalized trend of inflammatory markers during ruxolitinib treatment of secondary HLH. B, Laboratory values throughout ruxolitinib treatment. Abbreviations: Ampho = amphotericin, BM = bone marrow, Rux = ruxolitinib, Itra = itraconazole, CRP = C-reactive protein, AST = aspartate aminotransferase Secondary HLH is a life-threatening illness that requires prompt diagnosis and treatment of both the triggering disease process and the HLH syndrome. The current standard treatment of secondary HLH includes cytotoxic chemotherapy that has poor tolerability and efficacy, particularly in adults with comorbidities and secondary multiorgan failure.2 Our case highlights that ruxolitinib is a promising alternative to cytotoxic chemotherapy in HLH, garnering further support for a cytokine-targeted strategy in first-line therapy. In other contexts, ruxolitinib has been associated with cytopenias and hepatocellular injury, but this could not be evaluated in our case given the likelihood of multifactorial renal and hepatic injury. In our patient, multiorgan failure prompted a dose reduction compared to other protocols; however, a good clinical and laboratory response was still achieved. Our case also suggests that a short duration with a taper to avoid a rebound cytokine storm is sufficient to reverse the HLH syndrome. Further investigation with clinical trials is needed to identify the optimal dose, duration, and adverse effects of ruxolitinib in secondary HLH. Our case is the first to demonstrate the use of ruxolitinib as a first-line treatment option for critically ill patients with secondary HLH who may not be good candidates for traditional chemotherapy. The rapid improvement and promising outcome support the ongoing investigation of cytokine-directed approaches in front-line treatment of secondary HLH. Authors would like to thank our patient for generously agreeing to share her case for publication. The authors do not report any disclosures related to this manuscript.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune activation syndrome that should be recognized earlier for effective treatment. Adults usually have secondary HLH. An uncommon cause of secondary HLH is AIDS and simultaneous opportunistic infections. Acute human immunodeficiency virus (HIV) and opportunistic infections are also independent causes of HLH, so the presence of both should raise suspicion, especially if patients fulfill the criteria. HLH secondary to severe babesiosis is a rare entity as well. Some patients might not meet the full criteria of HLH on presentation, especially when some specific lab test results are still pending. A delay in diagnosis can happen in those cases. Here, we present two cases. The first case is of a 35-year-old homosexual male who presented with constitutional symptoms of one-week duration. He was diagnosed and started on the treatment of HIV. His fever was not resolving and further investigations led to a diagnosis of disseminated histoplasma infection. The patient fulfilled the criteria of HLH as well. Prompt therapy resulted in the improvement of clinical and laboratory parameters. The second case is of a 72-year-old female presenting with fever. A diagnosis of severe babesiosis and secondary HLH was made. Treatment of babesia resulted in the improvement of clinical and biochemical parameters.

To assess the etiologies and outcomes of patients with secondary hemophagocytic lymphohistiocytosis in the PICU. Prospective observational cohort study. A single PICU at a pediatric tertiary hospital in Hanoi, Vietnam. Pediatric patients meeting the criteria for secondary hemophagocytic lymphohistiocytosis. None. Between June 2017 and May 2018, 25 consecutive patients with a mean (SD) age of 23.3 months (21.6 mo) were included. Collected variables included etiologies of hemophagocytic lymphohistiocytosis and clinical and laboratory findings at admission. The Pediatric Index of Mortality 2 score at admission was calculated. Outcomes were death and multiple organ dysfunction. The severity of multiple organ dysfunction was assessed by the Pediatric Logistic Organ Dysfunction 2 score. The mean (SD) Pediatric Index of Mortality 2 predicted mortality rate was 5.6% (7.6%). Cytomegalovirus and Epstein-Barr virus coinfections (60%) were the most common suspected etiology of hemophagocytic lymphohistiocytosis. Other etiologies included Epstein-Barr virus sole infections (20%), cytomegalovirus sole infections (16%), and one unknown cause (4%). Multiple organ dysfunction (excluding hematologic failure) was found in 22 patients (88%) with death occurring in 14 patients (56%). The mean (SD) Pediatric Logistic Organ Dysfunction 2 predicted mortality rate among patients with multiple organ dysfunction was 11.9% (11.2%). Despite having lower Pediatric Index of Mortality 2 predicted mortality rates at admission, Epstein-Barr virus-cytomegalovirus coinfection cases with multiple organ dysfunction had slightly greater Pediatric Logistic Organ Dysfunction 2 predicted mortality rates than Epstein-Barr virus sole infection cases with multiple organ dysfunction: 12.2% (10.5%) versus 11.3% (11.0%). However, these rates were lower than cytomegalovirus sole infection cases with multiple organ dysfunction (14.4% [16.3%]). Area under the curve values for Pediatric Index of Mortality 2 and Pediatric Logistic Organ Dysfunction 2 were 0.74 (95% CI, 0.52-0.95) and 0.78 (95% CI, 0.52-1.00), respectively, suggesting that both scales were fair to good at predicting mortality. Viral infections, particularly Epstein-Barr virus-cytomegalovirus coinfections, were a common cause of secondary hemophagocytic lymphohistiocytosis. The implication of these coinfections on the clinical course of hemophagocytic lymphohistiocytosis needs to be delineated.