Fatal Hemophagocytic Lymphohistiocytosis Research Articles

Characterization of Human Engraftment and Hemophagocytic Lymphohistiocytosis in NSG-SGM3 Neonate Mice Engrafted with Purified CD34+ Hematopoietic Stem Cells

Immunodeficient mice bearing human immune systems, or "humanized" chimeric mice, are widely used in basic research, along with the preclinical stages of drug development. Nonobese diabetic-severe combined immunodeficiency (NOD-SCID) IL2Rγnull (NSG) mice expressing human stem cell factor, granulocyte-macrophage colony stimulating factor, and interleukin-3 (NSG-SGM3) support robust development of human myeloid cells and T cells but have reduced longevity due to the development of fatal hemophagocytic lymphohistiocytosis (HLH). Here, we describe an optimized protocol for development of human immune chimerism in NSG-SGM3 mice. We demonstrate that efficient human CD45+ reconstitution can be achieved and HLH delayed by engraftment of neonatal NSG-SGM3 with low numbers of human umbilical cord-derived CD34+ hematopoietic stem cells in the absence of preconditioning irradiation.

Novel RAB27A Variant Associated with Late-Onset Hemophagocytic Lymphohistiocytosis Alters Effector Protein Binding

Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8+ T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8+ T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.

Fatal hemophagocytic lymphohistiocytosis, probably secondary to leishmaniasis, in an immunocompetent adult, with no response to any treatment

Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome, attributed to genetic and acquired factors and is associated with overactivation of macrophages. There are better chances of treatment, when HLH is triggered by an infection. Herein, we describe a rare case which raises questions about this statement. A 53 year’s old, immunocompetent man, presented with relapsing fever for four months. The patient underwent a full workup with no diagnostic findings, apart from detectable IgG antibodies in the plasma and PCR positive for Leishmania in bone marrow aspirates. The patient received liposomal amphotericin B with no fever remission. Patient’s blood tests revealed thrombocytopenia, anemia, high ferritin levels and hypertriglyceridemia. Image analysis revealed splenomegaly. Diagnostic criteria of hemophagocytic syndrome were fulfilled. Genetic testing was negative. The patient received two additional cycles of liposomal amphotericin B, with no response. Finally, he received etoposide, cyclosporine and dexamethasone, according to 2004 HLH protocol. After a long hospitalization the patient passed away.

Fatal hemophagocytic lymphohistiocytosis due to visceral leishmaniasis in a patient with Wegener granulomatosis.

Fatal hemophagocytic lymphohistiocytosis due to visceral leishmaniasis in a patient with Wegener granulomatosis.

Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

Phospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.

Autoimmune Thrombotic Thrombocytopenic Purpura, Disseminated Intravascular Coagulation, Haemophagocytic Lympho Histiocytosis—(Following Corona Virus Infection), Secondary to Fragmented Germ Cells {Liberal Global Abortions, Contraception—(Red Riverways, Blood Moon, Weakened Earth’s Magnet)} and Absence of Abstinence—Retrospective Analysis: Proof of Concept Study

Background: Autoimmunity has increased significantly, alarmingly secondary to global contraception, abortion, fragmenting germ cells; herewith three types of life threatening manifestations, are analysed. Case-1: 28-year-old afebrile lady, vegetarian, presented to emergency with impaired responsiveness, deep jaundice, menorrhagia of one day duration and she had been taking native treatment with leaves for primary infertility for the past five years; she had a few ecchymotic patches, investigations showed severe anaemia, thrombocytopenia, haemolytic jaundice, peripheral smear confirmed thrombotic thrombocytopenic purpura; she developed profound hematuria; she received treatment with intravenous immunoglobulin, fresh frozen plasma, platelet transfusions, packed red blood cells transfusions, plasmapheresis was planned; she improved gradually. In her sincere effort to conceive a baby, for the past five years, due to cultural ignorance which teaches only three days abstinence, instead of seven days abstinence after last menstrual periods, exposure of germ cells to raw endometrial surface, from 4th to 7th days of menstrual cycle, resulted in the cumulative autoimmunity-thrombotic thrombocytopenic purpura status. Case-2: 24-year-old lady who had undergone puerperal sterilisation, on the fourth day after last menstrual periods, presented, with unresponsiveness, to emergency, her investigations revealed prolonged prothrombin time, prolonged activated partial thromboplastin time, more than a minute, thrombocytopenia, reduced fibrinogen levels suggesting disseminated intravascular coagulation; her ultra sonogram abdomen showed, absence of gestational sac in the uterus; she received fresh frozen plasma transfusions, but succumbed within few hours. With puerperal sterilisation, [non evidence based medical practice], 20 million germ cells are fragmented to chromatid breaks, a-centric fragments, ring chromosomes, which get exposed to partly regenerated endometrial surface, on the fourth day after last menstrual periods, due to lack of awareness of abstinence upto seven days, initiating severe cumulative autoimmunity, resulting in fatal disseminated intravascular coagulation. Case-3: Fatal haemo-phagocytic lympho-histiocytosis-soaring autoimmunity, detected in the victim host of corona virus infection, correlated directly with extensive tissue damage produced in the victim host, by prior surgical abortions. Conclusion: Cases one and two followed absence of abstinence, with exposure of germ cells, to partly healed endometrial surface in the former culminating in thrombotic thrombocytopenic purpura; in the latter by exposure of fragmented 20 million germ cells [by contraception] to partly healed endometrial surface, culminating in fatal disseminated intravascular coagulation. In case three fatal autoimmune hemophagocytic lymphohistiocytosis followed corona virus infection, secondary to extensive tissue damage, of liberal global abortions. Red Russian riverways, is another evidence for global warming due to global aborted blood pollution, melting Perma-Frost crashing the Diesel tanks, with oil spill reflecting on aborted blood polluted river, turns bright red, similar to blood moon by abortion polluted air. Innumerable human lives with their iron of blood flowing within blood vessels, repelling magnet of earth, is mandatory to strengthen earth’s magnet. Arctic ozone hole closed this May, environmental pollution cleared, by absence of global abortions, contraception, and their ozone depleting blood pollution, due to lock down of corona virus pandemic.

A Boy with Chronic Active EBV Infection Presented as Mosquito Bite Hypersensitivity Progressed to Fatal Hemophagocytic Lymphohistiocytosis due to NK Cell Neoplasm

A Boy with Chronic Active EBV Infection Presented as Mosquito Bite Hypersensitivity Progressed to Fatal Hemophagocytic Lymphohistiocytosis due to NK Cell Neoplasm

Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis: Case report and systematic literature review.

AIMTo systematically review liver disease associated with hemophagocytic lymphohistiocytosis (HLH), propose reasonable contraindications for liver transplantation for liver failure in HLH, and report an illustrative case.METHODSSystematic review according to PRISMA guidelines of hepatic manifestations of HLH using computerized literature search via PubMed of articles published since 1980 with keywords (“hemophagocytic lymphohistiocytosis” or “HLH”) AND (“liver” or “hepatic”). Two authors independently performed literature search and incorporated articles into this review by consensus. Illustrative case report presented based on review of medical chart, and expert re-review of endoscopic photographs, radiologic images, and pathologic slides.RESULTSA 47-year-old Caucasian male, was hospitalized with high-grade pyrexia, rash, total bilirubin = 45 g/dL, moderately elevated hepatic transaminases, ferritin of 3300 ng/dL, leukopenia, and profound neutropenia (absolute neutrophil count < 100 cells/mm³). Viral serologies for hepatitis A, B, and C were negative. Abdominal computed tomography scan and magnetic resonance imaging revealed no hepatic or biliary abnormalities. Pathologic analysis of liver biopsy revealed relatively well-preserved hepatic parenchyma without lymphocytic infiltrates or macrophage invasion, except for sparse, focal hepatocyte necrosis. Bone marrow biopsy and aspirate revealed foamy macrophages engulfing mature and precursor erythrocytes, consistent with HLH. Interleukin-2 receptor (CD25) was highly elevated, confirming diagnosis of HLH according to Histiocytic Society criteria. Patient initially improved after high-dose prednisone therapy. Patient was judged not to be a liver transplant candidate despite model for end stage liver disease (MELD) score = 33 because liver failure was secondary to severe systemic disease from HLH, including septic shock, focal centrilobular hepatocyte necrosis from hypotension, bone marrow failure, and explosive immune activation from HLH. The patient eventually succumbed to overwhelming sepsis, progressive liver failure, and disseminated intravascular coagulopathy. Systematic review reveals liver injury is very common in HLH, and liver failure can sometimes occur. Data on liver transplantation for patients with HLH are very limited, and so far the results have shown a generally much worse prognosis than for other liver transplant indications. Liver transplantation should not be guided solely by MELD score, but should include liver biopsy results and determination whether liver failure is from intrinsic liver injury vs multisystem (extrahepatic) organ failure from HLH.CONCLUSIONThis case report illustrates that liver transplantation may not be warranted when liver failure associated with HLH is primarily from multisystem failure from HLH. Liver biopsy may be very helpful in determining the severity and pathophysiology of the liver disease.

Hemophagocytic Lymphohistiocytosis Complicating Systemic Sarcoidosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by histiocyte proliferation and hemophagocytosis. Primary HLH is caused by genetic defects, whereas secondary HLH occurs in the setting of underlying diseases, such as infections, malignancies, or rheumatic diseases. Rheumatic diseases, such as systemic juvenile arthritis or systemic lupus erythematosus, have been associated with HLH. However, the association between sarcoidosis and HLH has been rarely reported in the literature. Herein, we report a case of a 36-year-old female who was recently diagnosed with sarcoidosis, and she developed fatal HLH that was not responsive to high-dose steroids.

An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome

BackgroundChediak-Higashi syndrome (CHS) is a rare disorder caused by biallelic mutations in the lysosomal trafficking regulator gene (LYST), resulting in formation of giant lysosomes or lysosome-related organelles in several cell types. The disease is characterized by immunodeficiency and a fatal hemophagocytic lymphohistiocytosis caused by impaired function of cytotoxic lymphocytes, including natural killer (NK) cells.ObjectiveWe sought to determine the underlying biochemical cause of the impaired cytotoxicity of NK cells in patients with CHS.MethodsWe generated a human cell model of CHS using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. We used a combination of classical techniques to evaluate lysosomal function and cell activity in the model system and super-resolution microscopy to visualize F-actin and lytic granules in normal and LYST-deficient NK cells.ResultsLoss of LYST function in a human NK cell line, NK92mi, resulted in inhibition of NK cell cytotoxicity and reproduced other aspects of the CHS cellular phenotype, including the presence of significantly enlarged lytic granules with defective exocytosis and impaired integrity of endolysosomal compartments. The large granules had an acidic pH and normal activity of lysosomal enzymes and were positive for the proteins essential for lytic granule exocytosis. Visualization of the actin meshwork openings at the immunologic synapse revealed that the cortical actin acts as a barrier for secretion of such large granules at the cell-cell contact site. Decreasing the cortical actin density at the immunologic synapse or decreasing the lytic granule size restored the ability of LYST-deficient NK cells to degranulate and kill target cells.ConclusionThe cortical actin and granule size play significant roles in NK cell cytotoxic function. We present evidence that the periodicity of subsynaptic actin is an important factor limiting the release of large lytic granules from NK cells from patients with CHS and could be a novel target for pharmaceutical intervention.

Fatal Hemophagocytic Lymphohistiocytosis associated with Influenza B

혈구포식 림프조직구증식증(HLH)은 대식세포와 림프구의 증식과 활성화가 ì¡°ì ˆë˜ì§€ 않아 발생하게 되는 드문 과염증 증후군으로, ì¹˜ëª ì ì¸ 예후를 초래하는 경우가 많다. ì €ìžë“¤ì€ ê¸°ì € 질환이 없는 환자에서 B형 인플루엔자 감염과 연관되어 발생한 혈구포식 림프조직구증식증으로 인하여 사망한 증례를 경험하여 이를 ë³´ê³ í•˜ëŠ” 바이다. 중심 단어: B형 인플루엔자; 혈구포식 림프조직구증식증

High Level of Perforin Expression Is Required for Effective Correction of Hemophagocytic Lymphohistiocytosis.

Perforin-1 mutations result in a potentially fatal hemophagocytic lymphohistiocytosis (HLH) with heightened immune activation, hypercytokinemia, pancytopenia, and end-organ damage. At present, hematopoietic stem cell (HSC) transplantation is curative, but limited by donor availability and associated mortality, making gene therapy an attractive alternative approach for HLH. We reported that perforin expression driven by cellular promoters in lentiviral (LV) vectors resulted in significant, albeit partial, correction of the inflammatory features in a murine model of HLH. We hypothesized that the level of perforin expression achieved per cell from ectopic moderate-strength cellular promoters (phosphoglycerate kinase gene/perforin-1 gene) is inadequate and thus engineered an LV vector using a viral promoter (MND; a modified Moloney murine leukemia virus long terminal repeat with myeloproliferative sarcoma virus enhancer) containing microRNA126 target sequences to restrict perforin expression in HSCs. We show here that the MND-LV vector restored perforin expression to normal levels in a perforin-deficient human natural killer cell line and perforin gene-corrected Perforin1-/- transplant recipients, whereas cellular promoters drove only partial correction. On lymphocytic choriomeningitis virus challenge, the clinical scores and survival improved only with the MND-LV vector, but inflammatory markers and cytotoxicity were improved with all LV vectors. Our studies suggest that although moderate levels of expression can result in partial amelioration of the HLH phenotype, high levels of perforin expression per cell are required for complete correction of HLH.

ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice

AbstractCytokine storm syndromes, such as familial hemophagocytic lymphohistiocytosis (FHL), are lethal disorders caused by uncontrolled, systemic immune activation. In the murine model of FHL, in which perforin-deficient (Prf1−/−) mice are infected with lymphocytic choriomeningitis virus (LCMV), disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8+ T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However, this paradigm is insufficient to explain several fundamental aspects of FHL, namely, the inability of many pathogenic antigens to induce hyperinflammation, and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor, ST2, in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1−/− mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1−/− mice and reduces the severity of multiple disease parameters, including serum levels of IFNγ. This decrease in IFNγ corresponds to a reduction in both the frequency of IFNγ+ LCMV-specific CD8+ and CD4+ T cells and the magnitude of IFNγ expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell–mediated production of IFNγ and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore, this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL.

Stem cell factor, GM-CSF, and IL-3-Transgenic humanized mice develop fatal hemophagocytic lymphohistiocytosis

Stem cell factor, GM-CSF, and IL-3-Transgenic humanized mice develop fatal hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

AbstractSyntaxin-11 (Stx11), an atypical member of the SNARE protein family, is part of the cytolytic machinery of T and NK cells and involved in the fusion of lytic granules with the plasmamembrane. Functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of T and NK cells. Furthermore, patients with STX11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a life-threatening disease of severe hyperinflammation. We established Stx11-deficient mice as an animal model for FHL4. Stx11-deficient mice exhibited severely reduced degranulation and cytolytic activity of CTL and NK cells and developed all clinical symptoms of hemophagocytic lymphohistiocytosis (HLH) after infection with lymphocytic choriomeningitis virus (LCMV). The HLH phenotype was further characterized by hyperactive CD8 T cells and continuous IFN-γ production. However, in contrast to perforin-deficient mice, which represent a model for FHL2, progression of HLH was not fatal. Survival of Stx11-deficient mice was determined by exhaustion of antigen-specific T cells, characterized by expression of inhibitory receptors, sequential loss of effector functions, and finally T-cell deletion. Blockade of inhibitory receptors on T cells in Stx11-deficient mice converted nonfatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.

Fatal hemophagocytic lymphohistiocytosis presenting as Reye’s syndrome: Report of two cases

We report two cases of rapidly fatal hemophagocytic lymphohistiocytosis (HLH) that presented as Reye’s syndrome (RS). The patients were referred to our hospital because of altered level of consciousness with hyperammonemia and hypoglycemia. The first patient, a 24-month-old girl (Case 1), died soon after arrival and was clinically diagnosed as having RS, but a diagnosis of HLH was established on the basis of autopsy findings. The other patient, a 4-month-old boy (Case 2), was diagnosed as having HLH in view of the bone marrow findings on admission, but immunosuppressive therapy failed to prevent a rapidly fatal course. Marked hypercytokinemia was found in both patients, and liver pathology demonstrated panlobular microvesicular steatosis of hepatocytes, resembling that in RS. Mononuclear cell infiltration with hemophagocytosis in the liver was evident in case 2, but not in case 1. In both cases, hypercytokinemia was thought to have caused mitochondrial dysfunction, resulting in RS-like microvesicular steatosis of hepatocytes. HLH is an important differential diagnosis of children presenting with RS-like picture.

High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma

IntroductionEnteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. Patients and methodsA retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n=7) and purine nucleotide analogues (n=6). ResultsMedian follow-up was 8.7 (1–97) months. Surgery was required in 10 patients (66%) for intestinal complications (n=7) or elective small bowel resection (n=3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan–Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p=0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. ConclusionEnteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy.

Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report

IntroductionHemophagocytic lymphohistiocytosis induced by viral diseases is a well recognized entity. Severe forms of H5N1 influenza are known to be associated with symptoms very similar to a reactive hemophagocytic syndrome. We report a case of fulminant lymphohistiocytosis associated with the pandemic A (H1N1) variant.Case presentationA 42-year-old Caucasian woman developed a syndrome of fatal hemophagocytic lymphohistiocytosis shortly after H1N1 influenza. Initial symptoms of the viral disease were unusual, with acute abdominal involvement. Our patient's course was complicated by diffuse skin rash and ileal ischemia. Our patient died of refractory shock and multi-organ failure. Skin, ileum and colon histology was consistent with an acute apoptosis combined with an increased cellular regeneration.ConclusionsInfluenza may be complicated by severe forms of hemophagocytic lymphohistiocytosis. To ensure early recognition and treatment, physicians should be aware of the possible induction of the syndrome by the novel H1N1 variant. The rapid occurrence of a multi-organ involvement with evocative biological features of macrophage activation should alert clinicians.

Hemophagocytic lymphohistiocytosis associated with influenza A (H1N1) infection in a patient with chronic lymphocytic leukemia: an autopsy case report and review of the literature

H1N1 influenza A virus can trigger fatal hemophagocytic lymphohistiocytosis in immunocompromised patients and in immunocompetent hosts, usually children. We present a case of a 50-year-old man with low-burden chronic lymphocytic leukemia who had sudden reactivation of his leukemia triggered by influenza A (H1N1) infection with hemophagocytic lymphohistiocytosis during the 2009 H1N1 pandemic. His rapid course was complicated by acute respiratory distress syndrome with diffuse alveolar damage, a 6-fold rise in lymphocyte count, disseminated intravascular coagulation, and, ultimately, cardiac arrest. Major findings at autopsy included: bilateral H1N1 pneumonitis with diffuse alveolar damage, intra-alveolar pulmonary hemorrhage, pulmonary microthromboemboli, pulmonary hemorrhagic infarction, hemophagocytic lymphohistiocytosis in multiple locations, and diffuse chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis is a serious and often fatal condition, which may be primary or secondary. It may be associated with high-grade lymphoproliferative malignancies, especially in patients with therapy-related leukocytopenia, but only rarely is it seen in uncomplicated chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis may be triggered by a variety of infections (viral, fungal, bacterial and parasitic), but H1N1 influenza A-associated hemophagocytic lymphohistiocytosis is often rapidly fatal, especially in children. This adult patient's clinical presentation with low tumor burden and leukocytosis is thus unique. We review the recently published autopsy findings in fatal influenza A (H1N1) infection and the association with resultant secondary hemophagocytic lymphohistiocytosis.

Fatal hemophagocytic lymphohistiocytosis in an extremely‐low‐birthweight infant

Fatal hemophagocytic lymphohistiocytosis in an extremely‐low‐birthweight infant