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1.  Fulminant hemophagocytic lymphohistiocytosis induced by pandemic A (H1N1) influenza: a case report 
Introduction
Hemophagocytic 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 presentation
A 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.
Conclusions
Influenza 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.
doi:10.1186/1752-1947-5-280
PMCID: PMC3141719  PMID: 21722406
2.  Diffuse large B-cell lymphoma in an adolescent female presenting with Epstein-Barr virus-driven hemophagocytic lymphohistiocytosis: a case report 
Introduction
Hemophagocytic lymphohistiocytosis is characterized by multisystem inflammation, resulting from prolonged and intense activation of macrophages, histiocytes and CD8+ T-cells. Due to its variable presentation and non-specific findings, timely diagnosis can be challenging. This condition has been associated with malignancies, most commonly with lymphomas and leukemias of T-cell lineage. This case report represents the less commonly associated B-cell lymphomas. We also highlight the difficulties in managing hemophagocytosis with an evolving malignancy. This case report will add to the increasing literature on the diagnosis, complications and management of this complex disorder.
Case presentation
A 15-year-old Caucasian girl, previously diagnosed with Crohn’s disease and treated with 6-mercaptopurine, developed Epstein-Barr virus infection-driven hemophagocytic lymphohistiocytosis. The diagnosis was challenging due to her critical illness and the lack of enough features to fulfill diagnostic criteria at presentation (moderately elevated ferritin, normal coagulation profiles and normal triglycerides). While receiving therapy for hemophagocytic lymphohistiocytosis, she developed bulky cervical lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma. Therapy for lymphoma was initiated and she tolerated the therapy well.
Conclusion
Hemophagocytic lymphohistiocytosis is a rare disorder, but potentially lethal if not diagnosed and treated in a timely manner. Our case highlights the importance of considering this diagnosis in critically ill patients who may not initially fulfill formal diagnostic criteria. In patients diagnosed with hemophagocytic lymphohistiocytosis, occult malignancies should be aggressively ruled out as they can manifest prior to the hemophagocytic lymphohistiocytosis diagnosis or appear during the treatment phase. An accurate diagnosis is also important because management of Epstein-Barr virus-driven hemophagocytic lymphohistiocytosis and Epstein-Barr virus-driven lymphoma differs due to the difference in pathophysiology and the involvement of different immune cell lines.
doi:10.1186/1752-1947-6-141
PMCID: PMC3412722  PMID: 22657725
3.  Hemophagocytic lymphohistiocytosis: a case series of a Brazilian institution 
Objective
To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosis in children treated at a referral institution.
Methods
A retrospective descriptive study was carried out of seven children diagnosed with hemophagocytic lymphohistiocytosis between 2010 and 2012. The criteria for diagnosis were those proposed by the Histiocyte Society. When indicated, immunochemotherapy was prescribed according to the HLH94 and HLH2004 protocols of the Histiocyte Society.
Results
The patients’ ages at diagnosis ranged from one month to nine years. All patients had splenomegaly, fever, anemia, thrombocytopenia, hyperferritinemia and hypertriglyceridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectious diseases triggered the syndrome. In two cases, associated with visceral leishmaniasis, remission was achieved after treatment of the underlying infection. Three patients, who had Epstein–Barr-related hemophagocytic lymphohistiocytosis, required treatment with immunochemotherapy. They are alive and in remission; one patient had symptoms of juvenile rheumatoid arthritis and another, who was suspected of having primary hemophagocytic lymphohistiocytosis, entered into remission after bone marrow transplantation. Two deaths (28.6%) occurred in patients with suspected primary hemophagocytic lymphohistiocytosis; one whose clinical picture was triggered by cytomegalovirus infection did not respond to immunochemotherapy and the other died before any specific treatment was provided.
Conclusion
As reported before, hemophagocytic lymphohistiocytosis has a multifaceted presentation with nonspecific signs and symptoms. In secondary forms, remission may be achieved by treating the underlying disease. In the primary forms, remission may be achieved with immunochemotherapy, but bone marrow transplantation is required for cure.
doi:10.1016/j.bjhh.2014.07.003
PMCID: PMC4318477  PMID: 25453655
Hemophagocytic lymphohistiocytosis; Visceral leishmaniasis; Therapeutics; Bone marrow transplantation
4.  Prolonged hemophagocytic lymphohistiocytosis syndrome as an initial presentation of Hodgkin lymphoma: a case report 
Introduction
Hemophagocytic lymphohistiocytosis is an immune-mediated syndrome that typically has a rapidly progressive course that can result in pancytopenia, coagulopathy, multi-system organ failure and death.
Case presentation
A 57-year-old Caucasian woman was referred in fulminant hemophagocytic lymphohistiocytosis, with fever, pancytopenia, splenomegaly, mental status changes and respiratory failure. She was found to have stage IV classical Hodgkin lymphoma, in addition to Epstein-Barr virus and cytomegalovirus viremia. Her presentation was preceded by a 3-year prodrome consisting of cytopenia and fever that were partially controlled by steroids and azathioprine.
Conclusion
Fulminant hemophagocytic lymphohistiocytosis may follow a prodromal phase that possesses features suggestive of a chronic form of hemophagocytic lymphohistiocytosis, but which may also resemble immune cytopenias of other causes. A diagnosis of hemophagocytic lymphohistiocytosis should be considered in the setting of chronic pancytopenia.
doi:10.1186/1752-1947-2-367
PMCID: PMC2613409  PMID: 19055804
5.  Not another case of mono: Epstein-Barr virus (EBV) associate hemophagocytic lymphohistiocytosis (HLH) 
Patient: Male, 30
Final Diagnosis: Hemophagocytic lymphohistiocytosis (LHL)
Symptoms: Abdominal pain • fever • hypotension • pancytopenia
Medication: —
Clinical Procedure:—
Specialty: Infectious Diseases
Objective:
Rare disease
Background:
Hemophagocytic lymphohistiocytosis (HLH) is a result of dysregulated cellular response system. Primary HLH is an autosomal recessive disorder of childhood, with defects in cellular cytotoxicity. Secondary HLH is an acquired syndrome that presents in young adulthood secondary to a variety of inflammatory conditions: viral infections, rheumatologic conditions, or malignant processes. The inflammatory nature of certain conditions triggers a cytokine release in individuals who have abnormal T cell activation.
Case Report:
A 30-year-old Hispanic male presented with worsening abdominal pain for 5 months and was found to have fever, pancytopenia, and hypotension. Serial CT scans of the abdomen/pelvis showed splenomegaly but no abscesses, areas of infection, or masses. Infectious causes were considered but results of all cultures and tests were negative except for a high Epstein-Barr viral load. The patient deteriorated and required intubation on hospital day 28. Repeat bone marrow biopsy on day 32 suggested a diagnosis of hemophagocytic lymphohistiocytosis, although there was no evidence of hemophagocytosis within the bone marrow. The patient continued to deteriorate and was too unstable to receive treatment with chemotherapy. He died on hospital day 34.
Conclusions:
This case highlights the importance of early consideration and treatment of secondary HLH in an individual presenting with progressive fever, hepatomegaly, and cytopenias.
doi:10.12659/AJCR.889322
PMCID: PMC3858201  PMID: 24340129
EBV; EBV associated with hemophagocytic lymphohistiocytosis; hemophagocytic lymphohistiocytosis
6.  Successful Treatment of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis with HLH-94 Protocol 
Journal of Korean Medical Science  2005;20(2):209-214.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, fatal disorder of children, affecting predominantly the mononuclear phagocytic system. Previous reports indicate that Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) can also be fatal in many cases, although the prognosis for EBV-HLH is better than for the familial form of hemophagocytic lymphohistiocytosis. We treated four patients with EBV-HLH using immunochemotherapy including steroid, etoposide (VP-16), and cyclosporin, according to the HLH-94 protocol. All patients experienced persistent fever, cytopenia, and hypertriglyceridemia. Serological testing for EBV showed reactivated EBV infections in all patients. EBV DNA detected by PCR and EBV-encoded small RNA measured by in situ hybridization were confirmed in the patients' bone marrow specimens. Hemophagocytosis was shown in bone marrow aspirates and liver biopsy specimen. Complete remission was achieved in all patients after induction and continuation therapy for 4-10 months (median, 7 months) and was maintained for 15-27 months (median, 19 months) without the need for bone marrow transplantation. These results suggest that EBV-HLH can be effectively controlled by immunochemotherapy using the HLH-94 protocol.
doi:10.3346/jkms.2005.20.2.209
PMCID: PMC2808593  PMID: 15831988
Epstein-Barr Virus Infections; Hemophagocytic Lymphohistiocytosis; Histiocytosis, Non-Langerhans-Cell; Etoposide; Cyclosporine; HLH-94; Child
7.  Presentation of hemophagocytic lymphohistiocytosis due to a novel MUNC 13–4 mutation masked by partial therapeutic immunosuppression 
Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. An associated gene mutation may be found which impairs cytolytic lymphocyte function. We describe a pediatric case of hemophagocytic lymphohistiocytosis with a novel mutation of MUNC 13–4 whose diagnosis was confounded by concurrent immunosuppression. Clinical reassessment for hemophagocytic lymphohistiocytosis is necessary in persistently febrile patients with laboratory derangements in the setting of immunosuppressive agent exposure.
doi:10.1186/1546-0096-10-13
PMCID: PMC3503647  PMID: 22554126
Hemophagocytic lymphohistiocytosis; MUNC 13–4; Macrophage activation syndrome
8.  Acute myelocytic leukemia in a patient with hemophagocytic lymphohistiocytosis: A case report 
Oncology Letters  2014;8(6):2634-2636.
Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is an aggressive hyperinflammatory condition characterized by prolonged fever, cytopenias and hepatosplenomegaly, as well as hemophagocytosis by activated, morphologically benign macrophages. HLH may be characterized into two forms, familial and secondary HLH. Familial HLH usually manifests in children with genetic abnormalities associated with the cytotoxic function of NK and T cells, whereas secondary HLH usually occurs in older patients in combination with an associated condition, such as infection or malignancy, without an identifiable genetic abnormality. Malignancy-associated hemophagocytic lymphohistiocytosis is mostly accompanied by lymphoid neoplasms. The present study reports a rare case of this syndrome in combination with acute myeloblastic leukemia (AML-M2), in a patient with clonal karyotypic abnormalities. The patient was successfully treated with chemotherapy comprising daunorubicin (40 mg/m2 i.v., days 1–3) and cytosine arabinoside (100 mg/m2, 1-h i.v. infusion, days 1–7). All clinical symptoms disappeared following chemotherapy.
doi:10.3892/ol.2014.2527
PMCID: PMC4214506  PMID: 25364441
hemophagocytic lymphohistiocytosis; leukemia; chemotherapy
9.  Hemophagocytic Lymphohistiocytosis (HLH) Associated with Plasmodium vivax Infection: Case Report and Review of the Literature 
Chonnam Medical Journal  2011;47(3):173-176.
Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and pathologic findings of hemophagocytosis in the bone marrow and other tissues. HLH may be familial or associated with different types of infections, autoimmune disorders, or malignancies. Infection-associated HLH has been reported in various viral, bacterial, fungal, and parasitic infections, and case reports of parasitic infections implicated in HLH include rare cases from Plasmodium vivax infection, which occasionally affects both military personnel and civilians in Korea. We describe an unusual case of HLH resulting from Plasmodium vivax infection and review the literature. This case suggests that clinical suspicion of HLH is important when P. vivax infection is accompanied by cytopenias. Administration of antimalarial drugs may prevent irreversible end organ damage resulting from P. vivax-associated HLH.
doi:10.4068/cmj.2011.47.3.173
PMCID: PMC3252507  PMID: 22247919
Hemophagocytic lymphohistiocytosis; Plasmodium vivax
10.  Hemophagocytic Lymphohistiocytosis in a Patient with Goodpasture’s Syndrome: A Rare Clinical Association 
Patient: Female, 31
Final Diagnosis: Hemophagocytic lymphohistiocytosis (LHL)
Symptoms: Hemopthysis
Medication: —
Clinical Procedure: —
Specialty: Oncology
Objective:
Rare disease
Background:
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome. HLH can occur in the setting of an autoimmune disease, chronic immunosuppression, malignancy, and infection. We discuss a rare case of a young woman who was diagnosed with Goodpasture’s syndrome that was most likely complicated by HLH. To the best of our knowledge, this is the first report of HLH in the setting of this rare autoimmune disease.
Case Report:
A 31-year-old woman who was diagnosed with Goodpasture’s syndrome 7 years prior presented with febrile neutropenia. She was initially receiving treatment with azathioprine and prednisone, which was subsequently switched to hydroxychloroquine. Over time, she had developed polyarthritis and was later diagnosed with MPO-ANCA-positive vasculitides. On this admission, her clinical status deteriorated from persistent pancytopenia. This was initially attributed to the immunosuppressive effect of hydroxychloroquine. A bone marrow biopsy was performed and revealed hypercellular bone marrow without any cytogenetic abnormalities. Due to a prolonged pancytopenia thought to be of autoimmune etiology, treatment with high-dose steroids was initiated. With the persistent febrile episodes, hepatosplenomegaly on examination, and laboratory workup that revealed hyperferritinemia and pancytopenia, HLH syndrome was suspected. A repeat bone marrow biopsy confirmed this diagnosis with the presence of hemophagocytosis, demonstrated by the presence of histiocytes engulfing erythroid cells. She also met 5 of 8 diagnostic criteria, which confirmed the diagnosis of HLH. The patient eventually died despite aggressive treatment with high-dose steroid therapy for her autoimmune disorder, as well intravenous antibiotics and supportive care for her underlying infections.
Conclusions:
HLH is a syndrome marked by a hyper-inflammatory state aggravated by specific triggers. To make the diagnosis of HLH, at least 5 of the 8 criteria must be met. Treatment involves suppression of the overwhelming inflammatory response by the use of immunomodulators. The mortality rate can range from 50–90% due to delayed recognition and onset of treatment. Here, we present a rare case of Goodpasture’s syndrome with overlap and pauci-immune vasculitis, which may have triggered the HLH. This correlation has not been described before in the literature.
doi:10.12659/AJCR.891067
PMCID: PMC4199464  PMID: 25284133
Anti-Glomerular Basement Membrane Disease; Cytokines; Lymphohistiocytosis, Hemophagocytic
11.  Cerebrospinal Fluid Involvement in a Case of Visceral Leishmaniasis Associated with Hemophagocytic Lymphohistiocytosis 
Hemophagocytic Lymphohistiocytosis (HLH) implies a benign generalized histiocytic proliferate with erythrophagocytosis and it includes familial hemophagocytic lymphohistiocytosis and secondary hemophgocytosis. Spinal fluid changes like mild to moderate pleocytosis (most of the cells are lymphocytes and macrophages) and sometimes hemophagocytosis are seen in primary HLH but are not reported in secondary HLH. Here we report a case of a previously healthy 10 months old male infant who was diagnosed as familial HLH with evidence of CSF hemophagocytosis. He was started on the HLH 2004 treatment protocol with no improvement. A second bone marrow aspiration revealed leshmania donovani antibodies and he was started on anti-leishmania treatment with dramatic response.To the best of our knowledge, this is the first case of secondary HLH with evidence of hemophagocytosis in cerebrospinal fluid.
PMCID: PMC3074877  PMID: 21748112
Lymphohistiocytosis; hemophagocytic; Leishmaniasis; Cerebrospinal fluid; Case Report; Oman
12.  Undiagnosed Chronic Granulomatous Disease, Burkholderia cepacia complex Pneumonia, and Acquired Hemophagocytic Lymphohistiocytosis: A Deadly Association 
Case Reports in Pulmonology  2013;2013:874197.
Background. Chronic granulomatous disease is a rare inherited disorder of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The clinical course of the disease is marked by recurrent infections, including Burkholderia cepacia complex infection. Case Report. Here we report the case of a 21-year-old male hospitalized for a Burkholderia cepacia complex pneumonia. Despite the broad spectrum antibiotic treatment, fever continued and patient's condition worsened. Anemia and thrombocytopenia developed together with hypofibrinogenemia. The patient died of multiple organ dysfunction 17 days after his admission. Autopsy revealed hemophagocytosis, suggesting the diagnosis of acquired hemophagocytic lymphohistiocytosis. DNA analysis showed a deletion in the p47phox gene, confirming the diagnosis of autosomal recessive chronic granulomatous disease. Discussion. In addition to chronic granulomatous disease, recent findings have demonstrated that Burkholderia cepacia complex can decrease activity of the NADPH oxidase. Interestingly, hemophagocytic lymphohistiocytosis is characterized by an impaired function of the T-cell mediated inflammation which is partly regulated by the NADPH oxidase. Physicians should therefore pay particular attention to this deadly association.
doi:10.1155/2013/874197
PMCID: PMC3766577  PMID: 24058739
13.  Hemophagocytic Lymphohistiocytosis Associated with Visceral Leishmaniasis in Late Adulthood 
We describe a case of hemophagocytic lymphohistiocytosis related to visceral leishmaniasis in late adulthood. Because clinical features of visceral leishmaniasis can mimic those of hemophagocytic lymphohistiocytosis, diagnosing leishmaniasis as the underlying etiology can be quite challenging. In our case, treatment with amphotericin B resulted in a dramatic resolution of clinical abnormalities.
doi:10.4269/ajtmh.12-0563
PMCID: PMC3592544  PMID: 23324220
14.  Familial Hemophagocytic Lymphohistiocytosis: When Rare Diseases Shed Light on Immune System Functioning 
The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes.
doi:10.3389/fimmu.2014.00167
PMCID: PMC3997030  PMID: 24795715
cellular cytotoxicity; natural killer; hemophagocytosis; mutation analysis
15.  Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis 
Pediatrics  2013;132(5):e1440-e1444.
Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative.
doi:10.1542/peds.2012-2748
PMCID: PMC3813387  PMID: 24101757
cytopenias; splenomegaly; lymphadenopathy; HLH; ALPS; apoptosis
16.  The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene 
About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin.
doi:10.1084/jem.20040776
PMCID: PMC2211966  PMID: 15365097
HLH; cytotoxic granule; NK cell; CTL; immunodeficiency
17.  Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report 
Introduction
Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy.
Case presentation
He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure.
Conclusions
Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.
doi:10.1186/1752-1947-8-288
PMCID: PMC4150421  PMID: 25163591
Epstein-Barr virus; T-cell lymphoproliferative disease; Childhood
18.  A Case of Hemophagocytic Syndrome due to Tuberculosis: Uncommon Manifestation of a Common Disease 
Case Reports in Medicine  2014;2014:613845.
Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is the manifestation of immune dysregulation. It is associated with ineffective but exaggerated immune response and infiltration of active lymphocytes and histiocytes in various organs. This devastating clinical condition has myriad of clinical and biochemical manifestations such as fever, splenomegaly, pancytopenia, hypertrygliceridemia, and hyperferritinemia. It can be either primary or secondary. Primary HLH usually presents in childhood. Secondary HLH occurs due to infection mostly viruses but other aetiologies are also important as early detection and treatment may improve survival. Hemophagocytosis due to tuberculosis is uncommon. Only handful of cases have been reported mostly in immunocompromised patients. We report a case of hemophagocytic syndrome associated with disseminated tuberculosis in an immunocompetent women highlighting early diagnosis and treatment is a demanding need in this devastating disease.
doi:10.1155/2014/613845
PMCID: PMC4227369  PMID: 25404945
19.  Hemophagocytic syndromes and infection. 
Emerging Infectious Diseases  2000;6(6):601-608.
Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, splenomegaly, jaundice, and the pathologic finding of hemophagocytosis (phagocytosis by macrophages of erythrocytes, leukocytes, platelets, and their precursors) in bone marrow and other tissues. HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection. Hyperproduction of cytokines, including interferon-gamma and tumor necrosis factor-alpha, by EBV- infected T lymphocytes may play a role in the pathogenesis of HLH. EBV-associated HLH may mimic T-cell lymphoma and is treated with cytotoxic chemotherapy, while hemophagocytic syndromes associated with nonviral pathogens often respond to treatment of the underlying infection.
PMCID: PMC2640913  PMID: 11076718
20.  A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome 
Annals of Hematology  2013;93(5):821-826.
Lymphoma-associated hemophagocytic syndrome (LAHS), which is the major subtype of adult-onset secondary hemophagocytic lymphohistiocytosis (HLH), has a poor outcome. Although the early diagnosis and treatment of LAHS contributes to a better outcome, the lack of mass formation and the absence of distinct lymph node enlargement often delay the diagnosis of underlying lymphoma. A recent study, which statistically analyzed HLH cases in the literature, showed that the serum soluble interleukin-2 receptor (sIL-2R)/ferritin ratio could be used as a marker to diagnosis of LAHS. To verify this finding, we retrospectively analyzed the laboratory findings of 21 patients with HLH (10 benign disease-associated HLH and 11 LAHS). No significant differences were observed in the levels of LDH or CRP levels. The mean sIL-2R levels (units per milliliter) were significantly higher in the LAHS group (4,176 vs. 13,451, p = 0.0031), and ferritin levels (nanogram per milliliter) were higher in the benign disease-associated HLH group (20,462 vs. 2,561, p = 0.0031). Consequently, the mean serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease-associated HLH (0.66 vs. 8.56, p = 0.0004). Thus, the results of this study demonstrated that the serum sIL-2R/ferritin ratio is a very useful marker for diagnosing of LAHS, which was further supported by clinical case analysis. Further studies to clarify the pathophysiology of secondary HLH caused by various triggers are needed.
doi:10.1007/s00277-013-1925-8
PMCID: PMC3976506  PMID: 24705932
Lymphoma-associated hemophagocytic syndrome; Malignant lymphoma; Soluble interleukin-2 receptor; Ferritin
21.  Hemophagocytic Syndrome Associated with Mycoplasma pneumoniae Pneumonia 
Case Reports in Pediatrics  2013;2013:586705.
Mycoplasma pneumoniae (Mp) sometimes causes immunological complications in children. We present a rare case of hemophagocytic syndrome (HPS) caused by Mp in a previously healthy 7-year-old Japanese girl. A chest radiograph obtained to evaluate the source of her fever showed infiltration in the lower right lung with mild splenomegaly. We could diagnose the patient with HPS on the basis of the hemophagocytic-lymphohistiocytosis- (HLH) 2004 criteria. She met the criteria for fever, splenomegaly, neutrophil count (<1,000/μL), platelet count (<10.0 × 104/μL), fasting triglyceride level (>265 mg/dL), and ferritin level (>500 ng/mL). Furthermore, a peripheral blood smear showed an increased number of monocytes/macrophages with erythrophagocytosis. Treatment with clarithromycin and prednisolone, which was initiated soon after the diagnosis, was successful. Mp infection might partly progress to HPS in certain conditions. Clinicians should be aware of HPS caused by Mp and start appropriate treatment as soon as possible if the disease is suspected.
doi:10.1155/2013/586705
PMCID: PMC3732643  PMID: 23970989
22.  Hemophagocytic Syndrome in Children and Adults 
Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a heterogenic syndrome, which leads to an acute, life-threatening inflammatory reaction. HLH occurs both in children and adults, and can be triggered by various inherited as well as acquired factors. Depending on the etiology, HLH can be divided into genetic (i.e., primary) and acquired (i.e., secondary) forms. Among genetic HLH forms, one can distinguish between familial HLH and other genetically conditioned forms of HLH. Acquired HLH can be typically triggered by infections, autoimmune diseases, and malignancies. The most common symptoms of HLH are unremitting fever, splenomegaly, and peripheral blood cytopenia. Some severely ill patients present with central nervous system involvement. Laboratory tests reveal hyperferritinemia (often >10,000 μg/L), increased serum concentration of soluble receptor α for interleukin-2 (>2,400 U/L), hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hyponatremia, hypoproteinemia, and elevated liver transaminases and bilirubin. Prognosis in HLH is very serious. Genetic HLH is always lethal if adequate therapy is not administered. Similarly, severe acquired cases often lead to death without appropriate treatment. Since HLH can be encountered by various specialists in the medical field, basic knowledge of this entity such as diagnostic criteria and treatment should be familiar to all physicians.
doi:10.1007/s00005-014-0274-1
PMCID: PMC4164855  PMID: 24509696
Hemophagocytic lymphohistiocytosis; Hemophagocytic syndrome; Children; Adults
23.  249 Risk Factors Associated to Mortality in Pediatric Patients with Hemophagocytic Lymphohistiocytosis 
The World Allergy Organization Journal  2012;5(Suppl 2):S98-S99.
Objective
Identify risk factors associated to mortality in pediatric patients with hemophagocytic lymphohistiocytosis.
Methods
Retrospective cross-sectional study of medical records with discharge diagnosis of Hemophagocytic syndrome/Hemophagocytic lymphohistiocytosis (ICD-10; D76.1/D76.2) from Jan2004-May2011 in a pediatric-tertiary-care-center. Descriptive and risk analysis were made on SPSS Statistics V17.0.
Results
Thirty medical records were analyzed. Median-for-age: 2 years 8 months, (range: 2 months-to-15 years). Sex distribution: 14 girls (47%), 16 boys (53%). Median of symptoms duration: 1 month (range: 3 days-to-7 years). Reported symptoms and physical signs at hospital admission: fever n = 28 (93%), asthenia/adynamia n = 11 (37%), skin findings n = 10 (33%), epistaxis n = 5 (17%), gastrointestinal bleeding n = 4 (13%), hepatomegaly n = 27 (90%), splenomegaly n = 21 (70%), lymphadenopathies n = 14 (47%), paleness n = 14 (47%), purpura n = 5 (17%). Laboratory findings: anemia n = 29 (97%), LDH elevation n = 28 (93%), hypoalbuminemia n = 27 (90%), thrombocytopenia n = 26 (87%), hypertransaminasemia n = 25 (83%), haemophagocytosis n = 22 (73%), hypertrigliceridemia n = 21 (70%), hypofibrinogenemia n = 20 (67%), leucopenia n = 19 (63%), hyperferritinemia n = 15(50%). In 18 patients (60%) active infection was evident at hospital admission: pneumonia n = 9(50%), gastroenteritis n = 2 (11%), meningitis n = 1 (5%), others n = 6 (33%). Epstein-Barr virus infection was diagnosed in 7 patients (23%). All patients were treated according to HLH-2004 guidelines. Overall mortality 63% (n = 19), 9(47%) died from septic-shock, 7 (36%) haemorraghic-shock, and 1(5%) with acute liver failure. Differences between non-survivours and survivours by (x2): hypofibrinogenemia (53%versus 13%; P = 0.039), epistaxis (17% versus 0%; P = 0.023), evident clinical infection (47%versus 13%; P = 0.044), elevated LDH levels (63% versus 30%; P = 0.039), hemophagocytosis (57% versus 17%; P = 0.024). Risk factors associated to mortality: history of epistaxis (OR = 1.78, 95% CI, 1.26-2.52; P = 0.023), evident clinical infection at hospital admission (OR = 2.41, 95% CI, 1.08-5.8; P = 0.044). Normal levels of LDH showed diminished mortality risk (OR = 0.32, 95%, CI, 0.18-0.55; P = 0.039).
Conclusions
The present study describes the most common clinical, physical and laboratory findings in patients with haemophagocytic lymphohistiocytosis attended in our hospital. We were able to identify risk factors associated to mortality, and 1 protective factor.
doi:10.1097/01.WOX.0000412006.76608.67
PMCID: PMC3512708
24.  Protection from Inflammatory Organ Damage in a Murine Model of Hemophagocytic Lymphohistiocytosis Using Treatment with IL-18 Binding Protein 
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.
doi:10.3389/fimmu.2012.00239
PMCID: PMC3413989  PMID: 22891066
IL-18; IL-18 binding protein; natural killer cells; hemophagocytic lymphohistiocytosis; macrophage activation syndrome
25.  First case report of bloodstream infection by Rhizomucor pusillus in a child with hemophagocytic lymphohistiocytosis 
We describe an unusual presentation of fatal infection due to Rhizomucor pusillus bloodstream infection in a 12-year old pediatric patient recently diagnosed with hemophagocytic lymphohistiocytosis. R. pusillus was isolated from one blood culture drawn on Day 11 of hospitalization.
doi:10.1016/j.mmcr.2014.05.002
PMCID: PMC4066188  PMID: 24967155
Rhizomucor; Blood culture; Fungemia; Mucormycosis

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