Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis hlh due to immune checkpoint inhibitor therapy. In 1991, the histiocyte society presented the first set of diagnostic guidelines for hlh 7, and in 1994 the first prospective international treatment protocol hlh 94. It is important to realize that the clinical condition of patients may deteriorate rapidly soon after. However, for patients who have genetic diseases which predispose them to the development of hemophagocytic lymphohistiocytosis hlh, ebv infection is a lifethreatening problem.
Lch 2006 02 hemophagocytic lymphohistiocytosis study group treatment protocol of the second international hlh study 2004 start of the study. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with hlh. The patient is still on the hlh 2004 protocol and waits for a suitable stem cell transplantation donor. It is also beneficial in a minority of young adults such as those with severe ebvassociated hlh, in which etoposide therapy within 4 weeks after the diagnosis is associated with significantly better survival. Clinical characteristics of liver failure with hemophagocytic. The patients clinical condition worsened on the 9th day of the hlh 2004 treatment protocol. An associated gene mutation may be found which impairs cytolytic lymphocyte function.
Allogenic sct based on hlh 94 protocol results in cure rate of 50. Combination immunosuppressive therapy including rituximab. Management is largely based on hlh 2004 protocol for secondary cases and almost all cases of primary hlh require. Severe hemophagocytic lymphohistiocytosis in a melanoma. Baishideng publishing group inc, 7041 koll center parkway, suite 160, pleasanton, ca 94566, usa. Read online histiocyte society hlh 2004 skion book pdf free download link book now. Macrophage activation syndrome mas is a rare disease characterised by aberrant immune hyperactivation of t lymphocytes and macrophages driven by cytokine dysfunction. The hlh 2004 criteria remain as the common diagnostic guide. The mean age of the hlh protocol group was 47 years, compared with 53 years of the supportive care group. The differences in survival between patients on supportive therapy versus patients on hlh2004 protocol were not statistically significant p0. Recommendations for the management of hemophagocytic. Further study of hlh in the critical care setting might provide important insights into the pathogenesis and clinical treatment of sepsis. The term secondary hlh is used when your doctor thinks the condition may have occurred for a variety of other noninherited reasons.
Treatment protocol the hlh94 treatment protocol includes 8 weeks of initial therapy, aiming. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. Epsteinbarr virus ebv is a ubiquitous virus that infects nearly all people worldwide without serious sequela. Pdf hemophagocytic lymphohistiocytosis hlh used to have a dismal prognosis. Confirmed efficacy of etoposide and dexamethasone in hlh. Hlh94 then hlh 2004 protocols, followed by bone marrow transplantation. The hlh 2004 treatment protocol is not of proven benefit in critically ill adults, but observational data suggest that aggressive immunosuppressive therapy should not be delayed. All books are in clear copy here, and all files are secure so dont worry about it. Further study of hlh in the critical care setting might provide important insights into. Unlike other iraes, hlh triggered by immune checkpoint blockade is not well described. Hlh 2004, jan 2004 2 contents addresses study committee, local coordinators, study data manager 3 data safety monitoring board, senior advisors 4 figure 1 flow sheet for children with hlh in hlh 2004 5 figure 2 treatment protocol overview for hlh 2004 6 figure 3 documentation sheet for the initial therapy in hlh 2004 7. Familial form of hlh disease, which is an autosomal recessive hematological disorder is due to diseasecausing mutations in several genes.
Hemophagocytic syndrome hfs is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent. Adultonset primary hemophagocytic lymphohistiocytosis. In this study, we compared the performances of adapted hemophagocytic lymphohistiocytosis hlh 2004 guidelines with those of the new diagnostic hscore to identify patients with hlh in a multicenter cohort consisting of adult and pediatric cases of suspected hlh. Hemophagocytic lymphohistiocytosis with immunotherapy. The hemophagocytic lymphohistiocytosis 2004 protocol produced by the american histiocyte society provided additional information. Treatment of hemophagocytic lymphohistiocytosis with hlh. Disease presentation is due to hyperinflammation due to inherited or acquired immune defects. The hereditary form of hlh is caused by defects in the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic t lymphocytes, and it can manifest in childhood or adulthood. Profile of hemophagocytic lymphohistiocytosis in children in. Histiocyte society hlh2004 skion pdf book manual free.
Listing a study does not mean it has been evaluated by the u. Hemophagocytic lymphohistiocytosis in children springerlink. Outcomes in children with hemophagocytic lymphohistiocytosis. They do not need the standard therapy hlh 2004 protocol which is decidedly more toxic. The hlh2004 protocol incorporated the addition of cyclosporine, but there has been no clear benefit related to early administration of cyclosporine, and it should be noted that cyclosporine can be associated with notable complications including hypertension, renal injury, and posterior reversible encephalopathy syndrome. Cureus hemophagocytic lymphohistiocytosis complicating. The hlh2004 protocol is also indicated in all patients younger than 18 years of age who have severe and persistent or reactivated hlh. Successful treatment of diffuse large bcell lymphoma with.
Haemophagocytic lymphohistiocytosis hlh describes a clinical syndrome of hyperinflammation resulting in an uncontrolled and ineffective immune response. Hemophagocytic lymphohistiocytosis hlh is a lifethreatening hyperinflammatory syndrome associated with a variety of underlying conditions. G164p dengue associated hemophagocytic lymphohistiocytosis. Henter ji1, horne a, arico m, egeler rm, filipovich ah, imashuku s, ladisch s, mcclain k, webb d, winiarski j, janka g.
The mortality rate was 53,7%, 46 66,6% in primary hlh and 37 42,8% in secondary hlh. The cumulative experiences from hlh94 and other studies have led to the development of a new treatment protocol presented here, hlh2004, which includesupdateddiagnosticand therapeutic guidelines from the. It can be further classified as primary and secondary hlh. The cumulative experiences from hlh94 and other studies have led to the development of a new treatment protocol presented here, hlh 2004, which includesupdateddiagnosticand therapeutic guidelines from the. Frontiers hemophagocytic lymphohistiocytosis in children. Hemophagocytic lymphohistiocytosis and progressive. A case report of novel mutation in prf1 gene, which causes. Hlh may also occur as a complication of hsct in patients with a prior history of malignancy usually haematological and pretreated and conditioned with chemotherapy. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias.
Treatment protocol for hemophagocytic lymphohistiocytosis 2004. It is a lifethreatening condition that can be defined as either primary or secondary hlh. Classically, treatment of primary hlh is directed towards use of the hlh2004 protocol including etoposide, dexamethasone, cyclosporine, consideration of intrathecal methotrexate and finally with hematopoietic stem cell transplantation. The treatment protocols hlh94 and hlh2004 have been established as scientific cornerstones. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria hlh 2004 are adopted from paediatric hlh and have not. Presentation of hemophagocytic lymphohistiocytosis due to a. Hlh2004, jan 2004 2 contents addresses study committee, local coordinators, study data manager 3 data safety monitoring board, senior advisors 4 figure 1 flow sheet for children with hlh in hlh2004 5 figure 2 treatment protocol overview for hlh2004 6 figure 3 documentation sheet for the initial therapy in hlh2004 7. Hlh in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the underlying trigger, disease severity and course, as well as genetic background. Treatment protocol for hemophagocytic lymphohistiocytosis 2004 the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis with leukoencephalopathy. Hemophagocytic lymphohistiocytosis hlh is an uncommon, aggressive hematological syndrome.
Successful treatment of epsteinbarr virusassociated hemophagocytic lymphohistiocytosis with hlh94 protocol. While paediatrichlh has been extensively characterised, similar studies in adults are limited. Treatment of hemophagocytic lymphohistiocytosis with hlh94 immunochemotherapy and bone marrow transplantation. Treatment of ebvhlh has been found to be effective based on the hlh94 and hlh 2004 type protocols19,20 and has been. Oc65 hemophagocytic lymphohistiocytosis the importance of. The hlh2004 treatment protocol is not of proven benefit in critically ill adults, but observational data suggest that aggressive immunosuppressive therapy should not be delayed. Review of haemophagocytic lymphohistiocytosis archives. In 1994, the histiocyte society organized the first treatment protocol for hlh hlh94. Hemophagocytic lymphohistiocytosis hlh is a lifethreatening, hyperinflammatory syndrome characterized by cytopenia, fever, hepatosplenomegaly, coagulation disorders, and multiorgan dysfunction. We describe a case of mas secondary to systemic lupus erythematosus in a young female that responded well to rituximab. Treatment of secondary hlh is less clear, but ultimately relies on treatment of the primary autoimmune disease. The hlh2004 protocol proposed by the histiocyte society has been widely adopted as the diagnostic criteria for hlh. Hemophagocytic lymphohistiocytosis hlh is a severe hyperinflammatory syndrome induced.
Treatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Hlh can be triggered by infection, autoimmune disease, or cancer. Hemophagocytic lymphohistiocytosis hlh has had a dismal prognosis. Eligibility criteria for this study were as follows. The diagnostic criteria of hlh were proposed by the histiocyte society hlh 2004 protocol 2,3. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis in a patient with. Haemophagocytic syndromes haemophagocytic lymphohistiocytosis have a wide range of causes, symptoms, and outcomes, but all lead to a hyperinflammatory response and organ damagemainly reported in paediatric patients, but reports of adult presentation are increasing. In 1991, the histiocyte society proposed a standardized set of 5 diagnostic criteria for hlh used for the prospective hlh94 clinical trial. Hlh 2004 protocol treatment dexamethasone, etoposide, cyclosporine was used in 8 patients 61% in 5 cases complete schema and in 3 cases partial treatment. The hlh 2004 protocol is also indicated in all patients younger than 18 years of age who have severe and persistent or reactivated hlh. Treatment of hemophagocytic lymphohistiocytosis with. Hlh may be primary or associated with different types of infections, autoimmune.
The study sample consisted of 147 cases, including 20 adults and 16 children with hlh. Treatment of epsteinbarr virusrelated hemophagocytic. Hemophagocytic lymphohistiocytosis hlh is a lifethreatening immunodeficiency and multiorgan disease that affects people of all ages and ethnic groups. How i treat hemophagocytic lymphohistiocytosis ncbi. Hemophagocytic lymphohistiocytosis hlh has been recognized as an inflammatory endpoint for a variety of conditions including autoimmune diseases, malignancies and infections. Aggressive nk cell leukemia with hemophagocytic lymphohistiocytosis.
It may develop subsequent to a number of recognised genetic mutations or in association with infection, malignancy, autoinflammatory or metabolic conditions. It is caused by an increased and unchecked proliferation of t lymphocytes and histiocytes. The hlh 2004 protocol is commonly used for the treatment of mas, but significant toxicities are associated. The hlh 2004 criteria remain as the common diagnostic. There are no validated guidelines for treating shlh posthsct and there are concerns about using the hlh 2004 protocol. A sixteenyearold girl with still disease diagnosis developed a progressive multiorgan failure including acute respiratory distress ards, anemia and thrombopenia. We here conducted a prospective study of 73 patients who were treated with hlh2004 protocol in japan. Novel use of rituximab in macrophage activation syndrome.
Confirmed efficacy of etoposide and dexamethasone in hlh treatment. We describe a pediatric case of hemophagocytic lymphohistiocytosis with a. This study aims to evaluate the significance of the hlh diagnostic criteria as well as other clinical parameters in adults with bone marrow evidence of haemophagocytosis. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as hlh94 and hlh2004, which may result in. Treatment may follow the hlh 2004 protocol, which uses induction immunochemotherapy with highdose dexamethasone, etoposide, and cyclosporine a followed by allogeneic hsct, although firm evidence for the protocol s effectiveness is lacking. Increased levels of various cytokines and soluble interleukin2 receptor are biological markers of hlh. Dec 21, 2017 confirmed efficacy of etoposide and dexamethasone in hlh treatment.
Filipovich, helmut gadner, shinsaku imashuku, diane komp, stephan ladisch, david webb, and gritta janka, for the histiocyte. Download histiocyte society hlh 2004 skion book pdf free download link or read online here in pdf. Given the success of the earlier hlh94 protocol, the hlh2004 protocol moved cyclosporine dosing to the beginning of induction and hydrocortisone was added to methotrexate as part of the intrathecal therapy. We would like to show you a description here but the site wont allow us. Analysis of the genetic and molecular pathophysiology of these syndromes have improved the understanding of the crosstalk. The first international treatment protocol for hlh was organized by the. Ebvhlh, familial hlh fhl, and hlh of unknown etiology were seen in 41, 9, and 23 patients, respectively. Hemophagocytic lymphohistiocytosis hlh, a rare but potentially fatal syndrome of immune hyperactivation, may be an underrecognized immunerelated adverse event irae. Hemophagocytic lymphohistiocytosis hlh is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. This work was supported in part by an appointment to the condition hemophagocytic lymphohistiocytosis hlh, applied epidemiology fellowship program administered by the council of state and territorial epidemiologists and funded by the centers for disease control and prevention cooperative agreement 5u38hm0004145. Ppt hemophagocytic lymphohistiocytosis hlh powerpoint. Aims haemophagocytic lymphohistiocytosis hlh is divided into paediatric primary and adult secondary types.
Children with familial hlh were initiated on hlh 2004 protocol but all of them expired due to disease progression. Even with the published diagnostic criteria it can be. Identifying hlh early and managing it, poses a significant challenge. Management is largely based on hlh2004 protocol for secondary cases and almost all cases of primary hlh require hematopeitic stem cell. Management is largely based on hlh2004 protocol for secondary cases and almost all cases of primary hlh require. The patient in this report also presented with a sepsislike syndrome and was tested positive for ebv. Because of high morbidity and mortality of this disease rapid diagnosis and treatment is necessary.
In a recent case report, the use of rituximab in conjunction with chemotherapy according to the hlh 2004 protocol was unsuccessful. Hlh is a disease that becomes rapidly fatal with mortality rates ranging between 8% and 22%. Epsteinbarr virus and hemophagocytic lymphohistiocytosis. Conclusion most children with dengue associated hlh recover with supportive management with a minority children with organ dysfunction and very high ferritin values requiring steroids or ivig. Therapeutic plasma exchange in primary hemophagocytic. Thirtyseven percent n 17 received intravenous iv immunoglobulin and steroids. Our objective is to raise the importance of hfs early diagnosis by presenting a representative case. Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. The children are under followup and doing clinically well. The aim of this study was to decipher clinical and laboratory characteristics of. Patients who were born with an hlhassociated molecular genetic abnormality or who meet at least five of the eight diagnostic criteria can be diagnosed with hlh. Hemophagocytic lymphohistiocytosis hlh is a rare hyperinflammatory syndrome that can be associated with inherited genetic mutations, malignancy, autoimmune disorders, and viral infections. Oct 27, 2016 hemophagocytic lymphohistiocytosis hlh is an aggressive and life threatening syndrome which results from excessive immune activation, that can rapidly deteriorate and lead to multiple organ failure and death. Early diagnosis is crucial for the promotion of early treatment.
On january 1, 2004, a modified study protocol hlh 2004, which is still open with revised diagnostic criteria was introduced. There was, however, no underlying rheumatic condition. May 31, 2019 liver failure with hemophagocytic lymphohistiocytosis hlh is a lifethreatening syndrome with high mortality. The predominant presenting features included prolonged fever and.
The hlh2004 protocol is commonly used for the treatment of mas, but significant toxicities are associated. Finally, for practical reasons, the hlh2004 diagnostic criteria do not include all. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis 2004 protocol, which resulted in the disappearance of the. View the article pdf and any associated supplements and figures for a period of 48 hours.
These cells secrete a large number of inflammatory cytokines and infiltrate various tissues causing multiorgan system failure. Hemophagocytic lymphohistiocytosis hlh is a rapidly progressive, lifethreatening syndrome of excessive immune activation. Tertiary care childrens teaching hospital in chennai, india. We here conducted a prospective study of 73 patients who were treated with hlh 2004 protocol in japan. Introduction haemophagocytic lymphohistiocytosis hlh in adults is characterised by toxic immune activation and a sepsislike syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. As a part of a themed collection of articles on ebv infection and human primary immune deficiencies. Full treatment following the hlh 2004 protocol would begin only if the patient was refractory to initial treatment with diseasespecific chemotherapy. The diagnosis and treatment of most hlh cases are performed by a protocol released by the histiocyte society called hlh2004 previously hlh94.