Fortytwo patients were treated according to hlh2004 protocol. Current treatment in adults is extrapolated from the hlh2004 protocol that. Hemophagocytic lymphohistiocytosis in an adult kidney transp. Hlh is not a single disease, but a clinical syndrome that may develop on the. Further study of hlh in the critical care setting might provide important insights into the pathogenesis and clinical treatment of sepsis. Download citation on aug 22, 20, jingrong zhang and others published hlh 2004 protocol. However increasing cervical lymphadenopathy was noted and a subsequent biopsy demonstrated diffuse large b cell lymphoma. French investigators have therefore proposed an adapted webbased diagnostic tool, the hscore, which comprises selected criteria from hlh 2004 with grading according to severity.
The hlh 2004 protocol 2 is normally aimed at treatment of patients with primary hlh prior to stem cell transplantation. Diagnostic and therapeutic guidelines for hemophagocytic. Cureus an intriguing presentation of epsteinbarr virus. Pdf prolonged neurologic course of familial hemophagocytic. After the international histiocyte society hlh 2004 treatment protocol was widely adopted, the 5year survival rate of patients with this condition increased from 54 to.
Epsteinbarr virus ebvassociated hemophagocytic lymphohistiocytosis hlh is highly prevalent in japan. The criteria for diagnosis of hlh were based on the guideline of the hlh 2004 protocol of henter et al. In hlh 94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis hlh, diagnosis was based on five criteria fever. Clinical and laboratory data were recorded and collected by a single investigator. Antibiotics were withdrawn and treatment with hlh 2004 protocol was commenced using dexamethasone and etoposide. Treatment protocol for hemophagocytic lymphohistiocytosis 2004 10 mgm2 daily wk 12 5 mgm2 daily wk 34 2. Current treatment in adults is extrapolated from the hlh 2004 protocol that specifies a regimen of etoposide, dexamethasone and cyclosporine. 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. The treatment protocols hlh94 and hlh 2004 have been established as scientific cornerstones for diagnosis, classifi cation, and treatment of hlh in patients. Clinical trials and observations, free research articles, immunobiology.
It involves the use of chemotherapy which is potentially toxic during pregnancy. 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. To date, no standard treatment for ebvhlh has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. This program was created by an international team of doctors in 2004 to attempt to address the poor survival rates of patients with hlh. Hemophagocytic lymphohistiocytosis caused by primary. We want to mention an alternative part of the initial therapy. The clinical presentation of hlh could be similar to those of many other conditions, making its diagnosis difficult. Diagnosing hlh in sickle cell disease, which inherently has high ferritin levels and pancytopenia, is. Hemophagocytic lymphohistiocytosis hlh is a severe. According to the hlh 2004 protocol, 3 this patient fulfilled six features out of the eightpoint diagnostic criteria for hlh, including a persistent fever, bicytopenia, hepatosplenomegaly on an ultrasound of the abdomen, low fibrinogen levels, raised ferritin levels, elevated triglycerides, and histiocytic activity on a bone marrow aspirate. The hlh2004 criteria include several of these findings as diagnostic criteria. Macrophage activation syndrome mas is a rare disease characterised by aberrant immune hyperactivation of t lymphocytes and macrophages driven by cytokine dysfunction. The full hlh 2004 protocol is available by contacting the histiocytosis association of america. This study suggests that hlh patients undergoing therapy with hlh 2004 protocol need monitoring for future malignancy, especially in the initial 2 to 3 years.
Hemophagocytic lymphohistiocytosis in children archives. We describe a case of mas secondary to systemic lupus erythematosus in a young female that responded. Of the deaths, 45% were secondary to septic shock, 45% were secondary to aggressive hlh andor advanced malignancy, and 9% were secondary to massive. A retrospective analysis of 56 children with hemophagocytic. B in hlh 2004, csa aiming at 200 gl trough value is administered already upfront during the initial therapy, a modification from hlh94 where csa is not administered until the continuation therapy. Hemophagocytic lymphohistiocytosis in a child with sickle. Hsct after the disease activity has been controlled by immunochemotherapy consisting of cyclosporine csa, etoposide vp. Although the hlh 2004 protocol uses ferritin 500 ngml, we generally view. Jan 24, 2007 treatment protocol for hemophagocytic lymphohistiocytosis 2004 the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Cureus chediakhigashi syndrome with epsteinbarr virus. Mas differs from primary hlh in that it is triggered by an infection, autoimmune process or malignancy, whereas primary hlh is caused by an underlying genetic abnormality. Of the six distinct diagnostic criteria, the hlh2004 criteria were by far the most commonly used.
The search strategy gathered 2492 articles and upon manual revie. Hemophagocytic lymphohistiocytosis in children archives of. A case of hemophagocytic lymphohistiocytosis in a patient. Acute myeloid leukemia following etoposide therapy for ebv. It is precipitated by an immunological trigger in a susceptible host resulting in immune activation and dysregulation leading to disruption of. Jul 20, 2019 hemophagocytic lymphohistiocytosis hlh is a disorder of the immune regulatory system with a high rate of mortality. Feb 26, 2021 protocol hlh 2004, opened on january 1, 2004, is based on the histiocyte societys original hlh94 protocol, which had previously opened on january 1, 1995, with some minor modifications. 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. How i treat primary haemophagocytic lymphohistiocytosis. Haemophagocytic lymphohistiocytosis is a rare inflammatory condition.
Hemophagocytic lymphohistiocytosis arising in a child with. Pregnancyinduced haemophagocytic lymphohistiocytosis kay. Confirmed efficacy of etoposide and dexamethasone in hlh. It can present in adult general medical patients and is a challenging diagnostic conundrum. As with diagnosis, treatment protocols for adult hpshlh are often. Haemophagocytic lymphohistiocytosis hlh is a syndrome of severe immune dysregulation, characterised. Hemophagocytic lymphohistiocytosis hlh is a lifethreatening hyperinflammatory syndrome which represents the extreme end of a severe uncontrolled hyperinflammatory reaction that can occur in many underlying conditions. Hlh 2004 protocol with etoposide and rituximab was therefore started ten days after his admission in our hospital. Cerebrospinal and treatment with the hlh 2004 protocol 1 and hematopoi fluid analysis in hemophagocytic lymphohistiocytosis pa etic stem cell transplantation could be life saving.
Secondary forms of hlh shlh frequently result from a reactive process to a number of infectious and oncologic conditions 5. According to hlh 2004 protocol for diagnostic guidelines 111, diagnosis of hlh can be established after fulfillment of either one or two of the following criteria. The mr imaging and ct findings of the cns infiltration have been reported in the past. Treatment of hemophagocytic lymphohistiocytosis with hlh. Diagnostic and therapeutic guidelines for childhood hemophagocytic lymphohistiocytosis find, read and.
Bc cancer protocol summary for treatment of hemophagocytic. Hemophagocytic lymphohistiocytosis caused by primary epstein. Lymphohistiocytosis hemophagocytic lymphohistiocytosis. Current hlh treatment protocols potentially inadequate. Hemophagocytic lymphohistiocytosis hlh emcrit project. This study retrospectively analyzed 31 adult patients, median age 46 years, who received hlh04 from 11 2004 to 512018.
Furthermore, % had recurrence of hlh, and 6% developed an invasive fungal infection. Novel use of rituximab in macrophage activation syndrome. Factors predicting the recurrence of epsteinbarr virus. Further study of hlh in the critical care setting might provide important insights into. Recommendations for the management of hemophagocytic. The hlh 2004 protocol does not as therapeutic intensity is reduced, such as during the later include a salvage protocol. Fiftysix children with hlh in wuhan union hospital. However, this type of treatment is not required for all cases of ebvhlh 23, 24. The eventfree survival of the patient till the last followup was 5. The current study was conducted on the children with hlh referred to the pediatric ward of imam reza hospital, mashhad, iran during nine years from 2010 to 2018.
A molecular diagnosis consistent with hlh, and or fulfillment of five out of eight of the following. She was diagnosed as having hemophagocytic lymphohistiocytosis and following treatment with the hemophagocytic lymphohistiocytosis 2004 protocol these symptoms, in addition to the biochemical and hematological markers, completely resolved. Treatment is nowadays applied according to hlh 2004 protocol, which is designed for primary hfs and also used in severe secondary hfs cases. Treatment protocol according to hlh 2004 group is designed for the patients with hlh, with or without evidence of familial or genetic disease, regardless of suspected or documented viral infections. Accordingly, a reactivation will approach of inducing remission, with a regimen including a commonly respond to an intensification of the initial therapy.
Hemophagocytic lymphohistiocytosis hlh is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Hemophagocytic lymphohistiocytosis in a newborn infant. This article provides an overview of the pathophysiology and clinical presentation of the syndrome for the general physician who will be rarely confronted with this problem but will have to act promptly when the situation arises. In hlh94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis hlh, diagnosis was based on five criteria fever, splenomegaly, bicytopenia, hypertriglyceridemia andor hypofibrinogenemia, and hemophagocytosis. Before steroid therapy was started, an active viral infection of the csf jcv, varizella zoster vzv. Given the constellation of other findingspersistent fever. Treatment of ebvhlh has been found to be effective based on the hlh94 and hlh 2004 type protocols 19, 20 and has been confirmed on a global scale 21, 22. Check that chemotherapy is mixed in preservative free normal saline.
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%. 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. She fulfilled 5 of 8 hlh 2004 criteria fever, splenomegaly, pancytopenia, ferritin level 500 l and sil2r 2400 iuml and was successfully treated by the hlh 2004 protocol for secondary hlh. Sep 21, 2020 traditionally, hlh has been treated with chemotherapeutic regimens e. Primary hlh patients of both genders, up to and including 18 years at diagnosis of hlh. Treatment of hemophagocytic lymphohistiocytosis with hlh94. Apr 16, 2010 hlh is currently treated with a protocol or treatment program called hlh 2004. Full text a retrospective analysis of 56 children with.
Soluble interleukin2 receptor is a sensitive diagnostic test in adult hlh. The predecessor of hlh 2004, the hlh94 protocol and subsequent bone marrow transplantation, has been associated with a 45% mortality rate for primary and secondary forms of hlh 6. Aggressive immunochemotherapy is given dexamethasone, cyclosporine a, etoposide and in patients with cns symptoms or abnormal csf, also intrathecal methotrexate and corticoids 2. A therapeutic challenge arises for milder cases where the harms of potent chemotherapy such as etoposide may outweigh its. She presented again 10 months later with fever, rash, and biochemical abnormalities suggestive of hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis hlh is a lifethreatening disorder due to uncontrolled activation of macrophage and cytokine release, which can be due to either genetic causes familial or secondary to infections malignancy and other less common cause. Efficacy data for the hlh04 protocol in adults is lacking. Hemophagocytic lymphohistiocytosis hlh is an immune related clinical syndrome with protean manifestations, varying presentation, clinically complex, with diverse causes, and is an underrecognized entity which carries high morbidity and mortality. Subsequent hematopoietic stem cell transplantation hsct is recommended for patients with familial disease or molecular diagnosis, and patients with severe and. On january 1, 2004, a modified study protocol hlh 2004, which is still. Treatment of epsteinbarr virusrelated hemophagocytic. Listing a study does not mean it has been evaluated by the u. Hemophagocytic lymphohistiocytosis hlh is a rare disorder of the immune system that is associated with frequent involvement of the central nervous system cns.
The patient clinically improved from a hlh point of view whilst on the hlh 2004 protocol. Prior to that point, a program known as hlh94 was used. Hemophagocytic syndromes hpss including hemophagocytic. Jul 07, 2017 diagnostic criteria developed for the pediatric hlh 2004 protocol have been widely adopted in adult medicine without systematic validation. Subsequent hematopoietic stem cell transplantation hsct is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent. Additionally, the majority of patients with macrophage activation syndrome mas treated with targeted diseasespecific therapy experienced a resolution of. Pregnancyinduced haemophagocytic lymphohistiocytosis. Treatment protocol for hemophagocytic lymphohistiocytosis 2004. Sep 22, 2016 the results of screening tests for known secondary causes were negative. The present prospective study recruited 27 children with ebvhlh who were also part of the hlh 2004 study. Hlh 2004 chemoimmunotherapy includes etoposide, dexamethasone, cyclosporine a upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Hlh2004 protocol modified the hlh94 criteria, adding low or absent nk cell activity, hyperferritinemia.
Diagnostic and therapeutic guidelines for childhood hemophagocytic lymphohistiocytosis august 20 zhongguo dang dai er ke za zhi. Haemophagocytic lymphohistiocytosis hlh can be a rapidly fatal disease. The hlh 2004 protocol is commonly used for the treatment of mas, but significant toxicities are associated. A heterozygous rab27a mutation associated with delayed. Gene testing for known hlhassociated mutations generally only done in. The diagnosis of hlh must be made on the basis of the following criteria as per hlh 2004 protocol. Lch 2006 02 hemophagocytic lymphohistiocytosis study group treatment protocol of the second international hlh study 2004 start of the study. Hemophagocytic lymphohistiocytosis responding to withdrawal. Adultonset stills disease complicated with haemophagocytic. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Etoposide, hemophagocytosis, secondary aml background hemophagocytic lymphohistiocytosis hlh is a lifethreatening disease of the immune system. Diffusionweighted cranial mr imaging findings in a.
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