|Year : 2013 | Volume
| Issue : 3 | Page : 96-99
Hemophagocytic lymphohistiocytosis: A case series of 10 patients from UAE
Najam Ahmed Awan, Hind A Alkhazraji, Eman Taryam, Altaf Jamil, Omar Trad, Layla Al Reyami, Rania Slika, Mustafa Baroudi, Muhammad Faisal Khanani
Division of Pediatric Hematology and Oncology, Departments of Hematology and Oncology and Paediatrics, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates
|Date of Web Publication||19-Dec-2013|
Muhammad Faisal Khanani
Division of Pediatric Hematology and Oncology, Departments of Hematology and Oncology and Paediatrics, Tawam Hospital, Al Ain, Abu Dhab
United Arab Emirates
Source of Support: None, Conflict of Interest: None
Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory syndrome characterized by fever, hepatosplenomegaly, bone marrow, skin, and central nervous system infiltration. Incidence of HLH is 1 per 50,000 live births worldwide. However, a delay in diagnosis and treatment would inevitably lead to a rapidly progressive and fatal course. In this case series, we present 10 cases of HLH in children; their presentation, course, and outcome.
Patients and Methods: We retrospectively looked at 10 cases of HLH who presented to our center at Pediatric Hematology/Oncology in UAE at Tawam Hospital between 2006 and 2012. Data was collected from computerized electronic medical records using the Cerner System at Tawam Hospital, in addition to referring to hard copies of patients' records. The median age at diagnosis was 1 year (age range 2 months-5 years). Diagnosis was based on fulfilling clinical and laboratory criteria.
Results: All patients initially presented with unremitting prolonged fever, splenomegaly and a bi- or trilineage cytopenia. Blood investigations showed elevated ferritin (n = 10), elevated liver enzymes (90%) and high lactate dehydrogenase (LDH) (80%), hypertriglyceridemia and hypofibrinogenemia in 80% (n = 8) . Central nervous system (CNS) involvement was reported in a total of five patients; three had convulsions, partial seizures, hemiplegia, and meningeal signs; while the other two patients showed high cerebrospinal fluid protein level. All patients were started on HLH 2004 therapeutic protocol. Only seven completed their treatment course, two patients died prematurely before starting induction therapy and third patient died from pulmonary hemorrhage during induction week #1. At a first reactivation episode, fourth patient succumbed to a gastrointestinal (GI) hemorrhage and died. Results of genetic mutation analysis were positive for three patients (STXBP2, STX-11, and PRF1 gene mutations), negative for six patients, and not completed for one patient. Epstein-Barr virus (EBV) serology was positive in eight (80%). Other associated infections were rhinomaxillary mucormycosis, Candida albicans septicemia in two patients, skin methicillin-resistant Staphylococcus aureus (MRSA), positive cytomegalovirus (CMV) serology, and influenza A infection. Only three patients received bone marrow transplantation and currently are stable on regular follow-up and are disease-free. Overall initial success rate was 70%, survival probability at 1- and 4-years was 60%. Only two patients had relapse (reactivation), one after a few months and the other after almost 3 years.
Conclusions: HLH is a rare but rapidly fatal disease and may present in a wide range of different presentations. A persistent and prolonged fever with associated progressive abdominal distention (hepatosplenomegaly) and cytopenias over an acute phase should raise the suspicion of HLH. Accordingly, early diagnosis and prompt aggressive treatment are vital for patients' survival and favorable outcome.
Keywords: Bone marrow, central nervous system, hemophagocytic lymphohistiocytosis
|How to cite this article:|
Awan NA, Alkhazraji HA, Taryam E, Jamil A, Trad O, Al Reyami L, Slika R, Baroudi M, Khanani MF. Hemophagocytic lymphohistiocytosis: A case series of 10 patients from UAE. J Appl Hematol 2013;4:96-9
|How to cite this URL:|
Awan NA, Alkhazraji HA, Taryam E, Jamil A, Trad O, Al Reyami L, Slika R, Baroudi M, Khanani MF. Hemophagocytic lymphohistiocytosis: A case series of 10 patients from UAE. J Appl Hematol [serial online] 2013 [cited 2020 May 29];4:96-9. Available from: http://www.jahjournal.org/text.asp?2013/4/3/96/123301
| Introduction|| |
Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory syndrome characterized by the aggressive nonmalignant proliferation of activated macrophages and histiocytes, which phagocytose other cells, namely red blood cells, white blood cells, and platelets, leading to the clinical symptoms of fever, hepatosplenomegaly, bone marrow, skin, and central nervous system (CNS) infiltration.  HLH occurs rarely worldwide with an incidence of 1 per 50,000 live births.  The presumed underlying pathogenesis is a highly-stimulated but ineffective immune response to antigens, mediated mainly by activated T-cells and associated macrophage activation that eventually heightens to a life-threatening cytokine storm. HLH is not a single disease; rather, it usually occurs in association with various underlying genetic and/or acquired conditions. In the genetic form (primary), which is inherited in an autosomal recessive fashion, HLH may occur as; (1) five types of familial HLH (FHLH) in which HLH is the primary and only manifestation, or (2) as a sporadic event in association with other immune deficiency disorders, most notably Griscelli syndrome type 2, Chediak-Higashi syndrome, and X-linked lymphoproliferative syndrome. In FHLH (primary), five genetic defects have been identified which account for 90% of all FHLH cases: Type 1 is due to a gene defect on chromosome 9, type 2 is due to mutations in the perforin gene, type 3 is due to mutations in the Munc-13-4 (UNC13D) gene, type 4 is due to mutations in the syntaxin 11 (STX11) gene, and type 5 is due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2).  The onset of disease in 70% of children is during the 1 st year of life for the familial form, but can be later for the secondary sporadic form, usually after age 6 years. ,
The acquired form of HLH may result from excessive activation of the immune system due to a severe infection (most commonly viral, Epstein-Barr virus (EBV), virus-associated, Hemophagocytic Syndrome, or malignancy). Other infectious agents have also been shown to be causal. ,, Despite this distinctive classification, great difficulty exists in severing out primary from secondary HLH. EBV may trigger both forms and so its presence does not exclude one or the other.
| Patients and Methods|| |
We retrospectively collected 10 cases of HLH in children diagnosed in our center in Pediatric Hematology/Oncology, UAE at Tawam Hospital between 2006 and 2012. The median age at diagnosis was 1 year (age range 2 months-5 years). Diagnosis was based on fulfilling clinical and laboratory criteria dictated by guidelines of the Histiocyte Society in the Revised Diagnostic Criteria for HLH.  Fulfilling at least five out of a total of eight criteria would elect for a diagnosis of HLH.
Data was gathered from computerized electronic medical records using the Cerner System at Tawam Hospital, in addition to referring to hard copies of patients' records. FHLH was suggested in the presence of any one of the following; (a) positive family history of HLH, (b) recurrence/reactivation of disease, or c) very early age at diagnosis <1 year. Furthermore, presence of molecular evidence (positive gene mutations) was confirmatory; in our study patients were tested for only four gene defects: Mutations affecting STXBP2, STX11 gene, perforin gene (PRF1), and Munc-13-4 (UNC13D) gene.
| Results|| |
Presentation and Characteristics
All patients initially presented with unremitting prolonged fever, most being referred cases from primary health clinics after failing to respond to several courses of antibiotics and antipyretics. All 10 patients had splenomegaly at presentation (100%), while only five had concomitant hepatomegaly. CNS involvement was reported in a total of five patients; four at the time of initial diagnosis, of which three had convulsions, partial seizures, hemiplegia, and meningeal signs; while one patient had high cerebrospinal fluid (CSF) protein without any positive clinical signs and a normal brain magnetic resonance imaging (MRI) report, and one patient at reactivation showing high CSF protein [Figure 1]. Results of genetic mutation analysis were positive for three patients (STXBP2, STX-11, and PRF1 gene mutations), negative for six patients, and not completed for one patient. On the other hand, eight patients were found to have positive EBV serology (EBV Capsid Antigen IgG, EBV Capsid Antigen IgM). Other associated infections were rhinomaxillary mucormycosis, Candida albicans septicemia in two patients, skin methicillin-resistant Staphylococcus aureus (MRSA), positive cytomegalovirus (CMV) serology and influenza A infection. Other comorbidities included congenital heart disease (CHD) in two patients; one with atrial septal defect and pulmonary stenosis and asthma, whereas the other had transposition of great arteries (TGA), one patient also had an underlying immune deficiency disorder.
All of our patients showed at least a bi- or trilineage cytopenia. Further blood testing showed hyperferritinemia (n = 10), elevated liver enzymes in 90% and high lactate dehydrogenase (LDH) in 80%, hypertriglyceridemia and hypofibrinogenemia in 80% (n = 8) [Figure 2].
All patients were started on HLH 2004 therapeutic protocol
Only seven patients completed their treatment course [Table 1], two died prematurely before starting induction therapy. These two patients had delays prior to be transferred to our center. The causes of death were brain herniation, convulsions, and coma in Patient #3, sepsis, gastrointestinal (GI) bleed and disseminated intravascular coagulopathy (DIC) in Patient #4 and Patient #6 died from pulmonary hemorrhage during induction week #1. Patient #1 died after the disease recurred a few months from finishing his first line therapy. Most patients were considered clinically to have familial HLH; two patients had a positive family history of affected siblings, two had recurrence of disease, and six patients were diagnosed at <1 year of age.
Only three patients received bone marrow transplantation and currently are stable on regular follow-up and are disease-free, while three more patients are still awaiting a compatible donor match. Overall initial success rate was 70%; survival probability at 1- and 4-years was 60%. Only two patients had relapse (reactivation), one after a few months and the other after almost 3 years [Table 1].
| Discussion|| |
In our study, results were closely comparable with general literature statistics. Most of our cases proved to be familial in origin, with a male predominance (80%), and 60% of patients below 1 year of age. Clinical presentation of HLH varies widely; which makes it an even more abysmal syndrome, as a delay in diagnosis often leads to fatal consequences. Most of our patients fulfilled the classical clinical criteria for HLH, although some initially presented with a CNS infection-like picture (meningitis/convulsions). Eight were EBV positive; however, one patient was discovered to have a coexisting immune-deficiency disorder (hypogammaglobinemia). Although molecular analysis was negative for most of our patients, early age and disease reactivation as well as presence of an affected sibling were enough to strongly suggest a primary cause. Also, genetic analysis screening was limited to only some, but not all known gene mutations. The survivalrate at 1- and 4-years was the same; 60% this could imply that patients who were able to survive the first acute attack of HLH (i.e., responded well to chemotherapy), did well later on. On the other hand, patients who did not respond optimally to initial chemotherapy sank into a severe and progressive clinical course and eventually died within a few days to weeks. Thus, initial response to chemotherapy may also have a role in predicting outcome.
A recent abstract published in Current Opinion in Paediatrics, February 2012, stresses on the central role of macrophages in the development of inflammation-associated cytopenias, and that this may indeed serve as a new therapeutic target for the future in the treatment of HLH. 
| Conclusion|| |
HLH is rapidly progressive and fatal and may masquerade as a sepsis syndrome, CNS infection, or other hematological malignancy. Therefore, physicians, essentially those working in primary healthcare centers, should be made aware of the signs and symptoms of HLH as to initiate early referral to higher care systems (tertiary care). Early diagnosis and prompt aggressive treatment are vital for patients' survival and favorable prognosis. In addition, initial response to chemotherapy is important and probably predictive of subsequent clinical progression. Finally, hematopoietic stem cell transplant (HSCT) remains the sole rescue for familial cases and relapsing disease.
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[Figure 1], [Figure 2]