|Year : 2018 | Volume
| Issue : 4 | Page : 184-192
The role of pre-B-cell colony-enhancing factor in Egyptian children with hemophagocytic lymphohistiocytosis
Wafaa E Ibrahim, Fatma S.E Ebeid, Reda M Mohamed
Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||31-Aug-2018|
|Date of Acceptance||31-Aug-2018|
|Date of Web Publication||10-Apr-2019|
Fatma S.E Ebeid
Thalassemia Center, Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11556
Source of Support: None, Conflict of Interest: None
Background Hemophagocytic lymphohistiocytosis (HLH) is caused by a highly active but ineffective immune response, including impaired or absent function of natural killer cells and cytotoxic T cells, and the release of proinflammatory cytokines. Pre-B-cell colony-enhancing factor (PBEF) is an inflammatory cytokine involved in several inflammatory diseases, and it has been identified to react with several cytokines involved in HLH.
Objective We aimed to study the clinicoepidemiological characteristics of Egyptian children with HLH and to evaluate the role of PBEF as a diagnostic and prognostic marker in Egyptian children with HLH.
Patients and methods This is a cross-sectional study that recruited fifteen children with HLH from the Pediatric Hematology/Oncology unit. There were 11 male and four female, and their median age (interquartile range) was 13 months. Patients underwent thorough clinical assessment, laying stress on disease manifestation, classification, treatment, and prognosis. Plasma concentration of PBEF was determined using an enzyme-linked immunosorbent assay.
Results Four patients were classified as having primary HLH, seven patients were as having secondary HLH and four patients had unknown classification owing to waiting for genotyping. The risk factors before presentation were as follow: four had viral infection, three patients had malignancy, and two patients had immune deficiency before presentation. Seven patients of the study group died and eight patients were still alive. PBEF was significantly increased in the patient group than the control group. PBEF level showed a significant positive correlation with serum ferritin and triglycerides level and a negative correlation with fibrinogen level.
Conclusion The elevated PBEF level and its correlation with the widely available biochemical markers for diagnosis of pediatric HLH indicates that it may be involved in its inflammatory process.
Keywords: childhood, cytokine, hemophagocytic lymphohistiocytosis, pre-B-cell colony-enhancing factors
|How to cite this article:|
Ibrahim WE, Ebeid FS, Mohamed RM. The role of pre-B-cell colony-enhancing factor in Egyptian children with hemophagocytic lymphohistiocytosis. Egypt J Haematol 2018;43:184-92
|How to cite this URL:|
Ibrahim WE, Ebeid FS, Mohamed RM. The role of pre-B-cell colony-enhancing factor in Egyptian children with hemophagocytic lymphohistiocytosis. Egypt J Haematol [serial online] 2018 [cited 2019 May 21];43:184-92. Available from: http://www.ehj.eg.net/text.asp?2018/43/4/184/255877
| Introduction|| |
Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome caused by a highly active but ineffective immune response, including impaired or absent function of natural killer (NK) cells and cytotoxic T cells, and the release of proinflammatory cytokines . Patients with HLH present with a wide spectrum of clinical manifestations and their conditions may rapidly deteriorate, resulting in considerable morbidity and mortality . HLH can be either genetic, inherited in an autosomal recessive pattern, or it can be acquired owing to trigger of viral infections, malignancies, or rheumatic diseases .
Treatment of patients with HLH is aimed at suppressing the severe hyperinflammation and killing pathogen-infected antigen-presenting cells to remove the stimulus for the ongoing but ineffective activation of cytotoxic cells. In genetic cases, the ultimate aim is stem cell transplantation to exchange the defective immune system by normally functioning cells. Treatment should be guided primarily by the severity of signs and symptoms, but also known familiarity of the disease, age of the patient, and underlying conditions have to be considered .
Pre-B-cell colony-enhancing factor (PBEF) is an inflammatory cytokine involved in several inflammatory diseases . It was first identified as a cytokine that acted synergistically with interleukin (IL)-7 and stem cell factor to stimulate early-stage B-cell formation . PBEF has been identified to react with several cytokines involved in HLH . The aim of the present work was to study the clinicoepidemiological characteristics of Egyptian children with HLH and to evaluate of the role of PBEF as a diagnostic and prognostic marker in children with HLH.
| Patients and methods|| |
This is a cross-sectional study that was conducted over one-year duration at the Paediatric Haematology/Oncology Unit, Children’s Hospital, Ain Shams University in Cairo, Egypt. The study recruited fifteen patients who fulfilled the diagnostic criteria for HLH based on diagnostic criteria adapted from the Histiocyte Society HLH-2004 protocol . All the recruited patients were followed up and treated at the Pediatric Hematology/Oncology Unit. The recruited patients underwent clinical assessment and laboratory investigation for assessment of diagnosis and follow-up of HLH and also measurement of plasma PBEF.
The data were collected by reviewing the patients’ files, follow-up sheets, as well as thorough clinical assessment with special emphasis on demographic date, clinical presentations of the disease, underlying risk factors, disease stages and classification, treatment received and its complications, and disease outcome. Follow-up was recorded by either laboratory investigation (ferritin–triglycerides–fibrinogen) or clinically.
Peripheral blood samples were collected under complete aseptic condition in a tube containing potassium ethylene diamine tetra-acetic acid (K2-EDTA) (1.2 mg/ml) as an anticoagulant for complete blood count. For chemical analysis and enzyme-linked immunosorbent assay (ELISA), clotted samples were obtained, and serum was separated by centrifugation for 15 min at 2000–3000 RPM and then stored at −80°C till subsequent use in ELISA. Withdrawal of 2 ml venous blood on sodium citrate was performed for quantitative determination of fibrinogen level.
Laboratory investigations included complete blood count using Sysmex XT-1800i (Sysmex, Kobe, Japan), and examination of Leishman-stained smears for differential white blood cell count was performed. Serum ferritin was measured at the time of diagnosis and on follow-up visit (Immulite 1000 Analyzer; Siemens Healthcare Diagnostics, Marburg, Germany). Normal range at our local laboratory was 13–150 μg/l. Normal range for serum fibrinogen at our local laboratory was from 1.8 to 3.6 g/l and for triglyceride level was less than 150 mg/dl.
Measurement of plasma PBEF
Human Visfatin ELISA Kit was used (Catalog No E0025Hu) (www.bt-laboratory.com, Shanghai, China). According to the manufacturer’s manual, all reagents, standard solutions, and samples were prepared. First, standard and testing samples were added to the standard and sample wells, respectively, and then anti-Visfatin antibody was added to sample wells. Thereafter, streptavidin-HRP was added to the sample and standard wells and mixed wells, then covered and incubated, and then washed. Subsequently, substrate solution A and then substrate solution B were added to each well and incubated. Finally, a stop solution was added to each well, where the blue color changed into yellow immediately. The optical density was determined (OD value) for each well immediately using a microplate reader set to 450 nm within 30 min after adding the stop solution. The concentration of plasma PBEF was determined by comparing the OD of the samples to the standard curve. Standard curve range of the used laboratory kits was 0.5–l00 ng/ml, and the sensitivity was 0.23 ng/ml.
Intra-assay precision (precision within an assay) was assessed by testing three samples of known concentration on one plate, whereas interassay precision (precision between assays) was assessed by testing three samples of known concentration in separate assays. Coefficient of variation % (CV %) was calculated as dividing the standard deviation by the mean, multiplying by 100. The average of the individual CVs is reported as the intra-assay, and it was CV less than 8%, whereas interassay was CV less than 10%.
Data were collected, revised, coded, and entered to the statistical package for the social sciences (SPSS; SPSS Inc., Chicago, Illinois, USA) version 20. Qualitative data were presented as number and percentages, whereas quantitative data were presented as mean, SD, and ranges. The comparison between the two groups with qualitative data was done by using χ2-test and/or Mann–Whitney test. Mann–Whitney test was used instead of χ2-test when the expected count in any cell was found to be less than 5.
The comparison between two independent groups with quantitative data and parametric distribution was done by using independent t-test. Pearson’s correlation coefficients were used to assess the relation between two studied parameters in the same group. The confidence interval was set to 95% and the margin of error accepted was set to 5%. So, the P value was considered significant if P less than 0.05.
| Results|| |
The present study recruited 15 patients. There were 11 (73.3%) male and four (26.7%) female patients. Their median age (interquartile range) was 13 (7–36) months, with the youngest being 6 months of age and the oldest being 10 years of age.
As illustrated in [Table 1] and [Table 2], the risk factors before presentation were as follow: four of our patients had viral infection [two had cytomegalovirus (CMV) and the other two had epstein-barr virus (EBV)], three patients had malignancy (two patients had acute lymphoblastic leukemia and one patient had Hodgkin lymphoma), and two patients had immune deficiency before presentation (one of them had Gracilla syndrome and the other one had primary immune deficiency). Four (26.7%) patients were classified as having primary HLH, seven (46.6%) patients were classified as having secondary HLH, and four patients had unknown classification owing to waiting for genotyping.
|Table 1 Clinical assessment and disease classification of the studied patients|
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The seven patients with secondary HLH had underlying disease: two patients had acute leymphoblastic leukemia (ALL), one patient had HL, one patient had severe combined immune deficiency, one patient had Gracille syndrome, and two patients had CMV infection.
All the 15 patients were treated with protocol HLH-2004. Six patients developed complication of steroid therapy; all of them had cushioned facies, one had also hypertension and another one had also myopathy related to dexamethasone. Five patients developed sign of disease progression: four had CNS infiltration and one patient had multiple reactivation.
Regarding survival, seven (46.7%) patients died and eight (53.3%) were alive. Of the seven patients who died, two patients died owing to complication of therapy, two patients owing to progression of the disease, one patient died owing to infection, and two patients died owing to underlying disease (ALL).
All patients had abnormal high serum ferritin and triglyceride (TG) level, except for only two patients who had normal TG level, and all had low fibrinogen level, except for five patients who had their serum fibrinogen level in the normal range. Two patients underwent assessment of D-Dimer level and only four patients underwent assessment of lactate dehydrogenase level.
A total of 11 (73.3%) patients underwent BMA at the time of diagnosis. It showed hypercellularity in six of them (54.5%), and four (36.4%) showed normcellularity; moreover, three (27.3%) patients had infiltrated marrow, and they were diagnosed as follows: two had ALL and one had HD.
Comparison between laboratory investigations at presentation and follow-up showed that there was a highly statistically significant improvement of hemoglobin level at follow-up (t=−4.383, P=0.001).
As illustrated in [Table 3], PBEF level was highly significantly increased for patient group than control group (P<0.001). The result of the control group were extracted from Chinese study by Gao et al. , and the 14 patients in the control group were healthy children who visited the hospital for a health examination and none were taking immunosuppressive drugs at the time of the visit.
|Table 3 Comparison between pre-B-cell colony enhancing factor level in patients and control group, and in alive and died patients with hemophagocytic lymphohistiocytosis patients|
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Regarding the comparison between died and alive patients, there was no statistically significant difference between two groups regarding age and sex, presenting symptoms, bone marrow aspirate at presentation, disease classification, complication of therapy and disease progression, follow-up laboratory investigations, and PBEF level. However, there was a statistically significant lower number of those who died, all of seven, had not preceding viral infection before presentation in comparison with the alive patients, four of them had (χ2=4.773, P=0.029). In addition, died patients had statistically significant higher alanine aminotransferase level than alive patients (u=−2.375, P=0.018).
Correlation between PBEF level and patients’ studied variable was assessed, and there was positive correlation between PBEF and total leukocyte count, ferritin level, and TAG level, and there was a negative correlation between PBEF and fibrinogen level at presentation as depicted in [Figure 1].
|Figure 1 Correlation between pre-B-cell colony enhancing factor level and total leukocyte count, serum ferritin, triglycerides, and fibrinogen level.|
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| Discussion|| |
HLH, a rare life-threatening hematologic disorder , is a syndrome of pathological immune dysregulation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. It is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation .
In the normal physiological context, granule-mediated cytotoxic function of NK cells and cytotoxic T lymphocytes (CTLs) is required for clearance of viral infection as well as regulation and termination of the inflammatory response . Thus, defects in NK cell and CTL granule-mediated cytotoxicity result in ineffective clearance of infection and defective suppression of antigen presentation, leading to persistent antigen exposure and prolonged cytotoxic T-cell activation .
Human PBEF was first identified as a cytokine that acted synergistically with IL-7 and stem cell factor to stimulate early-stage B-cell formation. A number of cancers have increased expression of Nampt/PBEF/visfatin, which regulates a variety of different signaling pathways , and PBEF has been found to be associated with several inflammatory diseases . However, there are not enough studies that have examined PBEF in childhood HLH. PBEF has been identified to react with several cytokines involved in HLH ; thus, we hypothesized that PBEF is involved in HLH, and understanding PBEF may be helpful for recognizing HLH. We therefore investigated the potential role of PBEF in childhood HLH.
Fifteen patients were recruited in the present study, and they were diagnosed with HLH based on both clinical and laboratory diagnostic criteria for HLH according to the Histocyte Society HLH-2004 protocol , and managed in our Paediatric Oncology Unit.
The median age of the recruited patients in the present study was 13 months; the youngest was six months and the oldest was 10 years. The age of onset is usually in people younger than 1 year for the familial form but can be later for the secondary sporadic form, usually after the age of 6 years ; in addition, the number of patients under 6 months of age is especially high . However, several late-onset cases in adolescence and even adulthood have been reported  and are still under-recognized . At this point, no criteria for age have been established, and an upper age limit does not exist .
Most recruited patients were male (73.3%) and only 26.7% were female. This was in agreement with the study by Ramachandran et al.  who found that most of the diagnosed cases with HLH were males. Sex distribution in FHL exhibits equality, but a slight predominance in males has also been reported. In contrast, other authors have reported that the disease has an equal distribution among males and females .
Despite increasing insights into its genetic and immunologic basis, HLH remains a syndromic disorder, defined and diagnosed by a unique pattern of clinical findings. Although the individual signs or symptoms of HLH may occur in a variety of clinical circumstances, the combination of these features, caused by pathologic inflammation, forms the pattern of HLH . Diagnosing HLH is the first critical step toward successful therapy but is challenging because of the rare occurrence, variable presentation, and nonspecific findings . The current Histiocyte Society treatment protocol, HLH‐2004, defines clinical and laboratory diagnostic criteria for HLH .
Fever of unknown origin (FUO) is a common diagnosis in general pediatric wards, and differentiating HLH from other causes of FUO may be challenging and need to be supported with other signs . In our study, fever was the second most common clinical presenting symptom in 93.3% of studied patients, a figure that is slightly lower than what was recorded by Palazzi et al. , who found that all patients presented by fever . Splenomegaly was the most common clinical findings in all recruited patients, a figure that slightly higher than what recorded by Palazzi et al. , who found that 94.7% of patients presented by hepatosplenomegaly. Infections were the presenting symptom presented in nearly one-third of the patients, and only one patient presented with lymphadenopathy, a figure that is much lower than what recorded by Palazzi et al. , who found that 68.4% of patients presented with lymphadenopathy.
Neurologic involvement is seen in ∼30–50% of patients with HLH . Symptoms at presentation include seizures, altered mental status, brain stem symptoms, and ataxia . As per the study by Thompson et al.  about the neurological adverse effects in patients with HLH, patients may present with CNS involvement or CNS inflammation may recur as treatment doses are being tapered posterior reversible encephalopathy syndrome. In our study, only one patient presented with neurological abnormality, and this patient died during the study period.
Jordan et al.  found that patients may have a variety of skin manifestations, with incidence of ranges from 6 to 65% in published series with highly pleomorphic presentations including generalized maculopapular erythematous rashes, generalized erythroderma, edema, panniculitis, morbilliform erythema, petechiae, and purpura. In our study, only one (6.7%) patient presented with skin rash.
The risk factors associated with disease initiation or recurrence have been studied. Kleynberg and Schiller  published that it is a very heterogeneous disorder and is often associated with various infections , rheumatologic diseases , malignancy , metabolic and acquired immune deficiency states, and drugs . In the present study, the distribution of these risk factors were as follow: viral infection (26.7%), malignancy (20%), and immune deficiency (13.3%). This was in agreement with the study by Otrock and Eby  who found that the likely causes of HLH were as follows: 41.1% infections followed by 28.8% malignancies and 6.8% attributed to autoimmune disorders.
HLH can be classified according to the underlying etiology into either be genetic, inherited in an autosomal recessive pattern, or it can be acquired . Our young patients in the present study were classified into primary HLH with 26.7% (four cases), secondary HLH with 46.6% (seven cases), and unknown HLH classification with 26.7% (four cases). However, labeling patients as having either primary or secondary HLH is often not possible and does not appear to add much value with respect to patient management. Thus, a careful search for underlying disease triggers should be performed in all patients, and most importantly, initial treatment should not be delayed or altered based on these categories .
As per the updated classification of human primary immunodeficiencies (PIDs) by the International Union of Immunological Societies (IUIS) Expert Committee on primary Immunodeficiency, genetic HLH is further classified as familial HLH and lymphoproliferative syndromes. Familial HLH is then further sub-classified as with and without hypopigmentation . Griscelli syndrome type 2 (GS2) is an autosomal recessive disease, caused by mutations in RAB27A, primary immunodeficiency syndromes associated with development of HLH in addition to a partial albinism . In the present study, of the seven patients with secondary HLH, one of them had severe combined immune deficiency and another patient had Gracille syndrome.
Acquired HLH can complicate an underlying disease in both children and adults. HLH can be caused by various infections, of which viral infections are the most common. EBV , CMV, adenovirus and influenza A also have been reported to cause HLH . Malignancy-associated HLH has most commonly been reported in patients with lymphomas and leukemias of T-cell or NK cell lineages but can also be associated with anaplastic large cell lymphomas, B lineage lymphoblastic leukemia, myeloid leukemia, mediastinal germ cell tumors, and other solid tumors . In the present study, of the seven patients with secondary HLH, two patients had ALL, one patient had HL and two patients had CMV infection.
For all patients with HLH, bone marrow puncture is mandatory not only to look for hemophagocytosis but also to exclude leukemia as a trigger of HLH. However, hemophagocytosis in bone marrow is neither very sensitive nor specific and may not be present during the early phase of disease, and therefore its absence does not exclude a diagnosis of HLH . Thus, a negative bone marrow analysis result should not preclude initiation of therapy if there is high clinical suspicion and laboratory evidence of HLH . Bone marrow aspirate was done in 73.3% of cases, and the most common finding was hypercellularity, then normal cellularity (26.7%) and infiltration (26.7%). This was agreed by Usmani et al.  who declared that bone marrow cellularity in HLH may be normcellular, hypocellular, or hypercellular.
Laboratory monitoring was done for all patients in our study at presentation and as a follow-up method, and a comparison between both was done. This included tests used in the criteria of diagnosis, that is, hematological profile, fibrinogen level, ferritin level, and triglycerides level. All patients had abnormal high serum ferritin and TG level, except for only two patients, who had normal TG level, and all had low fibrinogen level, except for five patients who had their serum fibrinogen in the normal range.
Ferritin, an acute-phase reactant, has been previously reported as useful and convenient screen of suspected cases of HLH . The sensitivity of the 500 µg/l cut-off was 84% in a cohort of 34 patients in the HLH-94 study , but is nonspecific and can been seen in other febrile illnesses; higher levels (>3000 or >10 000 µg/l) with presumed increased specificity in pediatric patients have been proposed . However, a value greater than 10 000 mg/l has been reported to be highly specific and diagnostic of HLH (90% sensitivity and 96% specificity) . Lin et al.  reported that a rapid fall of ferritin levels was associated with decreased mortality among pediatric patients with HLH.
High triglyceride levels have been attributed to a decreased level of lipoprotein lipase. At diagnosis, this criterion (>3.0 mmol/l) is fulfilled in 70% of cases . For clinical purposes, it is the least practical parameter as it is hardly possible to obtain true fasting levels of triglycerides in infants . Hypofibrinogenemia (<1.5 g/l) is present at diagnosis in approximately two-third of patients, whereas other clotting factors are usually in the normal range . Of note, fibrinogen as an acute-phase protein is usually increased in febrile illness. Thus, a level of fibrinogen in lower range of normal in a child with fever for several days is suspicious of incipient immune dysregulation, potentially leading to the full picture of HLH . Park et al.  found that an initial serum fibrinogen greater than 166 mg/dl was associated with better patient survival.
HLH treatment is focused on suppression of hyperactive immune system, silence the unregulated severe hyperinflammation, identify and treat the underlying triggers of HLH , and correction of underlying genetic defect. Treatment of infectious trigger alone is not sufficient even in secondary HLH, and prompt initiation of immunosuppressive and pro-apoptotic chemotherapy is essential for improved outcome . Both primary and secondary forms of HLH can initially be treated following the same protocol ; therefore, there is no need to wait for the results of genetic evaluation of these patients. Thereafter, knowledge of underlying genetic defect helps in planning for early HSCT . All the recruited patients were managed by protocol HLH-2004. Following initiation of treatment, patients must be closely monitored for signs of improvement and/or deterioration, as well as potential complications and drug toxicities .
Familial HLH is uniformly fatal if not treated; the median survival time reported in various studies is 2–6 months after diagnosis. The historical series collected by the International Hemophagocytic Lymphohistiocytosis Registry reports a less than 10% probability that the patient survives for 3 years . Even with treatment, only 21–26% can be expected to survive 5 years. Remission is always temporary, as the disease inevitably returns. Bone marrow transplant is the only hope for cure. The outcomes of secondary HLH vary .
During the 12-month period of this study, the case fatality rate was seven (46.7%) patients whereas eight (53.3%) patients survived. This survival rate is lower than the rate recorded in the study by Ramachandran et al. , where 76% of their cases survived and were discharged home. This may be explained by the high number of secondary HLH owing to malignancy in our study (three of 15). When we study the effect of different variables on the survival, there was no statistically significant difference between two groups regarding most of the studied variables. However, there was a statistically significant lower number of those who died, all of seven, had not preceding viral infection before presentation in comparison with the alive patients, four of them had. In addition, died patients had statistically significant higher alanine aminotransferase than alive patients.Numerous studies have indicated that PBEF acts as a cytokine  and has been found to upregulate a variety of inflammatory cytokines , and at high concentrations, PBEF can also cause the production of some anti-inflammatory cytokines . PBEF has been identified to react with several cytokines involved in HLH . Changes in these cytokines during the clinical course of HLH were identical to those for PBEF. Moreover, a positive correlation was observed between PBEF and interferon-γ, tumor necrosis factor-α, and sIL-2Ra. PBEF participates in the cytokine induction in HLH .
There was a highly significant increase in mean value of PBEF in patients group than control group with no significant difference between dead and alive patients. The work published by Gao et al.  supported our data, as they also found PBEF was significantly markedly elevated in patients with HLH. PBEF may be involved in the inflammatory process of HLH, may be involved in cytokine upregulation in HLH  and was correlated with the widely available biochemical markers for diagnosing HLH, as well as predominating cytokines involved in HLH. This may be useful in the diagnosis of HLH .
High levels of serum ferritin and triglycerides, as well as low fibrinogen, are widely used markers for the diagnosis of HLH. We also investigated the correlation between PBEF and all laboratory findings. PBEF level showed positive correlation between PBEF and total leukocyte count, ferritin level, and triglyceride level, and there was a negative correlation between PBEF and fibrinogen level at presentation. However, a correlation between PBEF level and patients’ demographic data and clinical data in the present study was performed, but we did not find any significant association between PBEF and other clinical parameters.
In study to examine PBEF in childhood HLH. Notably, children with HLH showed markedly elevated PBEF levels during the acute phase. Furthermore, PBEF level was well-correlated with disease activity of HLH, and decreasing PBEF levels were observed with disease improvement. After chemotherapy, also nonsurvivors showed much higher PBEF levels than survivors. PBEF level reflects the inflammatory reaction status. PBEF was correlated with the severity of HLH, and a higher PBEF level may be associated with worse clinical prognosis .
These findings support the hypothesis that PBEF participates in the cytokine induction in HLH. However, the causal relationship between PBEF and HLH requires further investigation. The results of this study may lay the foundation for the development of novel PBEF-targeted protocols to inhibit the abnormal inflammatory response in HLH .
Conclusion: HLH is a rare disease with nonspecific clinical symptoms so the disease should be put in mind for early detection and better prognosis. Consequently, new methods and laboratory marker are needed for diagnostic and prognostic probability. An elevated PBEF level was observed in children with HLH, indicating that it may be involved in the inflammatory process of HLH. PBEF was correlated with the widely available biochemical markers for diagnosis HLH; this may be useful in diagnosis of HLH. However, further study on a large number of patients is needed to confirm our findings.
There are no conflicts of interest
Conflicts of interest
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[Table 1], [Table 2], [Table 3]