Seval Ozen1, Alper Dai1, Enes Coskun1, Serdar Oztuzcu2, Sercan Ergun2, Elif Aktekin1, Sibel Yavuz1 and Ali Bay1,3
1 Gaziantep University Department of Pediatrics, Gaziantep, Turkey
2 Gaziantep University Department of Medical Biology, Gaziantep, Turkey
3 Gaziantep University Division of Pediatric Hematology Gaziantep, Turkey
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Background and objective: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory disease. It is difficult to differentiate between primary and secondary HLH based on clinical findings at the onset of disease. We aimed to find parameters that can help to differentiate primary and secondary HLH at initial diagnosis especially for physicians working in developing countries.
Patient and Method: We retrospectively analyzed data of 38 HLH patients who were admitted to the Pediatric Hematology Department of Gaziantep University between January 2009 and December 2013.
Results: Of 38 patients, 20 were defined as primary, and 18 were secondary HLH. The average age of primary and secondary HLH patients was 31±9 and 81±14 months, respectively (p=0.03). We found consanguinity rates significantly higher in primary HLH patients compared to secondary HLH patients (p=0.03). We found that total and direct bilirubin levels significantly increased in primary HLH patients compared to secondary HLH patients (p=0.006, p=0.044). Also, CRP levels were found markedly increased in secondary HLH patients compared to primary ones (p=0.017).
Conclusion: We showed that cholestasis and hyperbilirubinemia findings of HLH patients at the initial diagnosis should be considered in favor of primary HLH, and an increased level of CRP should be considered in favor of secondary HLH.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening
hyperinflammatory disease caused by an uncontrolled and dysfunctional
immune response. HLH has been categorized as primary or familial HLH
(FHLH), when there is a family history of HLH or known underlying
genetic defects. Reactive or secondary HLH occurs in the setting of
infection or underlying rheumatologic disorders or malignancy. HLH
occurring in the setting of a rheumatological illness is commonly
referred to as macrophage activation syndrome (MAS).
However, initial treatment should not govern disease classification (genetic or acquired). However, information about the underlying genetic defect is important for management because it will allow for an early search for a stem cell donor. Differentiation between primary and secondary forms of HLH has become increasingly blurred together as new genetic causes are identified. In many developing countries, these genetic tests are not performed, and blood had to be sent abroad for genetic testing. Elongation of the process causes difficulties in the follow-ups of these patients. It is difficult to differentiate between primary and secondary HLH based on clinical symptoms, history of infection, or the early clinical course at the onset of disease. Severity of disease and the identification of an infectious agent do not differentiate between genetic and acquired forms of HLH. Age is helpful to some extent a minority of children one year of age will have acquired HLH, but older age does not reliably exclude genetic HLH.
In this study, we aimed to find parameters that can help to differentiate primary and secondary HLH at initial diagnosis by comparing clinical laboratory findings of 38 HLH patients followed in our clinic for last four years. This procedure can be particularly useful for physicians working in developing countries.
Patients and methods
A total of 38 HLH patients is included into this study. Of 38
patients, 20 were defined as primary, and 18 were secondary HLH.
Perforin, sytaxin, and munc13-4 mutations were detected in 6, 3, and 1
of primary HLH patients, respectively. The remaining ten patients were
considered to have primary HLH based on family history, age of onset
and recurrence of the disease, even if the genetic mutations were not
Out of 20 patients with primary HLH, 12 (60%) were female, and 8 (40%) were male. Out of 18 patients with secondary HLH, 11 (61%) were female and 7 (39%) were male (39%). The average age of primary and secondary HLH patients was 31±9 and 81±14 months, respectively. Patients with primary HLH were significantly younger than those with secondary HLH (p=0.03) (Table 1).
We found consanguinity rates significantly higher in primary HLH patients compared to secondary HLH patients (p=0.03). Also, the sibling death history was present in 30% of primary patients but none in secondary HLH patients. We did not detect any significant difference between primary and secondary HLH patients when compared their clinical findings such as fever, hepatomegaly, and splenomegaly. Also, distribution of ethnicity can be seen on Table 1.
We also compared the laboratory findings of HLH patients and; we found that total and direct bilirubin levels significantly increased in primary HLH patients compared to secondary HLH patients (p=0.006, p=0.044) (Table 2). When we took the cut-off level 1,3 mg/dl for total bilirubin level, we calculated the sensitivity and specificity levels 60%, 95% respectively. By the way when we took the cut-off level 0,8 mg/dl for direct bilirubin levels, sensitivity and specificity levels were calculated 60% and 95% respectively (Table 3). Also, CRP levels were found markedly increased in secondary HLH patients compared to primary ones (p=0.017). We calculated the sensitivity and specificity levels 47% and 85% respectively, when we took the cut-off level 98 mg/dl (Table 3). We didn't find any significant difference between the two groups by comparing the levels of WBC, hemoglobin, platelet, triglyceride, fibrinogen, ferritin, transaminase, albumin, LDH, Na, K, P, Ca, PT, INR, aPTT, and the sedimentation rate.
|Table 1. Patient Characteristics, Age and Gender Distributions|
|Table 2. Biochemical Parameters of the Patients|
|Table 3. Sensitivity and Specificity Analysis of Total Bilirubin, Direct Bilirubin, and C-reactive protein|