الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
HLH is an underdiagnosed, life-threatening condition characterized by a state of activation and proliferation of cytotoxic T lymphocytes and macrophages that infiltrate multiple organs and result in overproduction of inflammatory cytokines. HLH has been classified into pHLH and sHLH.
The involvement of the CNS in patients with HLH is usually referred to as ”CNS-HLH”. The presence of CNS-HLH carries a bad prognosis; including increased risk of neurological abnormalities, future disabilities, and higher rate of mortality. Diagnosis of CNS-HLH traditionally rests on: presence of neurological signs/symptoms, abnormal neuroimaging, and/or abnormal CSF. Usually the involvement of the CNS is associated with systemic features, but sometimes neurological manifestations are the first and even the only manifestations of this disease.
All children diagnosed or suspected of HLH must perform neuroimaging, particularly MRI, and CSF analysis when the condition is stable, even in absence of neurological signs and symptoms. Abnormal CSF is known as CSF with pleocytosis or elevated CSF protein or both.
In the current study, we propose new CSF laboratory markers (ferritin, triglycerides, and LDH), as non-expensive and readily available markers of active involvement of the CNS in cases of HLH. We aimed to determine their correlation with classic markers (CSF proteins, leukocytes, and sCD25), known serum HLH laboratory markers, other CNS- HLH diagnostic criteria, different types of HLH (primary and secondary), and if either of them predominates in survivors or non-survivors group.
To the best of our knowledge, this is the first study to investigate the value of CSF laboratory markers (ferritin, LDH, and triglycerides) to use in the diagnosis of CNS-HLH. It is worth mentioning that these markers are already available in all laboratories, are non-expensive, and have been studied in other neurological conditions, including CNS infection, hemorrhage, and malignancy infiltration.
The current study was conducted retrospectively, prospectively on 36 patients with HLH (daignosed according to HLH-2004 protocol) who had available stored CSF samples, admitted to Alexandria University Children’s Hospital, Alexandria, Egypt, between January 2016 and December 2019. The patients’ age ranged from 1 month to 16 years, with a median of 16 months. Two-thirds were females, 26 (72.2%) of the patients had positive consanguinity, mostly first-degree cousins (58.3%). Patients were classified as of pHLH 11(30.6%), sHLH 13 (36.1%), and unknown in 12 (33.3%), as the genetic testing was unknown or still pending.
from the studied patients 29 patients (80.6%) were positive CNS-HLH, most of them 16(55.2%) were fulfilling only one criterion. A CSF abnormality was the commonest for diagnosis of CNS involvement as 23 (67.6%) patients out of 34 had positive CSF. Only 9 (25%) patients were found to have clinical neurological manifestations; the commonest was irritability. About half of the patients had positive neuroimaging results, including features of CNS infiltration, dilated ventricles, hyperintense signals, and diffusion restriction.
In terms of correlation between classic and new proposed markers, the current study found a statistically significant correlation between CSF triglycerides with CSF proteins and CSF leukocytes (p =0.036, 0.046), respectively. Furthermore, CSF triglycerides revealed a moderate significant correlation with CSF ferritin (p =0.033) and serum ferritin (p =0.037). Also noted, CSF ferritin revealed a statistically significant correlations with serum markers, including serum ferritin, LDH, and fibrinogen.
On the other hand, CSF sCD25 was the only CSF laboratory marker with a higher median level in group of the non-survivors than survivors (p =0.03) and those classified as pHLH than sHLH (p =0.002). Other CSF markers did not show significant differences among patients when looking for either prognosis or types of HLH.
Interestingly, we found positive laboratory markers to be the commonest among CNS-HLH diagnostic criteria and clinical neurological criteria were the least as clinical neurological manifestations were absent in most cases of both groups. Unexpectedly, CSF triglycerides were the only CSF marker that significantly differs (p =0.044) with clinical neurological manifestations as its median tends to be higher in cases of absent neurological manifestations than those with a positive one. However, no significant difference was found between CNS-HLH diagnostic criteria among both the survivors and non-survivors groups.
By the end of this study, 19 (52.8%) patients survived; (25%) living on HLH treatment, 44.4% of the patients have died primarily due to disease activity, and one of the patients was lost to follow up.
In conclusion, both CSF ferritin and CSF triglycerides have promising correlations that might be used in the diagnosis of CNS-HLH. While CSF sCD25 might have a prognostic and etiological value in cases with CNS-HLH. However, further studies are needed to verify these preliminary results