الفهرس 
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Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that represents an uncontrolled hyperinflammatory state associated with many underlying conditions. It is caused by severe hypercytokinemia resulting from a highly stimulated but ineffective immune response. HLH can be classified as primary (genetic) and secondary (acquired). Primary HLH is caused by gene mutations, either at one of the Familial HLH (FHL) loci or in a gene responsible for one of several immunodeficiency syndromes. Secondary HLH (sHLH) is considered the consequence of an acquired inability of the immune system to cope with a trigger which in most children is an infectious agent.
The most common findings of HLH are fever, hepatosplenomegaly and cytopenias. Other common findings include liver dysfunction, neurological symptoms, and coagulopathy. Histopathological findings include a widespread accumulation of lymphocytes and mature macrophages, sometimes with hemophagocytosis, affecting the spleen, lymph nodes, bone marrow (BM), liver, and cerebrospinal fluid (CSF). Other frequent abnormal laboratory findings in HLH are elevated serum ferritin, low NK-cell activity 10,11 and a hypercytokinemia, including elevated soluble CD25 (sCD25).
The diagnosis of HLH is based on fulfilling the diagnostic criteria of the HLH-2004 protocol. Although HLH is considered a rare disease, the true incidence of the disease is believed to be underreported as well as its high morbidity and mortality.
The present observational study reports the epidemiological data of pediatric HLH in Alexandria, Egypt. It was conducted over a four-year period from first of January 2016 to 31st December 2019 at Alexandria University Children’s Hospital, Alexandria, Egypt. The patients were classified “preliminarily” at diagnosis as having primary or secondary HLH. Genetic testing was done for most of the included patients and the HLH classification was modified according to the genetic results into “confirmed” primary and secondary HLH. All included patients were followed up during their hospital course; their treatment and outcome were recorded. The date of the last follow up was on 31st January 2020 for recording patients’ outcomes.
One-hundred-one patients were enrolled (44 males and 57 females) and the median age at presentation was 13.1 months (range: 1 day – 181.4 months). Almost 75% of the patients had consanguineous parents, and one-third had a history of an affected family member (HLH or HLH-like illness).
The median time interval between the first HLH symptom and diagnosis was 34 days. At diagnosis, patients were preliminarily classified as having primary HLH in 62 (61.4%) patients or secondary HLH in 39 (38.6%) patients. Genetic testing was done for 63 patients and the HLH classification was modified according to the genetic results into “confirmed” pHLH in 37 (58.7%) patients and sHLH in 26 (41.3%) patients. Fever and splenomegaly were the most common clinical criteria present before starting HLH-directed therapy (95% and 88%, respectively). The most common laboratory abnormalities were elevated serum soluble CD25 (96%), hyperferritinemia (84%), cytopenias (83%), hypertriglyceridemia (72%), and hemophagocytosis (43%).
The most common identified trigger was viral infections (EBV followed by CMV). CNS disease was found in 96.9% of patients who had complete neurological assessment. Out of the 37 patients with primary HLH; 8 (21.6%) patients were diagnosed with FHL2, 12 (32.4%) patients with FHL3, 1 (2.7%) patient with FHL5, 10 (27%) patients with CHS, 5 (13.5%) patients with GS2 and 1 (2.7%) patient with XLP1. The most common underlying disease in secondary HLH patients was CGD followed by ALPS and familial Mediterranean fever. The sensitivity of the preliminary classification to detect pHLH patients was 86.5%, which highlights the importance of the clinical diagnosis where genetic testing is unavailable.
The comparison between primary and secondary HLH patients was done in both preliminary and final classifications. The median age on admission was significantly lower in pHLH group in the preliminary classification. The presence of a positive consanguinity was significantly higher in pHLH in both preliminary and final classifications. Fever was the most common clinical presentation in the all studied groups. Among HLH-2004 diagnostic criteria, the absolute neutrophilic count was significantly lower in pHLH patients in the final classification. In addition, hyperferritinemia was significantly higher in sHLH patients in the final classification. Hemophagocytosis was also significantly higher in sHLH patients in the preliminary classification but it was not present in all patients.
The median CRP level was significantly higher in sHLH groups in both classifications. The serum ferritin level was significantly higher in the sHLH groups than pHLH in both classifications. The median serum sCD25 was higher in the pHLH group than sHLH but did not reach a statistically significant difference in both preliminary and confirmed HLH groups. The sCD25/ferritin ratio was higher in pHLH than sHLH with a statistically significant difference in the preliminary groups. Serum sodium, albumin, and TSB showed a statistically significant difference between pHLH and sHLH. Mortality and disease reactivation were significantly more frequent in the confirmed pHLH group as mortality reached 75.7% versus 38.5% in the sHLH.
The overall mortality of the whole patients’ cohort was 63%, most commonly due to uncontrolled disease activity. Only six (6%) patients could be treated with hematopoietic stem cell transplantation (HSCT). The overall probability of survival was significantly higher in the confirmed sHLH compared to pHLH, p = 0.012.
This descriptive study, one of the largest cohorts of pediatric HLH in Africa and the Middle East, sheds some light on the epidemiological characteristics of HLH patients and the available diagnostic and therapeutic tools. The heterogeneity of the patients’ population as it included both primary and secondary cases and the pending genetic testing results indicates the need for continuous work on the diagnosis and management of HLH patients, which should be improved for a better outcome.