Çocuklarda COVID-19 İlişkili Multisistemik Enflamatuvar Sendrom ile Hemofagositik Lenfohistiyositozun Özelliklerinin Karşılaştırılması
Özet
Tosun G.G., Comparison of the Characteristics of Multisystem Inflammatory Syndrome in Children and Haemophagocytic Lymphohistiocytosis, Hacettepe University Faculty of Medicine Pediatric Specialty Thesis, Ankara, 2024. Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening condition that develops after SARS-CoV-2 infection, usually requiring hospitalization, with persistent fever, multi-organ involvement, and markedly elevated inflammatory markers. Similar to severe COVID-19 in adults, it is evaluated under the umbrella diagnosis of cytokine storm syndrome (CSS) with haemophagocytic lymphohistiocytosis (HLH) due to elevated cytokine levels in the circulation and an overactive immune response. Since the first cases, some similarities and differences between MIS-C cases and other CSSs have attracted our attention, and we thought that a better understanding and analysis of these differences could contribute to understanding the pathogenesis of the disease, guiding the treatment, and predicting the prognosis. Therefore, we compared the groups of patients diagnosed with MIS-C and HLH who were treated and followed up in our hospital in terms of clinical and laboratory findings and treatment approaches. This study included 123 patients diagnosed with MIS-C who were followed up in our hospital between March 2020 and March 2022, and 198 patients aged 0-18 years diagnosed with HLH (26 of whom were primary HLH) who were followed up between January 2013 and March 2022. The median age at diagnosis of primary HLH patients (0.5 years) was significantly lower than both secondary HLH (7.5 years) and MIS-C patients (8.5 years). No significant difference was found between the age at diagnosis of MIS-C and secondary HLH patients. The rate of parental consanguinity was higher in primary HLH patients (65.4%) compared to MIS-C (12.2%) and secondary HLH patients (32.6%) (p<0.001). Skin rash was observed in more than half of MIS-C and HLH patients secondary to rheumatological diseases (macrophage activation syndrome; MAS) but only in 19.5% of HLH patients, excluding the MAS group. Oral mucosal changes were seen in only two patients (1%) with HLH but in 52.8% of MIS-C patients. Gastrointestinal symptoms were seen in 74.8% of MIS-C patients and 30.3% of HLH patients (p<0.001). Hepatomegaly or splenomegaly was seen in 16.3% of MIS-C patients and 64% of secondary HLH patients. Hepatosplenomegaly was found in 96.2% of patients with primary HLH and 58.3% of patients with HLH associated with malignancy. Arthritis was observed in only one patient (0.8%) and arthralgia in two patients (1.6%) in the MIS-C group. In the HLH group, arthritis was observed in a total of seven patients (3.5%), six of whom were in the MAS group, and arthralgia in 18 patients, 13 of whom were in the MAS group. Arthritis and arthralgia were more common in MAS patients compared to MIS-C patients (p=0.001 and p<0.001, respectively). MIS-C patients who were SARS-CoV-2 PCR positive were statistically significantly more likely to have respiratory symptoms, respiratory failure requiring intubation, and longer hospital and intensive care unit (ICU) stays. Renal failure requiring renal replacement therapy was found to be more common in secondary HLH patients (8.7%) compared to MIS-C patients (1.6%) (p=0.010). Cardiovascular system involvement was more common in MIS-C patients (76.4%) compared to HLH patients (63.6%) (p=0.016). Hypotension and troponin elevation at the time of diagnosis were more common in MIS-C patients than HLH patients (p<0.001). It was found that decompensated shock was more common in the follow-up of MIS-C patients compared to secondary HLH patients (p=0.004). Coronary artery involvement was observed at similar rates in MIS-C and MAS patients (7.3% and 9.1%, respectively). In contrast, it was not observed in patients with primary HLH or secondary HLH outside the MAS groups. MIS-C patients exhibited higher levels of hemoglobin, leukocytes, neutrophils, and platelets, as well as higher levels of CRP, ESR, and procalcitonin, and lower levels of ferritin, triglycerides, ALT, AST, and LDH than HLH patients. It was discovered that steroid treatment was administered to all patients with primary HLH, almost all patients with MIS-C (95.9%), and 66.3% of patients with secondary HLH. Pulse steroid treatment was used at similar rates in patients with MIS-C and secondary HLH (23.6% and 25.6%, respectively) (p=0.694). The duration of steroid usage during hospitalization was significantly shorter, and the cumulative steroid dose was significantly lower in patients with MIS-C compared to patients with primary and secondary HLH (p<0.001). Although no patients with primary HLH were treated with anakinra, it was used in 62.6% of MIS-C patients and 54.5% of MAS patients. Anakinra treatment was administered at higher doses but for a shorter duration in MIS-C patients than in MAS patients. The hospitalization duration after diagnosis was shorter in MIS-C patients compared to primary and secondary HLH patients (p<0.05). MIS-C patients who met the systemic JIA/MAS classification criteria had significantly more hypotension and decompensated shock, received more pulse steroid, anakinra, and plasma exchange therapy, had higher cumulative steroid doses and ICU admission rate, and had a longer ICU and hospital stay compared to the group who did not meet the classification criteria. Similarly, MIS-C patients with a ferritin/ESR ratio of 21.5 or higher had more hypotension and decompensated shock, received more pulse steroid and plasma exchange therapy, received higher cumulative doses of steroids, and had longer hospital stays. In the MIS-C group, the ferritin/ESR ratio at diagnosis was 21.5 or higher in all patients who died. The remission rate was 96.7% in patients with MIS-C and 77.9% in patients with secondary HLH. The best prognosis among HLH patients was observed in the MAS group, with a remission rate of 95.5%. The results of this study, in which we have demonstrated the similarities and differences between MIS-C and HLH patients, will help to shorten the diagnostic process for patients and guide the selection of effective treatment.
Keywords: Anakinra, HLH, MAS, MIS-C, Cytokine storm.
