Prognosis of Children with Virus-Associated Hemophagocytic Syndrome and Malignant Histiocytosis: Correlation with Levels of Serum Interleukin-1 and Tumor Necrosis Factor

Abstract

To clarify the correlation of cytokine level with the severity and prognosis of children with the hemophagocytic syndrome, we analyzed serum interleukin-1 (IL-1) and tumor necrosis factor (TNF) levels in 26 children with either the virus-associated hemophagocytic syndrome (VAHS, n = 12) or malignant histiocytosis (MH, n = 14). When compared to healthy controls, 13 children had an elevated IL-1 ( ≥ 20 pg/ml) and 21 children had an elevated TNF ( ≥10 pg/ml) level at diagnosis. There was, however, no significant difference in the frequency of these high levels between the patients with VAHS and MH. Neither IL-1 nor TNF levels correlated with other clinical or laboratory findings in either VAHS or MH. Two of the 12 patients with VAHS died of an intracranial hemorrhage and 7 of the 14 patients with MH died despite chemotherapy. The MH patients who had a high TNF level (≥50 pg/ml) had a poorer prognosis than those with a low TNF level ( < 50 pg/ml; p < 0.01). In MH patients, other parameters, such as coagulopathy and lactic dehydrogenase, ferritin and IL-1 levels, did not correlate with prognosis. In 3 patients (2 with VAHS and 1 with MH) analyzed periodically, the change in TNF level was closely associated with the clinical progression or regression of the diseases. Serum cytokine levels may thus be monitored not only for predicting the severity and prognosis of VAHS or MH but also for determining the indications for or timing of chemotherapy. Moreover, TNF may play an important role in the progression of VAHS and MH.

Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome.

“…Studies using T/NK or NK cell lines are mandatory to clarify whether EBV will also play a similar role in upregulating cytokine genes in these cells. Various types of inflammatory cytokines have been found to be elevated in HS patients (6)(7)(8)(9)(10)(11)(12), especially TNF-␣ and IL-1␣ (12). More recently, IL-6, IFN-␥, and GM-CSF were also reported to be elevated in subsequent studies (7,8,11,32).…”

“…In brief, 2 g of RNA mixture was heated at 70 Њ C for 10 min, and quick-chilled on ice. After collection by brief centrifugation, the reverse transcription reaction mixture that contained 200 U SuperScript™II RT, 40 mM Tris-HCl (pH ϭ 8.3), 125 mM KCl, 5 mM MgCl 2 , 0.2 mg/ml BSA, 1 l oligo (dT) [12][13][14][15][16][17][18] (500 g/ml), 10 mM dNTP mixture, and 0.1 M DTT, was added to the RNA, followed by incubating at room temperature for 10 min. The tubes were further incubated at 42 Њ C for 50 min and the reaction was terminated by incubating at 90 Њ C for 5 min.…”

“…Third, TNF-␣ has been shown to be the most important factor in macrophage activation during infection of murine cytomegalovirus, human herpes virus-6, and herpes simplex virus (23,24,(37)(38). Finally, the level of TNF-␣ has been reported to be an important indicator of prognosis in HS patients (12).…”

“…The bone marrow, liver, spleen, and lymphoid organs of patients with HS are often diffusely infiltrated with lymphoid cells and phagocytic histiocytes (macrophages) (1)(2)(3)(4)(5). The consistent elevation of inflammatory cytokines in patients' sera, particularly TNF-␣ , IFN-␥ and IL-1 ␣ , presumably released from the activated lymphoid cells and/or macrophages, has been suspected to be responsible for the pathogenesis of HS (6)(7)(8)(9)(10)(11)(12).…”

Hemophagocytic Lymphohistiocytosis Secondary to <i>Mycoplasma pneumoniae</i> Infection without Pneumonia

“…Hypercytokinemia plays an important role in the development of extrapulmonary manifestations, systemic inflammatory response syndrome (SIRS) and organ failure in patients infected with M. pneumoniae (13). Furthermore, hypercytokinemia is known to be related to the development of DIC and HLH (14)(15)(16)(17)(18). In the present case, only the acute-phase serum levels of sIL-2R, IL-6, IL-10, IL-18, IFN-gamma and M-CSF were high, and the ensuing hypercytokinemia was thought be the cause of the patient's extrapulmonary manifestations, including SIRS, DIC and HLH.…”