Sickness behaviour pushed too far – the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia. It is thus proposed that the pattern of pathology that comprises much of the systemic inflammatory syndrome occurs when one of the usually advantageous roles of pro-inflammatory cytokines – generating sickness behaviour by moderately repressing genes (Dbp, Tef, Hlf, Per1, Per2 and Per3, and the nuclear receptor Rev-erbα) that control circadian rhythm – becomes excessive. Although reversible encephalopathy and gene silencing are severe events with potentially fatal consequences, they can be viewed as having survival advantages through lowering energy demand. In contrast, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia may best be viewed as unfortunate consequences of extreme repression of these same genetic controls when the pro-inflammatory cytokines that cause sickness behaviour are produced excessively. As well as casting a new light on the previously unrationalized coexistence of these aspects of systemic inflammatory diseases, this concept is consistent with the case for a primary role for inflammatory cytokines in their pathogenesis across this range of diseases

Comparison of two different regimens of combined interferon-alpha 2a and lamivudine therapy in children with chronic hepatitis B infection

WOS: 000236640500013PubMed ID: 16640106Aim: To evaluate the efficacy of two regimens of combined interferon-alpha 2a (IFN-alpha 2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. Methods: A total of 177 patients received IFN-alpha 2a, 9 million units (MU)/m(2) for 6 months. In group 1 (112 patients, 8.7 +/- 3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-alpha 2a, in group 11 (65 patients, 9.6 +/- 3.8 years) 3TC was started 2 months prior to IFN-alpha 2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in non-responders. Results: Baseline alanine aminotransferase (ALT) was 134.2 +/- 34.1 and 147.0 +/- 45.3; histological activity index (HAI) was 7.4 +/- 2.7 and 7.1 +/- 2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and 11, respectively (P > 0.005). Complete response was 55.3% and 27.6% in groups I and 11, respectively (P 0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 +/- 4.6 and 14.1 +/- 5.1 months; and relapse rates were 6.8% and none in groups I and 11, respectively (P > 0.05, P > 0.05, P > 0.05). Responders had higher HAI (HAI > 6) and higher pre-treatment ALT than non-responders. Conclusion: Simultaneous 3TC+IFN-alpha 2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies