Serum interleukin‐6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation

Abstract

BACKGROUND. During the time of lowest white blood cell count (nadir) of allogeneic hematopoietic stem cell transplantation (allo‐HSCT), cancer patients suffer from tremendous symptom burden related to therapy that requires intensive patient care. However, the mechanism underlying the development of multiple symptoms has not been established. METHODS. To explore the role of inflammatory cytokines in the development of treatment‐related symptoms, we studied dynamic changes in symptoms and in serum concentrations of inflammatory cytokines (interleukin [IL]‐6, IL‐8, soluble tumor necrosis factor receptor 1 [sTNF‐R1], IL‐1 receptor antagonist, and IL‐12p40p70) from pretherapy throughout the first 30 days of allo‐HSCT in 30 patients with acute myelogenous leukemia or myelodysplastic syndrome. We measured multiple symptoms repeatedly using the M. D. Anderson Symptom Inventory. Mixed‐effects modeling was used to analyze longitudinal data. RESULTS. In response to conditioning and stem‐cell infusion, serum levels of IL‐6 and the severity of multiple symptoms increased rapidly and peaked at nadir. From baseline to nadir (approximately Day 8 post‐transplantation), increase in IL‐6 was significantly associated with worsening of the most severe symptoms (fatigue, poor appetite, pain, drowsiness, dry mouth, and disturbed sleep; P< .01). During the first 30 days after transplantation, increases in IL‐6 (P< .001) and sTNF‐R1 (P< .05) significantly predicted the increasing severity of these symptoms. CONCLUSIONS. These results suggest that release of systemic inflammatory cytokines, mainly IL‐6, corresponds to an increase in treatment‐related multiple‐symptom burden during the nadir period of allo‐HSCT. Cancer 2008. © American Cancer Society.

Biological pathways and genetic variables involved in pain

“…IL-6 knock-out mice showed a reduced analgesic response to morphine and a more rapid development of tolerance to the analgesic effect of morphine [56]. In patients who had undergone allogeneic hematopoietic stem cell transplantation, increase in levels of circulating IL-6 was found to be significantly related to increases in patients' reports of pain [57]. The C allele of -174G[C (rs1800795) SNP in IL-6 gene promoter region was found to be associated with significantly lower levels of plasma IL-6 in healthy subjects [58].…”

Risk factors for fatigue severity in primary brain tumor patients

“…It has been postulated that symptoms such as pain, fatigue, and insomnia may have a shared biologic mechanism, such as the sickness behavior seen in relation to cytokine administration or production. 32,33 Further studies are needed to evaluate the concordance of these symptoms over time and the relationship to shared biologic mechanisms in this patient population.…”

Nociceptor Sensitization by Proinflammatory Cytokines And Chemokines

“…IL-6 is produced and excreted by immune cells including macrophages, glia cells and even neurons (reviewed in [135]). Increased levels of IL-6 have been correlated with sickness behaviour in humans [136] and treatment associated symptoms like pain, fatigue and others [137]. Apart from controlling immune cell interactions, IL-6 may account for the pain and hypersensitivity associated with inflammation, neuropathy or cancer by directly regulating the gain of pain-sensing neurons.…”