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Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

ABSTRACT: The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.

SUBMITTER: Cheng LE

PROVIDER: S-EPMC2800791 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

Cheng Laurence E LE Kanwar Bittoo B Tcheurekdjian Haig H Grenert James P JP Muskat Mica M Heyman Melvin B MB McCune Joseph M JM Wara Diane W DW

Clinical immunology (Orlando, Fla.) 20090416 1

The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We obse ...[more]

PMID: 19375390

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Project description:We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level.We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14.Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings.Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS.Epidemiologic study, level III.

Project description:BACKGROUND:Associations among inflammatory cytokines, erythropoietin (EPO), and anemia in critically ill septic patients remain unclear. This study tested the hypothesis that elevated inflammatory cytokines and decreased EPO would be associated with iron-restricted anemia while accounting for operative blood loss, phlebotomy blood loss, and red blood cell (RBC) transfusion volume. METHODS:Prospective observational cohort study of 42 critically ill septic patients was conducted. Hemoglobin (Hb) at sepsis onset and hospital discharge were used to calculate ?Hb. Operative blood loss, phlebotomy blood loss, and RBC transfusion volume were used to calculate adjusted ?Hb (Adj?Hb) assuming that 300 mL RBC is equal to 1 g/dL Hb. Patients with Adj?Hb of greater than 0 (positive Adj?Hb, n = 18) were compared with patients with Adj?Hb of less than or equal to 0 (negative Adj?Hb, n = 24). RESULTS:Plasma tumor necrosis factor ?, granulocyte colony-stimulating factor, interleukin (IL)-6, IL-8, EPO, erythrocyte mean corpuscular volume, and serum transferrin receptor were measured on days 0, 1, 4, 7, and 14. Patients with negative Adj?Hb had significantly higher day 14 levels of IL-6 (37.4 vs. 15.2 pg/mL, p < 0.05), IL-8 (39.1 vs. 18.2 pg/mL, p = 0.01), and granulocyte colony-stimulating factor (101.3 vs. 60.5 pg/mL, p = 0.01), but not EPO. On linear regression analysis, lower Adj?Hb was associated with higher day 14 levels of IL-6 (r = 0.22, p < 0.01), IL-8 (r = 0.10, p = 0.04), stromal cell-derived factor 1 (r = 0.14, p = 0.02), and tumor necrosis factor ? (r = 0.13, p = 0.02), but not EPO. Patients with negative Adj?Hb had significantly lower mean corpuscular volume on days 4 (89.6 vs. 93.2 fL/cell, p = 0.04), 7 (92.3 vs. 94.9 fL/cell, p = 0.04), and 14 (92.1 vs. 96.0 fL/cell, p = 0.03) but similar serum transferrin receptor levels. CONCLUSION:Persistent elevation of inflammatory cytokines was associated with iron-restricted anemia among critically ill septic patients, occurring in the absence of systemic iron deficiency, independent of endogenous EPO. LEVEL OF EVIDENCE:Prognostic study, level II.

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Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

Publications

Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome.

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