Abstract:  Identifying markers for chronic illness in pediatric patients exposed to water damaged buildings: Linkage disequilibrium of HLA DR, MSH, MMP9 and autoantibodies

 Authors:  Ritchie C. Shoemaker¹, Courtney Holt¹, Dennis House¹, HK Hudnell²

¹Center for Research on Biotoxin Associated Illnesses, Pocomoke, Md; ²US EPA NHEERL, Research Triangle Park, NC

Background:  No studies have previously identified biomarkers adequate to create a case definition of illness associated with exposure to water damaged buildings (WDB) in pediatric patients.  Previous work from this facility has presented a case definition of illness in adults that includes exposure, symptoms and absence of confounders, together with biomarkers HLA DR genotypes of the immune response genes; deficiency of the hypothalamic immunomodulatory hormone, alpha melanocyte stimulating hormone (MSH); excess pro-inflammatory cytokine responses, represented by matrix metalloproteinase-9 (MMP9), deficits in visual contrast and pituitary hormone dysregulation.  We have seen an increased incidence of antibodies to gliadin, cardiolipin and myelin basic protein in adults with chronic illness following exposure to WDB.  Here we present data supporting a pediatric case definition using multiple biomarkers from 66 patients with illness following exposure to WDB.

Methods:  Patients under age 19 coming for treatment of chronic illness at a specialized medical clinic provided informed consent for evaluation and blood testing prior to initiation of definitive therapy for presumptive chronic, biotoxin associated illness.  Symptoms were recorded and blood was sent to national high complexity labs for analysis of HLA DR genotype, MSH, MMP9, anticardiolipins (ACLA), antigliadins (AGA) and myelin basic protein (MBP) antibodies. Lab parameters were compared to in-house registries of control patients and published registries. Following treatment and confirmation of diagnosis, cases were then analyzed by biomarker to identify unique diagnostic features.

Results:  Control populations have markedly different HLA DR genotype distributions from cases, with relative risks for illness identified for the same genotypes as reported previously in adults.  Affected patients had lower levels of MSH and MMP9 than controls.  Marked increase in incidence of antibodies to antigliadin IgG, anticardiolipin IgM and myelin basic protein antibodies was found in affected patients compared to controls.  Taken together, the combination of potential for exposure, absence of confounding diagnoses, presence of distinctive groupings of symptoms, including fatigue and cognitive problems identified over 85% of cases.  Adding HLA DR, MSH deficiency, AGA-IgG and ACLA-IgM increased the case detection rate to 100%.  For patients with MMP9 over 400, HLA DR and MSH deficiency alone identified all cases.

Conclusion:  Specific genetic, physiologic and neurotoxicologic factors can be identified in pediatric patients that identify cases of chronic illness due to exposure to WDB.  Physiologic mechanisms associated with increased production of particular autoantibodies will require further study.