Sick building syndrome (SBS) and exposure to water-damaged buildings: Time series study, clinical trial and mechanisms

Abstract

Occupants of water-damaged buildings (WDBs) with evidence of microbial amplification often describe a syndrome involving multiple organ systems, commonly referred to as “sick building syndrome” (SBS), following chronic exposure to the indoor air. Studies have demonstrated that the indoor air of WDBs often contains a complex mixture of fungi, mycotoxins, bacteria, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile compounds. A case-series study with medical assessments at five time points was conducted to characterize the syndrome after a double-blinded, placebo-controlled clinical trial conducted among a group of study participants investigated the efficacy of cholestyramine (CSM) therapy. The general hypothesis of the time series study was that chronic exposure to the indoor air of WDBs is associated with SBS. Consecutive clinical patients were screened for diagnosis of SBS using criteria of exposure potential, symptoms involving at least five organ systems, and the absence of confounding factors. Twenty-eight cases signed voluntary consent forms for participation in the time-series study and provided samples of microbial contaminants from water-damaged areas in the buildings they occupied. Twenty-six participants with a group-mean duration of illness of 11 months completed examinations at all five study time points. Thirteen of those participants also agreed to complete a double-blinded, placebo-controlled clinical trial. Data from Time Point 1 indicated a group-mean of 23 out of 37 symptoms evaluated; and visual contrast sensitivity (VCS), an indicator of neurological function, was abnormally low in all participants. Measurements of matrix metalloproteinase 9 (MMP9), leptin, alpha melanocyte stimulating hormone (MSH), vascular endothelial growth factor (VEGF), immunoglobulin E (IgE), and pulmonary function were abnormal in 22, 13, 25, 14, 1, and 7 participants, respectively. Following 2 weeks of CSM therapy to enhance toxin elimination rates, measurements at Time Point 2 indicated group-means of 4 symptoms with 65% improvement in VCS at mid-spatial frequency—both statistically significant improvements relative to Time Point 1. Moderate improvements were seen in MMP9, leptin, and VEGF serum levels. The improvements in health status were maintained at Time Point 3 following a 2-week period during which CSM therapy was suspended and the participants avoid re-exposure to the WDBs. Participants reoccupied the respective WDBs for 3 days without CSM therapy, and all participants reported relapse at Time Point 4. The group-mean number of symptoms increased from 4 at Time Point 2 to 15 and VCS at mid-spatial frequency declined by 42%, both statistically significant differences relative to Time Point 2. Statistically significant differences in the group-mean levels of MMP9 and leptin relative to Time Point 2 were also observed. CSM therapy was reinstated for 2 weeks prior to assessments at Time Point 5. Measurements at Time Point 5 indicated group-means of 3 symptoms and a 69% increase in VCS, both results statistically different from those at Time Points 1 and 4. Optically corrected Snellen Distance Equivalent visual acuity scores did not vary significantly over the course of the study. Group-mean levels of MMP9 and leptin showed statistically significant improvement at Time Point 5 relative to Time Points 1 and 4, and the proportion of participants with abnormal VEGF levels was significantly lower at Time Point 5 than at Time Point 1. The number of participants at Time Point 5 with abnormal levels of MMP9, leptin, VEGF, and pulmonary function were 10, 10, 9, and 7, respectively. The level of IgE was not re-measured because of the low incidence of abnormality at Time Point 1, and MSH was not re-measured because previously published data indicated a long time course for MSH improvement. The results from the time series study supported the general study hypothesis that exposure to the indoor air of WDBs is associated with SBS. High levels of MMP9 indicated that exposure to the complex mixture of substances in the indoor air of the WDBs triggered a pro-inflammatory cytokine response. A model describing modes of action along a pathway leading to biotoxin-associated illness is presented to organize current knowledge into testable hypotheses. The model links an inflammatory response with tissue hypoxia, as indicated by abnormal levels of VEGF, and disruption of the proopiomelanocortin pathway in the hypothalamus, as evidenced by abnormalities in leptin and MSH levels. Results from the clinical trial on CSM efficacy indicated highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline in the 7 participants randomly assigned to receive 2 weeks of CSM therapy, but no improvement in the 6 participants assigned placebo therapy during that time interval. However, those 6 participants also showed a highly significant improvement in group-mean number of symptoms and VCS scores relative to baseline following a subsequent 2-week period of CSM therapy. Because the only known benefit of CSM therapy is to enhance the elimination rates of substances that accumulate in bile by preventing re-absorption during enterohepatic re-circulation, results from the clinical trial also supported the general study hypothesis that SBS is associated with exposure to WDBs because the only relevant function of CSM is to bind and remove toxigenic compounds. Only research that focuses on the signs, symptoms, and biochemical markers of patients with persistent illness following acute and/or chronic exposure to WDBs can further the development of the model describing modes of action in the biotoxin-associated pathway and guide the development of innovative and efficacious therapeutic interventions.

Introduction

The hypothesis that chronic exposure to the indoor environments of water-damaged buildings (WBD) causes a multi-system illness, often referred to as “sick building syndrome” (SBS), remains controversial [2], [3], [4], [17], [24], [27]. Reviews by the authors and the California Research Board of the scientific literature on studies investigating the association between WBD exposure and SBS identified many studies that supported the hypothesis [95], [110]. The WDB environment supported microbial amplification in the indoor environment, and indoor air contained a complex mixture of substances, including toxigenic fungi, bacteria, mycotoxins, endotoxins, antigens, lipopolysaccharides, and biologically produced volatile organic compounds. Many occupants of the WDBs reported multiple-system symptoms. Objective measurements indicated that irritant and allergic characteristics of airborne particles adversely impacted pulmonary function. However, methodological limitations in the past had prohibited the definitive attribution of multiple-system illness to the WDB environment. Our previous reports described studies that attempted to overcome some of those limitations [95], [97]. Critical study components included a prospective experimental design in which clinical data were collected at five time points; the use of objective indicators of effect; the interventions of successful therapy; removal from exposure; and re-exposure [95]. The study results indicated that SBS acquired in WDBs might be a form of “biotoxin-associated illness”, a term used to indicate that some forms of illness may be caused by exposure to toxins produced by single-cell organisms such as fungi, dinoflagellates, cyanobacteria, diatoms, and bacteria. The multiple-system illness identified in patients previously exposed to aquatic environments inhabited by the suspected toxigenic dinoflagellates, Pfiesteria sp., represented a form of biotoxin-associated illness [40], [96], [103], termed “Possible Estuary Associated Syndrome” (PEAS) by the Centers for Disease Control and Prevention [23]. The current study attempted to confirm the previous observations and further characterize the physiological and biochemical characteristics of SBS acquired in WDBs.

Our previous reports described the results from SBS studies that used a powerful ABB′AB study design that allow participants to serve as their own controls. This design provided the advantage that the participants' environmental and genetic characteristics remained constant as they were monitored over time and experimental interventions were enacted. The interventions were the initiation of successful therapy, exposure avoidance, re-exposure, and a second round of therapy. The results showed a spectrum of multiple-system symptoms that were acquired by patients following chronic exposure to WDBs. High symptom prevalence was accompanied by large deficits in visual contrast sensitivity [95], [97], an indicator of neurologic function in the visual system [13], [48], [49], [50], [51], [52], [91], [103]. Most patients also reported upper airway symptoms, but pulmonary function tests indicated that few patients had obstructive or restrictive lung function. Elevated levels of leptin and decreased levels of alpha melanocyte stimulating hormone (MSH) indicated that the illness likely involved pathology in the hypothalamus. Increased levels of leptin indicated probable damage to leptin receptors in the hypothalamus [44], [62], [117] that could result from a toxin-triggered increase in the release of pro-inflammatory cytokines by adipose cells [60]. Inability of the damaged leptin receptors to be stimulated by leptin would result in overproduction of leptin [70] and reduced secretion of MSH [43]. MSH deficiency causes abnormal function in the pituitary gland [8], gastrointestinal system [26], and immunologic system [66], [67], and are associated with chronic pain [57] and sleep disturbance [18]. Participants received 2 weeks of treatment with cholestyramine (CSM). Cholestyramine is a non-absorbable polymer that removes a variety of toxins from bile through anion-exchange binding, thereby causing toxin elimination rather than reabsorption during enterohepatic recirculation [5], [9], [15], [16], [22], [25], [28], [29], [54], [58], [59], [64], [74], [75], [86], [87], [100], [111]. CSM therapy resulted in a dramatic decrease in symptom prevalence concomitant with normalization of VCS [95], [97]. Group-mean leptin levels were decreased and MSH levels were increased following CSM therapy [95], [97]. Health status continued to show marked improvement following CSM therapy while the study participants avoided re-exposure to the WDBs. However, all participants relapsed within 7 days of re-exposure to the WDBs. Readministration of CSM again resulted in a highly significant improvement in the health status indicators. The positive response to toxin-elimination therapy, the maintenance of good health without re-exposure to the WDBs, and the relapse with re-exposure strongly supported the hypothesis that illness was causally associated with exposure to the WDBs.

The current study again used a prospective experimental design with clinical assessments occurring at five points in time to test the general study hypothesis that SBS is associated with exposure to WDBs. Evaluations occurred immediately after the screening of potential study participants; after 2 weeks of CSM therapy; after the avoidance of exposure to WDBs; following re-exposure to the WDBs; and after a second course of CSM therapy. Symptom prevalence, VCS, pulmonary function, and leptin and MSH concentrations were measured in an attempt to confirm the previously observed results. Levels of immunoglobulin E (IgE), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor (VEGF) were measured to help further characterize underlying pathology. A double-blind, placebo-controlled clinical trial was conducted in 13 of the 26 study participants at the onset of the time series-study to assess the efficacy of CSM therapy on health status relative to placebo treatment. Following baseline assessments, the clinical trial participants were randomly assigned to either receive 2 weeks of placebo therapy prior to receiving 2 weeks of CSM therapy or to immediately receive 2 weeks of CSM therapy.