Exposure in water-damaged buildings (WDB) to airborne bioaerosols including metabolic products of toxigenic fungi, bacteria and actinomycetes; and inflammagens, can lead to a persistent innate immune inflammatory illness. This illness, termed a chronic inflammatory response syndrome (CIRS-WDB), is systemic with symptoms acquired from multiple organ systems. Treatment of CIRS-WDB has progressed rapidly as a better understanding of the inflammatory pathophysiology has led to targeted, sequential therapies. The fundamental basis of uncontrolled innate immune responses, the humoral deficiency of regulatory neuropeptides melanocyte stimulating hormone (MSH) or vasoactive intestinal polypeptide (VIP), seen in over 98% of pa tients, has not consistently responded to any treatment modality. Use of replacement VIP has been attempted anecdotally; VIP replacement therapies show promise in short term studies but longer therapies have not been attempted. Here we report an open label trial of 20 patients with refractory CIRS-WDB illness who took replacement VIP in a nasal spray for at least 18 months with confirmation of durable efficacy and absence of significant side effects. These 20 patients were similar in symptoms and lab find- ings to three previously published cohorts in- volving 1829 patients and 169 controls. Dosage of VIP was titrated downwards from four to zero doses a day to determine minimum effective dose, and retitrated upwards for maximum improvement over time. The trial showed that VIP therapy safely 1) reduced refractory symptoms to equal controls; 2) corrected inflammatory parameters C4a, TGF beta-1, VEGF, MMP9; 3) corrected estradiol, testosterone and 25-OH Vitamin D; 4) returned pulmonary artery systolic pressure (PASP) during exercise to normal; and 5) enhanced quality of life in 100% of trial patients. Subsequent identification of correction of T-regulatory cell levels supports the potential role of VIP in both innate and adaptive immune function.
Treatment of the multisystem, multisymptom illness acquired following exposure to the interior environment of buildings with a history of water intrusion and subsequent microbial growth (i.e. WDB) remained problematic until recent years because 1) no consistent pathophysiological mechanisms had been demonstrated; and 2) no biomarkers were consistently identified thereby preventing confirmatory laboratory diagnosis. Various alternative diagnoses have been ascribed to patients with this illness, including medically uncertain illness, fibromyalgia, and “Sick Building Syndrome”. Following publication of reports from the US GAO in 2008 [
This illness has been called a chronic systemic inflammatory illness (CIRS-WDB, [
VIP is a regulatory neuropeptide with diverse physicologic effects. Following activation of outer membranebased receptors, VIP is known to raise cAMP [
In addition to deficiency of VIP, patients with CIRSWDB will invariably have 1) deficiencies of another regulatory neuropeptide, melanocyte stimulating hormone (MSH) in plasma; 2) dysregulated inflammatory responses; and usually have 3) evidence of cellular immune abnormalities marked by elevated TGF beta-1 in plasma and reduced levels of Tregs in whole blood; 4) abnormal plasma levels of a split product of complement activation, C4a; 5) dysregulation of serum ACTH/cortisol, androgens and ADH/osmolality; 6) abnormal plasma levels of VEGF; 7) disorders of coagulation parameters seen in von Willebrand’s profiles; 8) presence of genomically active, multiple antibiotic resistant coagulase negative staphylococci (MARCoNS) in deep aerobic nasal spaces and 9) an abnormal rise in PASP in exercise. Treatment of CIRS-WDB involves multiple sequential steps (
Human research approval for this study was provided by Copernicus Group IRB, Cary, NC in 2010. After providing informed consent, 20 patients (11 Caucasian females, mean age 51.1; and 9 Caucasian males, mean age 48.2) with clinically-confirmed CIRS-WDB refractory to all prior treatment modalities (steps 1 - 10, as described below, in
For the experimental protocol, subjects self-administered 50 mcg VIP (Aviptadil; Bachem AG, Switzerland) four times a day via nasal aerosol and returned to the clinic to review symptoms and clinical course; and undergo interval physical exam and laboratory testing at scheduled intervals. Clinical data were collected before any treatments, at baseline (BASE); after all other treatments and before VIP (AC2); after 12 months of VIP (12 M); and after 18 months of VIP (18 M). Data collection included physician recorded symptoms in a medical history; levels of VIP, MSH, C4a, TGF beta-1, VEGF, MMP9, estradiol, testosterone, 25-OH vitamin D, lipase, CBC and CMP. Measurement of CD4+CD25+ T regulatory (Treg) cells was not available at BASE; Treg testing was performed at AC2 and 18 month time periods. Laboratory testing for all analytes was performed by high complexity CLIA-certified labs including LabCorp and Quest Diagnostics.
All data were compared to either established normative values or values from prior testing of healthy control populations (N = 850) performed at this clinic. Data were analyzed by two-sample T-tests for each of two study time points and one-sample T-tests that compared the specified data to the corresponding historical control
values. A Bonferroni correction to the p-values was done to control the experiment-wise error rate. A p value of < 0.001 was chosen as the determinant of significance for the study.
Standard Bruce protocols were employed during stress echocardiography testing. Target heart rate of 85% of maximum was obtained after baseline recording showed no evidence of PASP greater than 30 mmHg or left ventricular ejection fraction of less than 50%. All patients achieved target heart rate; none developed ischemic changes on EKG or chest pain during stress testing. Each had a repeat measurement of the tricuspid regurgitation jet (TR) immediately after exercise with recordings of TR performed within 30 seconds of cessation of exercise. Pulmonary artery pressure was calculated from the measurement of the TR based on a standard nomogram.
Patients tolerated the drug well and there were no dropouts due to adverse effects over the course of the 18 month study. Cases were similar at baseline to known cases of CIRS-WDB in large cohorts previously published [5,6] with excessive numbers of symptoms in cases compared to controls (
Use of replacement doses of the regulatory neuropeptide VIP in a nasal spray 1) safely reduced refractory symptoms to control levels; 2) corrected inflammatory parameters to be not significantly different from controls; 3) raised levels of VIP and MSH; 4) returned PASP during exercise to normal; and 5) enhanced quality of life in 20 patients in an open-label trial. Follow-up as long as 18 months after initiation of the study showed durable salutary responses, without significant adverse side effects. Labs and symptoms showed continued improvement over time to become similar to controls (
We have no other studies to use for comparison of results of VIP use as these patients were labeled as refractory to all modalities employed. There are no similar studies of long tem use of VIP in the world’s literature.
While significant differences (p < 0.001) were identified between controls and baseline lab values in patients for symptoms, MSH, VIP, MMP9, C4a, TGFb-1, 25-OH Vitamin D and testosterone in males, by the end of the trial patient values were not statistically different from controls, except for VIP and MSH. Flow cytometry showed a significant increase of CD4+CD25+ Treg cells from a mean of 8.9 to 22.5. No changes in CBC and CMP were noted. One patient had a transient elevated level of lipase without abdominal pain that resolved without cessation of use of VIP. After six months patients titrated use of VIP to these symptoms with verification of benefit obtained by clinical exam and blood testing at three month intervals. Eight patients consistently used VIP at three or four times a day; four patients used VIP once or twice a day. Three patients used VIP before strenuous activity only; five patients stopped using VIP at various points during the trial as they had correction of symptoms and no evidence of relapse without protocol medications. For these patients, only data obtained while using VIP was subjected to statistical calculation.
VIP is a 28 amino acid regulatory neuropeptide that has multiple salutary health effects. This study was designed to assess the benefits and potential risks of VIP use in severely affected patients who had previously completed all sequential treatments while attempting to correct the above illness parameters but were still quite ill (
3) eradication biofilm-forming coagulase negative staphylococci; 4) discontinuance of consumption of gluten if they had a positive antigliadin antibody titer (three months minimum required); 5) correction of abnormalities androgens; 6) correction of abnormalities in regulation of salt and water with synthetic desmopressin as shown by simultaneous ADH and osmolality; 7) normalizing MMP9 with pioglitazone 45 mg daily; 8) normalizing VEGF with high dose omega-3 fish oils (4.2 grams daily); 9) correction of C3a with high dose statins; 10) attempting to correct C4a with erythropoietin but only if entry criteria met; 11) attempting to correct TGF beta-1 with losartan 25 mg daily, monitoring blood pressure carefully. Our initial use of low dose VIP by nasal instilllation was shown to be safe in human volunteers; its use provided prompt reduction in symptoms and blunted accentuated pulmonary artery responses to exercise. However, benefit of replacement VIP in earlier trials was not observed to be universal. Presence of any one of three parameters was associated with reduced efficacy: 1) depressed visual contrast sensitivity (VCS); 2) measurement of fungal DNA in settled dust using QPCR that resulted in an Environmental Relative Mold Index (ERMI) > 2; and 3) presence of multiply antibiotic resistant biofilm-forming coagulase negative staphylococci (MARCoNS) in deep nasal aerobic spaces. Patients with these findings were excluded from the formal replacement trial.
Current therapies for CIRS-WDB can improve quality of life in patients, but symptom reduction and correction of inflammatory responses alone do not necessarily lead to full restoration of normal immune responses. The restoration of appropriate neuropeptide levels is critical for proper regulation of hormonal and immune system inflammatory responses. VIP replacement demonstrated its value in the correction of such regulation during this trial. Even though levels of MSH and VIP did not return to control values, they doubled compared to baseline, with additional improvement after all prior therapies were completed.
An important anti-inflammatory mechanism of VIP is its ability to generate tolerogenic dendritic cells, which in turn induce additional T regulatory cells that can suppress Th1 responses, generating a Th2 response and transfer such suppression to naïve hosts [
This study confirms our hypotheses that use of VIP in VIP-deficient patients is both durably safe and effective for up to 18 months. When used by nasal instillation VIP is well-tolerated, has few side effects and is unlikely to result in an over-dosage. Treatment with VIP restored clinical functioning in a cohort of CIRS-WDB patients with severe illness characterized by profound, refractory abnormalities in innate immune inflammatory responses (see BASE on
Evaluation of clinical use of VIP will require additional study. A double blinded, placebo controlled clinical trial has begun. The salutary but preliminary results reported here show safety and benefit in severely affected CIRS-WDB patients in an open-label trial. We have now used VIP by nasal instillation in over 600 hundred patients whose clinical findings are similar to those reported here. Now that patients with CIRS-WDB can be identified proteomically, with treatment protocols readily available (
Special thanks to William Meyer III, PhD for comments on the manuscript; and Debbie Waidner and Debra Bell for data processing and collation.
Acronyms used:
ACLA anticardiolipin antibodies ACTH adrenocorticotrophic hormone ADH antidiuretic hormone cAMP cyclic AMP CBC complete blood count CIRS chronic inflammatory response syndrome C3a split activation product of C3 C4a split activation product of C4 CMP comprehensive metabolic profile CSM cholestyramine ERMI Environmental Relative Moldiness Index HLA DR human leukocyte antigen Class II, DR locus MARCoNS multiply antibiotic resistant coagulase negative staphylococci MSH alpha melanocyte stimulating hormone MMP-9 matrix metalloproteinase 9 PASP pulmonary artery systolic pressure TGF beta-1 transforming growth factor beta-1 TNF tumor necrosis factor T reg T regulatory lymphocyte VCS visual contrast sensitivity VEGF vascular endothelial growth factor VIP vasoactive intestinal polypeptide vWF von Willebrand’s profile WDB water-damaged building