Vasoactive intestinal polypeptide (VIP) corrects …

1 , , 396-401 (2013) Health Vasoactive intestinal polypeptide (VIP) corrects chronic inflammatory response syndrome (CIRS). acquired following exposure to water-damaged buildings Ritchie C. Shoemaker *, Dennis House , James C. Ryan2. 1. Center for Research on Biotoxin Associated Illnesses, Pocomoke City, USA; *Corresponding Author: 2. Proteogenomics, LLC, Vero Beach, USA. Received 17 January 2013; revised 20 February 2013; accepted 27 February 2013. ABSTRACT corrected estradiol, testosterone and 25-OH Vi- tamin D; 4) returned pulmonary artery systolic Exposure in water-damaged buildings (WDB) to pressure (PASP) during exercise to normal; and airborne bioaerosols including metabolic pro- 5) enhanced quality of life in 100% of trial pa- ducts of toxigenic fungi, bacteria and actinomy- tients.

2 Subsequent identification of correction of cetes; and inflammagens, can lead to a persis- T-regulatory cell levels supports the potential tent innate immune inflammatory illness. This role of VIP in both innate and adaptive immune illness, termed a chronic inflammatory response function. syndrome (CIRS-WDB), is systemic with symp- toms acquired from multiple organ systems. Keywords: Vasoactive intestinal polypeptide (VIP);. Treatment of CIRS-WDB has progressed rapidly Chronic Inflammatory Response Syndrome (CIRS);. as a better understanding of the inflammatory TGF Beta-1; C4a; MSH; T Regulatory Cells;. pathophysiology has led to targeted, sequential Water-Damaged Buildings therapies. The fundamental basis of uncontroll- ed innate immune responses, the humoral defi- ciency of regulatory neuropeptides melanocyte 1.

3 INTRODUCTION. stimulating hormone (MSH) or Vasoactive intes- Treatment of the multisystem, multisymptom illness tinal polypeptide (VIP), seen in over 98% of pa- acquired following exposure to the interior environment tients, has not consistently responded to any of buildings with a history of water intrusion and subse- treatment modality. Use of replacement VIP has quent microbial growth ( WDB) remained problem- been attempted anecdotally; VIP replacement atic until recent years because 1) no consistent patho- therapies show promise in short term studies physiological mechanisms had been demonstrated; and 2). but longer therapies have not been attempted. no biomarkers were consistently identified thereby pre- Here we report an open label trial of 20 patients venting confirmatory laboratory diagnosis.

4 Various al- with refractory CIRS-WDB illness who took re- ternative diagnoses have been ascribed to patients with placement VIP in a nasal spray for at least 18 this illness, including medically uncertain illness, fi- months with confirmation of durable efficacy bromyalgia, and Sick Building Syndrome . Following and absence of significant side effects. These 20 publication of reports from the US GAO in 2008 [1], patients were similar in symptoms and lab find- WHO in 2009 [2] and the Consensus Statement of ings to three previously published cohorts in- Treating Physicians in 2010 [3], the role of chronic in- volving 1829 patients and 169 controls. Dosage flammation as a response to exposure has been recog- of VIP was titrated downwards from four to zero nized, providing for effective therapies to control most doses a day to determine minimum effective illness parameters.

5 In some cases, however, these thera- dose, and re-titrated upwards for maximum im- pies did not provide protection from relapse upon re- provement over time. The trial showed that VIP exposure to WDB; some patients remained severely af- therapy safely 1) reduced refractory symptoms fected. to equal controls; 2) corrected inflammatory This illness has been called a chronic systemic infla- parameters C4a, TGF beta-1, VEGF, MMP9; 3) mmatory illness (CIRS-WDB, [3]), paralleling a similar Copyright 2013 SciRes. Openly accessible at R. C. Shoemaker et al. / Health 5 (2013) 396-401 397. description of ciguatera, a biotoxin-associated illness [4] viding informed consent, 20 patients (11 Caucasian fe- caused by consumption of reef-dwelling, ciguatoxic fish.

6 Males, mean age ; and 9 Caucasian males, mean age In three case series of patients (N = 1829) with CIRS- ) with clinically-confirmed CIRS-WDB refractory to WDB, deficiency of the regulatory neuropeptide vasoac- all prior treatment modalities (steps 1 - 10, as described tive intestinal polypeptide (VIP) occurred in 98% of pa- below, in Figure 1) were enrolled in this trial. All pa- tients [5,6] while less than 10% of controls demonstrat- tients were confirmed to be exposed to WDB by obser- ed this deficiency. These data are consistent with nearly vation of illness acquisition solely following water intru- 5000 other CIRS-WDB patients and 850 control patients sion followed by presence of either 1) visible microbial documented in a single clinical practice (RCS).

7 Growth; 2) speciation of molds by QPCR DNA testing;. VIP is a regulatory neuropeptide with diverse physi- or 3) musty smells. All patients met the case criteria es- cologic effects. Following activation of outer membra- tablished by the GAO (US GAO 2008). Patients were nebased receptors, VIP is known to raise cAMP [7]; well known to the clinic with a 36 month mean duration lower pulmonary artery systolic pressure (PASP) re- of prior treatment following exposure to WDB. No pa- sponses to exercise [8]; block peripheral innate immune tients had been treated with VIP previously. Entry crite- activation [9]; raise VEGF [10]; restore circadian rhythm ria included a rise in PASP in exercise as measured by [11]; regulate dendritic cells [12]; regulate Th17 function stress echocardiography that exceeded 8 mmHg com- in autoimmunity [13]; and enhance IL-10 production pared to resting PASP.

8 [14]; VIP can also raise peripheral blood levels of For the experimental protocol, subjects self-adminis- CD4+CD25+ T regulatory (Treg) cells [15]; prevent de- tered 50 mcg VIP (Aviptadil; Bachem AG, Switzerland). velopment of an experimental model of rheumatoid ar- four times a day via nasal aerosol and returned to the thritis in mice [16] and inhibit TGF beta-1 production by clinic to review symptoms and clinical course; and un- macrophages [17]. Inhaled VIP use has also corrected dergo interval physical exam and laboratory testing at inflamematory markers seen in patients with sarcoid scheduled intervals. Clinical data were collected before [18]. any treatments, at baseline (BASE); after all other treat- In addition to deficiency of VIP, patients with CIRS- ments and before VIP (AC2); after 12 months of VIP (12.)

9 WDB will invariably have 1) deficiencies of another M); and after 18 months of VIP (18 M). Data collection regulatory neuropeptide, melanocyte stimulating hor- included physician recorded symptoms in a medical his- mone (MSH) in plasma; 2) dysregulated inflammatory tory; levels of VIP, MSH, C4a, TGF beta-1, VEGF, responses; and usually have 3) evidence of cellular im- MMP9, estradiol, testosterone, 25-OH vitamin D, lipase, mune abnormalities marked by elevated TGF beta-1 in CBC and CMP. Measurement of CD4+CD25+ T regula- plasma and reduced levels of Tregs in whole blood; 4) tory (Treg) cells was not available at BASE; Treg testing abnormal plasma levels of a split product of complement was performed at AC2 and 18 month time periods.

10 Labo- activation, C4a; 5) dysregulation of serum ACTH/corti- ratory testing for all analytes was performed by high sol, androgens and ADH/osmolality; 6) abnormal plasma complexity CLIA-certified labs including LabCorp and levels of VEGF; 7) disorders of coagulation parameters Quest Diagnostics. seen in von Willebrand's profiles; 8) presence of ge- All data were compared to either established norma- nomically active, multiple antibiotic resistant coagulase tive values or values from prior testing of healthy control negative staphylococci (MARCoNS) in deep aerobic populations (N = 850) performed at this clinic. Data were nasal spaces and 9) an abnormal rise in PASP in exercise. analyzed by two-sample T-tests for each of two study Treatment of CIRS-WDB involves multiple sequential time points and one-sample T-tests that compared the steps (Figure 1) that are aimed at 1) reducing inflamma- specified data to the corresponding historical control tory responses and 2) restoring normal hormonal rela- tionships, but these efforts will rarely restore levels of MSH and VIP to normal.