Gulf War Illness Nasal Irrigation Study

Background: Gulf War Illness (GWI) results in tremendous impact to quality of life. Symptoms
of chronic rhinosinusitis (CRS) and fatigue are the first (47%) and third (41%) most common
symptoms of patients with GWI, respectively. These symptoms are biologically characterized
by a milieu of elevated levels of proinflammatory cytokines; to date, the profile of these
cytokines in serum and nasal secretions is incompletely understood and has not been assessed
in response to therapy. Nasal irrigation (NI) is a therapy which bathes the nasal cavity
with a solution (liquid). There are two promising forms of NI; saline NI (S-NI) is
hypothesized to improve sinus symptoms by thinning and clearing mucus and inflammatory
mediators, decreasing mucosal edema and improving ciliary function. Xylitol NI (X-NI) has
been shown to change the salinity of the mucosal surface resulting in enhanced antimicrobial
properties. Although NI is an evidence-based adjunctive therapy for CRS and has been
reported to be effective for CRS and fatigue, it has not been assessed in a GWI population.

Specific Aims, Hypotheses and Study Design: The specific aims of this proposal are to
determine whether routine care plus S-NI, or X-NI, compared to routine care alone, result in
improved health-related quality of life (HRQoL), are cost-effective and decrease
proinflammatory bias in subjects with GWI who suffer from CRS and fatigue.

Consistent with our specific aims, we will test the following hypotheses: In an RCT setting,
at 26 weeks post-enrollment, adults with GWI and symptoms of CRI and fatigue, treated with
routine care plus S-NI or X-NI, compared to those treated with routine care alone, will
demonstrate:

H1: improved HRQoL: a) sinus-disease specific HRQoL as evaluated by the validated Sinonasal
Outcomes Test (SNOT-20) questionnaire (primary outcome measure); b) fatigue-specific HRQoL
as assessed by the validated questionnaire, the Multidimensional Fatigue Inventory (MFI);
and c) overall HRQoL as assessed by the validated questionnaire the Medical Outcomes Survey
Short Form-36 (SF-36; mental and physical health domains) augmented with 18 sleep- and
breathing related questions.

H.2: greater cost-effectiveness as measured by the average cost of the intervention divided
by the average effectiveness (as assessed by a improvement in SNOT-20 scores), and reported
as the "dollars spent per subject restored to health."

H.3: improved treatment satisfaction as assessed by a single-item treatment satisfaction
score and a qualitative exit interview.

H.4: improved proinflammatory bias: a) reduced activation and dysregulation of
proinflammatory pathways as determined by a reduction in URI-specific inflammatory cytokines
in serum and nasal secretions; and b) improved serum-based complete blood count,
sedimentation rate or C-reactive protein, or nasal swab-based neutrophil or eosinophil
counts.

Study Design: 26 week duration of follow-up, 3-arm RCT (N=75). All groups will utilize
routine care for their GWI and symptoms of CRS and fatigue. Groups 1 and 2 will in addition
add S-NI or X-NI twice daily to their routine care, respectively. Group 3 will continue to
use routine care with no other additions (control group); control group participants will be
offered NI training and related materials (xylitol or saline per subject preference) after
they complete their 26-week follow-up period.

Impact: Positive findings would suggest a number of important effects:

- Statistically positive results on HRQoL outcome measures would suggest that NI can
provide effective adjunctive therapy for CRS and fatigue in adults with GWI, improving
health of affected patients and potentially providing gains to society through reduced
health care utilization and absenteeism related costs.

- Positive biomarker findings would contribute to our better understanding of the
etiology of CRS and fatigue in the GWI population and of possible biological pathways
underlying the NI efficacy.

- The finding that either form of NI is cost effective would provide economic
justification for its clinical use.

Inclusion Criteria:

- English fluency and basic reading and writing literacy.

- Deployment to the Persian Gulf (e.g., Iraq, Kuwait, Saudi Arabia) for the purpose of
Operation Desert Shield or Operation Desert Storm during the first Gulf War
(1990-1991).

- Meeting criteria for a diagnosis of GWI as based on the "Kansas" GWI case definition;
only the Kansas case definition (from among the several currently used case
definitions) can differentiate between Gulf War-deployed and non-deployed Gulf era
veterans.

- Meeting criteria for a diagnosis of chronic rhinosinusitis (CRS) using self-reported
symptoms and based on clinical guidelines; eligible subjects will report: • sinonasal
symptoms for at least 12 weeks; • a constellation of sinonasal symptoms including
either two or more major factors, or 1 major and 2 minor factors (see Table 1 below),
or chronic nasal purulence for 12 or more weeks; and • a moderate to severe HRQoL
impact (≥ 3 points on a 0-10 Likert severity scale) as assessed by a single item
question:11 "What has been the average level of your sinus symptoms daily over the
past month on a 0-10 scale?" This item is consistent with eligibility criteria used
in prior NI studies.

- Chronic fatigue of moderate-to-severe severity defined as scoring at least 3 points
on a single question (0-10 Likert scale): "What has been the average level of your
daily fatigue over the past month on a 0-10 scale?"

Exclusion Criteria:

- Self-reported pregnancy.

- Current use of liquid NI or xylitol nasal spray; regular use is defined as 1 or more
irrigations weekly for 3 consecutive weeks.

- Self-reported neurological or musculoskeletal conditions that could facilitate
aspiration, or patients who otherwise cannot physically perform the NI procedure.

- Self-reported borderline personality disorder.

- Inability or stated reluctance to reliably participate in study activities.

- Severe or unstable mental health problems that would preclude safe or reliable study
participation as based on an in-person evaluation by a psychiatry team; active
delusional disorder, depressive disorder or alcohol/drug abuse or dependence will be
a primary target of this interview using both a structured clinical interview (MINI
ref) and psychiatry team evaluation.