Abstract
RationaleMonitoring clinical disease status in cystic fibrosis frequently requires invasive collection of clinical samples. Due to its noninvasive collection process and direct anatomic relationship with the lower airway, saliva shows great potential as a biological fluid for cystic fibrosis monitoring.ObjectivesTo measure the levels of multiple protein markers in human saliva supernatants and investigate the possibility of utilizing them to provide a more quantitative measure of disease state for use in research and monitoring of patients with cystic fibrosis clinically.MethodsWhole saliva samples were collected and processed from cystic fibrosis patients at two distinct time points (2010 and 2013) and measured by two separate platforms. In this cross sectional study, a convenience sample of 71 participants were recruited with samples measured by multiplexed fluorescence microarray (fiber microarray) and another 117 participant samples were measured by an automated, point-of-care, analyzer (SDReader) using a microsphere-based array via fluorescence sandwich immunoassay. For comparison, saliva from 56 and 50 healthy subjects were collected, respectively. The levels of six target proteins were quantified. Various demographic and clinical data, including spirometry, medical history, and clinicians’ assessments were also collected from patients with cystic fibrosis on the day of saliva collection.Measurements and Main ResultsSimilar trends were observed with both platforms and compared with healthy subjects, cystic fibrosis patients had significantly elevated levels of VEGF, IP-10, IL-8, and EGF as well as lower levels of MMP-9 (P ≤ 0.005) using fiber microarray and significantly elevated levels of IP-10, IL-8 with lower levels of MMP-9 and IL-1β (P ≤ 0.02) using the SDReader. The levels of the six proteins correlated with each other significantly, and in some cases, biomarker levels could be used to differentiate between subgroups of patients with different clinical presentations. For example, IP-10 levels significantly correlated with FEV1 and disease severity (as evaluated by clinicians) with both platforms (P < 0.05).ConclusionsSignificant variations of the levels of six proteins in saliva supernatants, and the correlations of these levels with clinical assessments, demonstrated the potential of saliva for cystic fibrosis research and monitoring.
Highlights
Cystic fibrosis (CF) is the most common life-threatening, genetically inherited disease for individuals of Northern European descent (1 in about 2500 newborns) [1,2,3]
Whole saliva and its components have already been shown to correlate with clinical disease markers in asthma [15], and its direct anatomic relationship with the lower airway may provide a window into the nature of the disease-specific response of the respiratory system in CF [16,17,18]
Our study participants are representative of CF patients in the general U.S population, except for the prevalence of specific bacterial infections that are different amongst our subjects [4]
Summary
Cystic fibrosis (CF) is the most common life-threatening, genetically inherited disease for individuals of Northern European descent (1 in about 2500 newborns) [1,2,3]. Advancements in medical care over the last several decades have led to improvement in clinical outcomes of patients with CF, resulting in a rise of the median predicted age of survival in the US from 27 years (1986) to 38 years (2010) [4] Despite these advancements, chronic airway infection and inflammation continue to result in significant morbidity and the prognosis for people from lower socio-economic classes lags far behind [5, 6]. Monitoring of CF includes sampling biofluids (e.g. oropharyngeal swab, induced sputum, serum, and bronchoalveolar lavage (BAL) fluids) that frequently require invasive and uncomfortable collection procedures, as well as expensive equipment and experienced personnel [7, 8] Because it can be collected noninvasively by personnel with minimal training, saliva has attracted much attention in recent years as a substitute for traditional diagnostic samples [9,10,11,12,13,14]. Whole saliva and its components have already been shown to correlate with clinical disease markers in asthma [15], and its direct anatomic relationship with the lower airway may provide a window into the nature of the disease-specific response of the respiratory system in CF [16,17,18]
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