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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Association of interleukin‐8 and neutrophils with nasal symptom severity during acute respiratory infection</title><author><name sortKey="Henriquez, Kelsey M" sort="Henriquez, Kelsey M" uniqKey="Henriquez K" first="Kelsey M." last="Henriquez">Kelsey M. Henriquez</name><affiliation><nlm:aff id="jmv24042-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Hayney, Mary S" sort="Hayney, Mary S" uniqKey="Hayney M" first="Mary S." last="Hayney">Mary S. Hayney</name><affiliation><nlm:aff id="jmv24042-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Xie, Yaoguo" sort="Xie, Yaoguo" uniqKey="Xie Y" first="Yaoguo" last="Xie">Yaoguo Xie</name><affiliation><nlm:aff id="jmv24042-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Zhengjun" sort="Zhang, Zhengjun" uniqKey="Zhang Z" first="Zhengjun" last="Zhang">Zhengjun Zhang</name><affiliation><nlm:aff id="jmv24042-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Barrett, Bruce" sort="Barrett, Bruce" uniqKey="Barrett B" first="Bruce" last="Barrett">Bruce Barrett</name><affiliation><nlm:aff id="jmv24042-aff-0003"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25132248</idno><idno type="pmc">4348013</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348013</idno><idno type="RBID">PMC:4348013</idno><idno type="doi">10.1002/jmv.24042</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000741</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000741</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Association of interleukin‐8 and neutrophils with nasal symptom severity during acute respiratory infection</title><author><name sortKey="Henriquez, Kelsey M" sort="Henriquez, Kelsey M" uniqKey="Henriquez K" first="Kelsey M." last="Henriquez">Kelsey M. Henriquez</name><affiliation><nlm:aff id="jmv24042-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Hayney, Mary S" sort="Hayney, Mary S" uniqKey="Hayney M" first="Mary S." last="Hayney">Mary S. Hayney</name><affiliation><nlm:aff id="jmv24042-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Xie, Yaoguo" sort="Xie, Yaoguo" uniqKey="Xie Y" first="Yaoguo" last="Xie">Yaoguo Xie</name><affiliation><nlm:aff id="jmv24042-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Zhengjun" sort="Zhang, Zhengjun" uniqKey="Zhang Z" first="Zhengjun" last="Zhang">Zhengjun Zhang</name><affiliation><nlm:aff id="jmv24042-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Barrett, Bruce" sort="Barrett, Bruce" uniqKey="Barrett B" first="Bruce" last="Barrett">Bruce Barrett</name><affiliation><nlm:aff id="jmv24042-aff-0003"></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Medical Virology</title><idno type="ISSN">0146-6615</idno><idno type="eISSN">1096-9071</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Using a large data set (n = 811), the relationship between acute respiratory infection illness severity and inflammatory biomarkers was investigated to determine whether certain symptoms are correlated more closely than others with the inflammatory biomarkers, interleukin‐8 (IL‐8) and nasal neutrophils. Participants with community acquired acute respiratory infection underwent nasal lavage for IL‐8 and neutrophil testing, in addition to multiplex polymerase chain reaction (PCR) methods for the detection and identification of respiratory viruses. Information about symptoms was obtained throughout the duration of the illness episode using the well‐validated Wisconsin Upper Respiratory Symptom Survey (WURSS‐21). Global symptom severity was calculated by the area under the curve (AUC) plotting duration versus WURSS total. Of the specimens tested, 56% were positively identified for one or more of nine different respiratory viruses. During acute respiratory infection illness, both IL‐8 and neutrophils positively correlate with AUC (r<sub>s</sub> = 0.082, <italic>P</italic> = 0.022; r<sub>s</sub> = 0.080, <italic>P</italic> = 0.030). IL‐8 and neutrophils correlate with nasal symptom severity: runny nose (r = 0.13, <italic>P</italic> = < 0.00001; r = 0.18, <italic>P</italic> = < 0.003), plugged nose (r = 0.045, <italic>P</italic> = 0.003; r = 0.14, <italic>P</italic> = 0.058), and sneezing (r = −0.02, <italic>P</italic> = < 0.0001; r = −0.0055, <italic>P</italic> = 0.31). Neutrophils correlate with some quality of life measures such as sleeping well (r = 0.15, <italic>P</italic> = 0.026). Thus, the study demonstrates that IL‐8 and neutrophils are correlated with severity of nasal symptoms during acute respiratory infection. Further research is necessary to determine if the concentration of these or other biomarkers can predict the overall duration and severity of acute respiratory infection illness. <bold><italic>J. Med. Virol. 87:330–337, 2015</italic>.</bold> © 2014 Wiley Periodicals, Inc.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Jamison, Dt" uniqKey="Jamison D">DT Jamison</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Med Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Virol</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)1096-9071</journal-id><journal-id journal-id-type="publisher-id">JMV</journal-id><journal-title-group><journal-title>Journal of Medical Virology</journal-title></journal-title-group><issn pub-type="ppub">0146-6615</issn><issn pub-type="epub">1096-9071</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25132248</article-id><article-id pub-id-type="pmc">4348013</article-id><article-id pub-id-type="doi">10.1002/jmv.24042</article-id><article-id pub-id-type="publisher-id">JMV24042</article-id><article-categories><subj-group subj-group-type="overline"><subject>Research Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group></article-categories><title-group><article-title>Association of interleukin‐8 and neutrophils with nasal symptom severity during acute respiratory infection</article-title><alt-title alt-title-type="right-running-head">Biomarkers for Respiratory Infection Symptoms</alt-title><alt-title alt-title-type="left-running-head">Henriquez et al</alt-title></title-group><contrib-group><contrib id="jmv24042-cr-0001" contrib-type="author" corresp="yes"><name><surname>Henriquez</surname><given-names>Kelsey M.</given-names></name><xref ref-type="aff" rid="jmv24042-aff-0001"><sup>1</sup></xref></contrib><contrib id="jmv24042-cr-0002" contrib-type="author"><name><surname>Hayney</surname><given-names>Mary S.</given-names></name><xref ref-type="aff" rid="jmv24042-aff-0001"><sup>1</sup></xref></contrib><contrib id="jmv24042-cr-0003" contrib-type="author"><name><surname>Xie</surname><given-names>Yaoguo</given-names></name><xref ref-type="aff" rid="jmv24042-aff-0002"><sup>2</sup></xref></contrib><contrib id="jmv24042-cr-0004" contrib-type="author"><name><surname>Zhang</surname><given-names>Zhengjun</given-names></name><xref ref-type="aff" rid="jmv24042-aff-0002"><sup>2</sup></xref></contrib><contrib id="jmv24042-cr-0005" contrib-type="author"><name><surname>Barrett</surname><given-names>Bruce</given-names></name><xref ref-type="aff" rid="jmv24042-aff-0003"><sup>3</sup></xref></contrib></contrib-group><aff id="jmv24042-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">School of Pharmacy</named-content><institution>University of Wisconsin‐Madison</institution><city>Madison</city><named-content content-type="country-part">Wisconsin</named-content></aff><aff id="jmv24042-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Department of Statistics</named-content><institution>University of Wisconsin‐Madison</institution><institution>School of Medicine and Public Health</institution><city>Madison</city><named-content content-type="country-part">Wisconsin</named-content></aff><aff id="jmv24042-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">Department of Family Medicine</named-content><institution>University of Wisconsin‐Madison</institution><institution>School of Medicine and Public Health</institution><city>Madison</city><named-content content-type="country-part">Wisconsin</named-content></aff><author-notes><corresp id="correspondenceTo"><label>*</label>Correspondence to: Kelsey M. Henriquez, BS, Research Specialist, University of Wisconsin School of Pharmacy, 777 Highland Avenue, Madison, WI 53705‐2222, USA<break></break>E‐mail:
<email>khenriquez@wisc.edu</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>17</day><month>8</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>2</month><year>2015</year></pub-date><volume>87</volume><issue>2</issue><issue-id pub-id-type="doi">10.1002/jmv.v87.2</issue-id><fpage>330</fpage><lpage>337</lpage><history><date date-type="accepted"><day>11</day><month>7</month><year>2014</year></date></history><permissions><pmc-comment> © 2014 Wiley Periodicals, Inc. </pmc-comment>
<copyright-statement content-type="article-copyright">© 2014 Wiley Periodicals, Inc.</copyright-statement><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="file://JMV-87-330.pdf"></self-uri><abstract><p>Using a large data set (n = 811), the relationship between acute respiratory infection illness severity and inflammatory biomarkers was investigated to determine whether certain symptoms are correlated more closely than others with the inflammatory biomarkers, interleukin‐8 (IL‐8) and nasal neutrophils. Participants with community acquired acute respiratory infection underwent nasal lavage for IL‐8 and neutrophil testing, in addition to multiplex polymerase chain reaction (PCR) methods for the detection and identification of respiratory viruses. Information about symptoms was obtained throughout the duration of the illness episode using the well‐validated Wisconsin Upper Respiratory Symptom Survey (WURSS‐21). Global symptom severity was calculated by the area under the curve (AUC) plotting duration versus WURSS total. Of the specimens tested, 56% were positively identified for one or more of nine different respiratory viruses. During acute respiratory infection illness, both IL‐8 and neutrophils positively correlate with AUC (r<sub>s</sub> = 0.082, <italic>P</italic> = 0.022; r<sub>s</sub> = 0.080, <italic>P</italic> = 0.030). IL‐8 and neutrophils correlate with nasal symptom severity: runny nose (r = 0.13, <italic>P</italic> = < 0.00001; r = 0.18, <italic>P</italic> = < 0.003), plugged nose (r = 0.045, <italic>P</italic> = 0.003; r = 0.14, <italic>P</italic> = 0.058), and sneezing (r = −0.02, <italic>P</italic> = < 0.0001; r = −0.0055, <italic>P</italic> = 0.31). Neutrophils correlate with some quality of life measures such as sleeping well (r = 0.15, <italic>P</italic> = 0.026). Thus, the study demonstrates that IL‐8 and neutrophils are correlated with severity of nasal symptoms during acute respiratory infection. Further research is necessary to determine if the concentration of these or other biomarkers can predict the overall duration and severity of acute respiratory infection illness. <bold><italic>J. Med. Virol. 87:330–337, 2015</italic>.</bold> © 2014 Wiley Periodicals, Inc.</p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="jmv24042-kwd-0001">upper respiratory infection</kwd><kwd id="jmv24042-kwd-0002">biomarkers</kwd><kwd id="jmv24042-kwd-0003">interleukin‐8</kwd><kwd id="jmv24042-kwd-0004">neutrophils</kwd><kwd id="jmv24042-kwd-0005">signs and symptoms</kwd><kwd id="jmv24042-kwd-0006">rhinitis</kwd></kwd-group><funding-group><award-group id="funding-0001"><funding-source>National Institutes of Health (NIH), National Center for Complementary and Alternative Medicine (NCCAM)</funding-source><award-id>R01AT001428</award-id><award-id>UL1RR025011 1R01AT004313</award-id><award-id>K23AT00051 K24AT006543</award-id></award-group></funding-group><counts><page-count count="8"></page-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>February 2015</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:15.04.2020</meta-value></custom-meta></custom-meta-group></article-meta><notes><fn-group><fn id="jmv24042-note-0006"><p>No competing financial interests exist.</p></fn></fn-group></notes></front><body><sec id="jmv24042-sec-0003"><title>INTRODUCTION</title><p>Acute respiratory infection illness (also known as the common cold, upper respiratory tract infection, or upper respiratory infection) is an acute infection, generally viral in etiology, involving structures of the upper airways [Simoes et al., <xref rid="jmv24042-bib-0045" ref-type="ref">2006</xref>]. The most common causative agent is rhinovirus, but several other respiratory viruses are also known to cause acute respiratory illness [Gwaltney, <xref rid="jmv24042-bib-0026" ref-type="ref">1985</xref>]. Acute respiratory infection is a common occurrence, yet detrimental to well‐being. Moreover, there is currently no cure or effective treatment option available [Cohen et al., <xref rid="jmv24042-bib-0017" ref-type="ref">1993</xref>; Carter, <xref rid="jmv24042-bib-0015" ref-type="ref">2002</xref>]. Symptoms of acute respiratory infection illness can be examined three‐dimensionally in the following groups: nasal, throat, and quality of life [Obasi et al., <xref rid="jmv24042-bib-0040" ref-type="ref">2013</xref>]. These unpleasant, and sometimes, severe symptoms cause people to miss work and to utilize healthcare services, which places a notable burden on the individual and society [Fendrick et al., <xref rid="jmv24042-bib-0020" ref-type="ref">2003</xref>; Eccles, <xref rid="jmv24042-bib-0019" ref-type="ref">2005</xref>; Fiore et al., <xref rid="jmv24042-bib-0022" ref-type="ref">2010</xref>; Ebell and Afonso, <xref rid="jmv24042-bib-0018" ref-type="ref">2011</xref>].</p><p>For many years, it has been known that some inflammatory cytokines, such as interleukin‐8 (IL‐8), play a role in the pathophysiology of the common cold, as levels are found to increase in individuals sick with viral rhinitis compared to healthy individuals [Choi and Jacoby, <xref rid="jmv24042-bib-0016" ref-type="ref">1992</xref>; Becker et al., <xref rid="jmv24042-bib-0010" ref-type="ref">1993</xref>; Noah et al., <xref rid="jmv24042-bib-0038" ref-type="ref">1995</xref>; Röseler et al., <xref rid="jmv24042-bib-0044" ref-type="ref">1995</xref>; Gern et al., <xref rid="jmv24042-bib-0025" ref-type="ref">1996</xref>; Johnston et al., <xref rid="jmv24042-bib-0030" ref-type="ref">1997</xref>; Zhu et al., <xref rid="jmv24042-bib-0052" ref-type="ref">1997</xref>; Kaul et al., <xref rid="jmv24042-bib-0031" ref-type="ref">2000</xref>; Parry et al., <xref rid="jmv24042-bib-0041" ref-type="ref">2000</xref>]. Within the immune system, IL‐8 acts to recruit and activate neutrophils, contributing to inflammation [Naclerio et al., <xref rid="jmv24042-bib-0037" ref-type="ref">1988</xref>; Teran et al., <xref rid="jmv24042-bib-0046" ref-type="ref">1997</xref>; Zeilhofer and Schorr, <xref rid="jmv24042-bib-0050" ref-type="ref">2000</xref>; Turner, <xref rid="jmv24042-bib-0047" ref-type="ref">2001</xref>]. However, little work has been done to correlate IL‐8 concentrations with specific acute respiratory infection symptoms and degree of illness. This paper presents important novel research boasting over 800 common cold cases with biomarkers and detailed records of acute respiratory infection severity making the breadth of our study unique. Additionally, not only is the relationship of the biomarkers with overall illness severity examined, but also more than 20 separate symptoms are considered one by one, and in meaningful clusters, in order to hone in on exactly what the relationship is between inflammatory biomarkers and certain cold symptoms. By investigating the relationship between acute respiratory infection illness severity and inflammatory biomarkers, the intent was to determine whether certain symptoms correlate more closely than others with inflammatory biomarkers such as IL‐8 and nasal neutrophils. An additional aim was to gain insight into the predictability of overall severity and duration of acute respiratory infection episodes based on change in IL‐8 and neutrophil levels during the first 3 days of illness.</p><p>In order to answer these questions, data sets from two studies [Barrett et al., <xref rid="jmv24042-bib-0003" ref-type="ref">2010</xref>; Barrett et al., <xref rid="jmv24042-bib-0007" ref-type="ref">2012</xref>] were combined to look at a total of 811 acute respiratory infection episodes. In both studies, a nasal lavage was performed within the first 72 hr of the onset of symptoms. In one of the studies, 685 participants returned about 48 hr later to provide a second nasal specimen during their acute respiratory infection. The nasal specimens were used to measure IL‐8 concentrations and neutrophil counts, and to undergo multiplex polymerase chain reaction (PCR) for the detection and identification of respiratory viruses. Throughout the duration of the acute respiratory infection episode participants provided information about their symptoms on a self‐report basis using the well‐validated Wisconsin Upper Respiratory Symptom Survey (WURSS‐21) [Barrett et al., <xref rid="jmv24042-bib-0008" ref-type="ref">2002</xref>; Barrett et al., <xref rid="jmv24042-bib-0002" ref-type="ref">2005</xref>; Barrett et al., <xref rid="jmv24042-bib-0006" ref-type="ref">2009</xref>]. The WURSS scores were then used to statistically analyze correlations of symptom severity with IL‐8 and neutrophil levels.</p><p>IL‐8 and nasal neutrophils were hypothesized to have a significant positive correlation with overall acute respiratory infection severity, measured by both area under the curve (AUC) and WURSS total. Upon examination of the 21 WURSS items, the nasal group symptoms (runny nose, plugged nose and sneezing) [Obasi et al., <xref rid="jmv24042-bib-0040" ref-type="ref">2013</xref>] were hypothesized to have the most significant correlations with the inflammatory biomarkers examined. Finally, it was hypothesized that higher IL‐8 and nasal neutrophil levels on Day 1 of the acute respiratory infection would be associated with lower WURSS total on Day 3 of the acute respiratory infection, due to the initial vigorous immune response leading to quicker amelioration of symptoms.</p></sec><sec id="jmv24042-sec-0004"><title>MATERIALS AND METHODS</title><p>For the purposes of this research, acute respiratory infection data from two randomized controlled trials were combined. Both trials' protocols and main results have been published elsewhere [Barrett et al., <xref rid="jmv24042-bib-0009" ref-type="ref">2007</xref>; Barrett et al., <xref rid="jmv24042-bib-0003" ref-type="ref">2010</xref>; Barrett et al., <xref rid="jmv24042-bib-0004" ref-type="ref">2011</xref>; Barrett et al., <xref rid="jmv24042-bib-0007" ref-type="ref">2012</xref>; Obasi et al., <xref rid="jmv24042-bib-0039" ref-type="ref">2012</xref>; Rakel et al., <xref rid="jmv24042-bib-0042" ref-type="ref">2013</xref>; Zgierska et al., <xref rid="jmv24042-bib-0051" ref-type="ref">2013</xref>; Hayney et al., <xref rid="jmv24042-bib-0027" ref-type="ref">2014</xref>]. Both trials from which the data came were approved and monitored by the University of Wisconsin Health Sciences Institutional Review Board and carried out in accordance with the ethical standards of the Declaration of Helsinki. All participants gave written informed consent.</p><sec id="jmv24042-sec-0005"><title>Participants</title><p>In the PEP trial (Physician, Echinacea, and Placebo), which is a shortened version of the trial title “Placebo: Physician or Pill: A Randomized Controlled Trial in a Common Cold Model” [Barrett et al., <xref rid="jmv24042-bib-0009" ref-type="ref">2007</xref>; Barrett et al., <xref rid="jmv24042-bib-0003" ref-type="ref">2010</xref>; Barrett et al., <xref rid="jmv24042-bib-0004" ref-type="ref">2011</xref>], n = 718 participants gave written informed consent, then were enrolled within the first 36 hr of new‐onset common cold symptoms and were followed until their colds resolved. The population consisted of community‐recruited 12 to 80 year olds. Enrollment and monitoring occurred over a period of about four and a half years from January 2004 until August 2008. Daily contact was made by telephone for the duration of participation.</p><p>In the MEPARI trial, Meditation or Exercise for Preventing Acute Respiratory Infection: A Randomized Controlled Trial [Barrett et al., <xref rid="jmv24042-bib-0007" ref-type="ref">2012</xref>], written informed consent was obtained from n = 154 healthy individuals aged 50 years and older who were recruited from the community. The first cohort (n = 94) was enrolled in September 2009, while the second cohort (n = 60) began in January 2010. Participants from both cohorts were followed until exiting in May 2010. During the entire trial, participants were asked to start documenting symptoms anytime they thought they were getting a cold. Participants were contacted two times a week by telephone throughout the duration of the study.</p></sec><sec id="jmv24042-sec-0006"><title>Acute Respiratory Infection Monitoring</title><p>Both trials used the same criteria to define an acute respiratory infection illness episode: 1) Answer “Yes” to either: “Do you think you are coming down with a cold?” or “Do you think you have a cold?” 2) Exhibit one or more of four cold symptoms ‐ nasal discharge, nasal obstruction, sneezing, sore throat, and 3) Score two points or more on the Jackson scale [Jackson et al., <xref rid="jmv24042-bib-0029" ref-type="ref">1962</xref>]. The Jackson score is calculated by summing eight symptom scores (sneezing, headache, malaise, chilliness, nasal discharge, nasal obstruction, sore throat, and cough), where each is rated 0 = absent, 1 = mild, 2 = moderate, 3 = severe. In the PEP trial, illness episode duration began at enrollment and continued through the last time the participant answered “yes” to, “Do you think you still have a cold?” To confirm that the illness had ended, the last “yes” answer had to be followed by a “no” answer for two days in a row. Monitoring was limited to a maximum of 14 days. In the MEPARI trial, the beginning of each acute respiratory infection illness episode was determined by the defining criteria described above. The last day of the illness episode was the last day the participant rated illness severity higher than 0 in response to “How sick do you feel today?” on the WURSS instrument. In both trials the date and time of self‐report questionnaires were recorded in order to assess illness duration.</p></sec><sec id="jmv24042-sec-0007"><title>Assessment of Symptoms</title><p>Acute respiratory infection severity was assessed using the Wisconsin Upper Respiratory Symptom Survey (WURSS) [Barrett et al., <xref rid="jmv24042-bib-0008" ref-type="ref">2002</xref>; Barrett et al., <xref rid="jmv24042-bib-0002" ref-type="ref">2005</xref>], which is a well validated illness specific quality of life outcome instrument. Items assess symptom severity and functional impairment, with a score of 1 considered to be very mild; 3, mild; 5, moderate; and 7, severe. Throughout the length of the illness, the WURSS‐21 [Barrett et al., <xref rid="jmv24042-bib-0006" ref-type="ref">2009</xref>] was self‐administered twice daily by each PEP participant, and the WURSS‐24 daily by MEPARI participants. The WURSS‐21 contains one item rating overall illness severity (How sick do you feel today?); 10 items rating cold symptoms (runny nose, plugged nose, sneezing, sore throat, scratchy throat, cough, hoarseness, head congestion, chest congestion, feeling tired); nine items rating how much the cold episode has interfered with function and quality of life (think clearly; sleep well; breathe easily; walk, climb stairs, exercise; accomplish daily activities; work outside the home; work inside the home; interact with others; live your personal life); and one item rating daily change (Compared to yesterday, I feel that my cold is…). WURSS‐24 is a derivation of the WURSS‐44, and includes all WURSS‐21 items plus three items rating influenza‐like symptoms. These three items were not included in this study in order to make the WURSS scores between the two trials parallel.</p></sec><sec id="jmv24042-sec-0008"><title>Calculation of Outcomes</title><p>Illness duration was assessed in hours and minutes according to the times of self‐report and then converted to decimalized days. For the PEP trial, morning and evening scores for each item of the WURSS‐21 were first averaged. In both trials, for each day of illness, WURSS total was calculated by summing 19 items on the WURSS‐21, not including the first item assessing overall illness severity or the last item assessing change since the previous day. To calculate area under the curve (AUC) for global severity, the sum of WURSS totals across all time points of the illness episode was used, and trapezoidal approximation was applied. Nasal AUC was calculated by using the sum of the WURSS scores from only the nasal symptoms (runny nose, plugged nose, sneezing) for the duration of the acute respiratory infection episode. Individual symptoms from the WURSS were analyzed with respect to the main variables using the WURSS score from Day 1 of the acute respiratory infection episode, which corresponds to the day the nasal specimens were collected for biomarker analyses.</p></sec><sec id="jmv24042-sec-0009"><title>Biomarkers</title><p>Samples were collected at enrollment (Day 1) and again on Day 3 of participation in the PEP trial. In the MEPARI trial, when a participant reported acute respiratory infection symptoms equaling two or greater on the Jackson scale, samples were collected within the first 72 hr of onset of symptoms. Nasal specimens were obtained by performing nasal lavage, and were used for analysis of IL‐8 and neutrophils as indicators of nasal inflammation. Nasal lavage specimens were also used for PCR‐based viral identification. In both trials, IL‐8 concentrations were measured in picograms per milliliter (pg/ml) using an enzyme‐linked immunosorbent assay test (ELISA), according to manufacturer's protocol. Polymorphonuclear leukocytes were counted using a standard hemocytometer in both trials, and expressed as neutrophils per milliliter (PMN/ml). Multiplex PCR methods developed and validated at UW‐Madison were used to detect and identify respiratory viruses in nasal wash samples. With this accurate high‐throughput assay, over 100 rhinovirus serotypes, as well as serotypes of influenza, parainfluenza, coronavirus, respiratory syncytial virus, adenovirus, enterovirus, and metapneumovirus can be identified. Overall sensitivity is estimated at 94%, with 99% specificity [Lee et al., <xref rid="jmv24042-bib-0033" ref-type="ref">2007</xref>].</p></sec><sec id="jmv24042-sec-0010"><title>Statistical Analyses</title><p>To assess the correlation among the variables, IL‐8, neutrophils, AUC, and acute respiratory infection duration, Spearman tests were done using SPSS version 20. Linear regression assessed the relationship between biomarkers and symptoms. Pearson correlation coefficients between biomarkers and certain symptoms were reported, and Student's <italic>t</italic> tests were used to test the significance of any specific symptom in the corresponding linear model (Table <xref rid="jmv24042-tbl-0003" ref-type="table">III</xref>). These tests were done using R version 3.0.2 (The R Foundation for Statistical Computing, <ext-link ext-link-type="uri" xlink:href="http://r-project.org/">http://r-project.org/</ext-link>). Preliminary analysis showed that the ranges of some variables were very wide and skewed, for example, the IL‐8 and neutrophil values, which ranged from zero to more than ten thousand. In this case, the Box–Cox transformation [Box and Cox, <xref rid="jmv24042-bib-0013" ref-type="ref">1964</xref>] was used to transform these values in order to make the data more normally distributed, thus improving the validity of measures of association such as the Pearson correlation between variables and for other data stabilization procedures.</p><p>For the results, regarding each model, the summary statistics are listed, including the estimated values for covariates, standard errors, <italic>t</italic>‐statistics and corresponding <italic>P</italic>‐values. The Pearson correlation coefficients between certain important variables are also reported to better explain the relationships of symptoms and biomarkers.</p></sec></sec><sec id="jmv24042-sec-0011"><title>RESULTS</title><p>A total of 811 acute respiratory infection episodes were analyzed making up 7,124 days of acute respiratory infection illness, with a mean global severity score (AUC) of 275. Of these, 56% tested positive for PCR identifiable respiratory viruses, including adenovirus, bocavirus, coronavirus, enterovirus, influenza virus, metapneumovirus, parainfluenzavirus, rhinovirus, and respiratory syncytial virus. The biomarkers examined showed the mean IL‐8 was 1,139 pg/ml and mean neutrophils were 68 PMN/ml (Table <xref rid="jmv24042-tbl-0001" ref-type="table">I</xref>).</p><table-wrap id="jmv24042-tbl-0001" xml:lang="en" orientation="portrait" position="float"><label>Table I</label><caption><p>Demographics of Study Population</p></caption><table frame="hsides" rules="groups"><col span="1"></col><col span="1"></col><tbody><tr><td align="left" rowspan="1" colspan="1">ARIs</td><td align="left" rowspan="1" colspan="1">811</td></tr><tr><td align="left" rowspan="1" colspan="1">Days of ARI illness</td><td align="left" rowspan="1" colspan="1">7124</td></tr><tr><td align="left" rowspan="1" colspan="1">Mean global severity (AUC)</td><td align="left" rowspan="1" colspan="1">275</td></tr><tr><td align="left" rowspan="1" colspan="1">Mean IL‐8 (pg/ml)</td><td align="left" rowspan="1" colspan="1">1,139</td></tr><tr><td align="left" rowspan="1" colspan="1">Mean neutrophils (PMN/ml)</td><td align="left" rowspan="1" colspan="1">68</td></tr><tr><td align="left" rowspan="1" colspan="1">Mean Age (years)</td><td align="left" rowspan="1" colspan="1">36</td></tr><tr><td colspan="2" align="left" rowspan="1">Gender</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Female</td><td align="left" rowspan="1" colspan="1">514</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Male</td><td align="left" rowspan="1" colspan="1">270</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Other</td><td align="left" rowspan="1" colspan="1">0</td></tr><tr><td colspan="2" align="left" rowspan="1">Virus detected</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Negative</td><td align="left" rowspan="1" colspan="1">357</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Rhinovirus</td><td align="left" rowspan="1" colspan="1">315</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Coronavirus</td><td align="left" rowspan="1" colspan="1">53</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Parainfluenza virus</td><td align="left" rowspan="1" colspan="1">19</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Influenza virus</td><td align="left" rowspan="1" colspan="1">18</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Metapneumovirus</td><td align="left" rowspan="1" colspan="1">17</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Respiratory syncytial virus</td><td align="left" rowspan="1" colspan="1">17</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Enterovirus</td><td align="left" rowspan="1" colspan="1">10</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Bocavirus</td><td align="left" rowspan="1" colspan="1">8</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Adenovirus</td><td align="left" rowspan="1" colspan="1">7</td></tr></tbody></table><table-wrap-foot><fn id="jmv24042-note-0001"><p>ARI = acute respiratory infection, AUC = area under curve (calculated as trapezoidal approximation using daily scores from Wisconsin Upper Respiratory Symptom Survey on y‐axis and duration of ARI illness on x‐axis), IL‐8 = interleukin 8, pg = picogram, ml = milliliter, PMN = polynorphonuclear leukocyte.</p></fn></table-wrap-foot><permissions><copyright-holder>© 2014 Wiley Periodicals, Inc.</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><p>Originally called neutrophil activating factor‐1 (NAF‐1), IL‐8 is a chemokine that recruits and activates neutrophils [Marsh and Kendall, <xref rid="jmv24042-bib-0036" ref-type="ref">1996</xref>; Zeilhofer and Schorr, <xref rid="jmv24042-bib-0050" ref-type="ref">2000</xref>]. As physiologically expected, IL‐8 correlated significantly with neutrophils in the positive direction (r = 0.58, <italic>P</italic> < 0.001) [Teran et al., <xref rid="jmv24042-bib-0046" ref-type="ref">1997</xref>; Turner et al., <xref rid="jmv24042-bib-0048" ref-type="ref">1998</xref>]. Participants who had higher levels of IL‐8 had consistently more nasal neutrophils (Fig. <xref rid="jmv24042-fig-0001" ref-type="fig">1</xref>).</p><fig fig-type="Figure" xml:lang="en" id="jmv24042-fig-0001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Correlation of interleukin‐8 with nasal neutrophils. Interleukin‐8 positively correlates with the number of nasal neutrophils present in a nasal lavage during an acute respiratory infection. (<italic>P</italic> < 0.001; r<sub>s </sub>= 0.583)</p></caption><graphic id="nlm-graphic-1" xlink:href="JMV-87-330-g001"><permissions><copyright-holder>© 2014 Wiley Periodicals, Inc.</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></graphic></fig><p>Significant positive correlation of both IL‐8 and neutrophils with AUC and acute respiratory infection duration was found. Participants who had a higher concentration of IL‐8 had colds that lasted longer and were more severe. Similarly, participants who had more nasal neutrophils had longer lasting and more severe colds (Table <xref rid="jmv24042-tbl-0002" ref-type="table">II</xref>). The correlation between IL‐8 and global severity of nasal specific symptoms, or nasal AUC, for the entire illness episode showed a positive trend (r = 0.0031, <italic>P</italic> = 0.066). Neutrophils also trended positively with nasal AUC (r = 0.0035, <italic>P</italic> = 0.088). On Day 1, IL‐8 significantly correlated with each of the three symptoms from the nasal group of WURSS: rhinorrhea, nasal obstruction, and sternutation (sneezing). Interestingly, IL‐8 on Day 1 of the illness also correlated with scratchy throat and with how participants responded to a question gauging overall symptom improvement. Nasal neutrophils correlated strongly with global severity measured by WURSS total, although the correlation was not maintained when nasal symptoms were considered individually, with the exception of runny nose. In addition to correlating with runny nose and global severity, neutrophils also correlated with scratchy throat, thinking clearly, and sleeping well (Table <xref rid="jmv24042-tbl-0003" ref-type="table">III</xref>).</p><table-wrap id="jmv24042-tbl-0002" xml:lang="en" orientation="portrait" position="float"><label>Table II</label><caption><p>Spearman Correlation Tests of Main Variables</p></caption><table frame="hsides" rules="groups"><col span="1"></col><col span="1"></col><col span="1"></col><thead valign="bottom"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="bottom" rowspan="1" colspan="1"></th><th align="center" valign="bottom" rowspan="1" colspan="1">Correlation coefficient</th><th align="left" valign="bottom" rowspan="1" colspan="1"><italic>P</italic> value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">IL‐8/AUC</td><td align="left" rowspan="1" colspan="1">0.082</td><td align="left" rowspan="1" colspan="1">0.022</td></tr><tr><td align="left" rowspan="1" colspan="1">IL‐8/ARI duration</td><td align="left" rowspan="1" colspan="1">0.141</td><td align="left" rowspan="1" colspan="1"><0.001</td></tr><tr><td align="left" rowspan="1" colspan="1">Neutrophils/AUC</td><td align="left" rowspan="1" colspan="1">0.080</td><td align="left" rowspan="1" colspan="1">0.030</td></tr><tr><td align="left" rowspan="1" colspan="1">Neutrophils/ARI duration</td><td align="left" rowspan="1" colspan="1">0.080</td><td align="left" rowspan="1" colspan="1">0.028</td></tr></tbody></table><table-wrap-foot><fn id="jmv24042-note-0002"><p>IL‐8 = Interleukin‐8, AUC = area under curve (calculated as trapezoidal approximation using daily scores from Wisconsin Upper Respiratory Symptom Survey on y‐axis and duration of ARI illness on x‐axis), ARI = acute respiratory infection.</p></fn></table-wrap-foot><permissions><copyright-holder>© 2014 Wiley Periodicals, Inc.</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><table-wrap id="jmv24042-tbl-0003" xml:lang="en" orientation="portrait" position="float"><label>Table III</label><caption><p>IL‐8 and Neutrophil Correlations with ARI Symptoms</p></caption><table frame="hsides" rules="groups"><col span="1"></col><col span="1"></col><col span="1"></col><col span="1"></col><thead valign="bottom"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="bottom" rowspan="1" colspan="1">Symptom score</th><th align="center" valign="bottom" rowspan="1" colspan="1">Pearson correlation coefficient</th><th align="center" valign="bottom" rowspan="1" colspan="1">Regression coefficient</th><th align="center" valign="bottom" rowspan="1" colspan="1"><italic>P</italic> value</th></tr></thead><tbody><tr><td colspan="4" align="left" rowspan="1">IL‐8</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1"><xref ref-type="fn" rid="jmv24042-note-0005">*</xref>WURSS total</td><td align="left" rowspan="1" colspan="1">0.068</td><td align="left" rowspan="1" colspan="1">0.0072</td><td align="left" rowspan="1" colspan="1"><0.008</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1"><xref ref-type="fn" rid="jmv24042-note-0005">*</xref>Nasal AUC</td><td align="left" rowspan="1" colspan="1">0.057</td><td align="left" rowspan="1" colspan="1">0.0031</td><td align="left" rowspan="1" colspan="1">0.066</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Runny nose</td><td align="left" rowspan="1" colspan="1">0.13</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1"><0.00001</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Plugged nose</td><td align="left" rowspan="1" colspan="1">0.045</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">0.003</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Sneezing</td><td align="left" rowspan="1" colspan="1">−0.024</td><td align="left" rowspan="1" colspan="1">−0.13</td><td align="left" rowspan="1" colspan="1"><0.0001</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Scratchy throat</td><td align="left" rowspan="1" colspan="1">0.017</td><td align="left" rowspan="1" colspan="1">−0.12</td><td align="left" rowspan="1" colspan="1">0.017</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Daily change</td><td align="left" rowspan="1" colspan="1">0.058</td><td align="left" rowspan="1" colspan="1">−0.18</td><td align="left" rowspan="1" colspan="1"><0.002</td></tr><tr><td colspan="4" align="left" rowspan="1">Neutrophils</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1"><xref ref-type="fn" rid="jmv24042-note-0005">*</xref>WURSS total</td><td align="left" rowspan="1" colspan="1">0.12</td><td align="left" rowspan="1" colspan="1">0.010</td><td align="left" rowspan="1" colspan="1"><0.002</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1"><xref ref-type="fn" rid="jmv24042-note-0005">*</xref>Nasal AUC</td><td align="left" rowspan="1" colspan="1">0.073</td><td align="left" rowspan="1" colspan="1">0.0035</td><td align="left" rowspan="1" colspan="1">0.089</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Runny nose</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">0.17</td><td align="left" rowspan="1" colspan="1"><0.003</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Plugged nose</td><td align="left" rowspan="1" colspan="1">0.14</td><td align="left" rowspan="1" colspan="1">0.11</td><td align="left" rowspan="1" colspan="1">0.058</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Sneezing</td><td align="left" rowspan="1" colspan="1">−0.0055</td><td align="left" rowspan="1" colspan="1">−0.05</td><td align="left" rowspan="1" colspan="1">0.31</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Overall illness severity</td><td align="left" rowspan="1" colspan="1">0.099</td><td align="left" rowspan="1" colspan="1">0.16</td><td align="left" rowspan="1" colspan="1">0.061</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Scratchy throat</td><td align="left" rowspan="1" colspan="1">−0.033</td><td align="left" rowspan="1" colspan="1">−0.13</td><td align="left" rowspan="1" colspan="1">0.034</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Think clearly</td><td align="left" rowspan="1" colspan="1">0.034</td><td align="left" rowspan="1" colspan="1">−0.15</td><td align="left" rowspan="1" colspan="1">0.026</td></tr><tr><td align="left" style="padding-left:10%" rowspan="1" colspan="1">Sleep well</td><td align="left" rowspan="1" colspan="1">0.15</td><td align="left" rowspan="1" colspan="1">0.11</td><td align="left" rowspan="1" colspan="1">0.026</td></tr></tbody></table><table-wrap-foot><title>Notes</title><fn id="jmv24042-note-0003"><p>Pearson's correlations are calculated using non‐transformed data. Regression coefficients are calculated from the linear model with these variables as covariates, and logarithm of IL‐8/Neutrophils as response variable. <italic>P</italic>‐values are based on the Student's <italic>t</italic> tests for testing whether specific regression coefficient equals 0.</p></fn><fn id="jmv24042-note-0004"><p>WURSS = Wisconsin Upper Respiratory Symptom Survey, AUC = area under curve.</p></fn><fn id="jmv24042-note-0005"><label>*</label><p>Regression coefficient from separate linear models with variable as covariate and log (Biomarker) as response variable: log(Biomarker) ∼ Intercept + WURSStotal or log(Biomarker) ∼ Intercept + NasaIAUC.</p></fn></table-wrap-foot><permissions><copyright-holder>© 2014 Wiley Periodicals, Inc.</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><p>In order to investigate whether the IL‐8 and neutrophil levels from Day 1 of an acute respiratory infection episode can predict characteristics of the illness a couple days later, a time points analysis was performed using biomarkers on Day 1 and WURSS total on Day 3 of the PEP trial. It was hypothesized that high levels of IL‐8 and neutrophils on Day 1 would predict low WURSS score on Day 3. However, the findings were insignificant.</p></sec><sec id="jmv24042-sec-0012"><title>DISCUSSION</title><p>The results of this study show there is a significant correlation between nasal IL‐8 and neutrophils with the severity of rhinorrhea, nasal obstruction, and sternutation during acute respiratory infection illness. These data support the hypothesis that IL‐8 and neutrophils play a significant role in respiratory infection‐related nasal symptoms. Looking at the interconnectedness between biomarkers, IL‐8, a pro‐inflammatory cytokine, was found to significantly correlate with neutrophils in the positive direction, which makes sense physiologically as IL‐8 is a chemoattractant for neutrophils [Teran et al., <xref rid="jmv24042-bib-0046" ref-type="ref">1997</xref>]. Several cytokine genes and gene products, including those for IL‐8, are known to play significant roles in the induction and modulation of inflammation in human nasal epithelium [Becker et al., <xref rid="jmv24042-bib-0010" ref-type="ref">1993</xref>]. A clear correlation of the biomarkers, IL‐8 and nasal neutrophils, with symptoms of the common cold is shown using this sizeable and diverse set of data.</p><p>Many in vitro studies have found a relationship between viral respiratory infection and IL‐8 expression and/or concentrations. One study found a 4‐ to 10‐fold increase in IL‐8 mRNA expression after infecting human nasal epithelium with respiratory syncytial virus (RSV) or stimulation with tumor necrosis factor or interleukin‐1 [Becker et al., <xref rid="jmv24042-bib-0010" ref-type="ref">1993</xref>]. They determined that IL‐8 is a major cytokine of human nasal epithelium, constitutively expressed and readily produced upon virus infection. RSV has also been found to increase both IL‐8 gene expression in human lung epithelial A549 cells [Fiedler et al., <xref rid="jmv24042-bib-0021" ref-type="ref">1995</xref>], and IL‐8 release by buffy coat cells, especially in the presence of lung surfactant protein A [Hickling et al., <xref rid="jmv24042-bib-0028" ref-type="ref">2000</xref>]. Another study showed that adenovirus‐induced Raf/MAPK activation contributes to IL‐8 production [Bruder and Kovesdi, <xref rid="jmv24042-bib-0014" ref-type="ref">1997</xref>]. Additionally influenza virus A has been determined to induce interleukin‐8 expression in human airway epithelial cells [Choi and Jacoby, <xref rid="jmv24042-bib-0016" ref-type="ref">1992</xref>].</p><p>Cytokine levels have also been examined in naturally acquired viral rhinitis. One group of investigators found elevated IL‐8 levels in patients with viral rhinitis when compared to control subjects, which suggests that IL‐8, among other cytokines, play a role in the pathophysiology of the common cold [Röseler et al., <xref rid="jmv24042-bib-0044" ref-type="ref">1995</xref>]. The current findings support and extend the known role of IL‐8 in acute respiratory infection. In addition to showing IL‐8 concentrations are high in individuals with acute respiratory infection, the current results show that the IL‐8 concentration correlates with symptom severity. While the previous study examined specimens from 20 patients with naturally acquired viral rhinitis, this study's sample size is much larger with nasal specimens for over 800 community‐acquired acute respiratory infections.</p><p>The elevation of certain biomarkers, such as IL‐8, during acute respiratory infection has been most studied in rhinovirus infection. Several authors have reported a direct correlation between the severity of symptoms associated with in vitro rhinovirus infection and the concentration of interleukin‐8 in nasal secretions. Biagioli et al. examined the mechanism of rhinovirus‐induced IL‐8 response and suggested that mediation occurs through production of oxidative species and the subsequent activation of NF‐kappaB [Biagioli et al., <xref rid="jmv24042-bib-0011" ref-type="ref">1999</xref>]. That study was carried out in vitro. The current study supports that study's findings and is more clinically applicable, as infections were naturally community‐acquired and are correlated with symptom severity. Global severity, measured by AUC, was found to correlate with biomarker concentrations of IL‐8 and neutrophils. Gern and colleagues report IL‐8 production contributes to acute respiratory infection symptom severity in children with rhinovirus or influenza A infection [Gern et al., <xref rid="jmv24042-bib-0024" ref-type="ref">2002</xref>]. While this study used a different symptom scale, it too found that IL‐8 correlated with acute respiratory infection severity when all the acute respiratory infection episodes reported in the studied adult population are considered. Among these 811 episodes, nine types of viruses were identified. An analysis by viral type was tried, but once divided by virus the number of acute respiratory infection episodes in each group had insufficient power to draw conclusions.</p><p>A general correlation has been shown between IL‐8 and overall acute respiratory infection severity. The recent goal, however, was to hone in on the specific symptoms, or groups of symptoms that correlate most closely with IL‐8 and neutrophils. The results highlight rhinitis related symptoms, and these findings are supported by the literature. One study examined the association between experimental rhinovirus infection and the elaboration of IL‐8 into nasal secretions, and also looked at rhinovirus‐associated common cold symptoms [Turner et al., <xref rid="jmv24042-bib-0048" ref-type="ref">1998</xref>]. They found IL‐8 concentrations were significantly higher in infected symptomatic subjects compared to infected asymptomatic or placebo‐infected subjects. More specifically, there was a correlation between severity of nasal obstruction and rhinorrhea with the change in IL‐8 concentration from baseline to 2–4 days after virus challenge.</p><p>In addition to correlating with nasal symptoms, IL‐8 correlated with scratchy throat, and with the item gauging overall symptom improvement. Neutrophils correlated with scratchy throat and two quality of life symptoms: thinking clearly and sleeping well. The scratchy throat correlation with IL‐8 and neutrophils could be explained as a result of postnasal drip triggered by acute respiratory infection. The correlation between neutrophils and sleep quality is an interesting issue. Healthy individuals who are sleep deprived are known to have increased neutrophils [Boudjeltia et al., <xref rid="jmv24042-bib-0012" ref-type="ref">2008</xref>; Ruiz et al., <xref rid="jmv24042-bib-0043" ref-type="ref">2012</xref>]. Similarly, night shift workers have been found to have increased levels of inflammatory markers, including neutrophils, compared to individuals who work day shift [Alireza et al., <xref rid="jmv24042-bib-0001" ref-type="ref">2011</xref>]. Additionally, individuals with obstructive sleep apnea syndrome (OSAS) have a higher percentage of sputum neutrophils compared to normal controls [Lacedonia et al., <xref rid="jmv24042-bib-0032" ref-type="ref">2011</xref>]. All of these examples imply that the poor sleep leads to the neutrophil increase. However, during an acute respiratory infection the neutrophils are likely due to the infection, which leads to poor sleep quality. Nasal symptoms due to neutrophil infiltrated non‐allergic rhinitis have been shown to have a large effect on sleep quality and quality of life [Gelardi et al., <xref rid="jmv24042-bib-0023" ref-type="ref">2008</xref>]. Even though the participants we studied exhibit a different disease state than sleep apnea, it shows an important and consistent relationship between nasal symptoms and sleep quality. Likely, the poor sleep quality is due to nasal neutrophils, but our study does not allow us to determine if the poor sleep quality is a result of the nasal neutrophils, or if the nasal neutrophils are a result of the poor sleep quality.</p><p>Previously, no biomarkers have correlated well with acute respiratory infection illness domains or specific symptoms, nor have they been shown to predict outcomes [Barrett et al., <xref rid="jmv24042-bib-0005" ref-type="ref">2006</xref>; Barrett et al., <xref rid="jmv24042-bib-0006" ref-type="ref">2009</xref>]. The current study's results show a strong correlation with the nasal domain of acute respiratory infection illness, namely non‐allergic rhinitis, and in fact most strongly with three specific symptoms: rhinorrhea, nasal obstruction, and sternutation. However, a biomarker or panel of biomarkers that correlate well with biological symptoms and quality of life measures remains elusive.</p><p>An important remaining question concerns the role of cytokines and cells in the clearance of acute respiratory infection virus in humans compared to the mediation of symptoms. IL‐8 has been shown to be linked to clearance of a porcine respiratory virus [Lunney et al., <xref rid="jmv24042-bib-0035" ref-type="ref">2010</xref>], and one study suggests that neutrophils do not play an important role in viral clearance during influenza virus infection in mice [Wareing et al., <xref rid="jmv24042-bib-0049" ref-type="ref">2007</xref>]. Furthermore, investigators have run human experiments that attempt to determine predictability of acute respiratory infection severity or duration. One group of researchers asked clinicians and patients to predict the severity and duration of acute respiratory infection at an initial visit and had the patient complete the WURSS [Longmier et al., <xref rid="jmv24042-bib-0034" ref-type="ref">2013</xref>]. There was no significant association found between participant and clinician predictions of severity or duration with the actual severity and duration of acute respiratory infection. In order to answer a similar question about predictability of cold severity, time‐points analysis that looked at IL‐8 and neutrophil levels on Day 1 of the acute respiratory infection episode was performed in relationship to WURSS score on Day 3 of the acute respiratory infection episode. The analysis gave insignificant results. Therefore, while IL‐8 is indicative of inflammation, it may not be a mediator affecting the chronological course of colds. Further research is necessary to determine if the concentration or change in concentration of cytokines throughout an acute respiratory infection episode can predict the overall duration and severity of the illness. For example, specimens from additional time points could be assayed, and a larger array of cytokines could be measured in order to create a better model of the importance of cells and cytokines for the mediation of symptoms and the control of viral replication. This insight could be useful for prevention and treatment options focusing on shortening the length of a cold, and abating symptoms.</p><p>In conclusion, the following nasal symptoms: rhinorrhea, nasal obstruction and sternutation, have been determined to correlate more closely with the biomarkers IL‐8 and neutrophils, than other symptoms on the WURSS‐21 item assessment tool. Additionally, both correlate with scratchy throat. Finally, within the quality of life group, neutrophils correlated with thinking clearly and sleeping well, while IL‐8 negatively correlated with how participants responded to a question gauging overall symptom improvement. While it has been known for years that cytokines like IL‐8 are involved in the disease process of acute respiratory infection illnesses, and while it is not surprising that the symptoms that correlate most closely with IL‐8 and neutrophils from nasal specimens are nasal symptoms, this relationship has not been well documented in detail, until now. With these findings, knowing more about acute respiratory infection symptomology and its relationship with inflammatory biomarkers opens doors to discovering more effective curative treatment methods and potential medications for the amelioration of unpleasant and burdensome symptoms.</p></sec></body><back><ack id="jmv24042-sec-0013"><title>ACKNOWLEDGEMENTS</title><p>The PEP trial was supported by grant R01AT001428 from the National Institutes of Health (NIH), National Center for Complementary and Alternative Medicine (NCCAM). The MEPARI trial was supported by NIH, NCCAM grant 1R01AT004313, and by NIH grant UL1RR025011 from the Clinical and Translational Science Award Program of the National Center for Research Resources. Dr. Barrett has been supported by career development grants from NIH NCCAM (K23AT00051; K24AT006543), and the Robert Wood Johnson Foundation Generalist Physician Faculty Scholars Program.</p><p>The authors would like to acknowledge and thank Tola Ewers, MS for managing the data sets and combining them for the purposes of this study; Daniel Muller, MD, PhD and medical student Paul Dorresteijn for writing assistance with technical editing and proofreading; Christopher L. Coe, PhD, David Rakel, MD, Aleksandra Zgierska, MD, PhD, Shari Barlow, BA, Rachel Sippy, MPH, Chidi Obasi, MD, Michele Gassman, MA, Mary Checovich, Amber Schemmel, and Supriya Hayer, MD for providing support and encouragement all along the way.</p></ack><ref-list id="jmv24042-bibl-0001" content-type="cited-references"><title>REFERENCES</title><ref id="jmv24042-bib-0001"><mixed-citation publication-type="journal" id="jmv24042-cit-0001"><string-name><surname>Alireza</surname><given-names>S</given-names></string-name>,
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