There are no perfect tools for assessing common cold. Laboratory measures of URI include identification of virus, quantitative viral titer, mucus weight, counts of neutrophils or other white blood cells, and quantitative assay of various cytokines [9-15]. As indicators of immune and inflammatory processes these biomarkers are useful, but none correlate well with illness domains (specific symptoms, functional impairments),[16] and none have been shown to predict important outcomes. The Jackson scale [17-19] (technically an index and not a scale[20]) is the most commonly used questionnaire used for defining and evaluating colds and flu. Jackson's index includes eight symptoms which are rated as absent, mild, moderate or severe by either self-assessment or with clinician/researcher assistance. Jackson's method has been compared to laboratory measures, but has not been psychometrically assessed, and does not include quality of life (QoL) measures. Aside from Jackson, there are no recognized questionnaire instruments able to assess URI illness severity in adults. The CARIFs scale includes QoL items,[21,22] but is designed to assess colds only among children.

The Wisconsin Upper Respiratory Symptom Survey (WURSS) was developed using individual interviews and focus groups among community-recruited people with Jackson-defined colds[23]. Semi-structured interviews included open-ended questions aimed at eliciting terminology and assessing health values related to experienced cold illness. Of more than 150 terms used to define symptomatic or functional impairment, 42 were chosen for inclusion in the WURSS-44[23]. In addition to the 42 specific items, one introductory question assesses global severity, and another final question assesses improvement or deterioration (change-since-yesterday). More information on the WURSS can be found at: http://www.fammed.wisc.edu/wurss.

The first stage of WURSS validation was based on data gathered during monitoring of 150 adults during 1,681 person-days of illness[24]. Factor analysis tentatively identified ten domains. Items assessing activity, quality of life, and functional impairment were rated as equally or more important than items assessing symptom severity. Minimal important difference and responsiveness were assessed following methods of Guyatt et al [25-29]. Using responsiveness and importance-to-patients as guides, we selected best items for inclusion in a short-form, the WURSS-21[24]. Table ​Table11 shows the items in the WURSS-44 and WURSS-21, along with the domains identified previously[24].

Our basic methodology was to recruit people early in the course of their colds, then follow them with twice daily self-assessments until their colds resolved, to a maximum of 14 days. Prospective participants responding to advertising or word of mouth were screened on the telephone, then met for informed consent and study enrollment. Half the sample filled out the WURSS-21 in the morning and the WURSS-44 in the evening; the other half completed the questionnaires in reverse order. In addition to the WURSS-21 and WURSS-44, participants filled out the Jackson scale [17-19] every day, and the SF-8 (24 hour recall) daily starting the day after enrollment. The SF-8 is a short form 24 hour recall version of the widely used SF-36, and yields separate summary scores for physical and mental health, calculated using algorithms recommended by the authors[42].

The protocol was approved by the University of Wisconsin Institutional Review Board's Human Subject Committee. Participants were recruited from the community in and around Madison, Wisconsin, using newspaper advertisements, flyers, posters, email messages, a promotional website, and targeted mailings of post cards and letters. Responders to advertisement were screened for eligibility criteria during a pre-enrollment phone interview. Presence and timing of symptom onset was assessed during phone screening and again in person just prior to enrollment. Inclusion required a Jackson score of 2 or higher, with symptom severity rated as 0 = absent, 1 = mild, 2 = moderate, or 3 = severe for each of the eight Jackson symptoms: sneezing, nasal discharge, nasal obstruction, sore throat, cough, headache, malaise, and chilliness. At least one of the first four "cold-specific" Jackson symptoms was required, and none these could have been present for more than 48 hours. Exclusion for allergy was based on a history of allergy combined with current eye or nose itching or sneezing. Exclusion for asthma was based on a history of asthma with current cough, wheezing or shortness of breath. Additionally, people were excluded if either the prospective participant or the enroller felt that any current symptoms were likely due to allergy, asthma, or other non-URI cause.

We defined cold illness to begin with first cold-specific Jackson symptom (nasal or throat), and to continue until the participant reported being "not sick" for two days in a row. Our protocol required that enrollment occurred within 48 hours of the first cold symptom. Participants were required to answer "Yes" to "Do you think you have a cold?" at the enrollment interview. In the morning and evening of each subsequent day, participants answered "How sick do you feel today?" by marking a 0 to 7 Likert-type severity scale, where 0 = Not sick, 1 = Very mildly, 3 = Mildly, 5 = Moderately, and 7 = Severely. Even numbers did not have descriptors. Colds were defined as ending when a participant marked "0 = Not sick" twice in a row on two subsequent days. If this did not occur by the 14^th day, participation was terminated. Protocol adherence was supported by regular telephone contact. Questionnaire instruments were returned at an in-person exit interview after the cold ended.

To assess importance-to-patients, we attached the question "How important is this to you?" to each of the WURSS-44 items at enrollment. Participants were told: "Some people may rate one symptom as fairly severe, but not think it is very important, while other, milder symptoms may really bother them. When answering the question, "How important is this to you?" please think about how bothersome a symptom is, or how much you dislike having it." The 5-point response option scale had the descriptors "Not," "Somewhat," and "Very" aligned with the numbers 1, 3 and 5.

Following MID methods attributable to Guyatt et al., [25-29] participants were first asked whether they were "better," "the same," or "worse," compared to the last time they answered the questionnaire. Those considering themselves "better" then rate improvement as: 1) Almost the same, hardly any better at all, 2) A little better, 3) Somewhat better, 4) Moderately better, 5) A good deal better, 6) A great deal better, or 7) A very great deal better. Those saying they were "worse" rate the degree of deterioration on a corresponding 7 point scale.

Operationally, MID is taken to be the average amount of instrument-assessed change for all subjects who rate themselves as "a little better" or "somewhat better"[27,28,43,44]. Guyatt's index of responsiveness is then calculated by dividing this MID by the square root of twice the mean square error (MSE) of stable participants (people who rate interval change as "the same.") Thus, Guyatt's Responsiveness Index is defined as MID/. We have previously adapted these methods for use in common cold,[16,24,45] and have proposed additional strategies for assessing patient-valued outcomes [46-49]. Cohen's standardized effect size and the standard error of measurement (SEM) represent alternative strategies that can be employed to compare change over time.

For acute illness, which has a beginning and an end, area under the curve (AUC) may be an appropriate parameter to consider for the primary outcome for clinical trials. While various strategies such as a fitting of curves or trapezoidal approximation could be used to assess AUC, the current study simply adds daily WURSS scores across all days of documented illness to arrive at the AUC measure reported here.

Factor analysis of the first WURSS validity data set tentatively suggested a factorial structure of ten dimensions[24]. The current study was designed to re-assess the dimensional structure of the WURSS-44, and to explore the structure of the WURSS-21. For both the previous and current studies, the general approach followed methods described by Kroonenberg and Lewis[50]. This approach combines exploratory and confirmatory procedures, using weighted least square estimates employing diagonal weight matrix techniques to seek common factors within empirically derived domains. For the current study, we did not assume that the factorial structure identified in the first WURSS validation effort was inherently sound, but instead started without any a priori grouping of items. Realizing that factors and dimensions are rarely orthogonal (truly independent), we allowed for the possibility of factors falling within multiple dimensions. Once best fit dimensional structures were found, construct reliability was estimated using methods originally proposed by Joreskog,[51] developed further by Bollen[52]. All factor analyses were conducted using Mplus Version 5.1[53].

Data were hand entered twice, with resolution of discrepancies by comparison to paper questionnaires. Missing data, disallowed values, and outliers were also hand-checked, and corrected if appropriate. Overall, >98% of intended data was collected. Formal missingness analysis was done for each instrument separately, following the approach set forth by Potthoff[54]. Assumptions were met for missing at random (MAR+),[54] therefore imputation using multivariate techniques was deemed acceptable. Reliability coefficients were calculated using methods of Joreskog[51] and Bollen,[52] with significance tested following Wald[55,56].

Reasons for exclusion included symptom duration greater than 48 hours (462), allergy or asthma symptoms (50), failure to meet Jackson cold criteria (44), intended use of symptom-modifying medications (33), and subject judged to be unreliable (24). Reasons for non-enrollment of eligible callers included: participant burden (74), failure to return phone calls (65), failure to show up for enrollment (21), "not interested" (17), transportation problems (14), and insufficient compensation (5). Of the nine lost to follow-up, three people never returned phone calls, three reported losing their folders and never came in for their exit, two called to withdraw and never came in for their exit interview, and one person staying at a homeless shelter could not be contacted. Table ​Table22 portrays enrollment, monitoring and sociodemographic characteristics for the population sampled.

Time from first symptom to enrollment averaged 33.1 hours (SD = 13.4), inter-quartile range (25 to 45). Adding pre-enrollment illness hours to duration monitored (mean = 193.8, SD = 86.9) yields our estimate of mean total illness duration 226.9 hours (SD = 87.5), or 9.45 days. This may be an underestimate of actual average illness duration, as 40 (17.4%) participants continued to assess themselves as at least very mildly sick at the end of the maximum 14 day monitoring period.

Colds tend to begin with specific nasal or throat symptoms, or with nonspecific or general feelings of tiredness or malaise, sometimes difficult to quantify in terms of onset timing. In this sample, 97 (42%) people reported a sore or scratchy throat as their first symptom, with 105 (46%) reporting nasal discharge, obstruction or sneezing, and only 7 (3%) reporting cough as their first symptom. At enrollment, less than 48 hours from first symptom, 223 (97%) reported at least one nasal symptom, 201 (87%) had sore throat, and some 150 (65%) reported cough. Nonspecific symptoms were also highly prevalent, with 142 (62%) reporting headache, 87 (38%) chilliness, and 184 (80%) malaise, tiredness or lack of energy.

Severity of illness at enrollment varied greatly across all measures: WURSS-44, Jackson, and SF-8. Means, (standard deviations), and [interquartile ranges] were as follows: 9.54, (3.68), [7,12] for Jackson, 100.6, (51.2), [59, 134] for the WURSS-44, 40.3 (9.42) [33.3, 47.7] for SF-8 physical health, and 47.1 (9.34) [42.4, 54.4] for SF-8 mental health. Corresponding values for the WURSS global-severity-today item at enrollment were 4.10, (1.26), [3,5] Summary scores for the WURSS-44 and WURSS-21 are simple sums of all responses except the introductory global-severity-today score and the concluding global-change-since-yesterday items. This deviates from first reporting of WURSS validity,[24] where global-severity-today was included in the summary score. We have since decided that "How sick do you feel today?" and "Please rate the average severity of your cold symptoms over the last 24 hours" refer to conceptually distinct time frames and hence should be not be lumped together in summary scores.

The pattern of experienced symptoms was characterized by the expected high frequency reporting of nasal symptoms (99.6%), sore or scratchy throat (97.8%), and cough (93.5%), reported at least once during the first seven days of illness. Sinus symptoms were also widely reported (92.2%), as were headache (89.6%) and body aches (88.7%). Other frequently reported symptoms were referable to the chest (73.9%), ears (77.0%), and eyes (83.5%). Swollen glands (67.4%), chilliness (63.9%) and feverishness (73.0%) were also experienced frequently. All N = 230 (100%) of our participants scored themselves as having some degree of tiredness, malaise, or feeling run down at least once during up to 7 days of illness. Some degree of functional limitation was also reported by 100% of our sample, with the following abilities receiving impairment scores above zero at least once during the first seven days of illness: think clearly (90%), speak clearly (83.5%), sleep well (91.3%), breathe easily (95.7%), accomplish daily activities (90.0%), interact with others (87.8%), and live your personal life (88.7%). The WURSS uses "very mild" as a response option. Frequency of items rated as mild, moderate or severe were somewhat lower.

Figure ​Figure11 shows daily change over time of illness severity as measured by the WURSS-21, the WURSS-44, the Jackson scale, and the SF-8 (both physical and mental health scores). Sample size decreases as participants report resolution of their illnesses, from N = 230 on Day 1 to N = 100 on Day 12, as only those with continuing colds are included. Day-to-day change would appear even more dramatic if those reporting resolution of illness were included in these figures. As measured by the SF-8, general physical health is impaired more and recovers more swiftly than mental health during common cold illness. Illness-specific health changes more rapidly than general health, whether measured by Jackson symptoms or by either version of WURSS. All changes are more rapid in the first several days than later on.

Figure ​Figure22 shows scatterplot correlations of the WURSS-21 and WURSS-44 with SF-8-assessed general physical and mental health, and with the Jackson score. Illness-specific health-related quality-of-life (WURSS) correlates more closely with physical than mental health, as expected. Jackson symptoms also correlate more strongly with SF-8 physical than mental health. Both versions of WURSS associate more strongly with Jackson and SF-8 than those two measures do with each other. Not unexpectedly, the strongest associations observed were the WURSS-21 with its parent WURSS-44, yielding Pearson correlation coefficients of 0.920, 0.925, and 0.937 on Days 2, 3 and 4, respectively. Together, we interpret these findings as evidence of convergent validity.

Tables ​Tables33 and ​and44 present item-by-item evaluation criteria for the WURSS-44 and WURSS-21. Each item is portrayed in terms of frequency, severity, minimal important difference (MID), mean squared error (MSE), used to generate Guyatt's responsiveness coefficient. Coefficients representing these criteria are strikingly similar to those in the first WURSS validation study[24]. WURSS-21 items also appear to perform similarly when included in the WURSS-44, and when rated separately in the short form WURSS-21. In general, items included in the WURSS-21 demonstrate greater responsiveness than the WURSS-44 items not included in the 21-item version. One exception is that WURSS-44 items #13 (feeling "run down") and #32 (lack of energy) perform very well, but are not included in the WURSS-21. When similar findings were noted in the first validation study, we decided not to include these in the short form WURSS-21 because of excessive overlap (redundancy) with item #18 (feeling tired). The instruments as a whole yielded similar MIDs and responsiveness indices to the first study,[24] with MID and responsiveness index of 18.5 and 0.75 for the WURSS-44, and 10.3 and 0.71 for the WURSS-21 in the current study, compared to 16.7 and 0.71 for the WURSS-44 and 9.48 and 0.80 for the WURSS-21 (as 19 items embedded in the WURSS-44) in the first study[24].

Arguably, importance-to-patients may be the most valuable criteria for determining which items should be included in any health-assessing questionnaire. Analysis of responses regarding importance confirmed and extended the findings from our previous WURSS validity study. Mean importance of items ranged from 2.77 (watery eyes) to 4.59 (sleep well) on a 1 to 5 scale, with very similar patterns to those found in the first study. Another previously noted finding is that functional quality-of-life items tend to be rated as more important than items rating symptoms. Among symptom-assessing items, the more frequent (nasal, sore throat, cough, head congestion, chest congestion) tend to be rated as more important than those less frequent (sweats, chills, swollen glands, eye symptoms). Overall, the majority of WURSS items, especially those selected for the WURSS-21, were rated as at least "somewhat important" by most of the people most of the time.

Tables ​Tables5,5, ​,66 and ​and77 show the results of factor analysis for the WURSS-44, and tables ​tables8,8, ​,99 and ​and1010 display corresponding results for the WURSS-21. Exploratory analysis began with Day 3 data, chosen because this day represents the breadth of symptomatic and functional impairment as well or better than any other day. Factorial structures were fit allowing for three to 43 dimensions for the WURSS-44. Very little added explanatory power was found for models with nine or more dimensions, hence we settled on an eight dimension model. For the WURSS-21, a 3-dimensional structure was chosen, after looking at fit indices for models with two to 20 dimensions. Tables ​Tables66 and ​and99 show additional coefficients for the models selected, as well as indicators of how these factorial models play out over time. Fit indices for both instruments are strong, easily meeting criteria suggested by Hu and Bentler[58]. Tables ​Tables77 and ​and1010 show individual items in the dimensional structures, along with indicators of reliability. Reliability coefficients derived by methods of Joreskog[51] and Bollen[52] were all significant at p < 0.01 using Wald testing[55,56].

Table ​Table1111 displays estimated sample size for two-armed randomized trials, using data gathered here, and common statistical assumptions used in power studies. Powering a common cold treatment trial on MID and responsiveness makes most sense when the therapy is hypothesized to influence the rate of recovery, and when trialists prefer to study participants for a week or less. The main limitation is that MID and daily change rates are neither intuitive nor supported by theory as primary outcomes. Powering a trial on area-under-the-curve makes more sense from a theoretical perspective, as overall illness-related quality-of-life is an intuitively understandable and conceptually consistent primary outcome. For the sample described here, mean AUC for the WURSS-21 was 310.1 with standard deviation 251.0. Corresponding values for the WURSS-44 were mean 570.6 and SD 504.5.

Overall, the results are encouraging. Coefficients representing reliability, responsiveness, and importance-to-patients are similar to those from the previous study. Items selected for the WURSS-21 perform similarly whether embedded within the WURSS-44 or separately in the WURSS-21. Convergence with external comparators (SF-8, Jackson) follows predictions from theory and previous experience. Our qualitative experience talking with research participants tells us that one reason the WURSS performs well is that it was designed to be user-friendly, with easy-to-understand questions and response ranges. Consideration of face validity tells us that WURSS is a better measure than Jackson, as it includes items that rate functional impairment and quality-of-life, which have been rated as important by people suffering from colds.

Despite these strengths, there are of course limitations. The original item-generation procedures may have failed to include representation of cold-related symptoms or functional impairments that are important to significant proportions of cold-sufferers. Alternative wording, formatting, and response range options have not been developed or tested. All of the work has been done in and around Madison Wisconsin, which may influence both the types of colds studied, and the linguistic and health value orientations of the population sampled. Finally, and perhaps most importantly, there are no gold standards for identifying, classifying, or assessing acute viral respiratory infections, hence criterion validity is not possible, and concepts such as sensitivity, specificity, and positive and negative predictive value cannot be used with confidence.

Following Guyatt, [25-29] we accept that the concepts of important difference and responsiveness are critical for assessing evaluative instruments, and have previously discussed related theory and methods in an article entitled: "Comparison of anchor-based and distributional approaches in estimating important difference in common cold"[45]. That paper compared MID to standardized effect size (ES) and standard error of measurement (SEM) as options to consider when seeking to evaluate change over time. Responsiveness, however, is not entirely satisfying for assessment of acute illness, which by definition has a beginning and an end, and thus both up sloping and down sloping severity curves. Deciding which time points to compare is not an easy task, as any specific choice brings with it corresponding limitations. To avoid severity-over-time complexities, some investigators may wish to use area under the severity duration curve (AUC) as the primary outcome for between-group comparison[59]. For these reasons, we have provided AUC descriptive statistics for the current study.

While it is clear that both versions of WURSS demonstrate broad-based construct validity, less confidence exists regarding underlying dimensional structure. The current study suggests an 8-dimensional structure for the WURSS-44, somewhat different from the 10-dimensional structure found in the first study. Factor analysis of the WURSS-21 in the current study suggests a 3-dimensional structure, substantially different from either of the two structures found for the WURSS-44. Perhaps this should not be too surprising, as dimensional representation was not used as criteria for deriving the short form. Nevertheless, we conclude that we have not yet reached confirmation of the true dimensional structure of either instrument, and thus cannot yet make recommendations regarding potential weighting of items within dimensions. Thus, we continue to recommend a simple sum of 42 items for the WURSS-44, and 19 items for the WURSS -21, as the most appropriate global severity score for these instruments. The first and last items are conceptually distinct, and hence should be analyzed and reported separately.

RB contributed to the design, conducted statistical analysis, and contributed to the manuscript.

MM contributed to the design, conducted statistical analysis, and contributed to the manuscript.

GT coordinated data collection and contributed to the manuscript.

SB conducted data collection, and contributed to the manuscript.

AH entered, cleaned and analyzed data, and contributed to the manuscript.

MB entered and cleaned data, and contributed to the manuscript.