Kawasaki Medical Journal 48：01−08，2022

doi：10.11482/KMJ-E202248001

1〈Regular Article〉

Accuracy of short-term insomnia onset andcomposite clinical score in the differential diagnosis ofcommon cold and influenza: A cross-sectional study
Simmon GOMI
Gomi Family Clinic

ABSTRACT

Influenza (IA) and the common cold (CC) may present with similar symptoms.

However, rapid IA diagnostic tests have a low sensitivity during the early stages of thedisease. Therefore, various diagnostic tools are needed. Mild short-term insomnia (MSTI)
occurs in patients with CC, but the incidence in patients with IA remains unknown. Hence,
we hypothesized the difference between the day of onset of MSTI and the date of fever
occurrence in IA to be shorter than that in CC. This study aimed to investigate the incidenceof MSTI in patients with CC and IA with fever (≥ 37.5℃) and the risk of developing acute-onset
MSTI (alone or as part of a composite clinical score) to aid in the differential diagnosis during
the early disease stage. The relationship between MSTI and other symptoms was analyzed
using quadratic logistic regression to model the number of IA cases with composite score day
progression from the onset of fever, namely origin day 0. The results revealed a day 0 axissymmetrical and inverted U-shaped relationship between the onset days of the composite
scores and estimated probability of IA. The coefficient of the quadratic term is negative andsignificantly different from zero, supporting the hypothesis that the onset of IA-related MSTIs
is more acute than that of CC-related MSTIs. Principal component analysis was also applied
to the onset days for five IA- and CC-related symptoms, in addition to fever (MSTI, cough,rhinorrhea, sore throat, and headache). The maximum day difference in fever onset and at least
one additional symptom was established as the cutoff day between IA and CC using receiver
operating characteristic analysis. The cutoff value was confirmed based on the MSTI-onsetderived variables using logistic regression. This cross-sectional survey included 100 and 106
CC and IA patients, respectively. The optimal cutoff day were one day before and one day
after the onset of fever. For those with CC and MSTI beyond the cutoff day, the diagnostic
sensitivity, specificity, and positive likelihood ratio were 7%, 99%, and 7.42, respectively.
For patients with CC and any composite clinical score symptoms beyond the cutoff day, thesensitivity, specificity, and positive likelihood ratios were 36%, 92%, and 4.77, respectively. A
composite clinical score and MSTI onset with a cutoff day of one day before and after fever
Corresponding author
Simmon Gomi
Internal Medicine, Gomi Family Clinic, 2 Chome-4-3
Oote Suwa-shi, Nagano 392-0026, Japan

Phone : 0266 52 1126
Fax : 0266 52 1150
E-mail: simmongomi@gmail.com

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Kawasaki Medical Journal

onset may help distinguish between early stage CC and IA.


doi：10.11482/KMJ-E202248001(Accepted on December 17, 2021)

Key words：Common cold, Differential diagnosis, Influenza, Mild short-term insomnia,
Respiratory infection
INTRODUCTION

prescriptions. Moreover, a composite measure

Respiratory infections, including influenza (IA)would assist healthcare providers and patients inand common cold (CC), may present with similardifferentiating CCs from IAs. Similar techniques

symptoms. Antiviral drugs have minimal therapeutic

may also aid in the differential diagnosis of otherbenefits if initiated more than 48 hours after IA

diseases including coronavirus disease 2019.

１）

onset . The rapid inﬂuenza diagnostic test (RIDT)

If IA presents with a more acute MSTI onset

has 35% sensitivity and 100% speciﬁcity within 12

than CC, MSTI may have diagnostic value inh and 66% sensitivity and 97% speciﬁcity between

distinguishing IA from CC. The hypothesis is that

12 h and 24 h２）. During an IA epidemic, excluding

the diﬀerence between the day of onset of MSTI and

IA during disease onset is diﬃcult even if the RIDT

the date of fever occurrence in IA is smaller thanresult is negative. Therefore, additional diagnostic

that in CC.

tools should be developed to diﬀerentiate between

This study aimed to propose a new statisticalmodel to aid in the differential diagnosis of CC

IA and CC.
IA has a more acute onset compared withand IA with fever ( ≥ 37.5℃) by evaluating the３）

occurrence of acute-onset MSTI in patients.

CC . However, CC often presents with acuteonset. Currently, there is no established model todistinguish acute-onset CC from IA. Several studies

MATERIALS AND METHODS

have proposed various tests to distinguish IA from

Study design and ethical approval４）

IA-like illnesses . However, diagnosing IA remains

This cross-sectional study was conducted ata challenge５）. Patients with CC and IA also exhibit

an outpatient family medicine clinic in Nagano,overlapping symptoms. Cough and headache are

Japan, between December 1, 2018, and February

more common in IA than in CC６）. Sore throat and28, 2019. Enrollment was limited to patients withrhinorrhea are common CC symptoms (ICD10,

a fever. This study was conducted in accordanceJ100) ７）. Therefore, the precise quantification ofwith the 1964 Declaration of Helsinki guidelines.

the onset of CC or cold-like illnesses should beThis study was approved by the ethics committee

established.

of the Japan Primary Care Association (approval

Mild short-term insomnia (MSTI) frequently
８）

number: 2019-007). Patients were informed that the

begins during early CC stages . Gomi firstdata obtained would be used for research purposes.

described the MSTI in 2019８）. It occurs in 75% (24The completion and return of the questionnaires/ 32) of patients with CC a few days before and after

confirmed participants’consent. All data wereCC onset and lasts up to several days. The use of theanonymized and all participants were allowed

MSTI as a potential criterion to distinguish between

to refuse to participate at any point without any

CC and IA has not yet been established. However,repercussions.

determining the association of MSTI with IA andCC may aid in diﬀerential diagnosis during the early

Enrolled participants

stages of the two conditions, reducing unnecessary

A medical checklist questionnaire was

examinations, re-examinations, and anti-IA drug

administered to all the patients. The symptoms

Gomi S : Short-term insomnia in common cold and influenza

were confirmed during a diagnostic interview

3

Fever was deﬁned as an axillary temperature of ≥with a physician. Based on the questionnaire,

37.5℃. The day of fever onset was defined as thedetails regarding the length of illness and nature

day when the patient was first aware of fever. Inof the symptoms were obtained. The questionnaire

particular, this also included temperatures within

included a checklist of the following symptoms:

a 37.0-37.5℃range on that day. Fever onset was

fever, sore throat, cough, sputum, rhinorrhea, joint

deﬁned as the day of disease onset.

pain, headache, abdominal pain, back pain, nausea,

Short-term insomnia was defined as difficulty

vomiting, weight loss, weight gain, diarrhea,

in falling asleep, awakening at night, or waking

constipation, loss of appetite, cold, shivering,

early in a person who typically sleeps well. Alldifficulty in breathing, fatigue, dizziness, andpatients diagnosed with CC or IA were included ininsomnia. For each question, a checkbox andthe study and divided into CC and IA groups. IA

free-response field were indicated. Following thewas diagnosed in a patient with a positive RIDT

diagnosis of a respiratory illness, new symptoms

result and a fever. CC was diagnosed based on thewere added to the list if they were consistent withphysician’s clinical judgment and negative RIDT

the diagnosis. MSTI assessment was performed

results and coded as J00 (acute nasopharyngitis)

using the following question:‘Did you sleep asaccording to the 10th revision of the International

usual?’Only symptoms that were apparent to family

Classification of Diseases (ICD-10) ７）. Atypicalmembers or guardians were described to patients

J100 cases were excluded, including those with

who could not express their symptoms. MSTI lengthcough only, rhinorrhea only, J100 with diarrhea, andwas determined to be a single day. Many patients

other diseases. Patients who did not undergo RIDT

with respiratory infections could not precisely recallor had other illnesses were excluded. Patients whose

when they woke up or the number of nighttime

medical records did not include the day of symptom

awakenings due to their illness.

onset were also excluded. The criteria for selecting

Fig. 1. Study ﬂowchart
The CC group included patients with fever, with two or more symptoms of cough, rhinorrhea, sore throat, and headache; withRIDT negative test; who were assigned an ICD-10 code J00; who were judged as not having a disease other than J00 in the ICD10, and whose time of appearance of each symptom was not indicated in the chart.
-IA group: patients with fever, with two or more symptoms of cough, rhinorrhea, sore throat, and headache; RIDT-positive results;
who were judged as not having a disease other than inﬂuenza; whose onset of each symptom was not indicated in the chart

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Kawasaki Medical Journal

the group of participants are shown in Fig. 1.

symptoms was analyzed using logistic regression.

The QuickNavi-Flu kit (Denka Seiken, Tokyo,

Quadratic logistic regression was used to model

Japan) was used to perform the RIDT. The detection

the number of IA cases with composite score day

limit of this kit was examined and its performance

progression from fever onset. The variance inﬂation９）

was comparable to that of other commercial kits .

factor (VIF) was used to detect multicollinearity

Data on IA/CC, cough, headache, sore throat,

between variables. Statistical significance was set

MSTI, sex, and age were collected. The minimumat P < 0.05. All statistical analyses were performed

sample size was 80, based on a minimum of 10

using R 3.6.0 (R Foundation for Statisticalevents per variable rule10）.

Computing, Vienna, Austria)12）. Odds ratios (ORs)were calculated using Fisher’s exact test for theStatistical analyses

univariate analysis and multiple logistic regression

Principal component analysis was applied to thefor the multivariate analysis.

onset days of five IA- and CC-related symptoms,

MSTI, cough, rhinorrhea, sore throat, andaside from fever (MSTI, cough, rhinorrhea, soreheadache are collectively referred to as 5Sx. The

throat, and headache). The scores of the firstpresence of symptoms was considered positive

principal component (65.7% of the total variance)

for 5Sx, whereas the absence of all symptoms waswere used as a composite clinical symptom

considered negative for 5Sx. Any 5Sx symptoms

variable, S1－representing the distance (numberthat developed on a day other than day 1 wereof days) from the origin－and day 0 (fever onset).

referred to as 5Sx-OD1, which was considered

However, as this was not sufficiently accurate topositive if the patient developed 5Sx outside thedescribe temporal changes in the ratio of IA to CC,

range of -1 to 1 d.

a quadratic term S2, defined as the square of S1

Any symptom that developed on any day otherwas also introduced to increase precision. Similarly,

than day 1 was marked with the suffix“OD1.”

an MSTI onset variable, M1, was defined as the

These variables were referred to as MSTI-OD1,

distance (number of days) from day 0, and M2 ascough-OD1, rhinorrhea-OD1, sore throat-OD1, andthe square of M1. To distinguish IA from CC basedheadache-OD1. Any symptom that developed on

on differences in the day of onset, the presence ofany day other than day 0 was marked with the suﬃx

fever and the other ﬁve symptoms and the maximum“OD0.”

difference in days between fever onset (day 0)
and the onset of at least one of the ﬁve symptoms

RESULTS

were calculated. The maximum day diﬀerence was

All patients (n = 591) with CC-like symptoms,

determined using receiver operating characteristic

including acute fever, cough, sputum production,(ROC) analysis with the Youden’s index. It wasrhinorrhea, sore throat, nausea, and headache, wereused as a cutoﬀ point to distinguish between IA andincluded in the analysis. In total, 243 patients wereCC. Probabilistic measures, including specificity,

excluded because they were not diagnosed withsensitivity, positive likelihood ratios (LH+),

CC or IA. Five patients were excluded because

negative likelihood ratios (LH-), and their 95%

their medical records did not indicate the day of

11）

conﬁdence intervals (CIs) , were used to assess thethe symptom onset. Furthermore, 105 patients withrelationship between CC and IA. The ROC curve

fever were excluded because their temperatures

cutoﬀ value within 24 h was determined as a single

did not meet the inclusion criteria. During the IAday. The relationship between MSTIs and otherseason, from December to February, 100 patients

Gomi S : Short-term insomnia in common cold and influenza

with CC (51 men; age range: 0.67 - 80 years) andobserved between the variables.

106 patients with IA (57 men; age range, 1- 8 1
years) were enrolled (Table 1).

5

The logistic regression of composite scoresshowed that the quadratic term S2 alone was

Akaike’s information criterion (AIC) was usedsignificantly negative (Table 2), suggesting a

to compare the fitness of the quadratic model,

symmetrical day 0 axis and an inverted U-shaped

including the variable S2 or M2, with that ofrelationship between the onset days of composite

the linear model, excluding them in the logistic

scores and the estimated probability of IA (Fig.

regression for the temporal trend of IA / CC,2a). Similarly, the logistic regression of the MSTI

adjusted for age and sex. Consequently, theshowed that the quadratic term M2 alone wasquadratic model best ﬁt the collected data (composite

significantly negative (Table 3), suggesting a day

clinical score: linear AIC = 284.70, quadratic AIC =0 axis-symmetrical and an inverted U-shaped

279.96; MSTI: linear AIC = 163.82, quadratic AIC

relationship between the onset days of the MSTI and= 156.85). All variables had a VIF value of less thanthe estimated probability of IA (Fig. 2b). Therefore,

two; therefore, no multicollinearity problem wasas the day progressed, both composite scores andTable 1. Characteristics and comparisons between patients with
common cold and those with influenza

Table 2. Results from multiple logistic regression analysis showing
the relationship between the onset days of the composite clinicalsymptom score and the estimated probability of IA

Male, n (%)
Female, n (%)
Age (years), mean (SD)Age group (years), n (%)≤910 - 19
20 - 49≥ 50
SD: standard deviation

A

Common cold(n = 100)
51 (51)49 (49)27.9 (21.4)

Inﬂuenza(n = 106)57 (54)49 (46)28 (22)30 (30)24 (24)30 (30)16 (16)28 (26)32 (30)26 (25)20 (19)Adjusted odds ratios with 95%
p valueconﬁdence intervals
S1
0.96 (0.78 - 1.2)0.742
S20.95 (0.9 - 0.99)
0.022＊The odds ratios were adjusted for age and sex. Statisticalsigniﬁcance was set at p < 0.05.
IA, inﬂuenza; S1, onset days of the composite clinical symptomscore; S2, square of S1

B

Fig. 2. Quadratic logistic regression estimates the likely proportion of patients with conﬁrmed IA in a sample comprising patientswith CC and IA. The horizontal axis represents the composite onset days of five symptoms (insomnia, cough, rhinorrhea,
headache, and sore throat) derived from the principal component analysis (A) and the onset day of insomnia (B). The curve
represents the quadratic logistic regression with a single signiﬁcant variable and the number of days squared. CC, common cold;IA, inﬂuenza

6

Kawasaki Medical Journal

MSTI increased in IA cases, peaked on day 0, anddecreased thereafter.

DISCUSSION

The diagnostic cutoff day for which the

In our study, MSTIs were a signiﬁcant symptom ofpresentation of symptoms indicated and increased

IA. Moreover, logistic regression analysis identiﬁed

the likelihood of CC was 1.00 (day 1). Therefore,

the MSTI as an independent event associated withthe diagnostic cutoﬀ day for MSTI was determinedrhinorrhea and cough. The probability of IA to CC

to be day 1, as the cutoﬀ value was < 1 d.

estimated from quadratic logistic regression showedCompared to IA, the sensitivity, speciﬁcity, LH-

a day 0 axis-symmetrical and inverted U-shaped

positive value, and LH-negative value of 5Sx-OD1

temporal variation in both the composite symptom

for CC were 36%, 92%, 4.77, and 0.69, respectively.

variable (Fig. 2a) and the MSTI onset variable

These results were statistically significant (Table(Fig. 2b). The coeﬃcient of the quadratic term was4). The sensitivity, speciﬁcity, LH+, and LH- of thenegative and significantly different from zero for

MSTI-OD1 for CC were 7%, 99%, 7.42, and 0.94,

both the variables (Tables 2 and 3). These results

respectively. This result was statistically signiﬁcantsupport the hypothesis that the onset of IA-related(Table 4).

MSTIs is more acute than CC-related MSTIs. In
patients with upper respiratory tract inflammation

Table 3. Results from multiple logistic regression analysis showing
the relationship between the onset days of MSTI and the estimatedprobability of IA

and fever during the IA season, the occurrence of

Adjusted odds ratios with 95%
p valueconﬁdence intervals
M1
1.52 (0.88 - 2.64)
0.14
M2
0.7 (0.5 - 0.98)
0.036＊The odds ratios were adjusted for age and sex. Statisticalsigniﬁcance was set at p < 0.05.
MSTI, mild short-term insomnia; IA, inﬂuenza; M1, onset days of
MSTI; M2, square of M1

is suggestive of CC and not IA. This study proposes

MSTI or 5Sx-OD1 before and after one day of fevera model for quantifying“rapid onset,”which
distinguishes IA from CC. This hallmark strongly
suggests that combined quadratic logistic regression
and principal component analyses can help define

Table 4. Univariate analysis results of the characteristics of patients with common cold versus that of patients with influenza
CCIA
Sensitivity Speciﬁcity
LH+
LHOR
95% CI
p-value
AUC(n = 100) (n = 106)
MSTI
54
63
54%
41%
0.91
1.13
0.80
0.46 - 1.40
0.48
MSTI-0
24
42
24%
60%
0.60
1.23
0.48
0.26 - 0.91
0.02
5Sx-OD1
36
8
36%
92%
4.77
0.69
6.83
3.1 - 16.5
< 0.01＊
MSTI-OD0
30
20
30%
81%
1.59
0.86
1.84
0.92 - 3.68
0.07
MSTI-OD1
7
1
7%
99%
7.42
0.94
7.84
1.06 - 177
0.03
0.62
0.60
Cough-OD1
16
4
16%
96%
4.24
0.87
4.82
1.50 - 16.25 < 0.01＊
Rhinorrhea-OD1
23
5
23%
95%
4.87
0.81
5.98
2.12 - 17.19 < 0.01＊
0.63
Sore throat-OD1
13
2
13%
98%
6.89
0.89
7.70
1.67 - 48.95 < 0.01＊
0.67
Headache-OD1
7
0
7%
100%
Inf
0.93
Inf
1.89 - Inf< 0.01＊0.55
CC, common cold; IA, inﬂuenza.
Odds ratios and p-values were calculated using Fisher’s exact test.
Statistical significance was set at p < 0.05.
Inf, inﬁnity
MSTI: mild short-term insomnia
MSTI-0, mild short-term insomnia that occurred on day 0, and fever onset.
5Sx, ﬁve symptoms (MSTI, cough, rhinorrhea, sore throat, and headache)
The presence of any of the symptoms was considered positive for 5Sx, while the absence of all symptoms was considered negative for
5Sx.
OD1, suﬃx for a symptom that developed on a day other than day 1
LH+, positive likelihood ratio
LH － , negative likelihood ratio
AUC, area under curve

Gomi S : Short-term insomnia in common cold and influenza

7

clinically useful cutoﬀ points to obtain an accurate

onset of fever, physicians may be able to distinguishdiagnosis.

between IA and CC in patients with early IA despite

Theoretically, MSTI onset should be consideredwithin hours rather than days. However, this is nota negative RIDT result. However, RIDT is notavailable in several countries.

realistic, because sleep typically occurs at night.

The results of this study may reduce unnecessary

Few people recall waking hours, particularly

medication use, tolerance risk, number of medical

when they are ill. Moreover, the 24-h unit was

visits, and prescribed sleep agents by facilitating

not diagnostically functional. Therefore, the mostaccurate differential diagnosis between patientspractical approach is to determine the MSTI

with IA and CC. Inappropriately prescribed IA

onset in days. In this study, all cutoff values were

medications may increase the risk of side eﬀects13）

determined within one day, indicating that a cutoﬀ

or lead to drug-resistant infections caused byon the day of onset (day 0) might not be useful.

viruses 14）. Therefore, doctors must be able to

Several considerations have been considered fromprecisely distinguish between patients who may or

a clinical perspective. The model developed in our

may not benefit from anti-IA medications. MSTI-

study required a non-IA diagnosis to confirm the

OD1 may play an important role; however, its low

presence of CC and a reduction in false-positive

sensitivity (7%) and high speciﬁcity (99%) should

IA cases. Hence, day 0 was not a realistic cutoff.

be considered when using MSTI-OD1 for IA

Thus, a range of ± 1 d was considered suitable.

assessment (Table 4).

High LH+ levels were observed in the 5Sx-OD1

As RIDT yields many false-negative results,

and MSTI-OD1 groups, indicating their diagnostic

IA cannot be ruled out in patients with CC-likeeﬀectiveness.

pathology even if the RIDT result is negative.

Some guidelines suggest cough as a diagnostic
６）

However, if patients with CC-like symptoms had adeterminant . However, coughing was notnegative RIDT result and were positive for MSTI-

associated with a high sensitivity or specificity in

OD1, they were more likely to have CC than IA.

this study, which may have aﬀected the guidelines

Therefore, these criteria may contribute to thefor RIDT use. Some patients with IA who tested

accurate diagnosis of IA.

negative in the RIDT may have been included in

Patients who were taking oral medications were

the CC group. However, these patients could not be

excluded from the study. As many patients with

excluded from this study. In a previous study８）, thecold-like symptoms take over-the-counter drugs,

sensitivity, specificity, LH+, and LH- were 19%,

excluding them is not a suitable diagnostic tool for

99%, 19.9, and 0.82, respectively, in the CC groupclinical practice.

(n = 32) with the MSTI-OD1 (n = 6). The values

This study had several limitations. First, thein the previous study exceeded those in the current

selection of onset-defining symptoms may havestudy, implying a higher clinical significance ofintroduced a bias. Second, this study did not

MSTI-OD1 positivity compared with that suggested

consider the inherent differences between theby our present results. The number of patientspatients who were more likely to have positive andwith MSTI-OD1 who were diagnosed with IA did

negative RIDT results. Third, as only one researcher

９）

not depend on the accuracy of RIDT . However,conducted this study, the inter-rater reliability of

depending on the RIDT kit type, patients with IA

diagnostic categorization is unknown and should be

may be misdiagnosed with CC owing to the low test

assessed in the future. Fourth, recall and reporting

sensitivity. As MSTI-OD1 may appear before thebiases might have affected data collection, as the8Kawasaki Medical Journalpatients only reported their symptoms in response

B, Senn N: Development and validation of a clinicalto a direct question. Fifth, this study only included

decision rule for the diagnosis of influenza. J Am

patients with fever; hence, future studies should
expand the participant eligibility. Finally, themethods utilized did not differentiate between CC
and IA over a period of less than a day.
In conclusion, during the IA season, MSTI, cough,rhinorrhea, sore throat, and headache appeared ondays other than day 1 before or after the onset ofBoard Fam Med. 2012; 25: 55-62. doi: 10.3122/
jabfm.2012.01.110161.
４）Fitzner J, Qasmieh S, Mounts AW, et al.: Revision ofclinical case deﬁnitions: inﬂuenza-like illness and severe
acute respiratory infection. Bull World Health Organ.
2018; 96: 122-128. doi: 10.2471/BLT.17.194514.
５）Dugas AF, Hsieh YH, LoVecchio F, Moran GJ, Steele
MT, Talan DA, Rothman RE, Emergency Department

fever and were more likely caused by CC than IA.

National Influenza Network Investigators: Derivation

Thus, our results may diﬀer between patients withand Validation of a Clinical Decision Guideline for

CC and IA during an IA epidemic.
ACKNOWLEDGEMENTS
We thank Yutaka Iguchi for the statistical guidance(https://biolab.sakura.ne.jp/). Editorial support in
the form of medical writing, assembling tables, andInﬂuenza testing in 4 US Emergency Departments. Clin
Infect Dis. 2020; 70: 49-58. doi: 10.1093/cid/ciz171.
６）Call SA, Vollenweider MA, Hornung CA, Simel DL,
McKinney WP: Does this patient have inﬂuenza? JAMA.
2005; 293: 987-997. doi: 10.1001/jama.293.8.987.
７）World Health Organization: ICD-10: International
Statistical Classification of Diseases and Related

creating high-resolution images based on authors’

Problems: tenth revision, 2nd ed Geneva, DIMDI. 2004.

detailed directions, collating authors’comments,

８）Gomi S: Short-term insomnia and common cold: A

copyediting, fact-checking, and referencing, wasprovided by Editage, Cactus Communications.
FUNDING
This study did not receive any speciﬁc grants fromfunding agencies in the public, commercial, or notfor-proﬁt sectors.

cross-sectional study. J Gen Fam Med. 2019; 20: 244250. doi: 10.1002/jgf2.278.
９）Sakai-Tagawa Y, Ozawa M, Yamada S, Uchida Y,
Saito T, Takahashi K, Sugaya N Tashiro M, Kawaoka
Y: Detection sensitivity of influenza rapid diagnostic
tests. Microbiol Immunol. 2014; 58: 600-606. doi:
10.1111/1348-0421.12185.
10）Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein
AR: A simulation study of the number of events

DECLARATIONS OF INTERESTNone
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