Association of Symptoms of Chronic Bronchitis and Frequent Flu-Like Illnesses With Stroke

Association of Symptoms of Chronic Bronchitis and
                Frequent Flu-Like Illnesses With Stroke
     Armin J. Grau, MD, PhD; Michael R. Preusch, MD; Frederik Palm, MD; Christoph Lichy, MD;
                             Heiko Becher, PhD; Florian Buggle, MD

Background and Purpose—Acute and several chronic infectious diseases increase the risk of stroke. We tested the
  hypothesis that chronic bronchitis and frequent flu-like illnesses are independently associated with the risk of stroke or
  transient ischemic attack (TIA).
Methods—We assessed symptoms of chronic bronchitis, frequency of flu-like illnesses, and behavior during acute febrile
  infection in 370 consecutive patients with ischemic or hemorrhagic stroke or TIA and 370 age- and sex-matched control
  subjects randomly selected from the population.
Results—Cough with phlegm during ⱖ3 months per year (grade 2 symptoms of chronic bronchitis) was associated with
  stroke or TIA independent from smoking history, other risk factors, and school education (odds ratio [OR] 2.63, 95%
  confidence interval [CI] 1.17 to 5.94; P⫽0.021). There was also an independent association between frequent flu-like
  infections (⬎2 per yr) and stroke/TIA (OR 3.54; 95% CI 1.52 to 8.27; P⫽0.003). Simultaneous assessment of chronic
  bronchitis and frequent flu-like infections did not attenuate the effect of either factor. Patients reported more often than
  control subjects to continue to work despite febrile infection (OR 3.68, 95% CI 1.80 to 7.52, multivariate analysis).
Conclusions—Our results suggest that chronic bronchitis is among those chronic infections that increase the risk of stroke.
  Independent from chronic bronchitis, a high frequency of flu-like illnesses may also be a stroke risk factor.
  Infection-related behavior may differ between stroke patients and control subjects. (Stroke. 2009;40:3206-3210.)
                                     Key Words: stroke 䡲 prevention 䡲 risk factor 䡲 infection

S    everal studies convincingly show that acute infection and
     particularly respiratory tract infection temporarily in-
creases the risk of stroke.1 Common chronic infections such
                                                                              We investigated 370 consecutive patients admitted to the Neurology
                                                                              Department of the University of Heidelberg for ischemic or hemor-
                                                                              rhagic stroke or TIA and 370 control subjects randomly selected
as periodontitis or infection with Helicobacter pylori may                    from the general population between November 2001 and April
also increase stroke risk.2 In a large cohort study, symptoms                 2003. Exclusion criteria were age ⬎80 years (⬎75 years after the
of chronic bronchitis independently predicted both incidence                  first 6 months of the study), residence outside the study area (city of
and mortality of coronary heart disease.3 Data on chronic                     Heidelberg and the neighboring county), and inability to give
                                                                              informed consent. Among 385 eligible patients, 370 (96.1%) agreed
respiratory infection and stroke are scarce. Two previous                     to study participation. All patients received a cranial CT or MRI
case– control studies reported that a history of recurrent or                 scan, extra- and transcranial Doppler sonography, ECG, and in most
chronic bronchitis is associated with stroke risk.4,5                         cases transthoracic or transesophageal echocardiography and Holter
   Chronic bronchitis is characterized by excessive tracheo-                  monitoring. Ischemic stroke was defined as either a central nervous
                                                                              deficit lasting ⱖ24 hours without evidence for nonvascular cause or
bronchial mucus production sufficient to cause cough with                     cerebral hemorrhage or by a new ischemic lesion on neuroimaging
expectoration for at least 3 months of the year. Bronchitic                   (including abnormalities on diffusion-weighted images unless only
inflammation predominantly consists of neutrophils and is                     detected after the first hours post ischemia) corresponding to acute
associated with systemic inflammation. There is a continuum                   neurological symptoms regardless of duration of symptoms. Diag-
                                                                              nosis of intracerebral hemorrhage was based on neuroradiological
and overlap between chronic bronchitis and chronic obstruc-                   evidence. TIA was diagnosed if a neurological deficit of vascular
tive lung disease (COLD), emphysema, or asthma.6                              origin lasted ⬍24 hours without new corresponding vascular lesion
   We performed a case– control study7,8 to investigate                       on neuroimaging. The TOAST criteria were used for further subtyp-
                                                                              ing cerebral ischemia.9
whether symptoms of chronic bronchitis or frequent acute
                                                                                 From the Inhabitant Registration Administration of our area we
flu-like illnesses are independently associated with the risk of              received a list containing name, age, sex, and address of a random
stroke or TIA.                                                                sample of 2% of all adult inhabitants aged ⱕ80 years. All inhabitants

  Received June 19, 2009; accepted July 10, 2009.
  From the Department of Neurology (A.J.G., F.P., F.B.), Klinikum der Stadt Ludwigshafen a.Rh; and the Departments of Internal Medicine III (M.R.P.),
Neurology (C.L.), and Tropical Hygiene and Public Health (H.B.), University of Heidelberg, Germany.
  Correspondence to Armin J. Grau, MD, PhD, Department of Neurology, Klinikum der Stadt Ludwigshafen a.Rh., Bremserstr. 79, 67063 Ludwigshafen
a.Rh., Germany. E-mail
  © 2009 American Heart Association, Inc.
  Stroke is available at                                                    DOI: 10.1161/STROKEAHA.109.561019

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Grau et al          Chronic Bronchitis, Frequent Respiratory Infection, and Stroke Risk                            3207

have to be registered there according to German law. Control             Table 1. Demographic Data, Risk Factors and Previous
subjects were randomly selected from this sample and matched to          Diseases in Patients and Control Subjects
patients one-to-one for age (⫾2 years), sex, and area of residence.
Within 1 week after a patient was included the first matching subject    Parameter                      Patients       Control Subjects   P Value
that could be identified in the random sample was contacted by mail      Age, mean y⫾SD               60.7⫾12.8          60.6⫾12.7
and thereafter by phone. Among 430 subjects who could be con-
tacted by phone, 370 (86.0%) agreed to study participation. The          Female sex                 115/370 (31.1%)    115/370 (31.1%)
Neurology Department of University of Heidelberg is the only             Symptoms of chronic         63/367 (17.2%)     33/368 (9.0%)      0.001
neurological hospital in the area, and most younger patients with        bronchitis (grade 1)
stroke/TIA (⬍75 years) are admitted there. Therefore, the patients       Symptoms of chronic         37/367 (10.1%)     18/368 (4.9%)      0.008
examined are reflective of the population of the surrounding area. All   bronchitis (grade 2)
subjects were interviewed by trained interviewers using a structured
questionnaire. Interviews were performed face-to-face in patients        Self-estimated mean
and by phone in control subjects. To avoid any classification bias       annual episodes of
between groups, self-reported risk factors and diseases were ac-         flu-like illness or cold
knowledged if subjects affirmed that a physician had made the              ⬍1                            66 (19.4 %)        59 (16.8%)     0.36
respective diagnosis before stroke or interview. The ethics commit-
                                                                           1                            158 (46.5%)        186 (52.8%)     0.09
tee approved the study protocol. All subjects gave informed consent.
   Symptoms of chronic bronchitis were assessed by 3 questions             2                             83 (24.4%)         89 (25.3%)     0.79
using the modification by Jousilahti and coworkers of the respiratory      ⬎2                            33 (9.7 %)         18 (5.1%)      0.021
questionnaire by Rose and Blackburn: (1) Do you usually have
                                                                         Behavior in febrile                                              ⬍0.001
cough with phlegm in the mornings in the winter? (2) Do you usually
have cough with phlegm during the day or at night in the winter? (3)     infection‡
And do you cough like this on most days or nights as much as 3           Visit a physician               80 (22.2%)         65 (17.8%)     0.14
months each year? Positive answers in either or both of the 2 first      Start self-treatment           161 (44.6%)        223 (61.4%)    ⬍0.0001
questions were classified as grade-1 symptoms, positive answers in       and rest
the third question were classified as grade-2 symptoms of chronic
bronchitis.3 Participants were furthermore asked how often they          Rest without any                69 (19.1%)         57 (15.6%)     0.21
suffered from acute respiratory tract infection or flu-like illness on   treatment
average during the last 5 years. Acute respiratory tract infection or    Continue to work                51 (14.1%)         19 (5.2%)     ⬍0.0001
flu-like illness was defined as any combination of fever or shivering,   Arterial hypertension      217/369 (58.8%)    151/370 (40.8%)    ⬍0.0001
cough, hoarseness, running nose, or sore throat lasting ⱖ3 days. To
assess infection-related behavior, subjects were asked the following     Diabetes mellitus           81/369 (22.0%)     49/370 (13.2%)     0.0019
question: Imagine you develop symptoms of a flu with fever of 39°C,      Hyperlipidemia             143/370 (38.7%)    114/370 (30.8%)     0.025
malaise, and arthralgia on one evening. What would you do if
                                                                         Previous stroke             69/370 (18.7%)     21/370 (5.7%)     ⬍0.0001
symptoms have not resolved the next morning? Subjects had to select
1 of the following 4 answers: (1) I go and see a physician; (2) I take   Previous TIA                74/327 (22.6%)     17/363 (4.7%)     ⬍0.0001
my house medication and rest; (3) I rest and wait at least 1 further     Myocardial infarction       37/370 (10.0%)     24/370 (6.5%)      0.082
day before any further action; (4) I continue as usual (eg, I go to
                                                                         Angina pectoris             42/352 (11.9%)     30/365 (8.2%)      0.098
work) expecting that symptoms resolve soon.
                                                                         Peripheral arterial         70/368 (18.9%)     45/370 (12.2%)     0.011
Statistical Analysis                                                     disease
Dichotomous variables were compared using ␹2 test. Odds ratios and       Current smoking            105/369 (28.5%)     70/370 (18.9%)     0.0023
95% confidence intervals (CI) are given for all risk factors. Condi-     Previous smoking           126/337 (37.4%)    131/362 (36.2%)     0.74
tional logistic regression analysis for matched pairs was used to
adjust for other variables and included all generally accepted stroke    Never smoking              106/337 (31.5%)    161/362 (44.5%)     0.0004
risk factors and associated diseases (hypertension, diabetes mellitus,   Alcohol consumption                                               0.0002
smoking, previous stroke/TIA, hyperlipidemia, coronary heart dis-          Never                         90 (24.4%)         57 (15.4%)     0.0022
ease) plus all those factors that were significant (P⬍0.05) in
univariate analysis. For analyses of an interaction between parame-        ⬍1 portion per               173 (46.9%)        215 (58.1%)
ters, an interaction term was introduced into the model. Because of        day
lower numbers of subjects, a reduced model was used for subgroup           1 portion per day             65 (17.6%)         77 (20.8%)
analyses containing only those risk factors that were significant in
                                                                           ⬎1 portion per                41 (11.1%)         21 (5.7%)      0.0077
multivariable analyses with all subjects. Patients with missing values
were excluded from the analyses. Data were analyzed using the
software package SAS.                                                    Body mass index            199/362 (55.0%)    180/368 (48.9%)     0.10
                             Results                                     Family history of          123/370 (33.2%)     79/370 (21.4%)     0.0003
Among the 370 patients, 244 had ischemic stroke, 76 had a                stroke
TIA, and 44 suffered from hemorrhagic stroke. As compared                School education*                                                 0.0050
to control subjects patients reported more often grade 1                   Lower level                  256 (71.3%)        219 (60.0%)
symptoms (OR 2.35, 95% CI 1.44 to 3.83; P⫽0.001) and                       Medium level                  44 (12.3%)         57 (15.6%)
grade 2 symptoms (OR 2.67; 95% CI 1.37 to 5.18; P⫽0.008)                   Higher level                  59 (16.4%)         89 (24.4%)
of chronic bronchitis (Table 1). Table 1 also depicts other risk
                                                                           *Final school exam after 9 school years (lower level), 10 school years
factors and diseases, many of which show significant differ-
                                                                         (medium level), or ⬎10 school years (higher level).
ences between groups. After adjustment for all covariables,
grade 2 symptoms of chronic bronchitis were significantly
associated with stroke or TIA (OR 2.63, 95% CI 1.17 to 5.94;
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3208           Stroke           October 2009

Table 2. Multivariate Analysis With Symptoms of Chronic                                 was lower in women than in men in both groups, and chronic
Bronchitis and Other Variables                                                          bronchitis was associated with stroke/TIA in men but not in
                                   Odds           95% confidence                        women (Table 3).
Risk Factor                        Ratio             Interval           P Value            Symptoms of chronic bronchitis increased the odds of
Chronic bronchitis                 2.63             1.17–5.94           0.020           stroke/TIA independent of current or previous smoking and
(Grade 2 symptoms)                                                                      within the model of Table 2 current smoking and symptoms
Hypertension                       1.98             1.32–2.98           0.001           of chronic bronchitis did not interact with each other
Diabetes mellitus                  1.14             0.63–2.04           0.67            (P⫽0.89). Frequency of chronic bronchitis was highest in
                                                                                        current smokers and lowest in never smokers among patients,
Hyperlipidemia                     1.23             0.81–1.87           0.33
                                                                                        and a similar trend was seen in control subjects (Table 3). The
Previous stroke/TIA                6.29             3.36–11.8         ⬍0.0001
                                                                                        mean number of cigarettes currently smoked by patients
Peripheral arterial                0.97             0.54–1.72           0.91
                                                                                        (19.4⫾11.7 per day) and control subjects (16.5⫾11.3 per
                                                                                        day) was not different (P⫽0.10). Symptoms of chronic
Current smoking                    1.74             1.05–2.91           0.033
                                                                                        bronchitis tended to be associated with increased odds of
Previous smoking                   0.98             0.59–1.63           0.94            stroke/TIA in current smokers, previous smokers, and never
Alcohol abstinence                 1.81             1.06–3.10           0.031           smokers, however a significant association was only found in
High alcohol                       2.71             1.18–6.24           0.019           previous smokers in univariate analysis (Table 3).
consumption                                                                                Symptoms of chronic bronchitis increased the odds of
Family history of                  1.65             1.04–2.61           0.032           stroke/TIA in subjects with lower level school education in
stroke                                                                                  univariate analysis and a strong trend was present after
School education                   1.53             1.01–2.33           0.046           adjustment for potential confounders, whereas no such effect
⬍10 years
                                                                                        was present in better educated subjects (Table 3). Grade 2
                                                                                        symptoms of chronic bronchitis were associated with in-
P⫽0.020; Table 2). Grade 1 symptoms of chronic bronchitis                               creased odds of ischemic stroke and of stroke/TIA attribut-
were also independently correlated with stroke/TIA (OR                                  able to large artery atherosclerosis and tended to increase the
3.11; 95% CI 1.64 to 5.91; P⫽0.0005). Effect size of                                    odds of cardioembolic stroke/TIA (Table 3).
symptoms of chronic bronchitis was not different between                                   Addition of influenza or pneumococcal vaccination during
younger and older patients. Prevalence of chronic bronchitis                            the last year to the model in Table 2 attenuates the risk

                 Table 3.      Symptoms (Grade 2) of Chronic Bronchitis and Risk of Stroke/TIA: Subgroup Analyses
                                                                        Prevalence of Chronic

                                                                                        Control            Odds Ratio                Odds Ratio*
                 Group of Subjects                                     Patients        Subjects       (Univariate Analysis)     (Multivariate Analysis)
                 Age ⬍60 years (n⫽149)                                  10.1%            4.1%           3.00 (0.97–9.30)          3.02 (0.90 –10.1)
                 Age ⱖ60 years (n⫽221)                                  10.1%            5.4%           2.37 (1.04–5.42)          2.24 (0.91–5.51)
                 Women (n⫽115)                                           4.4%            3.5%           1.33 (0.30–5.96)          1.02 (0.21–5.06)
                 Men (n⫽155)                                            12.7%            5.5%           3.11 (1.47–6.59)          3.25 (1.43–7.41)
                 Current smokers (n⫽105)                                15.2%           10.0%           1.62 (0.63–4.16)          1.78 (0.65–4.86)
                 Prev. smokers (n⫽126)                                  11.2%            3.9%           3.13 (1.09–8.96)          2.66 (0.86–8.26)
                 Never smokers (n⫽106)                                   5.1%            3.6%           1.55 (0.49–4.94)          1.48 (0.44–4.97)
                 Low-level school education (n⫽256)                     11.0%            5.5%           2.12 (1.05–4.27)          1.93 (0.92–4.05)
                 Medium-/high–level school education (n⫽103)             7.8%            4.1%           1.33 (0.46–3.84)          1.06 (0.31–3.57)
                 Etiologic subgroups
                      Ischemic stroke (n⫽244)                           11.5%            6.2%           2.30 (1.09–4.83)          2.45 (1.10–5.46)
                      TIA (n⫽76)                                         5.3%            1.3%           4.00 (0.45–35.8)          3.32 (0.23–48.4)
                      Hemorrhagic stroke (n⫽44)                         12.5%            5.0%           4.99 (0.58–42.8)          8.66 (0.52–144)
                      Etiologic subgroups of ischemic stroke/TIA
                      Large artery atherosclerosis (n⫽130)              11.5%            5.4%           3.00 (0.97–9.3)           4.77 (1.18–19.3)
                      Cardioembolism (n⫽63)                             12.7%            1.6%           8.00 (1.00–64)            6.75 (0.76–59.9)
                      Microangiopathy (n⫽30)                             6.7%            3.3%           2.00 (0.18–22.1)          1.85 (0.09–39.9)
                      Other etiologies (n⫽25)                            4.0%           12.0%           0.33 (0.04–3.21)          0.27 (0.019–3.93)
                      Cryptogenic (n⫽72)                                 8.5%            5.6%           2.00 (0.37–10.9)          1.45 (0.19–10.9)
                   *Adjusted for arterial hypertension, current smoking, alcohol abstinence, high alcohol consumption, family history of stroke, school

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Grau et al        Chronic Bronchitis, Frequent Respiratory Infection, and Stroke Risk                  3209

associated with grade 2 symptoms of chronic bronchitis to a            Lower socioeconomic status may be associated with higher
borderline significant level (OR 2.31; 95% CI 0.99 to 5.38).        risk of respiratory infections.14 Our data suggest that chronic
Symptoms of chronic bronchitis were associated with in-             bronchitis may play a more important role as stroke risk
creased risk of stroke/TIA during winter months (November           factor in subjects with lower than in those with higher
through April, n⫽261; OR 4.58; 95% CI 1.73 to 12.1) but not         education levels. Less educated subjects may reside in areas
significantly with those during summer months (n⫽106; OR            with more disadvantageous living conditions (eg, with higher
2.39; 95% CI 0.53 to 10.8) in multivariate analysis.                air pollution). Air pollution is an important risk factor for
   Patients reported more often than control subjects to suffer     chronic bronchitis,6 and an association with stroke was also
on average from ⬎2 episodes of flu-like illnesses annually          shown recently.15
during the last 5 years (OR 2.14; 95% CI 1.14 to 4.04;                 Symptoms of chronic bronchitis were independently asso-
P⫽0.019; Table 1). High frequency of flu-like illnesses was         ciated with ischemic stroke but not with TIA and intracere-
independently associated with the odds of stroke/TIA after          bral hemorrhage who both represented smaller groups of
adjustment for the covariables in Table 2 (OR 3.54; 95% CI 1.52     subjects. In general, subgroup analyses have to be viewed
to 8.27; P⫽0.003). Chronic bronchitis (OR 2.83; 95% CI 1.16 to      with caution because of insufficient statistical power and only
6.91) and frequent flu-like illnesses (OR 3.22; 95% CI 1.39 to      possess hypothesis-generating character. A significant asso-
7.49) were independently associated with stroke/TIA when            ciation was found for stroke/TIA attributable to large artery
simultaneously entered in the model in Table 2.                     atherosclerosis. Atherosclerosis is an inflammatory disease,
   The self-estimated reaction to symptoms of febrile infec-        and chronic inflammatory conditions (eg, rheumatoid arthri-
tion was different between groups (Table 1). More patients          tis) may promote atherogenesis and its complications.16
than control subjects reported that they would continue as          Proinflammatory changes as in chronic bronchitis can cause a
usual, including continuation of work despite high fever (OR        procoagulant state, thereby potentially increasing the risk of
2.68, 95% CI 1.59 to 4.55), and such behavioral pattern             thromboembolism (eg, cardioembolism and increased proteo-
remained associated with stroke/TIA in multivariate analysis        lytic activity) and potentially augmenting the risk of injury to
(OR 3.68, 95% CI 1.80 to 7.52). In contrast, less patients          the vascular wall and consecutive hemorrhage.2 However,
reported to use self-medication and to rest (OR 0.48, 95% CI        significant associations with cardioembolism and intracere-
0.35 to 0.66) and such self-reported attitude was also inde-        bral hemorrhage could not be shown in our study.
pendently associated with reduced odds of stroke/TIA (0.46;            Acute respiratory infection transiently increases the risk of
95% CI 0.30 to 0.68).                                               ischemic stroke.1 Therefore, a higher number of infectious
                                                                    episodes could augment the risk of cerebral ischemia. In our
                        Discussion                                  study, high frequency of respiratory infections was indepen-
Our results support the hypothesis that chronic bronchial           dently associated with stroke/TIA. These results are based on
inflammation is a risk factor for stroke. This finding strength-    subjects’ self-estimation and were not correlated with medi-
ens the concept that chronic infectious diseases of different       cal records. However, uncomplicated respiratory infection
origin may increase stroke risk.                                    does often not prompt a doctoral visit; therefore, verification
   The diagnosis of chronic bronchitis is made by history6 and      may be difficult. To the best of our knowledge, an association
commonly applied diagnostic criteria were used in our study.        between higher rates of infection and stroke risk has not been
Cough and sputum are nonspecific symptoms that can also             reported before. The cause of a higher rate of infections
result from other airway diseases or from cardiac disease.          among patients is unknown; living conditions (eg, poorer
Therefore, we use the term “symptoms of chronic bronchitis”         housing), environmental factors (eg, higher air pollution),
in accordance with previous epidemiological studies.3 Several       lifestyle factors (eg, inappropriate clothing), or genetically
confounders could explain the association between chronic           determined higher susceptibility to infection are among po-
bronchitis and stroke, particularly smoking and low socioeco-       tential explanations.
nomic status. As shown previously,10 prevalence of chronic             Acute respiratory infections are a risk factor for chronic
bronchitis varied along smoking status and was highest in           bronchitis, and vice-versa patients with chronic bronchitis
current smokers and lowest in never smokers in both groups.         more often suffer from acute exacerbations of upper airway
Symptoms of chronic bronchitis remained associated with             disease. Therefore, high frequency of respiratory infections
stroke/TIA when smoking status was adjusted for. Smoking            could influence the association between chronic bronchitis
and chronic obstructive airway disease both independently           and stroke. However, frequent infections and chronic bron-
increase the level of inflammatory markers such as C-reactive       chitis remained both significantly associated with stroke/TIA
protein,11 which is also a predictor of stroke.2 A genetically      in a combined model indicating an independent influence of
determined strong inflammatory response appears to be               both inflammatory conditions.
linked with both stroke and COLD and also influences the               The role of infections as vascular risk factor could be
association between smoking and stroke.12,13 We had hypoth-         influenced by the way subjects react to emerging infections.
esized that chronic bronchitis and smoking interact with each       Furthermore, reaction to infections may reflect subjects’
other in the sense that those current or previous smokers who       health-related lifestyle. We found that more stroke patients
react with stronger bronchial inflammation and develop              would continue to work and fewer stroke patients would use
symptoms of chronic bronchitis may have a particularly high         self-medication in acute febrile illness. Self-medication
risk of stroke; however, our data do not support such               would not include antibiotics, as those require prescription in
interaction.                                                        Germany. If such self-report is not biased by the experience
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3210        Stroke         October 2009

of stroke and in fact reflects prestroke behavior, it may                      3. Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Symptoms of chronic
represent an attitude in stroke patients that reflects greater                    bronchitis and the risk of coronary disease. Lancet. 1996;348:567–572.
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ignorance regarding health issues and less confidence in their                    A, Benesch C, Becher H, Hacke W. Association between acute cerebro-
own medical competence but possibly also more socioeco-                           vascular ischemia and chronic and recurrent infection. Stroke. 1997;28:
nomic pressure (eg, fear of unemployment).                                        1724 –1729.
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   Patients and control subjects originate from the same                          bronchitis and acute infections as new risk factors for ischemic stroke and
source population, and control subjects would have become                         the lack of protection offered by the influenza vaccination. Cerebrovasc
inpatients in the Neurology department with high probability                      Dis. 2008;26:339 –347.
                                                                               6. Honig EG, Ingram RH Jr. Chronic bronchitis, emphysema, and airways
if they suffered a stroke, constituting the comparability                         obstruction. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD,
between both groups. But several limitations exist regarding                      Martin JB, Kasper DL, Hauser SL, Longo DL (eds). Harrison’s Prin-
our study. We had to exclude severely disabled patients,                          ciples of Internal Medicine. 14th edition. New York: McGraw-Hill;
therefore results cannot be generalized to very severe and                     7. Grau AJ, Fischer B, Barth C, Ling P, Lichy C, Buggle F. Influenza
lethal strokes. Smoking history was detailed regarding current                    vaccination is associated with a reduced risk of stroke. Stroke. 2005;36:
smoking whereas calculation of pack-years was not possible                        1501–1506.
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                                                                                  Buggle F. Association between recent sports activity, sports activity in
with medical records was not performed in our study.                              young adulthood, and stroke. Stroke. 2009;40:426 – 431.
Residual confounding by factors not assessed, such as non-                     9. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL,
infectious inflammatory conditions, is possible. Furthermore,                     Marsh EE III. Classification of subtype of acute ischemic stroke. Defi-
                                                                                  nitions for use in a multicenter clinical trial. Trial of Org 10172 in Acute
differences in the interview situation and differences in the                     Stroke Treatment. Stroke. 1993;24:35– 41.
recall of previous minor diseases could have biased our                       10. Palmer KN. The role of smoking in bronchitis. BMJ. 1954;1:1473–1474.
results.                                                                      11. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic
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   In summary, our study supports the hypothesis that chronic                     review and a meta-analysis. Thorax. 2004;59:574 –580.
bronchitis is among those chronic infections that indepen-                    12. Cole JW, Brown DW, Giles WH, Stine OC, O’Connell JR, Mitchell BD,
dently increase the risk of stroke. It is possible that treatment                 Sorkin JD, Wozniak MA, Stern BJ, Sparks MJ, Dobbins MT, Shoffner
                                                                                  LT, Zappala NK, Reinhart LJ, Kittner SJ. Ischemic stroke risk, smoking,
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spectrum antibiotics, has contributed to the decline of stroke                    prevention in young women study. Thromb J. 2008;6:11.
during the last decades. It is also possible that chronic                     13. Gingo MR, Silveira LJ, Miller YE, Friedlander AL, Cosgrove GP, Chan
bronchitis that was associated with stroke only in winter                         ED, Maier LA, Bowler RP. Tumour necrosis factor gene polymorphisms
                                                                                  are associated with COPD. Eur Respir J. 2008;31:1005–1012.
months in our study contributes to the seasonal variation of                  14. Dowd JB, Zajacova A, Aiello A. Early origins of health disparities:
stroke incidence, with a peak during colder months that was                       Burden of infection, health, and socioeconomic status in U.S. children.
found in most respective studies.17 Such hypotheses deserve                       Soc Sci Med. 2009;68:699 –707.
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                            Disclosures                                           53–59.
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Association of Symptoms of Chronic Bronchitis and Frequent Flu-Like Illnesses With
Armin J. Grau, Michael R. Preusch, Frederik Palm, Christoph Lichy, Heiko Becher and Florian

            Stroke. 2009;40:3206-3210; originally published online August 13, 2009;
                            doi: 10.1161/STROKEAHA.109.561019
      Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
                    Copyright © 2009 American Heart Association, Inc. All rights reserved.
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