IJCDS Journal

Introduction

Chronic Obstructive Pulmonary Disease (COPD), ranked as the fourth leading global cause of death [1], and characterized by persistent respiratory symptoms and airflow limitation due to exposure to noxious particles or gases. Emerging evidence suggesting that COPD is not solely a pulmonary disease but may involve systemic inflammation, which could contribute to vascular changes and increase the risk of stroke. A few population-based studies [2] shows that colder temperatures have been shown to increase hospitalization and mortality rates in adults with COPD and cardiac disease [3]. Both COPD and stroke share common risk factors such as smoking, advanced age, and cardiovascular diseases. Each year, approximately 15,000 cases of stroke occur in Israel, of which about 85% are Acute Ischemic Stroke (AIS). Acute ischemic stroke is the third most common cause of chronic disability and the second cause of mortality in the Western world [4,5]. Mortality within 30 days of the stroke reaches up to 23%; about half of those who survive the event are likely to remain with a functional disability of varying degrees and about 40% with cognitive neurologic deficits.

The association between acute stroke and COPD has garnered increasing attention within the neurological field. Studies consistently indicated a notable prevalence of COPD among individuals who have experienced acute stroke. Recent data showed increased incidence of AIS in patients with COPD, [6-8] especially in the first two years after diagnosis. This interconnection is complex, involving shared risk factors such as smoking, advanced age, and cardiovascular conditions [9-13]. Moreover, the coexistence of COPD and acute stroke appears to be associated with adverse outcomes, potentially amplifying the challenges in the management of affected individuals [14]. One study found that 11.71% of adult patients hospitalized for stroke had COPD, with in-hospital mortality rates of 6.33%. The study revealed a modest but significant independent association between COPD and overall stroke mortality [14].

Understanding the intricate relationship between these two prevalent health issues is essential for optimizing patient care strategies and enhancing our comprehension of the broader impact that respiratory and cerebrovascular conditions can exert on one another. In this study, we investigated the seasonal variations and weekly distribution of patients with AIS and COPD in northern Israel, comparing them with a control group of AIS patients without COPD.

Methods

Cohort selection and geographic considerations

This study was approved by our medical center IRB committee. RHCC is a tertiary hospital, the largest in northern Israel, and serves a population of about 2 million, consisting mainly of two major ethnic groups - Jews and Arabs. The coast and northern Israel plateau are characterized by a Mediterranean climate with a warm, moist summer, and a mild winter with temperatures above 10° C. We included consecutive patients with COPD and AIS between 2004 and 2018. All patients were hospitalized at our center. AIS stroke was defined as patients who presented with acute neurological deficit to our emergency room in RMC. The diagnosis in each case was established clinically and by cerebral imaging (CT/CTP/CTA/MRI). COPD was defined classically by guidelines (Reference) and was reported when appeared in patients’ medical history.

Controls matching and variables

Controls were chronologically consecutive AIS patients, negative for COPD per diagnostic codes and symptoms; they were sex age matched to the COPD group. Data points extracted for any patient included demographics, date of hospitalization (weekday or weekend, month, season) as well as all vascular risk factors. AIS was defined as accepted in American heart association guidelines [15]. Vascular risk factors were defined as follows: hypertension (new diagnosis made in hospital, regular use of antihypertensive medications or diagnosis based on previous medical records); diabetes (new diagnosis in hospital, regular use of antidiabetic medications or previous diagnosis); hyperlipidemia: regular use of hyperlipidemia drugs or previous registries-based diagnosis; smoking (by patient's statement or by previous registries diagnosis); acute or chronic atrial fibrillation (new inpatient or previous registries diagnosis); ischemic heart disease (new diagnosis or known diagnosis from previous records). Seasons were defined as: Winter: December, January, and February; Spring: March, April, and May; Summer: June, July, and August; Fall: September, October and November. Friday and Saturday were defined as Weekend. A "warm" half-year was defined as the period from May to October.

Statistical Methods

All captured data was based on digitalized information collected from our computerized medical system capturing patients’ data from birth including HMO based information. To examine potential differences in weekly, monthly, and seasonal variability in hospitalization, we hypothesized that a random chance would be as follows: A 2:5 ratio for weekends versus weekdays, 1/12 per month per year, 1/4 probability for each season and 1/2 probability for each half-year. The main statistical analysis included chi-square tests of ratio True vs. Expected Probability of Randomized Scattering. The number of cases between weekends/weekends, months, seasons, and half-year were examined. When significant differences between true and expected probabilities were detected, subtests were performed based on a reference point defined as the time with the smallest number of cases. To examine the effect of the time of hospitalization on hospital stay, we performed another statistical analysis using the Wilcoxon non-parametric test, which was the result of the non-normal dispersal of the data. USA).

Results

Demographics and risk factors

We identified 329 consecutive hospitalizations of patients with COPD due to AIS, parallel with 347 AIS patients without COPD as age sex matched controls. The mean age of at the time of AIS in COPD groups was 74.9 ± 10.7 years versus 75.2 ± 11.5 years in the non-COPD group. Two hundred and seventeen patients (66%) in the COPD group and 204 patients in (58.8%) in the control group were males, NS. Distribution of vascular disease and vascular risk factors in patients of both groups shown in Table 1.  COPD group had significantly more risk factors including hypertension, hyperlipidemia, smoking, and ischemic heart disease.

*IHD=Ischemic Heart Disease

Table 1: Distribution of vascular risk factors and vascular diseases in AIS patients with and without COPD.

Seasonal variables

Distribution of hospitalizations by months, seasons and half-years are shown in Tables 2, 3 and 4. February was the month with the highest number of AIS in the COPD group, when the maximum admissions in the control group were in February and March, NS. Winter was the season with the maximum number of admissions in both groups, without a statistical difference in the whole distribution by seasons between groups. In addition, no difference was found in the half-year distribution of strokes between groups, when more strokes occurred in a cold half-year in both groups.  A statistically significant difference between the groups was found only in distribution of AIS by weekdays/weekends. In COPD patients, the number of AIS was higher on weekends as compared with the control group (90 (27.36%) AIS on weekends in the COPD group vs 59 (17%) AIS in the control group, p=0.0011, Table 5.

Table 3: Distribution of admissions by season in AIS patients with and without COPD.

Table 4: Distribution of admissions by half-year (cold-warm) in AIS patients with and without COPD.

Discussion

This study examines the seasonal, monthly, and weekly patterns of hospitalizations for ischemic stroke through a comparative analysis with an age- and sex-matched control group lacking COPD. Both groups exhibit congruent distributions, characterized by heightened hospitalizations during winter and a subsequent decline in summer. Notably, maximal hospitalization rates coincide in February and March for both cohorts. These findings align with existing literature on increased cardiovascular and cerebrovascular disease prevalence, including acute ischemic stroke, during winter months [16]. Results reveal a uniformity in seasonal, half-yearly, and monthly distributions for hospitalizations due to acute ischemic stroke in both cohorts. 

In most studies, AIS rates were higher in winter compared to summer [17,18]. However, in some studies, there were no seasonal differences at all, [19,20] while an increased prevalence of AIS was found in spring in others [21]. There are several studies demonstrating the increased incidence of COPD exacerbations in the winter season compared to summer [3,22,23]. The reasons are attributed to a high rate of viral respiratory diseases, lower levels of vitamin D in winter compared to summer [24,25] systemic inflammation and oxidative stress. There are some data on the possible association between seasonality and various components of AIS in COPD patients. One study suggests that, despite the increased incidence of AIS among COPD patients, COPD is not an independent risk factor for ischemic stroke [7].

The only significant finding in our study was the higher number of admissions of AIS patients with COPD on weekends as compared with the control group, Table 5. The data about weekly AIS distribution may also be found in the literature, but to a smaller extent than about seasonal variations. Here, also, various studies brought contradictory findings, some of which showed an increased prevalence of hospitalizations due to AIS on the first day of the week upon return to work [12,26,27], while no significant weekly differences were found in others. To the best of our knowledge, there is no data in the literature comparing rates of admissions in AIS patients with and without COPD on weekdays and weekends. Fewer admissions on weekends in AIS patients without COPD as compared with AIS patients with COPD may point to COPD as an independent risk factor for AIS, which is not influenced by stress or other psychosocial factors changing on weekends and influencing AIS patients without COPD.

The current study is subject to several limitations. Firstly, it is a retrospective, hospital-based investigation, entailing inherent constraints associated with this study design. Secondly, cases exhibiting subacute ischemic strokes upon imaging were excluded from the study. Thirdly, the sample size of the COPD patient group with stroke is relatively modest.

In conclusion, the results of the study indicate some impact of the chronobiological factors on AIS in COPD patients. We were not able to show any seasonal or monthly differences in the distribution of admissions in stroke patients of both groups. However, we did find differences on weekend and weekday admission rates in stroke patients with and without COPD. Identifying the specific mechanisms responsible for this difference requires further research.

Statement of Ethics and Acknowledgments

This study protocol was reviewed and approved by Rambam medical center ethics committee. Written informed consent was not required, the study has been granted an exemption from requiring written informed consent by the same committee. 

We have no acknowledgment to declare.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions    

H. E contributed to the design and implementation of the research, and to the writing of the manuscript.

H. M contributed to the writing of the manuscript.

S. E contributed to the writing of the manuscript.

H. R contributed to the writing of the manuscript.

T. G contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.

S. S contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.

Data Availability Statement

Data is available per reasonable request  

References

1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, et al. (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095-2128.
2. Donaldson GC, Goldring JJ, Wedzicha JA (2012) Influence of season on exacerbation characteristics in patients with COPD. Chest 141: 94-100.
3. So JY, Zhao H, Voelker H, Reed RM, Sin D, et al. (2018) Seasonal and Regional Variations in Chronic Obstructive Pulmonary Disease Exacerbation Rates in Adults without Cardiovascular Risk Factors. Ann Am Thorac Soc 15: 1296-1303.
4. Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D, et al. (2006) Long-term mortality after intracerebral hemorrhage. Neurology 66: 1182-1186.
5. Donkor ES (2018) Stroke in the 21^st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke Res Treat 2018: 3238165.
6. Austin V, Crack PJ, Bozinovski S, Miller AA, Vlahos R (2016) COPD and stroke: are systemic inflammation and oxidative stress the missing links? Clin Sci (Lond) 130: 1039-1050.
7. Corlateanu A, Covantev S, Mathioudakis AG, Botnaru V, Cazzola M, et al. (2018) Chronic Obstructive Pulmonary Disease and Stroke. COPD 15: 405-413.
8. Lahousse L, Tiemeier H, Ikram MA, Brusselle GG (2015) Chronic obstructive pulmonary disease and cerebrovascular disease: A comprehensive review. Respir Med 109: 1371-1380.
9. Shinkawa A, Ueda K, Hasuo Y, Kiyohara Y, Fujishima M (1990) Seasonal variation in stroke incidence in Hisayama, Japan. Stroke 21: 1262-1267.
10. Gallerani M, Trappella G, Manfredini R, Pasin M, Napolitano M, et al. (1994) Acute intracerebral haemorrhage: circadian and circannual patterns of onset. Acta Neurol Scand 89: 280-286.
11. Diaz A, Gerschcovich ER, Diaz AA, Antia F, Gonorazky S (2013) Seasonal variation and trends in stroke hospitalizations and mortality in a South American community hospital. J Stroke Cerebrovasc Dis 22: e66-69.
12. Wang H, Sekine M, Chen X, Kagamimori S (2002) A study of weekly and seasonal variation of stroke onset. Int J Biometeorol 47: 13-20.
13. Inagawa T (2003) Diurnal and seasonal variations in the onset of primary intracerebral hemorrhage in individuals living in Izumo City, Japan. J Neurosurg 98: 326-36.
14. Lekoubou A, Ovbiagele B (2017) Prevalance and Influence of Chronic Obstructive Pulmonary Disease on Stroke Outcomes in Hospitalized Stroke Patients. eNeurological Sci  6: 21-24.
15. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, et al. (2018) 2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke 49: e46-e110.
16. Hamedani AG, Thibault D, Willis AW (2013) Seasonal Variation in Neurologic Hospitalizations in the United States. Ann Neurol 93: 743-751.
17. Turin TC, Kita Y, Murakami Y, Rumana N, Sugihara H, et al. (2008) Higher stroke incidence in the spring season regardless of conventional risk factors: Takashima Stroke Registry, Japan, 1988-2001. Stroke 39: 745-752.
18. Li Y, Zhou Z, Chen N, He L, Zhou M (2019) Seasonal variation in the occurrence of ischemic stroke: A meta-analysis. Environ Geochem Health 41: 2113-2130.
19. Feigin VL, Nikitin YP, Bots ML, Vinogradova TE, Grobbee DE (2000) A population-based study of the associations of stroke occurrence with weather parameters in Siberia, Russia (1982-92). Eur J Neurol 7: 171-178.
20. Jakovljevic D, Salomaa V, Sivenius J, Tamminen M, Sarti C, et al. (1996) Seasonal variation in the occurrence of stroke in a Finnish adult population. The FINMONICA Stroke Register. Finnish Monitoring Trends and Determinants in Cardiovascular Disease. Stroke 27: 1774-1779.
21. Karagiannis A, Tziomalos K, Mikhailidis DP, Semertzidis P, Kountana E, et al. (2010) Seasonal variation in the occurrence of stroke in Northern Greece: a 10 year study in 8204 patients. Neurol Res 32: 326-331.
22. Wise RA, Calverley PM, Carter K, Clerisme-Beaty E, Metzdorf N, et al. (2018) Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR((R)) trial. Int J Chron Obstruct Pulmon Dis 13: 605-616.
23. Wilkinson TMA, Aris E, Bourne S, Clarke SC, Peeters M, et al. (2017) A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD. Thorax 72: 919-927.
24. Zhu M, Wang T, Wang C, Ji Y (2016) The association between vitamin D and COPD risk, severity, and exacerbation: an updated systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis 11: 2597-2607.
25. Jolliffe DA, Greenberg L, Hooper RL, Mathyssen C, Rafiq R, et al. (2019) Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 74: 337-345.
26. Baldwin HJ, Marashi-Pour S, Chen HY, Kaldor J, Sutherland K, et al. (2018) Is the weekend effect really ubiquitous? A retrospective clinical cohort analysis of 30-day mortality by day of week and time of day using linked population data from New South Wales, Australia. BMJ Open 8: e016943.
27. Lin HC, Lin SY, Lee HC, Hu CJ, Choy CS (2008) Weekly pattern of stroke onset in an Asian country: A nationwide population-based study. Chronobiol Int 25: 788-799.