4.1 Hemoglobin
This study is the first to discover that the decreased hemoglobin levels at admission may predict the occurrence of UTI. Hemoglobin is a protein responsible for carrying oxygen in an organism (38). Decreased hemoglobin content in the blood will result in a relative decrease in oxygen supply to the local tissues and organs, which may result in a decrease in the metabolism of tissues and organs, thereby facilitating secondary infection. The previous study has found that bacterial infections were associated with hemoglobin levels (39). Moreover, Eneroth's research has found that patients with anemia were prone to infection, suggesting that reduced hemoglobin might be a predictor of infection (40). In addition, Kotze's study has found that low-grade inflammation was inversely related to hemoglobin content, which meant that the lower the hemoglobin content, the higher the likelihood of an inflammatory response (41). The mechanism of this phenomenon may be that hemoglobin can naturally decompose in red blood cells, and then some larger fragments are generated and secreted into the blood. These fragments are further broken down into smaller fragments which form a "hemoglobin peptide library" in different tissues. The "hemoglobin peptide library" can produce different biological effects which include "antimicrobial hemoglobin-derived peptides". Then, the "antimicrobial hemoglobin-derived peptides" can produce antibacterial effects, thereby reducing inflammation caused by microbial infections (42).
4.2 Interleukin-6, NIHSS score, and Sex
Our study found that elevated levels of interleukin-6 and higher admission NIHSS score might be used as independent risk factors to predict UTI.
Interleukin-6 is a cytokine produced by monocytes, macrophages, lymphocytes, and so on, and belongs to the class of interleukins. It is an important mediator of the acute phase of inflammation. And, it will rise in the acute phase of inflammation (43). Bacterial infections can induce normal cells to produce interleukin-6. Subsequently, the interleukin-6 will stimulate the proliferation and differentiation of cells involved in the immune response, thereby enhancing the function of these cells. Finally, through this process, interleukin-6 plays an anti-infective role (44).The results of our study found that interleukin-6 might be used for the prediction of UTI after a stroke is about the same as previous studies(16, 17, 29).
The NIHSS score can assess the severity of a patient's stroke to some extent and can roughly predict the size of the stroke area (45). Previous research found that brain injury after an ischaemic stroke could lead to immunosuppression (3) which had been related to the increased risk of infection after stroke (46). Moreover, the severity of stroke is a risk factor for post-stroke immunosuppression (47). And, a large number of studies have previously demonstrated that higher NIHSS score at admission could be used for post-stroke infection predictions (14, 32, 48-50). The results were about repeated in our trial.
Our study has found that female was an independent risk factor for urinary tract infections. The reason is caused by the particularity of the structure of the female genitourinary system. Women's urethra is shorter than men, which is more conducive to bacterial invasion. Moreover, the female urethra is close to the vagina and anus which contain a lot of bacteria. And, vaginal secretions are also a good medium for bacteria to multiply. These conditions can be used to explain that women are more likely to get a urinary tract infection. At the same time, previous research has reached the same conclusion (51).
4.3 Smoking
Interestingly, our study found that smoking history was a protective factor for urinary tract infection after ischemic stroke. The phenomenon of protective effects on smoking was first discovered in the field of heart disease. In coronary myocardial infarction, patients with a history of smoking had a lower incidence, mortality, and myocardial reinfarction rate than those without a history of smoking. The study also found that no smoking history was an independent risk factor for myocardial infarction recurrence (52). Moreover, after an acute myocardial infarction, smokers exhibited a better clinical outcome than patients who have never smoked. In addition, coronary angiography showed that the area of coronary artery lesions in smokers was smaller (53). However, the above study only evaluated the history of smoking at admission and did not conduct subsequent assessments. It is speculated that the sudden cessation of smoking after admission may be used to explain the phenomenon of lower recurrent myocardial infarction and a better prognosis in patients with a history of smoking (54, 55).
Later, some studies also found that smokers showed a better prognosis in acute myocardial infarction (56-58). Novo summarized previous studies and speculated that possible causes of good prognosis in hospitalized patients with acute myocardial infarction included: (1) younger and less associated disease; (2) higher pre-hospital mortality; (3) smoking was more likely to cause myocardial infarction caused by thrombosis, which made patients obtain a better thrombolytic effect; (4) smoking could cause a protective effect similar to ischemic preconditioning. Moreover, he described the phenomenon of ischemic preconditioning in his research. It referred to a transient ischemic stimulus which gave cardiomyocytes better tolerance to subsequent ischemic events. The protective effect of ischemic preconditioning depended on functional channels of gap junction intercellular communication, which were specialized intercellular contacts that allowed electrical impulse propagation among cardiomyocytes. The main structure of the gap junction was composed of connexin 43, which played a major role in ischemic preconditioning. In addition, smoking could induce gap junction remodeling of cardiomyocytes, thereby increasing the function of gap junctions. And, the enhanced function could better protect cells. This phenomenon might explain the better prognosis in patients with myocardial infarction who had a history of smoking (59).
Previous research found that gap junctions existed between cells of various tissues, except for blood cells and skeletal muscle cells. Moreover, they were widely present between urinary tract cells, bronchial epithelial cells, alveolar epithelial cells, alveolar macrophages, smooth muscle cells, and pulmonary artery endothelial cells. The gap junction could help the cilia to clear the mucus, facilitate the secretion of alveolar surfactant, and promote the synchronous contraction of pulmonary vascular smooth muscle cells. It could also fight the lung inflammation and may even have a therapeutic effect on lung inflammation (60). Besides, connexin 43 could increase pulmonary vascular permeability, which was more conducive to anti-inflammatory cells to fight infection (61). So we speculate that gap junctions in urinary tract cells may also exert anti-inflammatory effects in the same way.
Since previous studies have found that smoking had a protective effect on the damage caused by acute myocardial infarction, then we have reason to speculate that smoking may exert anti-inflammatory effects by inducing remodeling of gap junctions. Moreover, isoflurane pretreatment can reduce the release of proinflammatory factors in the lungs and the mortality caused by sepsis (62). Pretreatment with sevoflurane and isoflurane can reduce the body's inflammatory response and pneumonia damage caused by sepsis (63). Cigarette smoke contains alkane components. It is speculated that smoking may have a similar pretreatment effect. Smoking thus has a similar protective effect on ischemic stroke infection. Cigarette smoke can also increase the function of macrophages to fight the infection caused by Leishmania donovani (64). More importantly, stroke patients will suddenly quit smoking after admission, which may also be the reason why the probability of urinary tract infection in stroke patients with smoking history found in this study is low. Besides, it was found that among all stroke patients included in our study, the age of smokers was significantly lower than that of non-smokers (P<0.05). The immunity and general condition of younger people may be better than those of the elderly, and past diseases may be less, resulting in a lower risk of infection. This finding may also be the reason why smoking is a protective factor for infection after ischemic stroke.
This study has some limitations. First, the number of cases included in this study is not large enough, and the conclusions obtained may not fully reflect the overall situation. There may be bias. Second, this study did not include all characteristics reported in previous studies as possible risk factors for infection, such as interleukin-10, IL-1ra, etc. Third, this study did not further observe the guiding role of these predictive models for antibiotic prophylaxis. Subsequent studies should include larger samples and further observation of the clinical effect of the predictive model for prophylactic antibiotic use.