Stroke-associated pneumonia (SAP) is a common post-stroke complication that generally occurs within 7 days of stroke onset in approximately one-third of patients with acute stroke.1,2 This infectious complication following stroke is associated with a 3-fold increased risk of mortality within 1 month, further contributing to the deleterious effects of stroke,2 a cerebrovascular event characterized by a rapid loss of neurologic functions which represents the second-leading cause of death across the globe.3-5

Over the past 20 years, there has been a significant improvement in the understanding of SAP, including its risk factors, diagnostic measures, and management strategies.1This article provides an overview of the current understanding of SAP, including the mechanisms underlying its development, significant risk factors for the complication, as well as potential management and prevention strategies.

Mechanisms Underlying SAP


Continue Reading

Several risk factors for SAP have been identified; however, the pathophysiological mechanisms of the condition are not as fully understood. Aspiration represents the most frequent cause of SAP, given that many hospitalized patients, particularly those with neurologic injury, experience weak swallowing reflexes and ultimately become vulnerable to aspiration.6

While an inserted endotracheal tube is used to protect against large-volume aspirations, this does not eliminate the potential for smaller aspirations of gastric or pharyngeal contents. Additionally, an endotracheal tube can interfere with coughing, a critical defense mechanism against aspirations and pneumonia.6 A strong cough not only protects against aspiration pneumonia, but it may also predict pneumonia risk in patients with acute stroke.7 Attenuation of cough and swallowing reflexes may be an important marker for increased risk of pneumonia in patients with dysphagia following stroke.7

Recent evidence suggests the 55-kDa protein transthyretin, which is involved in the transport of thyroxin and retinol-binding protein, may play a role in the development of SAP.8 This evidence was built on previous research studies which found strong relationships between transthyretin, infection, and stroke.9-11 Additionally, reductions in transthyretin may be associated with a corresponding increase in high-sensitivity C-reactive protein, an inflammatory marker associated with SAP, among other infections.12,13

Transthyretin levels appear to be significantly lower in patients with SAP compared with patients without this complication. Patients with low transthyretin levels measuring ≤252 mg/L may have a 3-fold increased odds of SAP.8 Transthyretin, when combined with A2DS2, may improve the diagnostic efficacy of SAP.8

In addition, attenuated cholinergic anti-inflammatory pathways have been implicated in the development of post-stroke pneumonia. Preclinical models indicate that inhibition of cholinergic signaling stimulated increased immune response and prevented pneumonia following stroke.14 Activation of the pathway by a central nervous system (CNS) injury, in the absence of an inflammatory stimulus, could inhibit first-line antimicrobial responses and therefore increase a patient’s susceptibility to infections following an acute CNS injury.14

Risk Factors for SAP

Severe hypertension, defined by a blood pressure of 200/120 mm Hg or higher, has been identified as an important risk factor for SAP.6 Dysphagia and aspiration are also significant risk factors for stroke-related pneumonia.2 Additional research suggests that female sex, older age, malnutrition, recumbency, and tube feeding are also risk factors for pneumonia among patients with stroke.6

Further research models have found that stroke-induced immunodeficiency increases the risk of post-aspiration pneumonia.6 Experiments indicate that immunodepression is a necessary component that drives the progression of bacterial aspiration to pneumonia.15 Among patients with acute ischemic stroke (AIS), acquired immune deficiency syndrome (AIDS) may significantly increase the risk of SAP.16

Several comorbidities may be associated with a higher risk of pneumonia among patients with stroke. These comorbid conditions include deficiency anemia, epilepsy, alcohol abuse, heart failure, pulmonary disease, diabetes, electrolyte disorders, paralysis, pulmonary circulation disorders, renal failure, and coagulopathy.16 Among hospitalized patients with AIS, other identified risk factors for pneumonia include noninvasive and invasive mechanical ventilation, nasogastric tube, length of hospital stay between 1 to 2 weeks and greater than 2 weeks, and hemorrhagic conversion.16

Chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis, have also been implicated in stroke-related pneumonia.17 With the potential complex interplay between different inflammatory conditions and SAP, more research is needed to determine whether chronic inflammatory diseases definitively increase or decrease the risk of post-stroke pneumonia.

In addition, the bacteria Streptococcus mitis, Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa have also been linked to aspiration pneumonia.6 Patients with acute stroke are at increased risk of colonization of respiratory pathogens during the recovery period.18 Pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli, may be increased in the saliva at 1 month following acute stroke, and the presence of these pathogens appears to be associated with respiratory events in this population.18

Predicting SAP

Given the serious nature of stroke-related pneumonia, there is a need for optimized interventions to prevent and manage the condition. Predicting the development of pneumonia in patients with stroke is especially needed both to minimize the occurrence of SAP and to optimize interventions used to manage the infection. Some research suggests that older age, greater stroke severity (as measured by the National Institutes of Health Stroke Scale score) on admission, atrial fibrillation, nasogastric tube intervention, mechanical ventilation, as well as elevated fibrinogen and leukocyte count are significant predictors of post-stroke pneumonia.19

Current prediction models are predominantly based on clinical features such as age, atrial fibrillation, diabetes mellitus, dysphagia, and stroke severity, among other variables.20 Despite their utility, these models have not been validated in patients undergoing endovascular therapy, a treatment approach that has become a global trend for AIS.20

Some evidence also suggests that blood parameters and their ratios with each other are associated with SAP.21-24 A recently developed index comprising stroke history, dysphagia, and lymphocyte count <1.00 × 103/μL (aka, the SDL index) demonstrated good discrimination for predicting stroke-related pneumonia in patients undergoing endovascular therapy for AIS.20 The SDL index was also simpler than existing prediction models, which may be preferred by clinicians who need to make rapid decisions about a patient’s immediate needs.20

Diagnosing SAP

To date, no consensus has been reached on standardized diagnostic criteria for lower respiratory tract infections in patients with stroke.6 Consensus operational criteria for the diagnosis of SAP, proposed in 2014 in the United Kingdom, state that the complication can be diagnosed by identifying progressively infiltrating lesions in post-stroke chest images.25

Additionally, the proposed criteria suggest clinicians could diagnose SAP if more than 2 of the following clinical symptoms of infection were observed: 38°C fever; newly occurring cough, productive cough, or exacerbation of preexisting respiratory disease symptoms with or without chest pain; signs of pulmonary consolidation and/or moist rales; and peripheral white blood cells >10×109/L or <4×109/L with or without a nuclear shift to the left.25

The modified Centers for Disease Control and Prevention (CDC) criteria for hospital-acquired pneumonia is frequently used to diagnose SAP.26 In 2015, the Pneumonia in Stroke Consensus Group proposed diagnostic recommendations for SAP based on the modified CDC criteria.25 These recommendations were made for the diagnosis of probable SAP (CDC criteria met yet chest X-ray changes absent after repeat or serial chest X-ray) and definite SAP (CDC criteria met including typical chest X-ray changes).25 Differential diagnosis that may mimic SAP include viral infection and inflammation, and these diagnoses should be ruled out to ensure a proper diagnosis.25

Interventions for SAP

Although antibiotic prophylaxis may theoretically provide benefit for preventing pneumonia in patients with stroke, this strategy does not invariably work in all patients. For instance, a UK study of 1217 patients with dysphasia following stroke found that the use of prophylactic antibiotics did not significantly reduce the incidence of post-stroke pneumonia compared with non-use of these agents.27 There is currently a lack of standardized antibiotic recommendations for stroke-related pneumonia, but previously proposed management criteria from Europe and the United Kingdom offer some insight into evidence-based management of the complication.6

In hospitalized patients with dysphagia following stroke, postural modification may prevent aspiration and thus play an important role for the prevention of SAP. Research suggests that different head and neck positions can either impede or aid swallowing and consequently impact risk of aspiration.28 More specifically, a reclining position may ease the passage of food due to gravity and is therefore a routine position for the prevention of aspiration.6

Systemic oral hygiene treatment is also associated with a lower rate of SAP when compared with no such treatment, according to a 2016 study.29 This treatment may reduce oral colonization with pathogenic bacteria and therefore reduce the risk of pneumonia following stroke.

A German study found that the use of beta-blockers prior to the onset of stroke and during the acute phase of stroke was associated with a reduced risk of pre- and post-stroke pneumonia.30 Cilostazol, a pluripotent phosphodiesterase III-specific inhibitor that features both anti-platelet and vasculogenic effects, has also shown utility in preventing SAP in patients with ischemic stroke who receive tube feeding.31 A retrospective analysis found that administration of cilostazol in hospitalized patients with ischemic stroke receiving tube feeding was associated with a reduced incidence of SAP; however, the treatment did not reduce the duration of stay in the hospital or intensive care unit.31

References

1. Chen Y, Yang H, Wei H, et al. Stroke-associated pneumonia: a bibliometric analysis of worldwide trends from 2003 to 2020. Medicine (Baltimore). 2021;100(38):e27321. doi:10.1097/MD.0000000000027321

2. Verma R. Stroke-associated pneumonia: management issues. J Neurosci Rural Pract. 2019;10(3):472-473. doi:10.1055/s-0039-1696743

3. Tadi P, Lui F. Acute Stroke. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Sep 29, 2021.

4. Patel UK, Dave M, Lekshminarayanan A, et al. Risk factors and incidence of acute ischemic stroke: a comparative study between young adults and older adults. Cureus. 2021;13(4):e14670. doi:10.7759/cureus.14670

5. Unnithan AKA, Mehta P. Hemorrhagic Stroke. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 5, 2022.

6. Grossmann I, Rodriguez K, Soni M, et al. Stroke and pneumonia: mechanisms, risk factors, management, and prevention. Cureus. 2021;13(11):e19912. doi:10.7759/cureus

7. Kulnik ST, Birring SS, Hodsoll J, et al. Higher cough flow is associated with lower risk of pneumonia in acute stroke. Thorax. 2016;71(5):474-475. doi:10.1136/thoraxjnl-2015-207810

8. Qiu H, Song J, Hu J, et al. Low serum transthyretin levels predict stroke-associated pneumonia. Nutr Metab Cardiovasc Dis. 2022;32(3):632-640. doi:10.1016/j.numecd.2021

9. Salvetti DJ, Tempel ZJ, Goldschmidt E, et al. Low preoperative serum prealbumin levels and the postoperative surgical site infection risk in elective spine surgery: a consecutive series. J Neurosurg Spine. 2018;29(5):549-552. doi:10.3171/2018.3.SPINE171183

10. Zhang SQ, Peng B, Stary CM, Jian ZH, Xiong XX, Chen QX. Serum prealbumin as an effective prognostic indicator for determining clinical status and prognosis in patients with hemorrhagic stroke. Neural Regen Res. 2017;12(7):1097-1102. doi:10.4103/1673-5374.211188

11. Zhang HF, Li LQ, Ge YL, et al. Serum prealbumin improves the sensitivity of pneumonia severity index in predicting 30-day mortality of CAP patients. Clin Lab. 2020;66(5). doi:10.7754/Clin.Lab.2019.190929

12. Tsuboi A, Terazawa-Watanabe M, Kazumi T, Fukuo K. Associations of decreased serum transthyretin with elevated high-sensitivity CRP, serum copper and decreased hemoglobin in ambulatory elderly women. Asia Pac J Clin Nutr. 2015;24(1):83-89. doi: 10.6133/apjcn.2015.24.1.18

13. Wu T, Zhang H, Tian X, Cao Y, Wei D, Wu X. Neutrophil-to-lymphocyte ratio better than high-sensitivity C-reactive protein in predicting stroke-associated pneumonia in afebrile patients. Neuropsychiatr Dis Treat. 2021;17:3589-3595. doi:10.2147/NDT.S340189

14. Engel O, Akyüz L, da Costa Goncalves AC, et al. Cholinergic pathway suppresses pulmonary innate immunity facilitating pneumonia after stroke. Stroke. 2015;46(11):3232-3240. doi:10.1161/STROKEAHA

15.  Prass K, Braun JS, Dirnagl U, Meisel C, Meisel A. Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke. 2006;37(10):2607-2612. doi:10.1161/01.STR.0000240409.68739.2b

16. Patel UK, Kodumuri N, Dave M, et al. Stroke-associated pneumonia: a retrospective study of risk factors and outcomes. Neurologist. 2020;25(3):39-48. doi:10.1097/NRL.0000000000000269

17. Dylla L, Herson PS, Poisson SN, Rice JD, Ginde AA. Association between chronic inflammatory diseases and stroke-associated pneumonia – an epidemiological study. J Stroke Cerebrovasc Dis. 2021;30(4):105605. doi:10.1016/j.jstrokecerebrovasdis.2021.105605

18. Perry SE, Huckabee ML, Tompkins G, Milne T. The association between oral bacteria, the cough reflex and pneumonia in patients with acute stroke and suspected dysphagia. J Oral Rehabil. 2020;47(3):386-394. doi: 10.1111/joor.12903

19. Huang GQ, Lin YT, Wu YM, Cheng QQ, Cheng HR, Wang Z. Individualized prediction of stroke-associated pneumonia for patients with acute ischemic stroke. Clin Interv Aging. 2019;14:1951-1962. doi:10.2147/CIA.S225039

20. Zhang B, Zhao W, Wu C, et al. SDL index predicts stroke-associated pneumonia in patients after endovascular therapy. Front Neurol. 2021;12:622272. doi:10.3389/fneur.2021.622272

21. Park MG, Kim MK, Chae SH, Kim HK, Han J, Park KP. Lymphocyte-to-monocyte ratio on day 7 is associated with outcomes in acute ischemic stroke. Neurol Sci. 2018;39(2):243-249. doi:10.1007/s10072-017-3163-7

22. Ren H, Liu X, Wang L, Gao Y. Lymphocyte-to-monocyte ratio: a novel predictor of the prognosis of acute ischemic stroke. J Stroke Cerebrovasc Dis. 2017;26(11):2595-2602. doi: 10.1016/j.jstrokecerebrovasdis.2017.06.019

23. Kartal O, Kartal AT. Value of neutrophil to lymphocyte and platelet to lymphocyte ratios in pneumonia. Bratisl Lek Listy. 2017;118(9):513-516. doi:10.4149/BLL_2017_099

24. Nam KW, Kim TJ, Lee JS, et al. High neutrophil-to-lymphocyte ratio predicts stroke-associated pneumonia. Stroke. 2018;49(8):1886-1892. doi:10.1161/STROKEAHA.118.021228

25. Smith CJ, Kishore AK, Vail A, et al. Diagnosis of stroke-associated pneumonia: recommendations from the pneumonia in stroke consensus group. Stroke. 2015;46(8):2335-2340. doi:10.1161/STROKEAHA.115.009617

26. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control. 1988;16(3):128-140. doi:10.1016/0196-6553(88)90053-3

27. Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet. 2015;386(10006):1835-1844. doi:10.1016/S0140-6736(15)00126-9

28. Alghadir AH, Zafar H, Al-Eisa ES, Iqbal ZA. Effect of posture on swallowing. Afr Health Sci. 2017;17(1):133-137. doi:10.4314/ahs.v17i1.17

29. Wagner C, Marchina S, Deveau JA, Frayne C, Sulmonte K, Kumar S. Risk of stroke-associated pneumonia and oral hygiene. Cerebrovasc Dis. 2016;41(1-2):35-39. doi:10.1159/000440733

30. Sykora M, Siarnik P, Diedler J; VISTA Acute Collaborators. β-blockers, pneumonia, and outcome after ischemic stroke: evidence from virtual international stroke trials archive. Stroke. 2015;46(5):1269-1274. doi:10.1161/STROKEAHA

31. Netsu S, Mizuma A, Sakamoto M, Yutani S, Nagata E, Takizawa S. Cilostazol is effective to prevent stroke-associated pneumonia in patients receiving tube feedingsss. Dysphagia. 2018;33(5):716-724. doi:10.1007/s00455-018-9897-4

This article originally appeared on Pulmonology Advisor