Predictors of community-acquired pneumonia severity in patients with chronic heart failure

Introduction

Community-acquired pneumonia (CAP) is a major public health problem due to its incidence (5-12 cases per 1,000 population), being the leading cause of mortality from infectious diseases, ranking sixth among the general causes of death. The incidence of community-acquired pneumonia increases with age, reaching 25-40% in the population over 65 years of age, and mortality from community-acquired pneumonia in intensive care units reaches 23-27% [1, 2].

Chronic heart failure (CHF) is a major problem worldwide, affecting mainly the elderly. Currently, the incidence of heart failure in Europe is approximately 3/1000 person-years (all age groups) or approximately 5/1000 person-years in adults. The prevalence rate in the general population is 1-2% of adults and increases rapidly with age: from approximately 1% for those under 55 years of age to more than 10% for those aged 70 years or older [3, 4].

Studying the inflammatory response in patients with CAP and CHF is of unquestionable value for establishing the diagnosis, predicting the severity, and evaluating the response to antibacterial treatment of pneumonia. Among the most commonly studied biomarkers in pneumonia are: C-reactive protein, procalcitonin (PCT), cytokines (interleukin-6, interleukin-10, tumor necrosis factor-alpha), leukocytes, erythrocyte sedimentation rate (ESR), neutrophil/lymphocyte ratio (N/L), fibrinogen, lactate dehydrogenase (LDH) [5, 6].

Recently, biomarkers of chronic heart failure have been intensively studied, allowing for accurate prognosis of CAP and timely identification of high-risk patients. Current guidelines for chronic heart failure recommend testing for B-type natriuretic peptide (BNP), or its precursor N-terminal pro-B-type natriuretic peptide (NT-proBNP). BNP is synthesized and released in response to pressure and volume overload of the heart, resulting in vasodilation and increased diuresis. NT-proBNP levels can help identify patients at increased risk of complications and guide personalized treatments, thus contributing to reduced mortality and improved survival [7, 8]. Therefore, determining the threshold values of NT-proBNP for predicting the severe progression of community-acquired pneumonia in patients with chronic heart failure requires further study and clarification.

Currently, changes in oxidative metabolism are considered one of the main pathogenic mechanisms in both the development and progression of CAP and CHF. Reactive oxygen species (ROS) and oxidative stress (OS) play a central role in the etiology of cellular dysfunction and tissue damage. Oxidative stress is a key part of the chain of events leading to inflammation caused by bacterial infection. ROS also modulate cellular signals that result in the transcription of activating factors and the release of inflammatory mediators [9].

Ischemia-modified albumin (IMA) is one of the most commonly studied pro-oxidant markers. IMA results from the modification of the N-terminal cobalt-binding sites of albumin, which derives from the release of free radicals from ischemic tissue. The formation of this new albumin molecule, which has lost its ability to bind cobalt, is one of the earliest predictors of ischemia. However, studies have shown that IMA, which is evaluated as a marker of cardiac ischemia, can also increase in other pathologies and affect other organs. Previous studies have shown that IMA levels increase significantly in sepsis. However, the role of IMA in patients with CAP who also have CHF has not been adequately investigated [10].

After diagnosing community-acquired pneumonia in patients with concomitant CHF, the key element is the ability to assess the severity of symptoms and the possible evolution of this pathological process. The use of severity scores is mandatory, as they estimate the probability of death for each patient, the need for hospitalization, and the location of medical care. CAP severity scores are important tools for assessing the severity of pneumonia and selecting treatment. Several scores, such as CURB-65, DS-CRB-65 or the pneumonia severity index (PORT/PSI), have been developed to help establish the diagnosis and initiate treatment, however, these scores have not been studied in CHF patients [11, 12].

Given that the combination of community-acquired pneumonia and chronic heart failure contributes to the worsening of pneumonia and decompensation of heart failure, this category of patients requires a more complex diagnostic approach. The development of a tool to predict the severity of CAP against a background of CHF would allow the correct management strategy to be introduced early, which would contribute to improving patient survival rates.

Material and methods

This is a prospective, observational study, that included 210 patients hospitalized with community-acquired pneumonia, divided into two groups according to the presence of chronic heart failure: Group 1 – 105 patients – with CAP and CHF, Group 2 – 105 patients – with CAP and without CHF. The study was approved by the Research Ethics Committee of Nicolae Testemițanu State University of Medicine and Pharmacy, no.18 from April 12, 2019.

Moderate pneumonia severity was defined by the presence of fever, moderate infectious manifestations, moderate respiratory insufficiency, particularly during exertion, and cardiovascular signs such as tachycardia and hypotension.

Severe pneumonia was established by the presence of at least two of the criteria indicating hospitalization in the intensive care unit: neurological manifestations (confusion, delirium); tachypnea (respiratory rate>30/minute); need for assisted ventilation; hypotension: systolic blood pressure <90 mmHg and/or diastolic blood pressure ≤60 mmHg, or blood pressure drop of more than 40 mmHg without another known cause; excessive tachycardia: heart rate >125/minute, or inappropriate for fever; hyperpyrexia (body temperature >39℃) or hypothermia (body temperature <36℃); extensive, multilobar (bilateral or more than one lobe) lung involvement; radiological expansion of opacity by more than 50% in 48 hours (progressive pneumonia); hyperleukocytosis (above 25 x 10³/ml) or leukopenia (below 4 x 10³/ml); urine output below 20 ml/hour.

The research was conducted based on clinical examination of patients, daily monitoring of the inflammatory process, assessment of comorbidities, and paraclinical investigations. The measurement of oxidative stress markers was performed in the biochemical laboratory of the Nicolae Testemițanu State University of Medicine and Pharmacy, and inflammatory markers in the biochemical laboratory of the Holy Trinity Municipal Clinical Hospital. The values of pro-oxidant markers (ischemia-modified albumin, advanced glycation end products, advanced oxidation protein products, malondialdehyde) and antioxidants (total antioxidant activity, superoxide dismutase, catalase) were determined and compared.

Light's criteria were used to distinguish exudative from transudative pleural effusions. A pleural effusion is classified as exudative if at least one of the following criteria is present: pleural fluid protein / serum protein ratio > 0.5; pleural fluid LDH / serum LDH ratio > 0.6; pleural fluid LDH > two-thirds of the upper limit of normal serum LDH.

The following scores for assessing CAP severity in CHF patients were evaluated: PORT/PSI score [13], CURB-65 [14] and DS-CRB-65 [15].

The obtained data were statistically processed using IBM SPSS Statistics 26.0 and Microsoft Office Excel 2010. By applying the conventional method for determining threshold values, namely using the lower limit of the confidence interval of the mean for IMA and for NT-proBNP values, the threshold values for severe CAP in patients with CHF were determined. In order to predict the severity of the disease based on different variables, logistic regression was used, including or excluding items in the prognosis equation as necessary.

Results

The age of patients in the study group ranged from 50 to 92 years, with a mean of 70.6 ± 8.89 years (95% CI [68.8–72.3]; Me = 70.0; IQR = 11). In the control group, the mean age was 68.7 ± 7.56 years (95% CI [64.2–68.2]; Me = 68.0; IQR = 11), (F = 18.109; p = 0.205). The groups were balanced in terms of gender distribution, with no significant differences between them. In Group 1, the proportion of women was 57 (54.3%; 95% CI [44.8-64.1]), and that of men was 48 (45.7%; 95% CI [35.9-55.2]). In Group 2, the proportion of men was higher than that of women: 54 (51.4%; 95% CI [42.3-61.0]) men and 51 (48.6%; 95% CI [39.0-57.7]) women, respectively (χ2 = 0.686; df = 1; p = 0.407).

Analyzing the severity of CAP, according to the National Clinical Protocol “Community-Acquired Pneumonia in Adults” [16], we determined that in Group 1, there were 48 (45.7%) patients with severe disease and 57 (54.3%) patients with moderate disease. In Group 2, there were 23 (21.9%) patients with severe pneumonia and 82 (78.1%) patients with moderate pneumonia (χ2 = 12.257; df = 1; p = 0.0005).

In the group of patients with CAP and CHF, mixed-type dyspnea at the first visit was present in 62 (59.0%; CI 95% [50.0-68.8]) patients and inspiratory dyspnea was reported in 37 (35.2%; CI 95% [25.7-44.3]) patients. The clinical picture also included dry cough – 42 (40.0%; 95% CI [30.6-49.4]) patients and cough with mucopurulent sputum – 21 (20.0%; 95% CI [11.4-26.8]) patients. Relevant objective changes in patients with CAP and CHF were: respiratory failure manifested by peripheral blood oxygen saturation less than 92% in 64 (61.0%) of cases; the reduction of localized vesicular breath sounds was determined in 74 (70.5%; CI 95% [60.6-78.6]) patients; bilateral crackles were observed in 41 (39.0%; 95% CI [30.6-48.6]) patients.

Analyzing the extent of lung involvement in patients with CAP and CHF, bilateral pulmonary infiltrate was more frequently determined – 63 (60.0%; 95% CI [50.5-69.1]) patients, followed by polysegmental involvement – 27 (25.7%; 95% CI [17.7-34.3]) patients. The presence of pleural effusion in the first radiological investigation was determined in 41 (39.0%; 95% CI [30.6-49.5]) patients. Bilateral pleural effusion was observed in 25 (60.9%; 95% CI [58.6–79.5]) patients in Group 1, while unilateral pleural effusion was observed in 16 (39.0%; 95% CI [24.6–49.2]) patients. In all cases of unilateral pleural effusion, to determine the nature of the pleural effusion, pleural puncture was performed. Thus, according to Light’s criteria, in 16 (39.0%) cases, we determined that pleural effusion was an exudate. Bacteriological examination of the pleural effusion revealed the presence of Klebsiella pneumoniae in 2 (12.5%) cases.

The inflammatory response in patients with CAP and CHF was expressed through increased ESR value, which was significantly higher in Group 1 compared to Group 2: 29.89 ± 19.47 mm/h and 21.17 ± 15.98 mm/h (F = 12.561; p < 0.0001), with the median values as follows: Me = 26.0; IQR = 29.0 compared to Me = 17.0; IQR = 20.0, respectively; increased serum lactate dehydrogenase value: 232.65 ± 109.80 u/L and 192.40 ± 44.98 u/L, respectively, (F = 12.076; p = 0.001). The median values were as follows: Me = 216.0; IQR = 76.0 and Me = 180.0; IQR = 46.0, respectively. The mean fibrinogen values were also higher in Group 1 (5.24 ± 1.78 g/L) compared to Group 2 (4.51 ± 1.60 g/L), statistically significant (F = 9.692; p = 0.002), and the median values were as follows: Me = 4.80; IQR = 2.90 and Me = 4.20; IQR = 2.25, respectively. C-reactive protein levels did not differ significantly between the two groups, with mean values of 35.98 ± 28.10 mg/L in Group 1 and 47.30 ± 30.04 mg/L in Group 2 (F = 1.625; p = 0.204).

The mean NT-proBNP values in patients with community-acquired pneumonia and chronic heart failure were 1371.88 ± 498.91 pg/ml, compared to the group without CHF: 58.19 ± 48.22 pg/ml, (F = 721.54; p < 0.0001). Subsequently, by applying the conventional method of determining threshold values, namely using the lower limit of the confidence interval of the mean for NT-proBNP values, a threshold value of 1665.73 pg/ml was identified (Table 1). This value is associated with the prediction of severe community-acquired pneumonia in patients with chronic heart failure.

The expression of pro-oxidant status was more evident in patients with CAP and CHF. Thus, ischemia-modified albumin had significantly higher values in patients in Group 1 compared to Group 2: 236.60 ± 64.35 µM/L and 229.77 ± 57.23 µM/L, respectively (F = 0.660; p = 0.045). By applying the conventional method for determining threshold values (using the lower limit of the confidence interval of the mean for IMA values), the IMA threshold value of 218.98 µM/L was determined for patients with CHF and severe CAP (Table 2).

Subsequently, we assessed the severity of CAP in patients with CHF using classic severity scores. According to the average PORT/PSI score, community-acquired pneumonia was more severe in patients in Group 1 compared to Group 2: 91.27 ± 19.18 and 67.89 ± 13.75, respectively (F = 103.004; p < 0.0001). According to the CURB-65 score, a tendency towards more severe CAP was also observed in Group 1 compared to Group 2: 1.27 ± 0.69 and 0.83 ± 0.72, respectively, (F = 19.876; p < 0.0001). The DS-CRB-65 score also recorded a higher mean value in patients in Group 1 (2.30 ± 0.82) compared to Group 2 (0.90 ± 0.77), respectively, (F = 160.570; p < 0.0001). In patients with CAP and CHF who had severe pneumonia and required hospitalization in the intensive care unit, the CURB-65 score had 47.12% sensitivity and 87.96% specificity, with an area under the ROC curve of 0.65 (Figure 1).

CURB-65

DS-CRB- 65

PORT/PSI

When evaluating the diagnostic accuracy of the PORT/PSI score, we observed that it had a sensitivity of 59.45% and specificity of 29.99% for patients with severe CAP who required hospitalization in the intensive care unit, and the area under the ROC curve was 0.84. At the same time, the DS-CRB-65 score demonstrated a sensitivity of 92.51% and specificity of 88.74%, and the area under the ROC curve was 0.88.

Assessment of pneumonia severity using classical scores has demonstrated some limitations in estimating the prognosis in patients with chronic heart failure, therefore, identifying patients with chronic heart failure and an increased risk of severe community-acquired pneumonia remains a challenge in clinical practice. In this regard, we set out to develop a method for predicting the severe progression of CAP in these patients. The innovation refers to the application in clinical practice by internists and cardiologists of a calculation formula, which includes parameters from the clinical examination, paraclinical data, and echocardiographic examination, which will help identify patients at high risk of severe community-acquired pneumonia (Innovator Certificate No. 6263 of 06/25/2024). For logistic regression, we included the following data: respiratory rate per minute, peripheral blood oxygen saturation (%), left ventricular ejection fraction (%),ischemia-modified albumin (µM/L), platelets (x10⁹/L), presence of pleural effusion, NT-proBNP value (pg/ml).

The final formula included statistically significant parameters: presence of pleural effusion, NT-proBNP values greater than or equal to 125 pg/ml, peripheral blood oxygen saturation less than 92%. This method allows early detection in 87.0% of cases of patients at high risk of severe community-acquired pneumonia. However, the method we propose also has some limitations: the lack of specificity of NT-proBNP, which may also have elevated values in other conditions (advanced age, pulmonary embolism, sepsis).

Discussion

Early identification of patients with chronic heart failure at risk of poor outcomes from community-acquired pneumonia is critical. Pneumonia severity scores are established clinical rules for estimating mortality from CAP, however, these CAP-specific scores have not been studied in patients with CHF. Therefore, in recent years increasing attention has been paid to research into objective biomarkers that might solve these concerns with the CAP-specific scores. Several humoral and cellular systems that mediate the host response against infection are activated during CAP in patients with concomitant CHF, so we determined some inflammatory and oxidative stress parameters, which might be valuable in the prediction of prognosis in this disease [14-16].

We evaluated the systemic inflammatory response in patients with community-acquired pneumonia and concomitant chronic heart failure. Among the clinical components of this syndrome, we observed a significantly higher frequency of respiratory rate in patients in the study group, which is confirmed by the more frequent recording of inspiratory and mixed dyspnea in this group of patients. In terms of laboratory data, we determined higher values of erythrocyte sedimentation rate, fibrinogen, and serum lactate dehydrogenase levels. Thus, although not very high, the mean ESR value was significantly higher in patients with community-acquired pneumonia and chronic heart failure - 29.89 ± 19.47 mm/h. Our data are supported by other studies investigating the role of ESR in patients with chronic heart failure. Thus, Cesari et al. and Vasan et al. showed that in patients with CHF, increased ESR values are associated with more severe forms of the disease and a more unfavorable prognosis [17, 18].

NT-proBNP levels in the present study were significantly higher in patients with community-acquired pneumonia and chronic heart failure compared to the control group: 1371.88 ± 498.91 pg/ml versus 58.19 ± 48.22 pg/ml, p < 0.0001. Using the conventional method (determination of the lower limit of the 95% CI of the NT-proBNP mean), the NT-proBNP threshold value for severe community-acquired pneumonia in patients with CHF was calculated to be 1665.73 pg/mL. Similar data were obtained in a study conducted by Yang S. et al., which aimed to evaluate the differential diagnostic accuracy of serum NT-proBNP levels in patients hospitalized with heart failure and community-acquired pneumonia. The study was designed as a prospective investigation and included 69 patients with CHF, 51 patients with CHF associated with community-acquired pneumonia, and 38 patients with isolated community-acquired pneumonia. As a result, median NT-proBNP values were significantly higher in patients with CHF associated with pneumonia [7.039 (1.008–24.672) pg/mL] compared to those with isolated CHF [3.147 (616–24.062) pg/mL] and isolated community-acquired pneumonia [911 (98–3.812) pg/mL], p < 0.0001. The area under the ROC curve for differentiating patients with CHF from those with community-acquired pneumonia was 0.808, indicating good diagnostic performance. The optimal threshold identified for NT-proBNP was 4.691 pg/ml, corresponding to a sensitivity of 74.5% and a specificity of 81.8% [19].

Thus, determining serum NT-proBNP levels may be a useful tool in predicting the severity of community-acquired pneumonia in patients with chronic heart failure. These results are also supported by the positive correlations obtained in our study between NT-proBNP values and pneumonia severity scores: the strongest correlation was determined with the PORT/PSI score (rs = 0.650; p < 0.0001), followed by the DS-CRB-65 score (rs = 0.326; p = 0.001) and the CURB-65 score (rs = 0.299; p = 0.002), coresponding to a sensitivity of 74.5% and a specificity of 81.8% [20].

Different studies indicate that IMA concentrations increase in several acute ischemic conditions, including cerebral infarction, myocardial infarction, pulmonary infarction, and mesenteric ischemia. Turedi et al. performed multiple studies to evaluate the diagnostic value of IMA across different clinical settings. In one investigation, they reported significantly elevated IMA levels in patients with pulmonary embolism compared with healthy controls. In another study assessing the diagnostic performance of IMA relative to D-dimer in pulmonary embolism, IMA was not superior to D-dimer; however, it was suggested as a potential alternative biomarker. Additionally, the authors emphasized that IMA testing is considerably more cost-effective [21, 22].

The diagnostic value of ischemia-modified albumin was investigated in patients with CAP in a study by Lee J. et al., which aimed to examine the relationship between IMA and C-reactive protein (CRP) with the PORT/PSI pneumonia severity score. The study included 81 patients hospitalized with CAP and 81 patients in the control group (healthy subjects), in whom the mean levels of IMA and CRP were compared. The mean levels of ischemia-modified albumin were significantly higher in the study group compared to the control group: 0.532 ± 0.117 IU/ml and 0.345 ± 0.082 IU/ml, respectively. The IMA level of 0.442 IU/ml had a sensitivity of 75.3% and specificity of 91.3% and had a positive correlation with CRP values (r = 0.506; p < 0.05), suggesting that IMA could be considered a new biomarker in the diagnosis and prognosis of CAP, which we investigated in the present study [23, 24].

Determining the severity of community-acquired pneumonia is one of the key objectives in managing this condition. Several severity scores are used for this purpose, such as: PORT/PSI score, CURB-65, DS-CRB-65, and others. These scores place great importance on age, which is a major factor in predicting 30-day mortality in patients with community-acquired pneumonia. The usefulness of the PORT/PSI score in elderly patients with multiple comorbidities has yielded controversial results in various studies. In our study, according to the mean PORT/PSI score, community-acquired pneumonia had a more severe course in patients with CAP and CHF compared to those without CHF: 91.27 ± 19.18 and 67.89 ± 13.75, respectively, p < 0.0001. At the same time, the PORT/PSI score had a sensitivity of 59.45% and specificity of 29.99% in predicting the severity of CAP in patients with CHF, and the area under the ROC curve was 0.84. The CURB-65 score had a sensitivity of 47.12% and specificity of 87.96%, with an area under the ROC curve of 0.65. The DS-CRB-65 score had a sensitivity of 92.51% and specificity of 88.74%, with an area under the ROC curve of 0.88 [25, 26].

Currently, there is no separate score for patients with community-acquired pneumonia developed against a background of chronic heart failure. In this regard, we set out to develop a method (calculation formula) for predicting the severe progression of community-acquired pneumonia in chronic heart failure. Our results have allowed us to propose threshold values for NT-proBNP and ischemia-modified albumin (as markers of severe pneumonia progression) and to develop a method (calculation formula) for assessing the prognosis of severe community-acquired pneumonia in patients with chronic heart failure.

Conclusions

Community-acquired pneumonia in patients with chronic heart failure is more frequently associated with a severe clinical course than in patients without heart failure. To identify patients with chronic heart failure who are at high risk of developing severe community-acquired pneumonia, we propose for clinical use the following threshold values: NT-proBNP ≥ 1665.73 pg/mL and ischemia-modified albumin ≥ 218.98 µmol/L, as well as our own formula for estimating the risk of severe community-acquired pneumonia in this patient population. These findings may contribute to improved risk stratification and may enable early therapeutic interventions aimed at preventing severe complications.

Competing interests

None declared.

Authors’ contributions

VC and TD conceived the study and participated in study design. NC, CT and EB helped drafting the manuscript and participated in data analysis. DF had a substantial contribution to acquisition of data. SM and LG contributed to final approval of the version to be published. All the authors reviewed the work critically and approved the final version of the manuscript.

Acknowledgements and funding

No external funding.

Ethics approval

The research project was approved by the Research Ethics Committee of Nicolae Testemițanu State University of Medicine and Pharmacy (Minutes no. 18 from 12.04.2019).

Patient consent

Obtained.

Provenance and peer review

Not commissioned, externally peer reviewed.

Authors’ ORCID IDs

Virginia Cascaval – https://orcid.org/0009-0008-5899-100X

Tatiana Dumitras – https://orcid.org/0000-0001-5538-189X

Diana Fetco-Mereuta – https://orcid.org/0000-0002-7469-045X

Livi Grib – https://orcid.org/0000-0001-6913-0864

Sergiu Matcovschi – https://orcid.org/0000-0003-1623-930X

Cornelia Talmaci – https://orcid.org/0000-0002-5603-2277

Natalia Capros – https://orcid.org/0000-0001-7283-8468

Elena Bivol – https://orcid.org/0009-0004-4040-7048

References

1. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-10. doi: 10.1159/000334441.
2. Rozenbaum MH, Mangen MJ, Huijts SM, van der Werf TS, Postma MJ. Incidence, direct costs and duration of hospitalization of patients hospitalized with community acquired pneumonia: a nationwide retrospective claims database analysis. Vaccine. 2015;33(28):3193-9. doi: 10.1016/j.vaccine.2015.05.001.
3. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail. 2020;22(8):1342-1356. doi: 10.1002/ejhf.1858.
4. Roger VL. Epidemiology of heart failure: a contemporary perspective. Circ Res. 2021;128(10):1421-1434. doi: 10.1161/CIRCRESAHA.121.318172.
5. Karakioulaki M, Stolz D. Biomarkers in pneumonia-beyond procalcitonin. Int J Mol Sci. 2019;20(8):2004. doi: 10.3390/ijms20082004.
6. Stucker F, Herrmann F, Graf JD, Michel JP, Krause KH, Gavazzi G. Procalcitonin and infection in elderly patients. J Am Geriatr Soc. 2005;53(8):1392-1395. doi: 10.1111/j.1532-5415.2005.53421.x.
7. Chang CL, Mills GD, Karalus NC, Jennings LC, Laing R, Murdoch DR, et al. Biomarkers of cardiac dysfunction and mortality from community-acquired pneumonia in adults. PLoS One. 2013;8(5):e62612. doi: 10.1371/journal.pone.0062612.
8. Dumitras T, Fetco-Mereuta D, Capros N, Chihai V, Terna E, Matcovschi S, Cascaval V. Assessment of oxidative stress markers in obese patients with community-acquired pneumonia. In: ICNBE-2023: 6th International conference on Nanotechnologies and Biomedical Engineering, 2023 Sept 20-23; Chisinau: Abstract book. Chisinau: Pontos; 2023. p. 384-391.
9. Ibadova O, Ergashova M, Gulandom Z. Community-acquired pneumonia and chronic heart failure. Web Sci Int Sci Res J. 2023;4(2):744-754. doi: 10.17605/OSF.IO/ZUYGW.
10. Bolatkale M, Duger M, Ülfer G, Can Ç, Acara AC, Yiğitbaşı T, et al. A novel biochemical marker for community-acquired pneumonia: ischemia-modified albumin. Am J Emerg Med. 2017;35(8):1121-1125. doi: 10.1016/j.ajem.2017.03.018.
11. Cascaval V, Matcovschi S, Grib L, Fetco-Mereuta D, Capros N, Dumitras T. Oxidative stress in patients with community-acquired pneumonia and pre-existing heart failure. Arch Balk Med Union. 2024;59(4):336-342. doi: 10.31688/ABMU.2024.59.4.02.
12. Keramat F, Ghasemi Basir H, Abdoli E, Shafiei Aghdam, Poorolajal J. Association of serum procalcitonin and C-reactive protein levels with CURB-65 criteria among patients with community-acquired pneumonia. Int J Gen Med. 2018;11:217-223. doi: 10.2147/IJGM.S165190.
13. Flanders WD, Tucker G, Krishnadasan A, et al. Validation of the pneumonia severity index. J Gen Intern Med. 1999; 14: 333–340. DOI: 10.1046/j.1525-1497.1999.00351.x.
14. Sun Y, Wang H, Gu M, Zhang X, Han X, Liu X. EMR combined with CRB-65 superior to CURB-65 in predicting mortality in patients with community-acquired pneumonia. Infect Drug Resist. 2024;17:463-473. doi: 10.2147/IDR.S443045.
15. Dwyer R, Hedlund J, Henriques-Normark B, Kalin M. Improvement of CRB-65 as a prognostic tool in adult patients with community-acquired pneumonia. BMJ Open Respir Res. 2014;1(1):e000038. doi: 10.1136/bmjresp-2014-000038.
16. Botnaru V, Rusu D. Pneumonia comunitară la adult. Protocol clinic național. Chișinău, 2020. 39 p.
17. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003;108(19):2317-22. doi: 10.1161/01.CIR.0000097109.90783.FC.
18. Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation. 2003;107(11):1486 -91. doi: 10.1161/01.cir.0000057810.48709.f6.
19. Yang S, Li L, Cao J, Yu H, Xu H. The differential diagnostic value of serum NT-proBNP in hospitalized patients of heart failure with pneumonia. J Clin Lab Anal. 2015;29(1):37-42. doi: 10.1002/jcla.21724.
20. Pfister R, Diedrichs H, Schiedermair A, Rosenkranz S, Hellmich M, Erdmann E, et al. Prognostic impact of NT-proBNP and renal function in comparison to contemporary multi-marker risk scores in heart failure patients. Eur J Heart Fail. 2008;10(3):315-320. doi: 10.1016/j.ejheart.2008.01.009.
21. Turedi S, Gunduz A, Mentese A, Karahan SC, Yilmaz SE, Eroglu O, et al. Value of ischemia-modified albumin in the diagnosis of pulmonary embolism. Am J Emerg Med. 2007;25(7):770-3. doi: 10.1016/j.ajem.2006.12.013.
22. Gunduz A, Turkmen S, Turedi S, Mentese A, Yulug E, Ulusoy H, et al. Time-dependent variations in ischemia-modified albumin levels in mesenteric ischemia. Acad Emerg Med. 2009;16(6):539-43. doi: 10.1111/j.1553-2712.2009.00414.x.
23. Cascaval V, Dumitras T, Grib L, Fetco-Mereuta D, Matcovschi S, Cealan A, Dumitras M. Assessment of oxidative stress related to clinical and imagistic peculiarities in hospitalized patients with community-acquired pneumonia and chronic heart failure. In: ICNBE-2025: 7th International conference on Nanotechnologies and Biomedical Engineering, 2025 Oct 7-10; Chisinau: Abstract book. Berlin: Springer; 2025. p. 56-65. doi: 10.1007/978-3-032-06497-4_6.
24. Lee JH, Kim J, Kim K, Jo YH, Rhee J, Kim TY, et al. Albumin and C-reactive protein have prognostic significance in patients with community-acquired pneumonia. J Crit Care. 2011;26(3):287-94. doi: 10.1016/j.jcrc.2010.10.007.
25. Dumitraș T, Cașcaval V, Țerna E. Pneumonia comunitară, insuficiența cardiacă și stresul oxidativ: Recomandare metodică [Community-acquired pneumonia, heart failure and oxidative stress: Methodological recommendation]. Chișinău: [s. n.]; 2025. 71 p. ISBN 978-5-85748-244-5. Romanian.
26. Kim MA, Park JS, Lee CW, Choi WI. Pneumonia severity index in viral community acquired pneumonia in adults. PLoS One. 2019;14(3):e0210102. doi: 10.1371/journal.pone.0210102.