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Original Article Risk Factors for Myocardial Damage and Its Effects on the Prognosis of Children with Severe Pneumonia: A Cross-sectional Study Y Mei, D Tang, L Zhao, M Peng, B Zhu Abstract Background: Severe pneumonia is a common paediatric respiratory infection that progresses rapidly and can lead to various complications. Heart failure as a complication of severe pneumonia is one of the important causes of death in children. Heart failure primarily occurs due to myocardial damage. The present study aimed to investigate the risk factors of myocardial damage in children with severe pneumonia and its influence on their prognosis to provide a reference for the early prevention, diagnosis, and treatment of myocardial damage. Methods: A total of 408 children with severe pneumonia from May 2020 to August 2022 were retrospectively analysed and assigned to two groups according to whether they had concomitant myocardial damage. The general data questionnaire designed by the researcher was used to collect the general characteristics of the included children. The relationship between clinical features and myocardial damage in children with severe pneumonia was analysed by t-test and chi-square test. Binary and multiple linear regression analyses were performed to determine the independent risk factors of myocardial damage and poor prognosis in children. Results: Of the included 408 children with severe pneumonia, 50 (12.3%) had a complication of myocardial injury. Binary logistic regression analysis showed that low age (odds ratio [OR] =0.879, P=0.041), concomitant hypoxaemia (OR=4.433, P=0.002), concomitant hypokalaemia (OR=4.548, P=0.001), concomitant hypoproteinaemia (OR=4.047, P=0.019), concomitant respiratory failure (OR=3.506, P=0.016), decreased pH (OR=0.000, P=0.002), decreased PaO2 (OR=0.922, P=0.007), decreased HCO3- concentration (OR=0.820, P=0.037), increased procalcitonin (OR=2.415, P=0.007), increased C-reactive protein (OR=1.083, P=0.016), elevated vascular endothelial growth factor (OR=1.544, P=0.012), and elevated cystatin C (CysC) (OR=1.737, P=0.039) were independent risk factors for concomitant myocardial damage in children with severe pneumonia. Multiple linear regression analysis also showed that concomitant myocardial damage (P=0.045) was an independent risk factor for the prognosis of children with severe pneumonia. Conclusion: The incidence of myocardial damage in children with severe pneumonia is still high, and it severely affects the prognosis of children. Clinicians should give utmost attention to the clinical characteristics and related serological markers of patients, identify relevant risk factors as early as possible, and actively implement corresponding therapeutic measures to reduce the incidence of myocardial damage in children. Keyword : Children; Myocardial damage; Retrospective study; Severe pneumonia IntroductionPneumonia is a leading cause of childhood morbidity and mortality worldwide. On average, pneumonia affects 1 in 66 children in high-income countries and 1 in 5 children in low- and middle-income countries.1 It is also the leading cause of death in children under 5 years of age, causing approximately 1 million deaths worldwide each year.2 Childhood deaths due to pneumonia occur disproportionately in low- and middle-income countries, with the highest numbers in South Asia and sub-Saharan Africa.3,4 Furthermore, the number of pneumonia-related deaths has declined at a slower rate than the number of deaths due to other childhood diseases. Rudan et al showed that in low- and middle-income countries, the incidence of clinical pneumonia in children under 5 years of age was approximately 0.29 times per year.5 This implies that there are 151.8 million cases per year, of which approximately 13.1 million cases (8.7%) progress from pneumonia to severe pneumonia that requires hospitalisation.1,5 Severe pneumonia is most likely to occur in children <6 years of age. As the immune system in this age group is not fully developed, and the immune function is poor, bacterial and viral infections can easily damage the lung tissue through the respiratory tract, leading to poor prognosis.6 The morbidity and mortality rate of severe pneumonia is 6-fold higher than that of nonsevere pneumonia (4.2% vs. 0.65%).7 In 2015, 22 million (16%) of the 138 million international cases of pneumonia were classified as severe according to the World Health Organization (WHO) criteria.7 As a common critical illness in the pediatric population, severe pneumonia is characterised clinically by shortness of breath, weak cough, persistent fever, and hypoxaemia, which can easily lead to respiratory failure, heart failure, pulmonary encephalopathy, and multiorgan failure, thereby posing as a severe life-threatening condition for the affected child.8 The early symptoms of severe pneumonia in children lack specificity, and the disease progresses rapidly with a poor prognosis. As a common respiratory infection in children, severe pneumonia is a rapidly progressive disease that can lead to various complications.9 In addition to respiratory impairment, myocardial damage, hypoxaemia, and acidosis can also occur in children with severe pneumonia and may involve multiple organs in various forms.10 A previous study showed that mycoplasma pneumonia is associated with extrapulmonary systemic damage, with a prevalence of 25-50%, wherein digestive system damage (liver damage) is the most common, followed by myocardial damage.11 Myocardial damage can occur in 18.5-25.2% of children with mycoplasma pneumonia and in up to 35.0% of children with severe mycoplasma pneumonia.12 The main reason for concomitant myocardial damage is the impairment of pulmonary ventilation and/or air exchange in children with severe pneumonia, which can lead to acidosis and hypoxaemia; this subsequently affects microcirculatory function, resulting in inadequate tissue perfusion, increased anaerobic metabolism, and reduced production of energy materials for cellular metabolism, thereby significantly increasing the risk of myocardial cell injury and myocardial damage.13,14 Therefore, myocardial damage is a common complication of severe pediatric pneumonia; moreover, children with severe damage or untimely diagnosis are prone to heart failure, which is a life-threatening condition and has received widespread attention from all sectors of society.15 Recently, clinicians and researchers have been increasingly investigating the risk factors for severe paediatric pneumonia. Nasrin et al16 showed that gender, longer duration of illness, fever, and severe stunting were significantly associated with the development of severe childhood pneumonia. However, studies on independent risk factors for concomitant myocardial damage with severe pneumonia are still limited. The current direction of research on myocardial damage in paediatric severe pneumonia is mainly focused on early diagnosis and predictive indicators or on severe pneumonia and viral myocarditis caused by COVID-19.17-19 Most studies involved animal experiments, and there is a lack of clinical studies. Hence, the present study aimed to investigate the relationship between the basic clinical features, serological indicators, and myocardial damage in children with severe pneumonia and to elucidate the independent risk factors for myocardial damage and its effect on the prognosis of children to provide a reference for improving the prognosis, preventing complications such as myocardial damage, and reducing mortality in patients with severe pneumonia. The article is presented in accordance with the STROBE reporting checklist. Materials and MethodsResearch Participants The inclusion criteria were as follows: (1) met the diagnostic criteria for severe pneumonia; (2) age ≤12 years; (3) diagnosed to have community-acquired pneumonia; (4) had complete clinical data; (5) did not receive immunosuppressive drugs in the past 3 months; and (6) no history of myocardial damage and no severe dysfunction of the liver and kidney. The exclusion criteria (Figure 1) were as follows: (1) presence of pulmonary tuberculosis, bronchial asthma, pulmonary dysplasia, lung tumour, and other respiratory diseases; (2) accompanied with malignant tumors, other systemic infections, or infectious diseases; (3) received mechanical ventilation or tracheotomy upon admission; (4) recent use of hyperhormone drugs; (5) transfer to hospital halfway during the disease course or incomplete clinical data; (6) those who died of nonmyocardial damage or heart failure during treatment; (7) presence of congenital developmental malformation or dysfunction; and (8) diagnosed to have neonatal severe pneumonia.
This cross-sectional study aimed to examine the relationship between severe pneumonia complicated by myocardial damage and prognosis in children admitted to the Paediatric Intensive Care Unit (PICU) ward. According to our previous study and related literature, the prevalence of severe pneumonia complicated by myocardial damage in children admitted to the PICU ward is approximately 13%. A tolerance error of 3% was considered, with a confidence level of 1-α = 0.95. The sample size (N) of 310 cases was calculated using the PASS 15 software. Assuming a nonresponse rate of 10%, a sample size of N=310/0.9 = 345 cases was required. Assuming a 90% pass rate, the total sample size required was N=345/0.9 = 383 cases. Therefore, the planned sample size for this study was 420 cases. The actual number of attrition and lost cases was 12, with a final count of 408 cases. The study was approved by the Ethics Committee of Children's Hospital of Nanjing Medical University (No. KYLC2020116). General Information Questionnaire Determination Criteria of Severe Pneumonia Paediatric Critical Illness Score Acute Physiology and Chronic Health Evaluation Ⅱ Sequential Organ Failure Assessment Methods for Determining Myocardial Damage Statistical AnalysisThe results of each scale were entered into a computer for score conversion. Statistical analysis was performed using SPSS 26 (IBM SPSS, USA). The measurement data were expressed as mean and standard deviation, while the count data were expressed as frequencies and percentages. A t-test and chi-square test were used for statistical analysis between the two groups. A binary logistic regression analysis was used for factors influencing myocardial damage complicated by severe pneumonia. A multiple linear regression analysis was used to determine the independent risk factors for the prognosis of the children. A two-sided P-value of <0.05 was considered statistically significant. ResultsBaseline Data
Comparison of Arterial Blood Gas Analysis Between the Two Groups
Comparison of Serum Inflammatory Indicators Between the Two Groups
Comparison of Serum Cardiac Indicators Between the Two Groups
Comparison of ECG Conditions Between the Two Groups
Binary Logistic Regression Analysis of Children with Concomitant Myocardial Damage
Comparison of Prognosis-related Scores between the Two Groups
Multiple Linear Regression Analysis of PICS
DiscussionPneumonia is a disease in which there is an inflammatory response in the alveoli and interstitial spaces of the lungs. Paediatric pneumonia has a high incidence among the diseases encountered in clinical paediatrics. A previous study23 showed that in 2017, a total of 1,117,779 children under the age of 5 years were admitted to the hospital, and respiratory diseases (accounting for 31.5% of the cases) were the most common reason for the hospital admission. During childhood, the immune system is in a state of development; consequently, the immune function is weak, and bacterial and viral infections can rapidly progress into a severe state following the acute onset. Furthermore, the respiratory tract of children is narrow, with many blood vessels and a weak mucosal lining, and the respiratory tract secreted less mucus and was relatively dry. Moreover, because of the young age and the lack of ciliary movement, children are unable to promptly remove the inhaled material; this is also the main reason for the gradual aggravation of pneumonia symptoms in children.24 Previous studies have shown that more than 1 million children die due to pneumonia every year worldwide, and severe pneumonia is the main cause of death in young children.25 The clinical symptoms of pneumonia in children vary greatly, ranging from simple respiratory symptoms to extrapulmonary system involvement, such as the skin mucosal system, cardiovascular system, nervous system, and digestive system.26 The relationship between severe pneumonia and acute heart damage has been recognised since the 1930s.27 Several clinical studies by Corrales-Medina enlightened the researchers about this severe complication of pneumonia.28,29 In severe pneumonia, inflammatory transmitters may be released, vascular endothelial cells may be damaged, and autoimmune disorders may occur. Following stimulation, children with pneumonia may produce antibodies that bind to myocardial antigens to form immune complexes, which then activate inflammatory immune cells and eventually lead to various extents of myocardial cell damage.11 Musher et al reported that up to 20% of patients with pneumococcal pneumonia develop congestive heart failure, arrhythmias, and myocardial infarction alone or in combination. These individuals were up to 4-fold more likely to die than those hospitalised with pneumococcal pneumonia but without heart complications.30 In recent years, several studies31,32 have also shown that in addition to respiratory symptoms, viral pneumonias such as COVID-19 can cause adverse effects on the cardiovascular system, including acute myocardial injury and chronic cardiovascular damage. Therefore, prompt and early identification of risk factors of myocardial damage in children with severe pneumonia is crucial for improving the prognosis of children. However, there is no report on the severity and tendency of myocardial damage caused by comparing bacterial pneumonia as well as viral pneumonia, which will be the next focus of this study. The present study found that the serum levels of CK-MB, CTnI, and NT-proBNP in children with severe pneumonia with myocardial damage were significantly higher than those in children without myocardial damage; this finding suggests that the serum levels of CK-MB, cTnI, and NT-proBNP can reflect the phenomenon of myocardial damage in children with severe pneumonia. Currently, CK-MB, cTnI, and NT-proBNP are the common biochemical markers for the clinical evaluation of myocardial damage. CK-MB is a cardiomyocyte-specific inositase, and it is considered the "gold standard" in evaluating myocardial damage.33 cTnT is a cardiac troponin with high specificity and sensitivity for evaluating myocardial damage.34 In severe pneumonia, the release of inflammatory mediators can lead to extensive microcirculation disturbance in the myocardial tissue, thereby resulting in severe ischaemia, hypoxia, damage to myocardial cells, and an increase in CK-MB and CTnI levels. NT-pro BNP is a cleavage product of BNP precursor substances under the action of protease. It is stable, has a long half-life, and can be easily detected; thus, it can be used as a diagnostic and prognostic indicator of myocardial injury and heart failure.35 NT-pro BNP appears to be elevated in the serum of children with severe pneumonia; this may be related to the accelerated secretion of BNP precursor substances stimulated by myocardial damage, pulmonary hypertension, and reduced cardiac blood output due to severe pneumonia.36 The specific mechanism of myocardial injury in children with severe pneumonia is unknown; however, some researchers consider that the mechanism is related to the inflammatory response. The effect of inflammatory mediators (including cytokines and endotoxins) in the blood and/or the direct infection of myocardial cells by pneumonia pathogens can cause nonischemic myocardial injury. The systemic inflammatory response decreases endothelial function and vascular response, increases peripheral vascular resistance, and enhances the reflection of the middle and large arteries to the pulse wave, thereby increasing the left ventricular load. Inflammation also increases myocardial oxygen consumption, which reduces myocardial oxygen delivery capacity and increases pulmonary artery pressure and ventricular load; the reduction in myocardial oxygen supply can further cause myocardial cell necrosis. As the systemic inflammatory response increases in children with severe pneumonia and damage occurs due to hypoxia, acidosis, and oxygen free radicals, the cardiac load increases significantly, myocardial damage increases, and the release of cardiac enzymes and troponin increases, with a subsequent increase in their serum levels.37 This study showed that low age; concomitant occurrence of hypoxaemia, hypokalaemia, hypoproteinaemia, and respiratory failure; decreased levels of pH, PaO2, and HCO3-; and increased levels of PCT, CRP, VEGF, and CysC were the independent risk factors for myocardial damage in children with severe pneumonia. This finding is consistent with previous reports on the factors affecting the poor prognosis of children with severe pneumonia in China and abroad,38,39 thus, confirming that these factors are indeed harmful. The delicate internal organs, poor self-regulation and recovery ability, poor tolerance to drugs, rapid progression of the disease, and poor health awareness in young children can easily cause disease exacerbation and damage to the myocardial structures. The complications of hypoxaemia, hypokalaemia, hypoproteinaemia, and respiratory failure imply microcirculatory disorders; this can lead to tissue perfusion, affect normal metabolism, and involve multiple organ structures and functions, thus, posing a high risk of myocardial damage. An abnormal pH level is the main feature of the decompensated acid-base imbalance. In the early stage of severe pneumonia, ventilation dysfunction is more predominant, and if this condition is not promptly improved, severe hypoxia and metabolic acidosis will soon occur due to ventilation dysfunction, thereby leading to microcirculatory dysfunction, insufficient tissue perfusion, increased anaerobic metabolism, decreased adenosine triphosphate production, and damage to cardiac myocytes. Hypoxia also impairs myocardial energy metabolism and causes metabolic disorders of various nutrients and some humoral factors, such as oxygen free radicals, cardiac natriuretic peptide, endothelin, and calcitonin, thereby leading to cardiac dysfunction.40 PCT, a procalcitonin peptide with no hormonal activity, is synthesized and released in large quantities after infection by bacterial toxins and cytokine stimulation. A significant increase in the serum PCT level suggests that the pathogenic bacteria are releasing toxins to damage the structures and tissues of the body.41 CRP is a class of acute temporal response proteins that play a critical role in infectious diseases and structural damage. The in vivo levels of CRP are extremely sensitive to changes and can effectively predict poor prognosis in children with severe pneumonia.42 In this study, multiple linear regression analysis showed that concomitant myocardial damage is a risk factor affecting the prognosis of children. Therefore, paediatric clinicians should caution the parents/guardians of children with severe pneumonia about the occurrence of myocardial damage. The prognosis of children with severe pneumonia should be improved, and the mortality rate should be reduced by actively treating the primary disease, improving ventilation and ventilatory function, and providing mechanical ventilation if required. Attention should also be given to cardiac function support, such as regulating the amount and rate of fluid intake, nutritional myocardial therapy, and dynamically observing changes in myocardial enzymology, blood gas levels, electrocardiogram results, and serum inflammatory indices. Effective measures should thus be taken according to the extent of myocardial damage. In conclusion, several risk factors affect the occurrence of myocardial damage in children with severe pneumonia. The occurrence of myocardial damage can substantially affect the prognosis of children with severe pneumonia; hence, early identification of risk factors and adoption of targeted preventive measures are beneficial to improve the quality of life and promote the healthy growth of children. The limitations of this study are that fewer cases were included due to limited human resources and time; moreover, the study indices were taken from the same hospital data; hence, it is recommended to expand the sample size and enrich the data sources in the future studies. In addition, this study did not differentiate between bacterial and viral pneumonia, which may have biased the results and will be the next focus of this study. ConclusionThe incidence of myocardial damage in children with severe pneumonia is still high, and it severely affects the prognosis of children. Clinicians should give utmost attention to the clinical characteristics and related serological markers of patients, identify relevant risk factors as early as possible, and actively implement corresponding therapeutic measures to reduce the incidence of myocardial damage in children. FundingNo sources of financial assistance were available. Conflicts of InterestThe authors have no conflicts of interest to declare. Ethical StatementThe authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Ethics Committee of Children's Hospital of Nanjing Medical University (No. KYLC2020116). Informed ConsentAs this study involves retrospective analysis, the patient's identity is anonymised, thus exempting the need for obtaining informed consent. References1. Nair H, Simões EA, Rudan I, et al. Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis. Lancet 2013;381:1380-90. 2. Perin J, Mulick A, Yeung D, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health 2022;6:106-15. 3. Amouzou A, Velez LC, Tarekegn H, et al. One is too many: ending child deaths from pneumonia and diarrhoea. UNICEF. New York, NY, 2016. 4. Bank TW. Levels and trends in child mortality : estimates developed by the UN Inter-agency Group for Child Mortality Estimation (IGME) - report 2015. New York United Nations Children's Fund September 2015. 5. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ 2008;86:408-16. 6. Same RG, Amoah J, Hsu AJ, et al. The Association of Antibiotic Duration With Successful Treatment of Community-Acquired Pneumonia in Children. J Pediatric Infect Dis Soc 2021;10:267-73. 7. McAllister DA, Liu L, Shi T, et al. 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Aging Clin Exp Res 2014;26:607-13. 37. Jin JK, Blackwood EA, Azizi K, et al. ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circ Res 2017;120:862-75. 38. Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 2018;18:391-400. 39. Ito A, Ishida T, Washio Y, Yamazaki A, Tachibana H. Legionella pneumonia due to non- Legionella pneumophila serogroup 1: usefulness of the six-point scoring system. BMC Pulm Med 2017;17:211. 40. Darr S, Madisch I, Heim A. Antiviral activity of cidofovir and ribavirin against the new human adenovirus subtype 14a that is associated with severe pneumonia. Clin Infect Dis 2008;47:731-2. 41. Mahmoud EIE, Algendy MA, Al-Ansary AM, Noaman MK. 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