Keywords
Ventricular septal defect, Pneumonia, Pulmonary hypertension, Anaemia
Ventricular septal defect, Pneumonia, Pulmonary hypertension, Anaemia
On behalf of co-authors, I wish to pass our heartfelt gratitude to the reviewer for his professionalism and sincerity, and the raised points deserve clarification. The main differences between the old and revised version are put forward as per reviewer concerns:
The introduction section has been summarized and repair techniques clarified with references.
Diagnosis modality of PH has been clarified and reference cited. While we understand the variation in etiologies of pneumonia, cardio-pulmonary hemodynamic changes provide a fertile ground for persistent infections (dereferences available).
SPSS version has been given in full.
Discussion has been expanded by two paragraphs and references provided.
Conclusion has been furnished.
We have changed the addresses to suit institutional requirement
Its our sincere hope that our revised version answers the few but cardinal concerns raised by our reviewer.
Your time and dedication to reviewing our manuscript is highly appreciated.
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Anaemia is a common complication of a myriad medical conditions often met in general ward. Its etiology is complex and multifactorial, encompassing intrinsic and extrinsic factors1–3. Additionally, large intracardiac defects (cyanotic ventricular septal defects) can cause pulmonary vascular overload, infection and anaemia2. Further, pulmonay hypertension (PH) due to pulmonary vascular overload can elicit a cascade of events leading to poor quality of life, morbidity and mortality4,5. In the developing world with no heart surgery centers, pneumonia (PNA) due to large intracardiac defect(s) (cyanotic VSDs) is responsible for retardation, persistent morbidity and mortality2,6.
Nevertheless, the effect(s) of small to moderate VSD’s on the occurrence of both PNA and PH amongst paediatric patients, especially infants has not been fully explored. Adults and older children may tolerate and survive the effects. However, infants with limited iron storage and supply (exclusive breast milk) may not with stand7,8. For these reasons, we hypothesize that paediatric patients with solitary acyanotic VSD coexisting with PNA or PH retain a risk of developing anaemia. In this retrospective study, we aim to establish the prevalence of anaemia in patients with solitary acyanotic VSD in comorbid with PNA or PH.
Between February 2014 and September 2018, 90 case files of patients with solitary acyanotic-VSD, who underwent either surgical or minimal invasive closure in our Department of Cardiac Surgery, Shandong Provincial Hospital Affiliate of Shandong University were primarily selected for this study.
However, only 75 case files met study criteria, which included patients with recurrent (history of...) pneumonia of proven PNA by chest radiography with positive bacterial culture of trans-tracheal aspirate or polymerize chain reaction from nasopharyngeal swab. Pulmonary hypertension diagnosis was echocardiography based, except in 5 patients from PNA group, who presented in heart failure state. Excluded from this study were 15 files of patients: 7, sickle cell; 4, β-Thalassemia; 4, blood transfusion.
Among the 75 files were 48 males (75.64%) and 27 females with mean age and weight of 8.3±5.7 (3–24) months and 3.8±3.0 kilograms, respectively. Depending on the associated complication, the cohort was then divided into three groups: A, PNA (n=30); B, PH (n=25); and C, control (n=20). Based on age, the cohort was further split into two groups: I, young children (≥3–≤6); II, older children (>6–≤24) months. The patient demographic and clinic characteristics (Table 1) and hematologic profile (Table 2) reflects pre-procedure state.
Statistical analysis. Data was analysed using SPSS-IBM-21 software (one-way-ANOVA) and all statistics expressed as mean ± standard deviation. Intergroup haemoglobin level was compared using independent samples student’s t-test. Statistical comparison of proportions was analysed using Tukey HSD Test, and the probability value of less than 0.05 was considered significant. Patient proportions are expressed in number and percentage (n, %).
In this case study, we used hemoglobin reference ranges based on age as follow: (I) young children (95–135) and (II) older children were (105–135) gram per liter, as per local protocol. According to data analysis reflected in Table 3, 27 patients (36%) in total had anaemia. Of the anaemia cohort, 16(59.3%) had PNA, 9 (33.3%) PH and 2(7.4%) asymptomatic. Of the cohort, 42 were young children with anaemia prevalence of 19/42(45.2%), while the older children had 24.2%. Hemoglobin Intergroup (ANOVA) independent sample t-test was significant (p<0.05). In addition, intergroup Tukey HSD test for hemoglobin: A/B(p>0.05), A/C(p<0.01), B/C(p<0.01). The mean WBC in PNA was higher and intergroup p-value was significant. Other hematologic and laboratory are reflected in the respective group
Of the cohort, 42 were young children, and of those 19 had anaemia (45.2%), while 24.2% of the older children had anaemia. Haemoglobin intergroup (ANOVA) independent sample t-test was significant (p<0.05). In addition, intergroup Tukey HSD test for haemoglobin: A/B (p>0.05), A/C (p<0.01), B/C (p<0.01). The mean white blood cells in patients with PNA was higher and intergroup p-value was significant (p<0.05).
Anaemia, defined as haemoglobin (Hb) concentration below the 5th percentile for age at sea-level, is a common complication of a myriad medical conditions often met in the general ward1. Its aetiology is complex and multifactorial, encompassing intrinsic and extrinsic factors. Both pneumonia (PNA) and pulmonary hypertension (PH) due to cyanotic congenital heart defect (CHD) have been implicated in the occurrence of anaemia2,3,6. In addition, sporadic reports linking anaemia to PNA or PH amongst patients with acyanotic ventricular septal defect (VSD) have been publish.
VSD is the second commonest CHD after bicuspid aortic valve4,9, and solitary cases account for almost 20%. One of the most common defects associated with elevated pulmonary artery pressure is a large VSD. Elevated pulmonary artery pressure in CHD can be due to pulmonary hyper-circulation, pulmonary vasoconstriction, and pulmonary vascular disease, either alone or in combination. In an infant, despite pulmonary pressure being at systemic level, pulmonary vascular resistance is low; therefore, minor shunt easily elicits hyper-circulation2,4,6,10.
PH, defined as mean pulmonary artery pressure of ≥25mmHg at rest as measured by cardiac catheterization in children aged ≥3months, is a serious disorder with a high morbidity and mortality rate2. Blood shunt may cause haemolysis due to shear stress and produce free haemoglobin, which in turn depletes nitric oxide leading to endothelial dysfunction, vasoconstriction, pulmonary oedema and hypoxia. Furthermore, haemolysis produces arginase, which converts L-arginine to ornithine; therefore, bypassing nitric oxide production2,8,11.
PNA as defined by Ozdemir and colleagues is a serious reason for morbidity and mortality in children (≤2years) with hemodynamic significant VSD5,12. Both PNA and PH share a common interface; inflammation, homostasis, hypoxia, and subsequent upregulation of erythropoiesis7,13. Prolonged upregulated erythropoiesis in young children with low iron store and limited iron supplement leads to anaemia1. In addition, microangiopathic hemolytic anaemia in CHD and PH has been reported3, a complication commonly observed in primary PH. Unlike in PH, Mycoplasma Pneumonia and Plebsiella are known to cause anaemia in PNA14–16.
This study shows that acyanotic VSD within mean sizes: 1.2±0.3 and 0.89±0.2 centimeters, thus, defect measured from the left ventricular septal side are prone to pulmonary vascular infection/dysfunction. Both transthoracic and transoesophageal echocardiography were employed in the diagnosis and delineation of VSD and PH17. Although, right heart catheterization (RHC) is regarded as gold standard, our center favor echocardiography due to less vascular and technical challenges, especially in clinically compromised infants. According to 2018 guidelines issued by British Society of Echocardiography, aforementioned is recommended and RHC superiority is insignificant18. Young infants (3moths old) with small defects were considered for closure if defect(s) showed no trait of spontaneous closure in the presence of symptoms after 2 consective follow-up at 2-month interval. Apical VSDs (Swiss cheese) seldom achieved closure, hence, inclusion.
Although this study is not focused on closure techniques, suffice to mention that surgical and minimally invasive. i.e. 1. perventricular19, 2. peratrial20 and 3. percutaneous (<10%) device closure were used. Surgical was employed when device implation proved futile, while percutaneous was limited to a small potion due to vascular limitation and possible complications. Recent publication cited small weight and age as recipe for complication during percutaneous intervention21. In addition, surgical technique was employed with utmost care due to bypass related complication and blood transfusion complications related in PH subjects. Its worthy mentioning that this study does not include prevalence of anaemia post intervention. Symptomatic subjects became asymptomatic at dismissal, and both aforementioned and asymptotic ones progressively improved anthropometric parameters during sequential follow-ups22.
Paediatric patients without hematologic disorders, diagnosed with hemodynamic significant acyanotic VSD in comorbid with pneumonia or pulmonary hypertension are 8 and 4 times susceptible to develop anaemia compared to asymptomatic counterparts. Susceptibility is even high amongst young children (3–6 months). However, a long post closure follow-up study is required to exclude possibly missed intrinsic (genetical/gastro-intestinal) and extrinsic (economical) etiologies and validate findings.
The Shandong Provincial Hospital Ethics Committee approved this study, and waived individual patient consent as the study was based on archived data.
Harvard Dataverse: Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension; a retrospective study of 75 paediatric cases, https://doi.org/10.7910/DVN/2B328D22.
Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
We thank the management and staff of the Department of Cardiovascular Surgery and Imaging of Shandong Provincial Hospital, affiliated to Shandong University.
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Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Pediatrics, Pediatric cardiology, Pediatric interventionnal cardiology.
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Fetal medicine, fetal cardiology.
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Pediatrics, Pediatric cardiology, Pediatric interventionnal cardiology.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Fetal medicine, prenatal diagnosis of fetal malformations
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Version 1 25 Jan 19 |
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