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Research Article
Revised

Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases

[version 2; peer review: 2 approved with reservations]
PUBLISHED 19 Nov 2019
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Abstract

Background: Ventricular septal defects (VSD) are the second commonest congenital heart defects after bicuspid aortic valve. When left unrepaired, they can undergo spontaneous closure or elicit a spectrum of complications including pneumonia (PNA) or pulmonary hypertension (PH) with subsequent anaemia. In this retrospective study, we aim to establish and compare the prevalence of anaemia in patients with solitary acyanotic VSD in comorbid with PNA or PH.
Methods: A total of 75 case files of patients with solitary acyanotic VSD, who underwent surgical closure or device occlusion had haemoglobin level analysed prior to the procedure. The cohort included patients with (history of) PNA and PH, and asymptomatic. The cohort included 27 females and 48 males with mean age and weight of 8.3±5.72 (3-24) months and 5.9±3.9 (2.7-17.8) kilograms, respectively. Depending on  associated complication and age, the cohort was divided: PNA (A), PH (B) and Control (C); and (I) young children (≥3-6≤) and (II) older children (>6-≤24) months. We used 95 and 105 grams per litre as haemoglobin lower threshold level for (I) and (II), respectively.
Results: According to data analysis 27 patients (36%) in total had anaemia. Of the anaemia cohort 16 (59.3%) had PNA, 9 (33.3%) PH and 2 (7.4%) were asymptomatic. Of the cohort, 42 were young children, with anaemia prevalence of 19/42 (45.2%), while 24.2% of the older children had anaemia. 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).
 Conclusion: Paediatric patients with acyanotic VSD in comorbid with PNA or PH are 8 and 4 times more susceptible to develop anaemia compared to asymptomatic counterparts. Susceptibility is even higher among young children (3-6months). However, a prospective study is needed to validate our findings.

Keywords

Ventricular septal defect, Pneumonia, Pulmonary hypertension, Anaemia

Revised Amendments from Version 1

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.

To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.

Introduction

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 factors13. 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.

Methods

Case file details and classification

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.

Table 1. Patient demography and clinical characteristics.

VariableTotalGroups
ABC
N75302520
Age, months, mean± SD8.3±5.72 (range, 3–24)10.8±1911.5±12.88.8±5.1
Gender (female/male)27/489/2110/158/12
Weight, kgs, mean±SD5.9±3.9 (range, 2.7–17.8)4.9±3.26.5±4.86.7±3.4
Ventricular septal defect, cm, mean±SD0.93±0.31 (range, 0.4–1.6)1.2±0.30.89±0.20.65±0.2
Pulmonary hypertension, mmHg, mean±SD25.5±8 (range, 16–55)21.2±3.434±8.221.4±2.7

Table 2. Mean hematologic profile and laboratory results according to age groups.

VariableYoung children (≥3–≤6months
months)
Older children (>6–≤24 months)p-value
A*B*C*
Haemoglobin (g/l; mean±SD)109±25.1108.3±21.2132.2±18109.8±25.8117.9±15.4133.6±6.8*0.04
ˆ0.008
Mean corpuscular volume (f/l)76.9±7.385.7±2.183.9±974.6±582.8±6.685.6±4.8*0.001
ˆ0.0003
Mean corpuscular haemoglobin (pg; mean±SD)27±3.130.3±2.128.4±1.833.9±7.229±2.930.4±2*0.006
ˆ0.039
Lactate dehydrogenase (mean±SD)236.8±76.8222.4±61.6213.6±61.6300.9±119.2174.3±50147±30*0.68
ˆ0.0001
White blood cell (×109/L; mean±SD)12.5±5.37.8±2.46.9±0.915.4±5.76.7±1.55.9±2.1*0.003
ˆ0.0001
Red blood cell (×1012/L; mean±SD)3.8±0.93.6±0.93.8±0.43.2±0.54.3±0.64.8±0.4*0.9
ˆ0.0001

Data variables

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, %).

Results

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

Table 3. Association between age and anaemia prevalence.

GroupN; age (months; mean±SD)Haemoglobin (%)
AnaemiaNormal
Young children (≥3–≤6months; n=42)19; 4.85±1.0745.254.8
Older children (>6–≤24months; n=33)6; 12.69±6.0218.2.81.8
Association between complication and anaemia distribution
N (%)
AnaemiaNormal
A16; 3053.346.7
B9; 253668
C2; 201090

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).

Discussion

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 PNA1416.

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.

Conclusion

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.

Ethical considerations

The Shandong Provincial Hospital Ethics Committee approved this study, and waived individual patient consent as the study was based on archived data.

Data availability

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).

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Changwe GJ, Zhang H, Li H et al. Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases [version 2; peer review: 2 approved with reservations]. F1000Research 2019, 8:101 (https://doi.org/10.12688/f1000research.17907.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 19 Nov 2019
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Reviewer Report 05 Dec 2019
Raymond N. Haddad, Department of Pediatrics, Hotel Dieu de France University Medical Center, Saint Joseph University, Beirut, Lebanon 
Approved with Reservations
VIEWS 5
  • The entire article must be grammatically reviewed (however I can't propose corrections as I don't have the article lines numbered):
    • A lot of pleonasm.
    • A lot of
... Continue reading
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Haddad RN. Reviewer Report For: Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases [version 2; peer review: 2 approved with reservations]. F1000Research 2019, 8:101 (https://doi.org/10.5256/f1000research.23523.r56774)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 02 Dec 2019
Shengli Li, Department of Ultrasound, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China 
Yimei Liao, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Guangzhou, China 
Approved with Reservations
VIEWS 5
  1. This is a small-size retrospective study with only 75 patients, which is not enough to support their conclusions.
     
  2. In the previous review comments, we asked two questions:
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Li S and Liao Y. Reviewer Report For: Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases [version 2; peer review: 2 approved with reservations]. F1000Research 2019, 8:101 (https://doi.org/10.5256/f1000research.23523.r56775)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
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PUBLISHED 25 Jan 2019
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Reviewer Report 15 Oct 2019
Raymond N. Haddad, Department of Pediatrics, Hotel Dieu de France University Medical Center, Saint Joseph University, Beirut, Lebanon 
Approved with Reservations
VIEWS 8
Firstly, I want to thank The Editorial Team of F1000Research for this opportunity to review the following manuscript.

I want to also thank the authors for recommending as a reviewer for their manuscript. Although this comparative concept is ... Continue reading
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HOW TO CITE THIS REPORT
Haddad RN. Reviewer Report For: Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases [version 2; peer review: 2 approved with reservations]. F1000Research 2019, 8:101 (https://doi.org/10.5256/f1000research.19583.r54739)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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14
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Reviewer Report 27 Mar 2019
Shengli Li, Department of Ultrasound, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China 
Approved with Reservations
VIEWS 14
  1. The manuscript is a small-size retrospective study about the prevalence of anaemia in patients with solitary acyanotic VSD in comorbid with PNA or PH; they find that patients with acyanotic VSD in comorbid with PNA or PH
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Li S. Reviewer Report For: Anaemia in solitary acyanotic ventricular septal defect in comorbid with pneumonia or pulmonary hypertension: A retrospective study of 75 paediatric cases [version 2; peer review: 2 approved with reservations]. F1000Research 2019, 8:101 (https://doi.org/10.5256/f1000research.19583.r44745)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 25 Jan 2019
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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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