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

Introduction

Anaemia is a common complication of a myriad medical conditions often met in general ward. Its aetiology is complex and multifactorial, encompassing intrinsic and extrinsic factors^1–3. Cyanotic congenital heart defects are known to severely derail smooth blood flow with subsequent iron homeostasis dysregulation. Prevalence of anaemia amongst patients with cyanotic VSD is known and well documented in a variety of world literature². On the contrary, solitary acyanotic ventricular septal defect (VSD) exhibit a relatively smooth blood with unremarkable iron homeostasis dysregulation. However, depending on size and duration, solitary VSD can lead to pulmonary hyper-circulation with subsequent complications, including recurrent lower respiratory tract infection (pneumonia; PNA), pulmonary hypertension (PH), pulmonary vascular disease, heart failure and death^4,5.

PNA is known to cause local hypoxia with subsequent upregulation of erythropoiesis. In addition, certain causatives of PNA are known to compete for iron with the host, while others induce haemolysis, both leading to anaemia⁶. Equally, PH has been associated with severe forms of haemolytic anaemia in patients with haemoglobin disorder and erythrocyte membranopathies^2,7. In addition, free haemoglobin produced as a result of haemolysis depletes nitric oxide with subsequent vessel constriction, local hypoxia and exacerbation of PH^8,9. Both PNA and PH exhibit tendencies of inducing local hypoxia, leading to upregulation of erythrocyte synthesis. Adults and older children with enough iron store can tolerate such a condition without developing anaemia. However, infants and young children have inadequate iron stores. In addition, children below the age of 6-months fed exclusively on breast milk have limited source of iron replacement. For the reasons mentioned above, 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

Results

In this study, the haemoglobin reference range for groups: I and II were (95–135g/L) and (105–135g/L) respectively. This thus, conforms with local protocol.

According to data analysis in Table 3, 27 patients (36%) in total had anaemia. Of the anaemia cohort, 16 (59.3%) had PNA, 9 (33.3%) had PH, and 2 (7.4%) were asymptomatic. These results can be expressed as ratios 16:9:2=8:4.5:1; therefore, patients with PNA and PH are 8 and 4 times more susceptible to developing anaemia than asymptomatic patients.

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 5^th 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 anaemia^2,3,7. 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 valve^4,10, 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-circulation^2,4,7,11.

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 production^2,9,12.

PNA, defined as an inflammation of alveoli (with or without pus) due to an infection is a serious morbidity and mortality reason for children (≤2years) with hemodynamic significant VSD^5,13. Similar to PH, inflammatory state in PNA causes pulmonary oedema, homeostasis and hypoxia, with subsequent upregulation of erythrocyte synthesis^8,14. Prolonged upregulated erythropoiesis in young children with low iron store and limited iron source (exclusive breast milk) can develop low haemoglobin levels¹. In addition, microangiopathic haemolytic anaemia in CHD and PH has been reported³, a complication commonly observed in primary PH. Unlike PH, a number of PNA causatives are known to cause haemolytic and iron deficient anaemia. Mycoplasma pneumonia has been reported to cause severe haemolytic anaemia^15,16. In addition, Klebsiella is known to compete for iron with host via siderophores⁶.

Our study shows that patients with acyanotic VSD within mean sizes 1.2±0.3 and 0.89±0.2 cm were prone to develop recurrent lower respiratory tract infection and pulmonary vascular disorder. The two pathological conditions primarily share common features including pulmonary oedema, haemostasis and hypoxia, with an immediate non-hemodynamic response in form of increased erythropoiesis. However, unlike PH, toxins from certain causatives (bacteria) in PNA induce haemolysis, while other pathogens compete for iron with the host. Owing to LDH and WBC elevation in group A, it’s evident that there was some haemolysis of a certain degree as a result of an infection. Other potential causes include microangiopathic haemolysis in CHD with PH, feeding difficulties and malabsorption. Given the high proportion of anaemia in the ‘young children’ group, it is logical to assume they were fed exclusively on breast (artificial) milk, possibly limiting the source of iron. From our study, it is evident that diagnosis of hemodynamic significant acyanotic VSD in comorbid with PNA or PH should heighten the suspicion index of anaemia. However, we acknowledge that aetiology of anaemia is multifactorial, and so many intrinsic and extrinsic factors are at play, hence, every case requires a holistic approach.

Conclusion

Paediatric patients without hematologic disorders, diagnosed with hemodynamic significant acyanotic VSD in comorbid with PNA or PH are 8 and 4 times susceptible to develop anaemia compared to asymptomatic counterparts. Susceptibility is even high amongst young children (3–6months).

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/2B328D¹⁷.

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).