Pulmonary function tests in children with beta-thalassemia major

INTRODUCTION

Thalassemia is an autosomal recessive disorder and is the most common monogenic disorder worldwide. About 10% of the total world thalassemics are born in India every year.^[1] In India, the prevalence of beta-thalassemia is 1–17% and carrier frequency is 3–4%.^[2] Over the past three decades, regular blood transfusions (BTs) and iron chelation have dramatically improved the quality of life and thalassemia is transformed from a rapidly fatal disease to a chronic disease and is compatible with prolonged life. Regular BT causes generalized iron overloading in organs such as heart, liver, and pancreas. Lung impairment in thalassemia is also noted. Although, it does not produce any symptoms and is not the most significant clinical manifestation of thalassemia.

Most studies found that restrictive dysfunction is the predominant pattern of lung function abnormality,^[3-11] although some others found obstructive lung dysfunction^[12-14] and combined^[15] pattern also. The precise causes and pattern of pulmonary dysfunction in thalassemia has not yet been established. Most of the studies have tried to correlate serum ferritin levels with pulmonary function abnormalities, but the results are conflicting.^{[3-6,9,12,16]} However, lung dysfunction has never been adequately focused upon and remains to be one of the least understood complications, hence, we propose to study the pattern of lung functions in thalassemia major children and correlation of lung function test with serum ferritin.

MATERIALS AND METHODS

Prospective hospital-based cross-sectional study, during January 1, 2017, to December 31, 2017, in children aged between 5 and 15 years with beta-thalassemia major admitted for periodic BT in pediatric ward, at Karnataka Institute of Medical Sciences, Hubli.

RESULTS

Total number of children included in the study was 45. Thirty-seven (82.2%) children were <10 years and 8 children (17.8%) were more than or equal to 10 years, with mean age 7.78 ± 2.4 and male:female ratio 1.6:1. All children (100%) presented with easy fatigability and progressive pallor. Only 2 (4.4%) children had presented with cough secondary to URTI. None of the children presented with rapid breathing, chest in drawing, and chest pain. On per abdomen examination, all children had hepatomegaly (100%) and 34 children (75.5%) had splenomegaly, remaining 11 (24.5%) children were splenectomized. [Table 1] shows baseline character of enrolled children.

Total number of children with abnormal PFTs was 35 (77.8%). Among 35 children with pulmonary dysfunction, 31 (88.5%) children had restrictive pattern, 2 (5.71%) children had obstructive pattern, and 2 (5.71%) children had combined pattern.

[Table 2] shows mean values of various parameters of PFT. Twenty-five (55.5%) children had reduced FEV1 and 33 (73.3%) had reduced FVC. However, 41 (91.1%) had normal FEV₁/FVC%, whereas PEFR and FEF 25–75% were reduced in 22 (51.1%) children each.

[Tables 3 and 4] show risk factors for pulmonary dysfunction. There was a significant negative correlation between age and height with respect to FVC%, FEV₁%, and PEFR, but there was no significant correlation between BMI and PFT parameters (P > 0.05). [Figure 1] depicts scattered plot showing comparison between height and FVC% predicted (negative correlation). There was a significant difference in mean FVC%, FEV₁%, and PEFR with respect to the duration of chelation (P < 0.05%). Mean FVC%, FEV₁%, and PEFR were significantly reduced among those with duration of chelation (>5 years).

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Figure 1:

Scattered plot showing comparison between height and forced vital capacity % predicted.

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Mean serum ferritin levels in children with normal PFT, restrictive pattern, obstructive pattern, and combined pattern were 2868.70 ± 2985.58, 3267.93 ± 1995.89, 2792.40 ± 2096.01, and 1633.15 ± 32.03, respectively. There was no significant difference in mean values of PFT parameters, age, BMI, and pre-transfusion Hb with respect to serum ferritin levels; however, FVC and FEV1, PEFR, and PEF 25–75% values were found to be decreased in children with a high ferritin level (>2500 ng/ml) as compared with children with a low ferritin level (<2500 ng/ml), but these differences were statistically not significant [Tables 5 and 6].

DISCUSSION

Lung dysfunction is among the least studied complication in children with beta-thalassemia major, probably due to the lack of pulmonary symptoms presenting compared to cardiomyopathy or endocrine complication.^[16] We observed that 35 (77.8%) children had abnormal PFT. The pulmonary functional abnormality of frequency was restrictive 31 (88.5%), obstructive 4 (5.7%), and combined 4 (5.7%) pattern. Impairment in respiratory function among thalassemia children has been reported in the range of 29–86%.^[7-9]

Restrictive lung function abnormality was observed as major pulmonary abnormality in our study. Several other studies^[3-11] have shown similar restrictive pattern as major pulmonary dysfunction. However, none of them found exact etiopathogenesis. We analyzed various risk factors for abnormal lung function including age, height, BMI, number of BT, duration of chelation therapy, organomegaly, and serum ferritin. Of these, age, height, and duration of chelation therapy (>5 years) were significantly associated with pulmonary dysfunction (FVC%, FEV₁, and PEFR). Our findings were consistent with the previous literature, as reported by others.^[4,8] The severity of restrictive abnormalities of thalassemic children was found to increase with age. In many other studies, different etiopathogenetic mechanisms for the development of restrictive lung dysfunction were reported such as multiple BT,^[18] hypoxia,^[18] iron overload,^[4,5,9] drug like desferrioximine,^[8,18] and genetic structure.^[18]

Four children (5.7%) had obstructive type of lung dysfunction. Similar results were found in other studies.^[6,9] However, Gulhan et al.^[12] found more number of obstructive dysfunction (46.2%). We also observed the combined pattern in 4 children (5.7%). Similar finding was also observed in Said^[15] (3.1%). The probable reason for small number of cases could be due to limitations in screening.

The mean values of various parameters of PFTs were reduced. A reduced FVC% 33 (73.3%), a reduced FEV1 25 (55.5%), a normal FEV₁/FVC ratio 41 (91.2%), and a reduced FEF 25–75% 23 (51.1%) were observed. In our study, pulmonary function abnormality may be partially explained by insufficient anatomic and functional development of lung during early infancy,^[4] as we observed age and height negatively correlated with various parameters of PFT. The other reasons could be iron overload as serum ferritin (>2500 ng/ml) had significantly associated with pulmonary dysfunction.

Although the measurement of serum ferritin is not the best quantitative estimate of body iron stores, thalassemic patients with a serum ferritin concentration of ≥3000 ng/dL have been reported to have a high probability of lung injury.^[19] Levels >2500 ng/dL have been reported to be associated with a 4-fold higher risk of death.^[3] In the present study, no correlation was found between serum ferritin levels and PFT; however, we observed, FVC and FEV₁, PEFR, and FEF 25–75% values were found to be decreased in patients with a high ferritin level (>2500 ng/dL) as compared with children with a low ferritin level (<2500 ng/dL), but these differences were statistically not significant. Probably, as our numbers are less. A complex mechanism in addition to iron overload has been proposed to play important role in the development of lung dysfunction.^[13]

In the present study, age and height were inversely correlated with FVC%, FEV₁%, and PEFR. There was a significant negative correlation between height and FVC%, FEV₁%, and PEFR, that is, with increase in height, there was a decrease in FVC%, FEV₁%, and PEFR. Probable cause could be the growth retardation which was observed in thalassemic children and the predictive lung volume, which was derived from age and height, might not be an accurate value, even if the effect of thalassemia on lung growth could be different from one on general growth.^[18,20]

Keens et al.^[21] suggested that good compliance to chelation therapy is crucial to prevent complications in these children. In our study, FVC%, FEV1%, and PEFR were significantly reduced among those with duration of chelation (>5 years). Even though all children had received chelation therapy, still we found significant reduction in PFT parameters; this could be probably due to inadequate dosage or non-compliance of the drug. Similar results found Said study.^[15]

CONCLUSION

Majority of our thalassemia children (78%) had abnormal patterns of lung function even though none of these children had any respiratory symptoms. We suggest, all children with thalassemia on regular BT should undergo PFT annually to prevent the sequelae.