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ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 1009-1013

The effect of iron overload on pulmonary function tests in children with thalassemia major


1 Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
2 Department of Chest, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt

Date of Submission25-Feb-2021
Date of Decision17-May-2021
Date of Acceptance30-May-2021
Date of Web Publication18-Oct-2021

Correspondence Address:
Heba M Ahmed
Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_52_21

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  Abstract 


Objective
The aim was to determine pulmonary function abnormalities in children with thalassemia major (TM) and assess the relation between these abnormalities and iron overload.
Introduction
Regular blood transfusion program is among the most important factors that help in improving the survival of patients with TM; however, it leads to iron deposition in many organs such as lung. Most studied concerned about effect of iron on lung functions, revealed abnormalities, but limited data were observed.
Patients and methods
This cross-sectional study had included 50 children aged between 6 and 18 years (34 males and 16 females) with TM. All included children were subjected to full clinical examination and laboratory investigations including complete blood counts and serum ferritin. Pulmonary function tests (PFTs) were assessed in all included children using spirometry.
Results
Overall, 82% of the study group had abnormal pattern of PFTs. The majority of them were restrictive and of mild severity. Moreover, serum ferritin levels were found to be significantly higher in patients with thalassemia with abnormal PFTs (1456.65 ± 650.39) than patients with thalassemia with normal PFTs (744.34 ± 541.27) (P = 0.03).
Conclusion
Most children involved in the study had abnormal pattern of PFTs, and most frequent abnormality is restrictive pattern. In addition, there was a strong relationship between serum ferritin level and lung affection.

Keywords: iron overload, obstructive lung disease, pulmonary function tests, restrictive lung disease, thalassemia


How to cite this article:
Ahmed HM, Meabed MH, Ibraheem HK, Elsherif HM. The effect of iron overload on pulmonary function tests in children with thalassemia major. Menoufia Med J 2021;34:1009-13

How to cite this URL:
Ahmed HM, Meabed MH, Ibraheem HK, Elsherif HM. The effect of iron overload on pulmonary function tests in children with thalassemia major. Menoufia Med J [serial online] 2021 [cited 2024 Mar 28];34:1009-13. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/1009/328342




  Introduction Top


Thalassemia is a common hematological disease in Egypt and other Mediterranean countries, resulting from a defect in globin synthesis, leading to decreased quantity of globin chains. It represents a major popular health problem; however, the exact number of patient surviving to date is not available [1]. Survival of patients with thalassemia major (TM) has significantly improved during recent decades, mostly because of developed treatment protocols [2]. TM is a chronic disorder requiring regular blood transfusions [3]. It is characterized by abnormal hemoglobin (Hb) production, which results in decreased delivery of oxygen to the tissues and ineffective erythropoiesis. So, to elevate capacity of the blood to carry oxygen, the patients should receive regular transfusions [4],[5]. Ineffective erythropoiesis and regular blood transfusions lead to increased absorption of iron from gut, which will lead to iron overload. Although iron overload can be prevented by iron chelation therapy, iron is still deposited in many organs, especially the liver, lung, heart, and pancreas [2]. Many studies about the nature of lung function abnormality had conflicting results. Most studies on pediatric and adult patients revealed a predominant restrictive pattern on spirometry [6]. On the contrary, some studies indicated a predominant obstructive pattern. These contradictory results may originate from the different nature of the population in each study regarding the age, treatment protocols, or ethnical origin [7]. Different patterns of pulmonary function abnormalities have been observed in patients with TM. However, the specific etiology of the pulmonary dysfunction remains unknown. Several pathological mechanisms causing the pulmonary dysfunction in thalassemia had been described, such as iron overload and correlation with transfusion and allergy, but none of these had given a satisfactory explanation [2]. So far, in the literature, the most frequent abnormal pattern had been reported in the pulmonary function test (PFT) in patients with thalassemia is the restrictive pattern [8],[9]. In contrast, there are limited data observed in patients with thalassemia regarding the prevalence of the pulmonary function abnormalities [3]. The aim of this study was to determine pulmonary function abnormalities in children with TM and assess the relation between these abnormalities and iron overload.


  Patients and methods Top


This 'cross-sectional' observational study was conducted on 50 patients (34 males and 16 females) known to have TM based on the results of Hb electrophoresis during the period from September 2018 to September 2019. The inclusion criteria were ages between 6 and 18 years of both sexes (children able to perform PFTs) and patients with TM on regular blood transfusion program. The exclusion criteria were patients who have history of chronic respiratory disease, patients with severe infection, patients with C-reactive protein positive, patients with history of cardiac problem or heart failure within 6 months of the study, and patients with other hemoglobinopathies. All included patients were subjected to full history taking, including age, sex, consanguinity, age of onset and duration of disease, frequency of blood transfusion, chelation therapy, history of splenectomy or cholecystectomy, and family history of similar conditions; full clinical examination, including vital signs, anthropometric, measurements, and head and neck examination for features of thalassemia (pallor, prominent maxilla, and narrow nasal bridge); systemic examination, including chest, heart and abdomen; routine laboratory investigations (pretransfusion Hb, serum ferritin, and C-reactive protein); and PFTs using resting spirometry, which was performed by Master Screen (Jaeger-Hochberg, Germany) PFT (No: 781040). Preparation: anthropometric measures were taken, such as age, sex weight, and height. The test was performed 2 weeks after blood transfusion for all patients. Patients were instructed about the procedure and how and when to inhale and exhale. The patients were instructed to sit and were asked to tightly close their lips around the rubber mouthpiece, which was sterilized by alcohol before use and then washed by water, and lastly, dried by a clean dressing. A nose clip was used to make sure that the patient did not breathe through his nose. Procedure: first, the patient was asked first to breathe through his/her mouth normally. Second, after a few breaths, the patient was asked to inhale maximally and then exhale forcefully and for as long as he/she can. Third, the test was repeated (again for three times and the best reading taken). Fourth, the best of three readings was taken. Fifth, measurements were obtained for forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and ratio between them, peak expiratory flow, and forced expiratory flow (FEF25%, FEF50%, and FEF75%).

This study was approved by the local ethical committee, and an informed written consent was obtained from the caregivers of the included children.

Statistical analysis

All analyses were performed using SPSS, version 20 (SPSS Inc., Chicago, Illinois, USA). Continuous data were reported by using mean ± SD and categorical data as frequency and percentage. t-Tests were used to compare normally distributed continuous data. For categorical variables, a χ2 test was used. Pearson's correlation test was used to correlate quantitative variables fulfilling normal distribution. Binary regression test was used to assess the association between sex, chelation therapy, and splenectomy and PFT pattern. A two-sided P value less than 0.05 was considered to be statistically significant.


  Results Top


This study included 50 patients with TM (34 males and 16 females). Demographic, laboratory, and PFT data of the study group are shown in [Table 1]. The mean age at first transfusion was 5.8 ± 3.1 months, and the mean transfusion interval was 30.24 ± 5.65 days. A total of 39 (78%) children were on chelation therapy. Hepatomegaly was reported in 41 (82%) patients, and splenectomy was done to 19 (38%) patients. PFTs showed that 82% of the study group had abnormal pattern (56% restrictive, 4% obstructive, and 22% mixed pattern), 42% had mild restrictive lung disease (RLD), and 14% had moderate RLD. No significant differences were found between the two sex groups regarding demographic, laboratory, and PFT data, except for severity of RLD, as mild RLD was more common than moderate RLD in males (85.7%), whereas in females, moderate RLD was found in 57.2% (P = 0.04). Serum ferritin levels were significantly higher in patients with abnormal PFT than in patients with normal PFT [Table 2]. There was a significant negative correlation between platelet count and values of PFT. Low Hb levels and high ferritin levels were good predictors for the development of abnormal PFTs, as shown in [Table 3]. By binary regression test, there was no association between sex, chelation therapy, or splenectomy and PFT pattern. By binary logistic regression, there was a significant association between female sex and severity of RLD (B = 2.75, P = 0.035).
Table 1: Descriptive data of the study group

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Table 2: Comparison between different PFT patterns regarding clinical and laboratory data

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Table 3: Linear regression between abnormal PFT and other variables

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  Discussion Top


In thalassemia disease, there is a varying degree of ineffective hemopoiesis, intermittent hemolysis, and iron overload, which correspondingly lead to excessive iron deposits in organs such as lung, heart, liver, and endocrine [10]. The optimization of transfusion schedules and advances in iron chelation therapy have significantly prolonged the life expectancy of patients with thalassemia [11], which imply the possibility of developing of new complications not observed in past, including pulmonary disorders [12]. Lung dysfunction is among the least studied complications in children with thalassemia, probably owing to the lack of pulmonary symptoms presenting compared with cardiomyopathy or endocrine complications. Pulmonary dysfunction in children with thalassemia can be restrictive, large airway obstructive, diffusion impairment, or small airway disease [4]. Spirometry is the most useful and available test of pulmonary functions. General-practice physicians and pulmonologists usually use spirometry in their offices in the assessment and management of lung disease [13]. In our work, we aimed to determine the effect of iron overload on lung functions in children with thalassemia by assessment PFTs using spirometry. In our study, we found 82% of study population had abnormal pattern of PFT and the most common pattern was restrictive pattern. The exclusion of children with a known history of lung disease and asthma may account for the low percentage of obstructive pattern of PFT. This result comes in agreement with Abd El Hakeem et al. [10], who demonstrated that although all the patients with thalassemia were clinically asymptomatic, 70% (33 patients) of them had abnormal pattern of PFTs (32% had restrictive pattern), but none of them had obstructive pattern. A similar finding was also reported by Guidotti et al. [12], as 35% of patients had restrictive PFT, 40% normal, and none had a pure obstructive disease. Many other studies have reported finding similar to ours [6],[14],[15]. A higher percentage of subjected children (95%) had restrictive pulmonary function pattern in the study by Boddu et al. [16]. This predominance may be owing to the fact that they did not measure diffusion lung capacities, and they targeted patients with adult thalassemia in their study. According to Azarkeivan et al. [17], RLD was the most common abnormality found in PFT (72.7%), 2.2% (35 patients) had combined pattern and 25.1% (35 patients) had normal pattern. In our study, RLD was found to be mild in 75% and moderate in 25%. This result is similar to that found in the study by Abd El Hakeem et al. [10], in which a high percentage of restrictive pattern of PFTs were mild (53%), followed by moderate (23.5%) and severe (23.5%), whereas Gadiparthi et al. [15] found the majority of RLD is severe. Despite the high mean serum ferritin level of their subjects, they found the reason of the restrictive pattern (73.5%) is still not clear. In contrast to our finding, Boddu et al. [16] reported that majority of tested children with restrictive defect were moderate (59.9%) followed by 23.8% mild and 11.9% severe. Similar to our study, Alyasin et al. [4] did not report any severe restrictive pattern of PFT, whereas Eidani et al. [14] did not find any mild RLD. This difference may owing to that this study had older patients than ours. The causes of these respiratory changes may be multifactorial, with tissue iron deposition being one of the most important factors in the development of a restrictive pattern of lung dysfunction [18]. In our study, we did not find any relation between splenectomy and PFT abnormalities. Similar to our results, Boddu et al. [16] reported no significant differences in lung functions when patients with hepatosplenomegaly had been splenectomized. In addition, Abu et al. [8] had reported no correlations between splenectomy and lung abnormalities. Contrariwise, Rahim et al. [18] had shown increasing vital capacity and expiratory volumes in patients with thalassemia following splenectomy, explaining that hepatosplenomegaly can lead to a lung restrictive pattern by decreasing chest wall compliance, whereas splenectomy results in increases in vital capacity and expiratory reserve volume. The present study revealed that serum ferritin levels were significantly higher in patients with abnormal PFT than patients with normal PFT, and there was a significant association between s. ferritin and development of abnormal PFT when using binary regression, which reflects the strong association between serum ferritin level and lung affection. This result agrees with Abd El Hakeem et al. [10], who observed that children with TM who developed abnormal PFT (restrictive pattern) had significant high serum ferritin level when compared with patients with thalassemia with normal PFT. Guidotti et al. [12] and Bourli et al. [6] reported the same results, as they observed higher serum ferritin levels in the group of patients with restrictive pulmonary abnormality than group of normal patients. Boddu et al. [16] mentioned that serum ferritin levels were high in most of the children with severe respiratory dysfunction. Conversely, some few studies found no relation between serum ferritin level and the abnormality of PFT. Among them, Gadiparthi et al. [15] explained that ferritin is a product of hepatocellular damage, and it can be elevated in infection, congestive heart failure and hepatitis; therefore, they found high ferritin levels in children with normal PFT. The reason behind the restrictive pattern is still not clear. In a study by Witzelban et al. [19], necropsy data showed that iron was predominantly found in bronchial glands and epithelial cells rather than in the parenchyma. Tai et al. [20] proposed that diffusional impairment caused owing to the defect in the alveolocapillary membrane could account for the altered lung function, as studied in a significant number of subjects with thalassemia. Many other studies reflected that both degree and duration of iron overload may be important and postulated that iron might be responsible for this dysfunction through a free radical-induced injury [5]. The current study observed no significant difference between males and females regarding clinically and laboratory data, except mild RLD was more common than moderate in males, whereas moderate RLD was reported in most females. Many other studies have had a close observation with ours. Recently, Gadiparthi et al. [15] observed similar values in both males and females. However, Boddu et al. [16] and Alyasin et al. [4] reported no correlation between sex and pattern of pulmonary dysfunction. In our study, we did not find any relation between age and abnormalities of PFT. Guidotti et al. [12] and Alyasin et al. [4] had reported similar results. However, Azarkeivan et al. [17] observed a weak correlation between PFT abnormalities and age. However, many studies showed that PFT abnormalities were increasing with age [3],[6],[10],[15]. In our study, chelation therapy is not a predictor for the abnormalities of PFT, similar to what was reported by other studies [8],[10],[15]. Conversely, Boddu et al. [16] have shown deterioration of lung function with inadequate chelation. In our study, low pretransfusion Hb level was a good predictor for the development of PFT abnormalities. A very few studies discussed Hb level and its relation to PFT abnormalities. The study by Ozyörük et al. [3] demonstrated a significant positive correlation between Hb level and FEV1/FVC, whereas Eidani et al. [14] observed a significant positive correlation between both FEV1 and FEF and Hb. Our results revealed a negative correlation between platelet count and PFT values (FVC, FEV1, and FEV1/FVC). In a study done by Cappellini et al. [21], autopsies of a large series of patients with β-thalassemia revealed thrombotic lesions in the pulmonary arteries. This pulmonary arterial thromboembolism may have been owing to circulating platelet aggregates. Similar findings of multiple microthrombi, which were composed mainly of platelets, were seen in the pulmonary arterioles and microcirculation in autopsies of two splenectomized patients with thalassemia. However, a laboratory study done by Yaish et al. [22], on patients with thalassemia, found that platelet count was usually normal, unless the spleen is markedly enlarged. Reported abnormalities are varied and include restrictive pulmonary disease [5]. Although the liver, heart, and pancreas are the most frequently involved target organs and in which massive iron-induced injury is regularly observed at necropsy, abnormalities of pulmonary mechanisms have been reported by almost all studies of individuals with TM, whether restrictive or obstructive [14].


  Conclusion Top


Most children involved in the study had abnormal pattern of PFTs, and most of these abnormalities are restrictive pattern. Mild RLD was more common in males, whereas moderate RLD was more common in females. There is a strong relationship between serum ferritin level and lung affection. Low Hb level is a good predictor for the development of PFT abnormalities. There was a significant negative correlation between platelet count and values of PFT and a positive correlation between BMI with PFT.

Acknowledgments

Study concept by professor Dr Mohamed Hussein Meabed. Study design by Dr Mohamed Hussein Meabed, Dr Heba Mostafa, and Dr Heba Kamal. Literature search by Dr Heba Mamdouh and Dr Heba Mostafa. Clinical study by Dr Heba Kamal and Dr Heba Mamdouh. Data acquisition, data analysis, and statistical analysis by Heba Mostafa Ahmed. Manuscript preparation and editing by Heba Mostafa Ahmed and Heba Mamdouh. Manuscript review by Mohamed Hussein Meabed, Dr Heba Mostafa, and Dr Heba Kamal.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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