|Year : 2018 | Volume
| Issue : 4 | Page : 73-79
Pulmonary function abnormalities in Nigerian children with sickle cell anaemia: Prevalence, pattern and predictive factors
Bankole Peter Kuti, Samuel Ademola Adegoke
Department of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife, Nigeria
|Date of Web Publication||28-Dec-2018|
Bankole Peter Kuti
Department of Paediatrics and Child Health, Obafemi Awolowo University, PMB 013, Ile-Ife
Source of Support: None, Conflict of Interest: None
Background: Advances in care of children with sickle cell anaemia (SCA) have increased their chances of survival to adolescence and adulthood though this is often associated with multi-organ system pathologies including lung dysfunctions. This study aimed to determine the prevalence, pattern and factors associated with pulmonary function abnormalities in Nigerian children with SCA. Methods: Pulmonary functions of 104 children with SCA in steady state and 104 age- and sex-matched haemoglobin AA controls aged 6 to 16 years at the Wesley Guild Hospital, Ilesa Nigeria, were assessed using Spirolab III (Medical International Research, Italy) spirometer following standard protocol. Socio-demographic characteristics, nutritional status and pulmonary function parameters of these children were compared, and the predictive factors of pulmonary function abnormalities in SCA children were determined using binary logistic regression. Results: SCA children had lower lung volumes and capacities and higher prevalence of pulmonary function abnormalities compared to controls, and a restrictive ventilatory pattern (22.1%) was the most predominant form. Adolescent age, previous acute chest syndrome (ACS), repeated painful crises and multiple hospitalisations in the previous year were significantly associated with pulmonary function abnormalities (P < 0.05). Only adolescent age group (odds ratio [OR] = 3.738; 95% confidence interval [CI] = 1.480–9.440; P = 0.005) and previous ACS (OR = 8.500; 95% CI = 2.044–12.959; P = 0.044) independently predicted pulmonary function impairments among the SCA children. Conclusion: SCA predisposes children to pulmonary dysfunction, particularly during adolescent years and in those with ACS, multiple crises and hospitalisations. Routine pulmonary function assessment in these children will facilitate early recognition and prompt management.
Keywords: Acute chest syndrome, painful crisis, pulmonary function, sickle cell anaemia
|How to cite this article:|
Kuti BP, Adegoke SA. Pulmonary function abnormalities in Nigerian children with sickle cell anaemia: Prevalence, pattern and predictive factors. Pediatr Respirol Crit Care Med 2018;2:73-9
|How to cite this URL:|
Kuti BP, Adegoke SA. Pulmonary function abnormalities in Nigerian children with sickle cell anaemia: Prevalence, pattern and predictive factors. Pediatr Respirol Crit Care Med [serial online] 2018 [cited 2019 Mar 24];2:73-9. Available from: http://www.prccm.org/text.asp?2018/2/4/73/249001
| Introduction|| |
Sickle cell anaemia (SCA) is an autosomal recessively inherited haemoglobinopathy characterised by both acute and chronic haemolytic anaemia, acute episodes of vaso-occlusive events and multi-organ dysfunctions due to repeated sickling phenomenon. It results from a single-gene mutation in the deoxyribonucleic acid base sequence of the short arm of human chromosome 11, leading to the substitution of valine for glutamic acid in the sixth position of the β-globin chain of haemoglobin (Hb).
SCA is a disease of public health significance, particularly in Sub-Saharan Africa where an estimated six million individuals with SCA live and the disease contributes to more than 5% of childhood mortality. In Nigeria, more than 150, 000 homozygous infants were estimated to be born yearly, with about four million individuals affected by the disease. Nigeria, therefore, bears the lion's share of the global burden of SCA.
Advances in health-care delivery services even in developing countries had increased the chances of survival of children with SCA to adolescence and adulthood. The better survival allows more morbidities to manifest in different systems, including the respiratory system. The respiratory system like the other systems of the body is affected by infections and infarctions which characterise the disease., Children with SCA are predisposed to recurrent chest infections, pulmonary infarctions, acute chest syndrome (ACS) and pulmonary thromboembolism including fat embolism and pulmonary hypertension., Some of the pathogenetic mechanisms causing pulmonary disorders in this group of children include haemolysis, endothelial cell dysfunction and vasculopathy., These respiratory disorders, particularly ACS, have been reported as a leading cause of hospitalisation, including admission to intensive care unit and premature death in individuals with sickle cell disease., Consequently, pulmonary function assessments in children with SCA had been explored to facilitate early detection of pulmonary dysfunctions in these children with variable reports of predominantly restrictive, obstructive and even mixed ventilatory patterns.,,,,, Reported risk factors for lung function abnormalities among SCA children varied. For instance, Arteta et al. reported increasing age, personal or family history of wheezing and evidence of haemolysis as risk factors of abnormal lung functions observed in 39% of American children with sickle cell disease. Previous hospital admission due to acute lung diseases was found as a predictor of lung function abnormalities in Brazilian children with SCA. There is a paucity of reports, however, on the socio-demographic and clinical factors associated with pulmonary function abnormalities in these children, particularly in developing countries including Nigeria where the burden of the disease is large. This study sets out to determine the prevalence and pattern of pulmonary function abnormalities among children with SCA and their age- and sex-matched counterparts with Hb genotype AA and to determine the predictive factors associated with pulmonary function abnormalities in sickle cell anaemic children presenting to a tertiary health facility in Nigeria.
| Methods|| |
This was a hospital-based, comparative cross-sectional study.
This study was conducted at the paediatric haematology and children welfare clinics of the Wesley Guild Hospital (WGH), Ilesa, Nigeria. The haematology clinic runs once a week for children with haemato-oncologic disorders, while the welfare clinic runs daily for children with minor illness, pre-school entry medical examinations and minor surgical conditions. The WGH is a tertiary arm of the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Southwest Nigeria. Ilesa is situated on latitude 7°35'N of the equator and longitude 4°51'E of the meridian and is the largest town in Ijesaland.
Consecutively, children aged 6 to 16 years with Hb genotype SS in steady state (free of crises, infections or other illnesses for more than 4 weeks and not being transfused for more than 3 months) who presented for routine clinic visits during the study were recruited. SCA children with stroke, congenital or acquired heart diseases and those who could not perform an acceptable or useable spirometry test were excluded.
The children in the comparative group were recruited from apparently healthy children with Hb genotype AA who presented to the child welfare clinic of the hospital for routine preschool entry medical examinations. These children were age, sex and ethnic matched with the SCA group.
Sample size determination
The minimum sample size for this study was estimated using OpenEpi sample size software®. Using 5% significance (alpha) level, 80% study power and 95% confidence interval (CI), with the assumptions that: the mean difference of forced vital capacity (FVC) among children with Hb genotype SS and those with AA Hb genotype = 0.36 L and the standard deviation (SD) of 0.57 and 0.55 L for SS and AA children, respectively (Achigbu et al.) and the ratio of SS to AA children was 1:1, the minimum sample size was estimated to be n = 200 (100 each for SCA and Hb AA children) but 208 (104 each for the groups) eligible children during the study period were studied.
Ethical approval of this study was granted by the Ethics and Research Committee of the OAUTHC, Ile-Ife, Nigeria (Approval no ERC/2015/08/05). Informed consent and assent as appropriate were obtained from the caregivers and study participants.
Using a data pro forma specifically designed for the study, a history obtained from the study participants and/or their caregivers included their age, sex and duration since the disease was diagnosed. The socio-economic classes of the children were obtained by rank assessment of parental occupation, highest level of educational qualification and income distribution as described by Ogunlesi et al. Among the children with SS, the frequency of hospitalisation, blood transfusion and painful crises that required hospital visits were obtained from the clinical notes of the study participants. ACS was recorded as defined in the clinical notes as an acute illness characterised by fever and respiratory symptoms (dyspnoea and chest pain with or without cough) accompanied by new pulmonary infiltrates on chest radiograph. Other complications such as chronic leg ulcer and avascular necrosis of femoral neck were also recorded.
The weight and height of the study participants were measured using a weighing scale and an RGZ-160 stadiometer (Laerdal Medical Ltd., Orpington, Bromley, United Kingdom), respectively. Nutritional status of the children was then determined using the World Health Organization (WHO) growth reference chart. Stunting, underweight and wasting were defined as height for age, Z score <−2SD from the mean; body mass index (BMI) (weight in Kg/height2 in m2) Z score <−2SD and weight for height Z score <−2SD from the mean, respectively, while overweight was defined as BMI > Z score + 2SD on the WHO growth reference chart.
Lung function assessment of study participants
Lung function assessment was done using a spirometer (MIR Spirolab III, Medical International Research Srl, Italy) following the American Thoracic Society/European Respiratory Society guidelines. After demonstrating the procedure to the children, they were instructed to inspire to maximum capacity (total lung capacity) and blow through the mouthpiece as fast and as long as possible (to residual volume). The measurement was done in sitting position and with the study participants wearing a nose clip. Lung function assessments were done, for a minimum of three times and not more than eight times. The parameters of interest, i.e., forced expiratory volume in 1 s (FEV1), FVC, Tiffeneau index (FEV1/FVC ratio) and peaked expiratory flow rate (PEFR), were recorded from the best reading that met the acceptability criteria. The reference value used for this study was based on the data of Knudson.
Diagnosis of obstructive ventilatory pattern was made when FEV1/FVC ratio was <80%, FEV1% <80% predicted and FVC% >80% predicted or concavity in the flow-volume curve of spirogram. These were tested with short-acting bronchodilator to assess for significant reversibility (increased in actual FEV1 ≥12% from the baseline). A restrictive ventilatory pattern was presumed when FVC% was <80% predicted, FEV1/FVC >80% with the flow-volume spirogram curve showing convex shape. Those with FVC% <80% predicted for age, sex and height with FEV1/FVC <80% were classified as having mixed impairment.
Data analysis was performed using the Statistical Package for the Social Sciences software Version 17.0 (SPSS Inc., Chicago 2008, IL, USA). The age, weight and height as well as lung function parameters of the children were summarised using mean and SD. Proportions and percentages were determined for their sex, nutritional status and ventilatory pattern categories. Differences between the mean (SD) lung function parameters of the SCA and their Hb AA counterparts were analysed using Student's t-test, whereas categorical variables were analysed using Pearson's Chi-square test and Fisher's exact test as appropriate. Pearson's correlation tests were performed to determine the relationship between ages of the SCA and their lung function parameters. Binary logistic regression analysis was used to determine the predictive factors for lung function impairment in the children with SCA. The results were interpreted with odds ratios (ORs) and 95% CI. Statistical significance was established when the CI did not embrace unity and level of significance taken at P < 0.05.
| Results|| |
From October 2016 to September 2017, 208 children (104 each for SCA and age- and sex-matched Hb AA) were recruited for the study. Fifteen children with SCA were excluded including six with residual muscle weakness from a previous stroke, five with cardiac lesions and four children who could not perform acceptable spirometry tests.
The ages of the children ranged from 6 to 16 years with a mean (SD) age of 10.1 (3.0) years. There was no significant difference in the age distribution, gender and parental socio-economic status of the children with SCA and their Hb genotype AA counterparts [Table 1]. The mean age at diagnosis of SCA was 4.1 (2.7) years (range: 7 months to 12 years). The mean (SD) weight and height of the children with Hb AA was significantly higher than that of children with SCA [Table 2]. Likewise, there was a higher prevalence of undernutrition among the children with SCA compared to their Hb AA counterparts [Table 1].
|Table 1: Distribution of the study participants according to age, gender, social class, nutritional status and ventilatory pattern|
Click here to view
|Table 2: Anthropometric and pulmonary function parameters of the study participants|
Click here to view
The means (SD) of FEV1, FVC and PEFR of the children with HB AA were significantly higher than that of the children with SCA [Table 2]. The age and sex distribution of the children with SCA and Hb AA as related to their pulmonary function parameters also showed significantly higher FEV1 (FEV1% predicted) and FVC among the children with Hb AA compared to those with SCA. [Table 3] The FVC% predicted was particularly lower in male adolescents. Furthermore, significantly more proportion of the SCA children had pulmonary function abnormalities compared to those with HB AA (29.8% vs. 3.6%; χ2 = 27.875; P < 0.001), and a restrictive ventilatory pattern was the most predominant pulmonary function impairment observed [Table 1] and [Figure 1]. Of the 6 (5.8%) SCA children with obstructive ventilatory pattern, 4 (3.8%) had significant reversibility with a short-acting bronchodilator.
|Table 3: Age distribution of the male and female study participants as related to pulmonary function parameters|
Click here to view
|Figure 1: The distribution of the pattern of lung function abnormalities recorded in the study participants.|
Click here to view
There was a significant but weakly negative correlation between the ages of the children with SCA and their lung function parameters (age and. FEV1%; Pearson's correlation = −0.326; P = 0.001, age and FVC%; Pearson's correlation = −0.286; P = 0.005, age vs. PEFR%; Pearson's correlation = −0.322; P = 0.019, age and FEV1/FVC Pearson's correlation = −0.297; P = 0.004).
More adolescents (study participants aged 11 to 16 years) had pulmonary function abnormalities, as 21 (43.8%) of the 48 adolescents compared to 10 (17.9%) of the 56 pre-adolescents had lung function impairments (χ2 = 8.282; P = 0.004). Likewise, children with multiple hospitalisations (>3 in the last year) (60.0% vs. 36.2%; χ2 = 4.820; P = 0.028), multiple painful crises (48.0% vs. 31.78%; χ2 = 3.830; P = 0.023) and previous ACS (75.0% vs. 26.0%; χ2 = 7.611; P = 0.006) were significantly more likely to have pulmonary function abnormalities. Socio-demographic characteristics, frequency of blood transfusion, age at diagnosis of SCA and other SCA complications were not significantly related to the presence of pulmonary function abnormalities in the children [Table 4].
|Table 4: Factors associated with pulmonary functions abnormalities among children with sickle cell anaemia|
Click here to view
Using binary logistic regression analysis, adolescent age group (OR = 3.738; 95% CI = 1.480–9.440; P = 0.005) and previous ACS (OR = 8.500; 95% CI = 2.044–12.959; P = 0.044) were independent predictors of lung function impairment among the children with SCA [Table 5].
|Table 5: Predictors of pulmonary function impairment among the children with sickle cell anaemia using logistic regression analysis|
Click here to view
| Discussion|| |
This study highlighted the prevalence and distribution of pulmonary function abnormalities in Nigerian children with SCA and determined the predictive factors for lung function abnormalities among children with SCA. Children with SCA were shorter, lighter and had a higher prevalence of undernutrition compared to their HB AA counterparts. These findings were similarly reported by other authors.,, SCA was reported to affect growth and development of children.,, This may arise from the chronic anaemic state, resulting in folate and other micronutrient wasting, chronic hypoxaemia from the resultant anaemia and growth hormone deficiency which was reported in these children. Hence, routine growth monitoring, folate and micronutrients supplementation are important parts of management of children with SCA.
Lower lung volumes and capacities were observed in children with SCA compared to their matched Hb AA controls. This difference in lung volumes was more pronounced during adolescence. Lung volume parameters were found to decline significantly with age. Similar findings had also been reported from developing and developed countries.,, MacLean et al. estimated that the average decline of FEV1 and total lung capacity were 2.93% and 2.15% predicted per year for boys and 2.95% and 2.43% predicted per year for girls with sickle cell disease, respectively. Decline in lung function in children with SCA with age had been linked to poor somatic growth as lung growth and development continues through the first two decades of life., Furthermore, with chronic haemolysis and release of intracellular red cell arginase and free Hb, there is a degradation of arginine which is an important substrate of nitric oxide synthase. This depletion of arginine and consequent nitric oxide deficiency results in endothelial dysfunction and pulmonary arterial hypertension., The presence of pulmonary hypertension was reported in up to one-fifth of Nigerian school-age children with SCA and was associated with exercise intolerance and progressive decline in pulmonary function.
Pulmonary function impairment was observed in about one-third of the children with SCA in this study, with possible restrictive ventilatory pattern being the most predominant form. A restrictive ventilatory pattern observed in 22.1% of our cohort of children with SCA was also reported to be the predominant pulmonary function pattern by Vieira et al. and MacLean et al. among Brazilian and American children with SCA, respectively. However, predominantly obstructive ventilatory pattern was reported by other authors., The difference in the predominance of the ventilatory abnormalities reported by various studies may be related to the difference in the age of the cohort of SCA children study. For instance, while Knight-Madden et al. studied SCA with a much younger mean age of 7.7 years, the present study like that of Vieira et al. studied much older age group with the mean age of over 10 years. It is speculated that pulmonary function evolves in children and adolescents with SCA from normal to obstructive and then to restrictive ventilatory pattern. The exact age when abnormalities set in is still largely unknown. In the present study, adolescents were found to have more pulmonary abnormalities than their younger age group. This was also corroborated by MacLean et al. who reported that 18.7% of adolescents as compared to 0.9% of 8-year-old children had a restrictive pattern. The importance of routine pulmonary function assessment in children and adolescents with SCA cannot, therefore, be overemphasised.
Apart from advancing age, ACS was observed as a predictive factor of pulmonary function abnormalities in this study. ACS has been reported as a leading cause of premature death in individuals with SCA and the second most common cause of hospitalisation, affecting up to 50% of individuals with SCA at least once in their lifetime.,, It was related to lung function abnormalities in SCA by other authors., ACS is related to infection and infarction which are the major reasons for hospitalisation in children with SCA. In our study, repeated painful crises and multiple hospitalisations in the previous year were associated with pulmonary function abnormalities in the cohort of children studied. This implies that prevention of infarction and infections and by extension multiple hospitalisations by adequate hydration, appropriate immunisation, optimal hygiene practices and early diagnosis and prompt treatment as well as ensuring anti-sickling measures may also ensure lung health in children with SCA.,,,
Worthy of note from this study is that 5.8% of the SCA children had an obstructive ventilatory pattern and only 4 (3.8%) children had a significant reversal of the obstruction with a short-acting bronchodilator. Although the prevalence of spirometry diagnosed asthma (3.8%) among SCA children in this study may not be significantly different from the prevalence in general paediatric population, asthma, however, carries a far more risk and burden in SCA children than non-SCA children.,, Lower airway obstruction and asthma had been reported by other authors in SCA children and found to be associated with worse disease severity as asthma and other lower airway obstructions predispose them to ACS and poor prognosis.,, Thus, routine pulmonary function assessment of children with SCA as part of standard care is of paramount importance.
The main limitations of the present study were the absence of total lung capacity, functional residual volume and diffusion capacity of carbon monoxide which could have further characterise the type of pulmonary function abnormalities observed in these children.
| Conclusion|| |
About one-third of Nigerian children with SCA had pulmonary function abnormalities with predominant restrictive ventilatory pattern. Advancing age, lifetime ACS and repeated painful crises and hospitalisation are factors associated with pulmonary function abnormalities in these children. Routine assessment of pulmonary functions and prevention of crises and hospitalisation will ensure better lung health and overall improved quality of life in these children.
The authors are grateful to the clinicians at the Paediatric Department of the Wesley Guild Hospital, who assisted in patient recruitment and the children with their caregivers who kindly accepted to participate in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
DeBaun MR, Vichinsky E. Hemoglobinopaties. In: Kliegman RM, Behman RE, Jenson HB, Stanton BF, editors. Nelson Textbook of Paediatrics. 18th
ed. Philadelphia: Saunders; 2007. p. 2025-38.
Makani J, Cox SE, Soka D, Komba AN, Oruo J, Mwamtemi H, et al.
Mortality in sickle cell anemia in Africa: A prospective cohort study in Tanzania. PLoS One 2011;6:e14699.
Lucky L. Mulumba LL, Wilson L. Sickle cell disease among children in Africa: An integrative literature review and global recommendations. IJANS
Strunk RC, DeBaun MR. The lung in sickle cell disease In: Wilmott RW, Chernick V, Boat TF, Deterding RR, Bush A, Ratjen F, editors. Kendig and Chernick's Disorders of the Respiratory tracts in Children. Vol. 8. Philadelphia: Saunders Elsevier; 2012. p. 1019-25.
Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008;359:2254-65.
Achigbu KI, Odetunde OI, Chinawa JM, Achigbu EO, Ikefuna AN, Emodi IJ, et al.
Pulmonary function indices in children with sickle cell anemia in Enugu, South-East Nigeria. Saudi Med J 2015;36:928-34.
Sylvester KP, Patey RA, Milligan P, Dick M, Rafferty GF, Rees D, et al.
Pulmonary function abnormalities in children with sickle cell disease. Thorax 2004;59:67-70.
Arteta M, Campbell A, Nouraie M, Rana S, Onyekwere OC, Ensing G, et al.
Abnormal pulmonary function and associated risk factors in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol 2014;36:185-9.
Knight-Madden JM, Forrester TS, Lewis NA, Greenough A. Asthma in children with sickle cell disease and its association with acute chest syndrome. Thorax 2005;60:206-10.
Koumbourlis AC, Zar HJ, Hurlet-Jensen A, Goldberg MR. Prevalence and reversibility of lower airway obstruction in children with sickle cell disease. J Pediatr 2001;138:188-92.
Fonseca CZ, Araújo-Melo CA, de Carvalho RM, Barreto-Neto J, Araújo JG, Cipolotti R. Lung function in patients with sickle cell anemia. Rev Paul Pediatr 2011;29:85-90.
Ballas SK, Lieff S, Benjamin LJ, Dampier CD, Heeney MM, Hoppe C, et al.
Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol 2010;85:6-13.
Dean AG, Sullivan KM, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version 3.01. Available from: www. OpenEpi.com, Updated 2013 Apr 06, [Last accessed on 2018 Dec 10].
Ogunlesi AO, Dedeke IO, Kuponiyi OT. Socioeconomic classification of children attending specialist paediatric centres in Ogun state. Niger Med Pract 2008;54:21-5.
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al.
General considerations for lung function testing. Eur Respir J 2005;26:153-61.
Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725-34.
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al.
Interpretative strategies for lung function tests. Eur Respir J 2005;26:948-68.
Al-Saqladi AW, Cipolotti R, Fijnvandraat K, Brabin BJ. Growth and nutritional status of children with homozygous sickle cell disease. Ann Trop Paediatr 2008;28:165-89.
Cipolotti R, Caskey MF, Franco RP, Mello EV, Dal Fabbro AL, Gurgel RQ, et al.
Childhood and adolescent growth of patients with sickle cell disease in Aracaju, Sergipe, North-East Brazil. Ann Trop Paediatr 2000;20:109-13.
Esezobor CI, Akintan P, Akinsulie A, Temiye E, Adeyemo T. Wasting and stunting are still prevalent in children with sickle cell anaemia in Lagos, Nigeria. Ital J Pediatr 2016;42:45.
Dekker LH, Fijnvandraat K, Brabin BJ, van Hensbroek MB. Micronutrients and sickle cell disease, effects on growth, infection and vaso-occlusive crisis: A systematic review. Pediatr Blood Cancer 2012;59:211-5.
Nunlee-Bland G, Rana SR, Houston-Yu PE, Odonkor W. Growth hormone deficiency in patients with sickle cell disease and growth failure. J Pediatr Endocrinol Metab 2004;17:601-6.
MacLean JE, Atenafu E, Kirby-Allen M, MacLusky IB, Stephens D, Grasemann H, et al.
Longitudinal decline in lung volume in a population of children with sickle cell disease. Am J Respir Crit Care Med 2008;178:1055-9.
Koumbourlis AC, Lee DJ, Lee A. Longitudinal changes in lung function and somatic growth in children with sickle cell disease. Pediatr Pulmonol 2007;42:483-8.
Gaultier C. Developmental anatomy and physiology of the respiratory system. In: Taussig LM, Landau L, Le Souëf PN, Morgan WJ, Martinez FD, Sly PD editors. Pediatric Respiratory Medicine. 1st
ed. St. Louis: Mosby; 1999. p. 18-37.
Morris CR, Gladwin MT, Kato GJ. Nitric oxide and arginine dysregulation: A novel pathway to pulmonary hypertension in hemolytic disorders. Curr Mol Med 2008;8:620-32.
Sokunbi OJ, Ekure EN, Temiye EO, Anyanwu R, Okoromah CA. Pulmonary hypertension among 5 to 18 year old children with sickle cell anaemia in Nigeria. PLoS One 2017;12:e0184287.
Kato GJ, Onyekwere OC, Gladwin MT. Pulmonary hypertension in sickle cell disease: Relevance to children. Pediatr Hematol Oncol 2007;24:159-70.
Vieira AK, Alvim CG, Carneiro MC, Ibiapina CD. Pulmonary function in children and adolescents with sickle cell disease: Have we paid proper attention to this problem? J Bras Pneumol 2016;42:409-15.
Sylvester KP, Patey RA, Milligan P, Rafferty GF, Broughton S, Rees D, et al.
Impact of acute chest syndrome on lung function of children with sickle cell disease. J Pediatr 2006;149:17-22.
Boyd JH, DeBaun MR, Morgan WJ, Mao J, Strunk RC. Lower airway obstruction is associated with increased morbidity in children with sickle cell disease. Pediatr Pulmonol 2009;44:290-6.
Galadanci NA, Liang W, Aliyu M, Jibir BW, Karaye I, Inusa BP, et al.
Increased prevalence of asthma symptoms in Nigerian children with sickle cell disease compared to children without sickle cell disease. Blood 2012;120:4760. Available from: http://www.bloodjournal.org/content/120/21/4760
. [Last accessed on 2018 Oct 18].
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]