Lung function decline is accelerated in South Africans with cystic fibrosis South African Family Practice is co-published by Medpharm Publications, NISC (Pty) Ltd and Cogent, Taylor & Francis Group S Afr Fam Pract ISSN 2078-6190 EISSN 2078-6204 © 2016 The Author(s) RESEARCH South African Family Practice 2016; 58(1):24–27 http://dx.doi.org/10.1080/20786190.2015.1078156 Open Access article distributed under the terms of the Creative Commons License [CC BY-NC-ND 4.0] http://creativecommons.org/licenses/by-nc-nd/4.0 Lung function decline is accelerated in South Africans with cystic fibrosis R Masekelaa,b*, S Olorunjuc, RJ Greena and NT Magidimisaa a Faculty of Health Sciences, Department of Paediatrics and Child Health, Division of Paediatric Pulmonology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa b Department of Maternal and Child Health, Nelson R Mandela School of Medicine, School of Health Sciences, University of KwaZulu Natal, Durban, South Africa c Biostatistics Unit, Medical Research Council of South Africa, Pretoria, South Africa *Corresponding author, email: masekelar@ukzn.ac.za Background: Poor nutritional status has been shown to be associated with a significant decline in lung function in patients with cystic fibrosis. There are few data published on the lung function decline and the effects of nutritional status in cystic fibrosis (CF) in South Africa. Aim: To assess anthropometric parameters (weight, height, body mass index Z-score) in relation to lung function parameters in CF patients. Methodology: A retrospective chart review of clinical records of participants over the age of five years attending the CF clinic at Steve Biko Academic Hospital from 2005 to 2010. Results: Twenty files were reviewed for lung function, anthropometric measurements, gender and CF-causing mutations. For anthropometric measurements the average changes were –0.8, –0.5 and 2.0 for weight, BMI and height Z-scores, respectively. A decline in FEV 1 of –25.3 (95% CI 39.4; –13.3) over the five-year period was noted, with an average decline of 5.3% per year. For FEF 25-75 , the average change was –22.4 (95% CI-34.6; –10.2) with a decline of 4.5% per year. Using multivariate analysis, the FEV 1 was found to be significantly influenced by: age –3.96 (95% CI –7.4; –0.5); p = 0.03, weight 1.8 (95% CI –3.4; –0.9); p = 0.04, BMI Z-score 4.3 (95% CI 5.3; 23.3); p = 0.02 and gender (p = 0.02). The FEF 25-75 was significantly influenced by BMI Z-score and gender. Conclusion: The average lung function decline per year for FEV 1 was higher than that seen in developed countries. The decline in FEV 1 was related to gender, age, weight and BMI. The decline in FEF 25-75 was affected only by BMI Z-score and gender. Keywords: body mass index, growth, nutrition, pancreatic insufficiency, spirometry Introduction Cystic fibrosis (CF) is a common life-altering autosomal recessive inherited disorder due to mutations in the CF gene on chromo- some 7 that code for the cystic fibrosis transmembrane conduct- ance regulator (CFTR) protein. Over 1 900 mutations have been defined in the CFTR gene to date.1 The abnormal protein leads to disruption of chloride secretion in the epithelial cells, with result- ant production of abnormal viscid mucus and consequent obstruction of the pulmonary conducting airways and pancreatic ducts. CF occurs in diverse populations with differing rates. In South Africa the incidence is approximately 1 in every 2 800 in Caucasians, 1 in every 10 000 in mixed race and 1 in every 32 000 in black Africans.2 Worldwide p.F508del accounts for around 70% of all CF-causing mutations.3 In South Africa the p.F508del accounts for 74% of chromosomes in Caucasians with the 3120+1G→A being present in 46% of CF causing alleles in the black African population.4–6 Several studies have shown that CFTR genotype has an influence on the phenotype of CF.6,7 Subjects who are homozygous for p.F508del were found to have more severe clinical manifestations as compared with those who are heterozygous for the mutation.6–8 The main difference in the phenotypic presentation is thought to be related to the influence of CFTR genotype on pancreatic func- tion, with p.F508del homozygous subjects having pancreatic insufficiency at an earlier age and having worse nutritional param- eters.7–10 The relationship between CFTR genotype and severity of lung disease has been reported previously, where p.F508del homozygous patients were found to have a higher rate of lung function decline when compared with heterozygous subjects.11 The primary cause of morbidity and mortality in patients with CF is progressive obstructive lung disease associated with infection and intense neutrophilic inflammation.8 At an early age, impair- ment of airway function may have long-term consequences in the disease where the majority of patients die because of pulmo- nary involvement.8,11 Pulmonary function tests, particularly measurement of forced expiratory volume in 1 second (FEV 1 ) is a practical and objective way of monitoring the severity and progression of CF lung disease. FEV 1 has been found to be strongly associated with mortality, while forced expiratory flow during 25–75% of forced vital capacity (FEF 25-75 ) is a sensitive index of small-airway function and is affected earlier in CF lung disease.11 The pattern of lung function decline has been reported to be predictable in developed countries, with an annual rate of decline in the FEV 1 of less than 2% predicted for children born after 1980. The annual rate of FEV 1 declined in South African chil- dren with CF in a relatively short-term longitudinal study, which suggested an average rate of decline in FEV 1 of less than 1% per year.12 These values are similar to those of Xu et al., who found that patients born between 1985 and 1990 had an average rate of decline of 0.8%.13 In a subsequent follow-up study by Morrow et al., between 1999 and 2006, lung function tests were found to have increased by 20% over an eight-year period. Predicted FEV 1 was 61% in the first quarter of 1999 and 81% in the last quarter of 2006.14 This likely reflects improved care of South African children with CF. Malnutrition in cystic fibrosis is due to the relationship between nutrient balance and nutrient requirements. CF patients lose weight and fail to grow normally if the intake is less than their total daily mailto:masekelar@ukzn.ac.za 25 S Afr Fam Pract 2016; 58(1):24–27 energy expenditure. Multiple factors also have the potential to con- tribute to reduced energy intake including anorexia, gastroesopha- geal reflux, maldigestion and pancreatic insufficiency leading to re- duced intake. Other factors such as lung inflammation may be associated with increase in resting metabolic rate (RMR), which leads to increased energy expenditure. This was proved in previous studies where RMR in CF patients was found to increase as the lung function declines.15 Other parameters such as abnormal CFTR probably affect lung growth, host defences and the ability to repair lung injury. The resulting chronic lung disease may also affect energy expenditure and caloric needs, which in turn impacts on somatic growth.16 Poor nutritional status has been shown to be associated with a significant decline in lung function; children who weigh more and who gain weight at an appropriate rate have better FEV 1 Z-scores. Weight-for-age and height-for-age are also positively associated with FEV 1 % predicted.16–18 In a study conducted by Steinkamp et al. in Germany, the authors revealed that a fall in weight-for- height of 5% predicted or more within one year was associated with a parallel decrease in FEV 1 , whereas patients with improved nutrition showed constant or even improved FEV 1 .19 There are few published data on the effects of nutritional status on lung func- tion decline in CF patients in South Africa. This study was therefore conducted with the primary aim to assess various anthropometric parameters in relation to the lung function over time. The secondary aim is to assess the impact of CF mutations on lung function and finally to determine the rate of lung function decline over a period of five years. Methods A retrospective chart review was performed of clinical records of children over five years of age attending the CF clinic at Steve Biko Academic Hospital in Pretoria between 2005 and 2010. For inclusion in the study patients had to have a confirmed diagnosis of CF with two positive sweat tests and/or genetic testing. Partic- ipants had to have regular follow-up at the clinic over the five- year period under study. Participants also had to have a minimum of three lung function tests per year during the study period and a record of at least two anthropometric parameters per year dur- ing the study period. Clinical data recorded included age, gender, CF genotype, anthro- pometric measurements, lung function parameters and use of pancreatic enzyme supplementation. Lung functions (FEV 1 , FVC, FEV 1 /FVC and FEF 25-75 ) were measured using the Viasys SpiroPro Jaeger Spirometer (Hoechberg, Germany). Approval of this study was obtained from the University of Pretoria, Faculty of Health Sciences Human Research Ethics Committee. Statistical analysis For the statistical analysis, summary statistics reported included mean, 95% confidence intervals and median values for lung func- tion parameters and anthropometric measurements and these were categorised by gender and CF mutation. A two-sample t-test with unequal variances was used to compare lung function parameters and anthropometric measurements, mutations and gender. A multivariate regression model was used to determine which variables had an effect on lung function parameters (FEV 1 and FEF 25-75 ). Results At the time of the data collection, 37 files were screened and only 20 patients met the eligibility criteria. The majority of the partici- pants were aged between 10 and 20  years of age, (age range: 5–31  years), with more females (12/8) (Table 1). Information on genotype was available for 18 and 2 had unknown mutations or were unidentified. All participants were pancreatic insufficient and were on pancreatic enzyme supplementation. The mean Z-scores for all the growth parameters were within the normal range for the participants. The mean predicted FEV 1 and FEF 25-75 were 69% and 48%, respectively. For anthropometric measurements the mean weight by mutation at entry to exit from the study was higher for p.F508del homozy- gous compared with p.F508del heterozygous participants (Table 2). There was statistically significant change for weight over time for the whole study population, with a mean change of –19.4 (–35.4; -3.2); (p = 0.02). The mean weight Z-scores declined by –0.8 over the study period. For the height Z-scores the change was –1.15 (–1.69; –0.61) at study entry to 0.86 [–0.07; 1.80] at study exit and this was statistically significant; p = 0.0005. When comparing the mean BMI by mutation, p.F508del heterozygous participants had lower BMI when compared with homozygous participants at both study entry and study exit. The mean BMI Z-score changed from –0.5 (–1.34; –0.33) at study entry to –1.28 (–2.0; –0.56) at study exit; p = 0.25. The change over time for the whole study population from study entry to study end for the observed BMI Z-scores was –0.8 and this was not statistically significant, p > 0.05. For the lung function parameters, there was no effect of either gender or CF mutation observed for all the changes in relation to FEV 1 on FEF 25-75 over time (Table 3). The mean change for FEV 1 over five years was –25.3 (–39.4; –13.3); (p = 0.005) and for FEF 25-75 the mean change over the same period was –22.4 (–34.6; –10.2); (p = 0.001). The average lung function decline per year for FEV 1 and FEF 25-75 was 5.3% and 4.5%, respectively. There was a slightly steeper decline in FEV 1 for females when compared with males, although this was not statistically significant (Figure 1). Table 1: Demographic data for study population at entry (n = 20) Notes: p.F508del = delta F508 deletion; FEV 1 % = percentage predicted forced expiratory volume in one second; FEF 25-75 % = percentage predicted forced expiratory flow during 25–75%; BMI = body mass index. Variable Mean (% of total) Age (years) 16 Age groups 5–9 5 (25) 10–20 10 (50) > 20 5 (25) Gender (M/F) 8/12 (40/60) Mutation p.F508del homozygous 15 (75) p.F508del heterozygous 3 (15) Unidentified 2 (10) Lung function FEV 1 % 69.0 FEF 25-75 % 48.2 Anthropometric measurements Weight (kg) 41.4 Weight Z-score –1.0 Height (cm) 145 Height Z-score –1.5 BMI (kg/m2) 18.6 BMI Z-score –0.5 Lung function decline is accelerated in South Africans with cystic fibrosis 26 Using multivariate analysis, the FEV 1 was found to be significantly influenced by age, weight and BMI Z-score. The correlation coeffi- cients for the parameters were: age –3.96 (–7.4; –0.5); (p = 0.03), weight 1.8 (–3.4; –0.9); (p = 0.04); BMI Z-score 14.3 (5.3; 23.3); (p = 0.02). FEF 25-75 was significantly influenced in the multivariate analysis by BMI Z-score (p = 0.03) and gender (p = 0.001). FEF 25-75 was not significantly affected by age, weight and height change (all p-values > 0.05). Both FEV 1 and FEF 25-75 were not found to be significantly affected by mutation, using the same analysis. Discussion In this single-centre cystic fibrosis clinic, we found a significant change over time for the anthropometric parameters of these pancreatic-insufficient participants. The weight mean Z-score declined by –0.5 over the five-year study period and this was sta- tistically significant. No statistically significant change was ob- served in both the mean height and BMI Z-scores over the same period. There was significant decline over time observed for lung function at study entry when compared with study end for both FEV 1 and FEF 25-75 . The average lung function decline per year was 5.3% for FEV 1 and 4.5% for FEF 25-75 . Gender and the type of muta- tion did not seem to impact on the lung function, although the decline in FEV 1 for females was steeper than that in the males but this was not statistically significant. In the multivariate analysis FEF 25-75 seemed to be influenced by gender but this is limited by the small numbers in the study population. In the present study CFTR mutation did not impact on both lung function and anthropometric parameters. This observation sup- ports a result from a previous study conducted at our centre.20 This is contrary to other studies which revealed that a p.F508del homozygous status predicts more severe lung disease when com- pared with patients who were heterozygous for the p.F508del mutation.11,21 In the studies conducted by Morrow et al. and Corey et al. it was found that the rate of lung function decline was more rapid in p.F508del homozygous patients when compared with Table 2: Anthropometry measurements in relation to CF mutation Notes: CI = confidence intervals; Wt = weight in kilograms; Ht = height in centimetres; BMI = body mass index; p.F508del hete/U = p.F508del heterozygous and unidentified mutations; p.F508del homo = p.F508del homozygous; NS: not statistically significant. Variable Study entry Study exit p-value Mean 95% CI Mean 95% CI Wt — mutation (kg) p.F508del hete/U 30.5 2.0; 59.0 48.5 7.5; 89.5 p.F508del homo 45.0 37.9; 52.2 54.4 49.2; 59.7 NS BMI — mutation(kg/m2) p.F508del hete/U 16.8 13.1; 20.5 18.8 11.0; 26.6 NS p.F508del homo 19.1 17.3; 21.0 19.5 17.8; 21.3 BMI Z-score –0.5 –1.34; 0.33 –1.28 –2.0; –0.56 NS Ht Z-score –1.15 –1.6; –0.6 0.86 –0.07; 1.80 0.0005 0 50 −50 −100 −150 Female Male Figure 1: Box plot of relative change of FEV1 (light blue), FEF25/75 (medium blue), BMI Z-score (dark blue) and height according to gender. Table 3: Comparison of lung function between mutation and gender Notes: CI = confidence interval; FEV1 = forced expiratory volume; FEF25-75 = forced expiratory flow during 25 – 75%; p.F508del hete/U = p.F508del heterozygous and unidentified mutations; p.F508del homo = p.F508del homozygous; entry = study entry; exit = study exit; Diff = difference between mutations mean or gender mean. FEV 1 FEF 25-75 Study time Mutation/gender Mean 95% CI p-value Study time Mutation/gender Mean 95% CI p-value Entry p.F508del hete/U 76.04 35.7; 117.0 Entry p.F508del hete 56.4 7.3; 120 p.F508del homo 66.6 51.1; 82.1 p.F508del homo 45.4 28.3; 62.5 Diff 9.8 –30.0; 49.6 0.54 Diff 11.0 31.4; 64.9 0.67 Exit p.F508del hete/U 50.8 9.6; 92.0 Exit p.F508del hete 31.8 6.1; 69.7 p.F508del homo 40.0 22.0; 58.0 p.F508del homo 23.7 9.2; 38.3 Diff 10.8 –29.8; 51.4 0.54 Diff 8.0 –29.0; 45.2 0.61 Entry Female 75.6 56.6; 94.6 Entry Female 53.1 30.2; 75.8 Male 59.3 38.3; 80.2 Male 40.7 10.0; 71.5 Diff 16.3 –9.8; 42.0 0.4 Diff 12.3 –23.1; 47.8 0.5 Exit Female 47.4 26.3; 68.5 Exit Female 26.8 10.2; 43.5 Male 35.6 9.5; 61.8 Male 24.1 0.5; 48.7 Diff 11.8 –19.2; 42.8 0.4 Diff 2.7 –24.9; 36.3 0.8 27 S Afr Fam Pract 2016; 58(1):24–27 2. Goldman A, Graf C, Ramsay M, et al. Molecular diagnosis of cystic fibro- sis in South African populations. S Afr Med J. 2003;93:518–9. 3. Mutesa L, Bours V. Diagnostic challenges of cystic fibrosis in patients of African origin. J Trop Pediatr. 2009;55:281–6. 4. Goldman A, Labrum R, Claustres M, et al. The molecular basis of cystic fibrosis in South Africa. Clin Genet. 2001;59:37–41. 5. Westwood T. Diagnosing cystic fibrosis in South Africa. S Afr Med J. 2006;96:304–6. 6. Rowntree RK, Harris A. The phenotypic consequences of CFTR muta- tions. Ann Hum Genet. 2003;67:471–85. 7. de Gracia J, Mata F, Alvarez A, et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005;60:558–63. 8. Ranganathan SC, Stocks J, Dezateux C, et al. The evolution of airway function in early childhood following clinical diagnosis of cystic fibro- sis. Am J Respir Crit Care Med. 2004;169:929–33. 9. Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and ad- olescents with cystic fibrosis. J Pediatr. 2007;151:134–9. 10. Navarro J, Rainisio M, Harms HK, et al. Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. Eur Respir J. 2001;18:298–305. 11. Schaedel C, de Monestrol I, Hjelte L, et al. Predictors of deterioration of lung function in cystic fibrosis. Pediatr Pulmonol. 2002;33:483–91. 12. Morrow BM, Argent AC, Zar HJ, et al. Rate of pulmonary function decline in South African children with cystic fibrosis. S Afr J Child Health. 2009;3:73–6. 13. Xu W, Subbarao P, Corey M. Changing patterns of lung function decline in children with cystic fibrosis. J Cystic Fibros. 2004;3:S116–8. 14. Morrow BM, Argent AC, Zar HJ, et al. Improvements in lung function of a pediatric cystic fibrosis population in a developing country. J Pediatr. 2008;84:403–9. 15. Pencharz PB, Durie PR. Pathogenesis of malnutrition in cystic fibrosis, and its treatment. Clin Nutr. 2000;19:387–94. 16. Konstan MW, Butler SM, Wohl ME, et al. Growth and nutritional index- es in early life predict pulmonary function in cystic fibrosis. J Pediatr. 2003;142:624–30. 17. Callaghan BD, Hoo AF, Dinwiddie R, et al. Growth and lung function in Asian patient with cystic fibrosis. Arch Dis Child. 2005;90:1029–32. 18. Zemel BS, Jawad AF, FitzSimmons S, et al. Longitudinal relationship among growth, nutritional status, and pulmonary function in children with cystic fibrosis: Analysis of the cystic fibrosis foundation national CF patient registry. J Pediatr. 2000;137:374–80. 19. Steinkamp G, Weidemann B. Relationship between nutritional status and lung function in cystic fibrosis: cross sectional and longitudinal analyses from the German CF quality assurance (CFQA) project. Tho- rax. 2002;57:596–601. 20. Pentz A, Becker P, Masekela R, et al. The impact of chronic pseudomo- nal infection on pulmonary function testing in individuals with cystic fibrosis in Pretoria, South Africa. S Afr Med J. 2014;104:191–194. 21. Johansen HK, Nir M, Koch C., et al. Severity of cystic fibrosis in patients homozygous and heterozygous for ΔF508 mutation. Lancet. 1991;337:631–4. 22. Corey M, Edwards L, Levison H, et al. Longitudinal analysis of pul- monary function decline in patients with cystic fibrosis. J Pediatr. 1997;131:809–14. 23. Lucidi V, Alghisi F, Raia V, et al. Growth assessment of paediatric patients with CF comparing different auxologic indicators: a multi- centre Italian study. J Pediatr Gastroenterol Nutr. 2009;49:335–42. 24. Lai HC, Kosorok MR, Sondel SA, et al. Growth status in children with cystic fibrosis based on the national cystic fibrosis patient registry data: evaluation of various criteria used to identify malnutrition. J Pediatr. 1998;132:478–85. 25. Corey M, McLaughlin FJ, Williams M, et al. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Bos- ton and Toronto. J Clin Epidemiol. 1988;41:583–91. 26. Bell SC, Bowerman AR, Davies CA, et al. Nutrition in adults with cystic fibrosis. Clin Nutr. 1998;17:211–5. 27. Nir M, Lanng S, Johansen HK, et al. Long-term survival and nutrition- al data in patients with cystic fibrosis treated in a Danish centre. Thorax 1996;51:1023–7. those who were heterozygous for the mutation.11,22 The contradic- tory findings between the previous studies and the current study may be due to factors such as age group and our small population size. Pancreatic insufficiency carries the risk for maldigestion, malab- sorption and low energy intake in relation to increased faecal nutrient losses. In a study conducted by Lucidi et al., weight, height and BMI Z-scores were significantly associated with pan- creatic status.23 Lai et al. revealed that prevalence of low weight- for-age and low height-for-age was fairly stable between ages 6 and 12 for boys, whereas for girls there was a sharp increase in the prevalence of growth failure between age 8 and 12 years.24 Zemel et al. also found that growth status was not stable in the mid-child- hood in children with CF and progressed with age.18 In this study, the population group had an average age of 16 years (with more females) and all the participants were pancreatic insufficient. We found greater improvement and preservation of stature in com- parison with an increasing reduction in mass, with weight Z-scores declining over time. In a multi-centre study in Toronto, patients were prescribed a high-fat and high-calorie diet together with a higher dose of pancreatic enzymes and this was found to be associated with improved stature.25 In the current study, FEV 1 decline was found to be higher than the 2% predicted for children born after 1980 in developed countries and higher than the FEV 1 decline in South African children with CF, in a relatively short-term longitudinal study where an average rate of decline in FEV 1 was less than 1% per year.12 Early reports showed significant association between the degree of malnutrition and the rate of decline in pulmonary function.18,22 Bell et al. and Nir et al. revealed a strong association between FEV 1 and BMI.26,27 The cur- rent study found that FEV 1 is significantly influenced by BMI Z-score, in line with the published literature, but it was found that FEV 1 was influenced by other variables such as age and weight. In a study conducted in Germany, by Steinkamp et al., the authors revealed that a fall in weight-for-height of 5% predicted or more within one year was associated with a parallel decrease in FEV 1 , whereas patients with improved nutrition demonstrated constant or even improved FEV 1 .19 In the present study, FEV 1 and FEF 25-75 were signifi- cantly affected by BMI, which crudely reflects body fat content and is in agreement with the Steinkamp study. The strength of the current study is that it has assessed factors which may impact growth and lung function in a CF clinic in a developing country. Our recommendations would be for CF prac- titioners and other healthcare practitioners to pay special atten- tion to anthropometry and growth in all CF patients, as this impacts on their lung functions and, ultimately, survival. The limi- tations of this study were the small study population group, which limited the ability to make any conclusions with regard to the impact of the studied variables on specific age categories. All participants were Caucasians and the age at diagnosis was not specified. The study also did not assess the impact of the organ- isms cultured from the lower respiratory tract. Conclusion The average lung function decline per year for FEV 1 was higher than that seen in developed countries. The decline in FEV 1 was related to gender, age, weight and body mass index. The decline in FEF 25-75 was affected only by BMI Z-score and gender. References 1. Cystic Fibrosis Mutation Database. 2011 Apr [cited 2014 Aug 4]. Avail- able from: http://www.genet.sickkids.on.ca/Homehtml Received: 20-05-2015 Accepted: 19-07-2015 http://www.genet.sickkids.on.ca/Homehtml Introduction Methods Statistical analysis Results Discussion Conclusion References