search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Peterson, M. L. Articles by Milla, C. E. Search for Related Content PubMed PubMed Citation Articles by Peterson, M. L. Articles by Milla, C. E. Related Collections Respiratory Tract

Longitudinal Changes in Growth Parameters Are Correlated With Changes in Pulmonary Function in Children With Cystic Fibrosis

Michelle L. Peterson, MPH^*, David R. Jacobs, Jr, PhD^, and Carlos E. Milla, MD||

^* Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota
Institute for Nutrition Research, University of Oslo, Oslo, Norway
Minnesota Cystic Fibrosis Center, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Objective. Nutritional status is associated with pulmonary health and survival in children with cystic fibrosis (CF). This study evaluated the weight gain pattern of children with CF in relation to the longitudinal trends of their pulmonary function. Our hypothesis was that children who experience continuous weight gain at a given rate will have better average forced expiratory volume in 1 second (FEV₁) and change in FEV₁ than children who have weight gain patterns that deviate from this rate, even when total weight gain seems adequate.

Methods. Prospectively collected data were examined in 319 children, aged 6 to 8, who were routinely followed at the Minnesota Cystic Fibrosis Center. One to 67 measurements of weight (kg), height (cm), and FEV₁ (mL) were taken per child during this 2-year period. The data were analyzed by repeated measure regression analysis and by growth pattern analysis.

Results. At baseline, a 1-kg higher initial weight was associated with a 55-mL higher average FEV₁. During the follow-up period, a 1-kg gain in weight was associated with an increase in FEV₁ by 32 mL. Children who had a steady weight gain tended to experience greater increases in FEV₁ than children who experienced periodic losses in weight.

Conclusions. We established that children who weigh more and who gain weight at an appropriate and uninterrupted rate have a better FEV₁ trajectory. Aggressive nutritional support to maintain growth in these children may therefore improve FEV₁, which can be taken as a surrogate for better lung health, and may ultimately lead to better survival.

Key Words: cystic fibrosis • growth • pulmonary function • longitudinal studies

Abbreviations: CF, cystic fibrosis • FEV₁, forced expiratory volume in 1 second • FVC, forced vital capacity

Cystic fibrosis (CF) is the most common life-shortening disease in white individuals and is characterized by multiorgan involvement with primarily pulmonary and gastrointestinal manifestations, as well as abnormally high levels of chloride in the sweat, male infertility, and, less frequently, diabetes.^1–3 Although severity of the disease is variable, a large proportion of affected individuals develop obstructive lung disease with progressive loss of pulmonary function. Mucus plugging, poor ciliary function, and chronic inflammation and infection of the airways all contribute to pulmonary function abnormalities.¹ Survival of patients with CF is largely dependent on the progression of its associated lung disease.⁴ Current multidisciplinary therapy not only targets this lung disease but also focuses on gastrointestinal manifestations and nutritional deficiency.

Nutritional deficiency, as a result of pancreatic insufficiency and malabsorption, often manifests as poor growth and weight gain during early childhood. Data reported from the Cystic Fibrosis Foundation 2001 Patient Registry show that 18% of children with CF fall below the Centers for Disease Control and Prevention’s fifth percentile for weight and 16% of children fall below the Centers for Disease Control and Prevention’s fifth percentile for height.² For maintaining a nutritional status similar to that of a healthy child, dietary recommendations suggest that children with CF should reach 120% to 150% of the typical recommended daily caloric intake.^4,5 However, studies have shown that the actual dietary intake of CF patients falls short of these recommendations.⁴ This low energy intake coupled with pancreatic exocrine dysfunction results in malabsorption and malnutrition.

Previous studies have shown that worsening pulmonary function in children with CF is associated with malnourishment.⁶ Without evidence of a causal relationship, it is not clear whether poor weight gain and/or linear growth predicts clinical lung disease or whether progressing lung disease inhibits appetite and leads to poor weight gain and slow linear growth. Clarification of this relationship has not yet been defined, but it is clear that children with CF have difficulty gaining weight or, for that matter, even maintaining weight. Fluctuations in pulmonary function may be a result of the lack of maintenance of a normal weight.

Thus, studies have shown that there is an association between growth and pulmonary function, but this relationship is poorly understood.⁷ The purpose of this study was to evaluate how the weight gain pattern of children with CF affects their pulmonary function development. To do so, in the present study, we examined pulmonary function and its changes in children with CF, comparing children who had abnormal weight gain patterns with children with CF who gained weight consistently. Our hypothesis was that children who experience uninterrupted weight gain have higher average forced expiratory volume in 1 second (FEV₁) and change in FEV₁ than children who have an inadequate and inconsistent weight gain pattern.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
To examine the relationship between weight and pulmonary function in children with CF, we analyzed data that were collected from patients who were seen at the Minnesota Cystic Fibrosis Center. The Minnesota Cystic Fibrosis Center was established in 1961 and has treated >1000 patients with CF. The Institutional Review Board at the University of Minnesota approved the protocol for this study. Patients who seek treatment at the center give signed consent allowing permission to study data collected at clinic or hospital visits.

Prospectively collected data were examined in 319 children (166 girls, 153 boys) who were examined at age 6 and followed through age 8. These children represent the most recent cohort of children under follow-up at the Minnesota Cystic Fibrosis Center. Patients at the center are diagnosed on the basis of sweat chloride testing and/or CFTR genotype. At each clinic visit, the child’s weight, height, and pulmonary function were measured, following standard procedures as we have described before.⁸ Pulmonary function was assessed using spirometry and following the standard criteria established by American Thoracic Society standards.⁹ Forced vital capacity (FVC) and FEV₁ were measured in liters at each visit.

The number of visits per child during the 2 years of follow-up ranged from 1 to 67. Most (97.6%) of the children had also been observed before the age of 6; however, pulmonary function testing done before the age of 6 was not included in the present analyses. Rather, these tests were considered as training of the child to enable future reliable testing.

Total weight change (kg/mo) between the child’s first and last visits was examined as a marker of cumulative growth during the 2-year period of interest. Children were categorized into 2 groups on the basis of whether their total weight change fell above (high weight change category) or below (low weight change category) the median total weight change for the group as a whole. Total height change (cm/mo) was treated analogously. Informed by visual examination of the weight change graphs for each child, 4 weight gain pattern categories were defined on the basis of their worst interexamination weight change: 1) ever lost at least 0.2 kg/mo, 2) ever lost weight, 3) never lost weight but never gained 0.1 kg/mo or more, and 4) always gained at least 0.1 kg/mo. The criterion of 0.1 kg/mo was selected as a minimal cutoff for good weight gain for children with CF, based on previously published findings. For a child without CF between the ages of 6 and 8, a weight gain of 0.2 kg/mo is at the 50th percentile of growth.³ A study done by Lai et al¹⁰ reported that children with CF have mean height for age percentiles and weight for age percentiles at approximately the 30th percentile. They also reported that 20% of children were below the fifth percentile for height for age percentiles and weight for age percentiles in 1993.¹⁰

Statistical analyses were performed using SAS (SAS Institute, Cary, NC). For evaluating the association between changes in growth parameters and FEV₁, the data were analyzed by repeated measures regression analysis, using the compound symmetry variance assumption. Models were generated with FEV₁ (dependent variable) regressed on various combinations of age, weight, change in weight and age, weight gain categories, and slope of weight gain between first and last visits.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
During the 2-year follow-up, 291 children had >1 visit to the center with a mean of 7.40 visits (±4.95). Twenty-eight children visited the center only once. Including all 319 children, there was an average of 6.84 visits (±5.07). Male and female patients were similar in height. Boys tended to weigh more than girls (P = .0003 in their sixth year and P = .0002 in their seventh year; Table 1). Boys also had a higher body mass index in both their sixth and seventh years (P < .0001). FEV₁ values were not different between boys and girls in their sixth year (P = .47) but were higher in boys in the children’s seventh year (P = .04).

View larger version (14K): [in this window] [in a new window]   Fig 1. Children’s total overall weight change (kg) by total overall height change (cm) over a 2-year period (ages 6–8).

The average number of tests performed on each child was much less for children who always gained at least 0.1 kg/mo than for children in the other weight gain patterns, probably because they required less frequent visits for treatment (Table 3). This is consistent across total weight and height change groupings. Regardless of total height change, children in the high weight change category tended to be seen less often than children in the low weight change category. Children who lost at least 0.2 kg/mo and were in the low height change category were seen on average the most often.

In an additional repeated measure regression analysis, age, weight, and height were treated as continuous variables (see Table 4). Sex and age at diagnosis did not play a role in patients’ longitudinal trends in pulmonary function. Ages at first visit and change in age from first visit were not significantly associated with FEV₁ (P = .16 and P = .07, respectively). Average FEV₁ during follow-up was associated with weight at first observation. A 1-kg higher initial weight was associated with a 55-mL difference in average FEV₁ (P < .0001). Weight gain during the 2-year follow-up was also strongly and similarly associated with change in FEV₁. During follow-up, an increase in weight of 1 kg was associated with a 32-mL increase in FEV₁ (P < .0001). Neither height nor change in height from first observation were significantly associated with FEV₁ values (P = .08 and P = .20, respectively).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

Since therapeutic strategies for the management of CF were first described,¹¹ aggressive nutritional support has been a fundamental part of the recommended treatment regimens. However, most of the morbidity and mortality associated with CF is related to the pulmonary manifestations of the disease. Chronic infection and progressive airway obstruction lead to severe destructive changes in the lung and early death.¹ Although previous studies of patients with CF have shown that pulmonary function is the primary predictor of death and that the yearly rate of decline of FEV₁ is the most important variable predicting mortality,^6,8 the factors responsible for long-term preservation of lung function in some patients remain unknown. Multiple previous studies suggest that nutritional status is tightly intertwined in this process. The classic Boston-Toronto study demonstrated clear-cut differences in the survival of these 2 cohorts of patients, with the survival advantage of the Toronto cohort being ascribed to their better nutritional status.¹² Most interesting was that pulmonary function parameters were comparable between the groups; thus, survival seemed more strongly associated with growth. Other studies that have examined the relationship between morbidity and nutritional status concur that CF growth abnormalities and development of lung disease are linked^13,14 and that weight gain is associated with improvements in pulmonary function.¹⁵ These results are in accordance with ours and lend support to the hypothesis that weight gain is intimately connected to lung health in children with CF.

A somewhat unexpected finding to us was that children who consistently gained at least 0.1 kg/mo did not have significantly higher mean FEV₁ values than other children. These children also tended to visit the center less often. The average number of visits for children who always gained 0.1 kg/mo was 4.25 visits during the 2-year period. For all other children who did not consistently gain at least 0.1 kg/mo, the mean number of visits was 7.36. The Cystic Fibrosis Foundation recommends that children with CF be evaluated at a CF center a minimum of 4 times a year.⁵ The children who consistently gained at least 0.1 kg/mo were probably judged to be doing well and therefore were seen less often for treatment, but they also had, on average, a relatively low final FEV₁ value when compared with their peers. A more controlled study would need to be done to decipher whether these results are attributable to subtle clinical findings being missed by the infrequent monitoring or simply to poor spirometry skills from lack of familiarity with the test. We speculate that these children’s lung health would have benefited from more frequent clinic visits.

Although severe obstructive lung disease increases energy expenditure from the high demands of the work of breathing¹⁶ and this is prominent in older patients with CF and severe lung compromise,^16–20 the temporal and potential causal relationship between malnutrition and pulmonary dysfunction in children remains unknown. It is intuitive to assume that during the early stages of the child’s growth and development, any impairments may affect the rate at which the lungs grow, and this in turn will become a strong determinant for the development of lung disease.²¹ There is some support for this possibility in the observation that patients who have CF and do not experience pancreatic insufficiency have not only better nutritional parameters but also a lower rate of pulmonary deterioration.²² Outside of CF, both animal studies and human studies have provided evidence for a causal association between poor nutritional status and pulmonary abnormalities,^23–26 with clear effects demonstrable in the early stages of postnatal lung development.^27,28 Thomson et al,²⁹ in a prospective evaluation of their CF patient population, were able to identify important relationships between changes in growth and pulmonary function. In their study, accretion of body cell mass within expected range was associated with a decline in FEV₁ at a rate of less than half that observed in children who were not able to accrue at an acceptable rate. Given the deterioration that the lungs experience with time in CF, long-term studies are necessary to characterize better the association between nutritional status and pulmonary dysfunction and to identify which factors are most intimately involved in this process so that appropriate, timely interventions can be developed.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Our findings demonstrate the importance of monitoring weight changes and improving weight gain in children with CF. As established, children who weigh more and, more important, who gain weight at an appropriate rate have better FEV₁ and a better FEV₁ trajectory. From these results, it can be inferred that aggressive nutritional support through the use of caloric supplements to optimize growth in children with CF may improve FEV₁. Improvements in FEV₁ can be taken as a surrogate for better lung health and may ultimately lead to better survival. This study also supports the recommendation of the Cystic Fibrosis Foundation to evaluate these children on a quarterly basis. This frequency will not only enable medical professionals to monitor weight gain but also permit early intervention.

	ACKNOWLEDGMENTS

 
This work was supported in part by a US Cystic Fibrosis Foundation Center Grant.

	FOOTNOTES

 
Received for publication Oct 17, 2002; Accepted Mar 25, 2003.

Reprint requests to (C.E.M.) MMC 742, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: milla005{at}umn.edu

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Davis PB, Drumm ML, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med.1996; 154 :1229 –1256[ISI][Medline]
2. Cystic Fibrosis Foundation. Patient Registry 2001: Annual Report. Bethesda, MD: Cystic Fibrosis Foundation; 2002
3. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol.2001; 53 :345 –352
4. Berry HK, Kellogg FW, Hunt MM, Ingberg RL, Richter L, Gutjahr C. Dietary supplement and nutrition in children with cystic fibrosis. Am J Dis Child.1975; 129 :165 –171[Abstract]
5. Cystic Fibrosis Foundation. Clinical Practice Guidelines for CF. Bethesda, MD: Cystic Fibrosis Foundation; 1997
6. Kerem E, Reisman J, Corey M, Carrey G, Levinson H. Prediction of mortality of patients with cystic fibrosis. N Engl J Med.1992; 32 :1187 –1191
7. Zemel B, Kawchak D, Cnann A, Zhao H, Scanlin T, Stallings V. Prospective evaluation of resting energy expenditure, nutritional status, pulmonary function, and genotype in children with cystic fibrosis. Pediatr Res.1996; 40 :578 –586[ISI][Medline]
8. Milla CE, Warwick WJ. Risk of death in cystic fibrosis patients with severely compromised lung function. Chest.1998; 113 :1230 –1234[Abstract/Free Full Text]
9. Standardization of spirometry, 1994 update. American Thoracic Society. Am J Respir Crit Care Med.1995; 152 :1107 –1136[ISI][Medline]
10. Lai H, Kosorok M, Sondel S, 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 –485[CrossRef][ISI][Medline]
11. Doershuk CF, Mathews LW, Tucker AS, Spector S. Evaluation of a prophylactic and therapeutic program for patients with cystic fibrosis. Pediatrics.1965; 36 :675 –678[Abstract/Free Full Text]
12. Corey M, McLaughlin F, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol.1988; 41 :583 –591[CrossRef][ISI][Medline]
13. Kraemer R, Rudeberg A, Hardorn HB, Rossi E. Relative underweight in cystic fibrosis and its prognostic value. Acta Paediatr.1978; 67 :33 –37
14. Nir M, Lanng H, Johansen HK, Koch C. Long-term survival and nutrition in patients with cystic fibrosis treated in a Danish Centre. Thorax.1996; 51 :1023 –1027[Abstract]
15. Schoni MH, Casaulta-Aebischer C. Nutrition and lung function in cystic fibrosis patients: review. Clin Nutr.2000; 19 :79 –85[CrossRef][ISI][Medline]
16. Wilson DO, Rogers RM, Hoffman RM. Nutrition and chronic lung disease. Am Rev Respir Dis.1985; 132 :1347 –1365[ISI][Medline]
17. Vaisman N, Pencharz PB, Corey M, Canny GJ, Hahn E. Energy expenditure of patients with cystic fibrosis. J Pediatr.1987; 111 :496 –500[CrossRef][ISI][Medline]
18. Elborn JS, Cordon PJ, Western I, Macdonald A, Shale DJ. Tumor necrosis factor-alpha, resting energy expenditure and cachexia in cystic fibrosis. Clin Sci.1993; 85 :563 –568[Medline]
19. Bell SC, Saunders MJ, Elborn JS, Shale DJ. Resting energy expenditure and oxygen cost of breathing in patients with cystic fibrosis. Thorax.1996; 51 :126 –131[Abstract]
20. Wilson DC, Pencharz PB. Nutrition and cystic fibrosis. Nutrition.1998; 14 :792 –795[CrossRef][ISI][Medline]
21. Elborn JS, Bell SC. Nutrition and survival in cystic fibrosis. Thorax.1996; 51 :971 –972[ISI][Medline]
22. Gaskin KJ, Waters DL, Soutter VL, Allen BJ, Blagojevic N, Parson D. Body composition in cystic fibrosis. Basic Life Sci.1990; 55 :15 –21[Medline]
23. Winick M, Noble A. Cellular response in rats during malnutrition at various ages. J Nutr.1966; 89 :300 –306
24. Sahebjami H, Wirman JA. Emphysema-like changes in the lungs of rats. Am Rev Respir Dis.1981; 124 :619 –624[ISI][Medline]
25. Primhak R, Coates FS. Malnutrition and peak expiratory flow rate. Eur Respir J.1988; 1 :801 –803[Abstract]
26. Gaultier C. Malnutrition and lung growth. Pediatr Pulmonol.1991; 10 :278 –286[ISI][Medline]
27. Das RM. The effects of intermittent starvation on lung development in suckling rats. Am J Pathol.1984; 117 :326 –332[Abstract]
28. Massaro D, Teich N, Maxwell S, Massaro GD, Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest.1985; 76 :1297 –1305
29. Thomson MA, Quirk P, Swanson CE, et al. Nutrition growth retardation is associated with defective lung growth in cystic fibrosis: a preventable determinant of progressive pulmonary dysfunction. Nutrition.1995; 11 :350 –354[ISI][Medline]

This article has been cited by other articles:

				J. M. Erskine, C. Lingard, and M. Sontag Update on Enteral Nutrition Support for Cystic Fibrosis Nutr Clin Pract, April 1, 2007; 22(2): 223 - 232. [Abstract] [Full Text] [PDF]

				J. Trabulsi, J. I Schall, R. F Ittenbach, I. E Olsen, M. Yudkoff, Y. Daikhin, B. S Zemel, and V. A Stallings Energy balance and the accuracy of reported energy intake in preadolescent children with cystic fibrosis. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 523 - 530. [Abstract] [Full Text] [PDF]

				S. W. Powers, C. Piazza-Waggoner, J. S. Jones, K. S. Ferguson, C. Daines, and J. D. Acton Examining Clinical Trial Results with Single-Subject Analysis: An Example Involving Behavioral and Nutrition Treatment for Young Children with Cystic Fibrosis J. Pediatr. Psychol., July 1, 2006; 31(6): 574 - 581. [Abstract] [Full Text] [PDF]

				M. Kappler and M. Griese Nutritional supplements in cystic fibrosis. BMJ, March 18, 2006; 332(7542): 618 - 619. [Full Text] [PDF]

				V. J Poustie, J. E Russell, R. M Watling, D. Ashby, R. L Smyth, and CALICO Trial Collaborative Group Oral protein energy supplements for children with cystic fibrosis: CALICO multicentre randomised controlled trial BMJ, March 18, 2006; 332(7542): 632 - 636. [Abstract] [Full Text] [PDF]

				S. W. Powers, J. S. Jones, K. S. Ferguson, C. Piazza-Waggoner, C. Daines, and J. D. Acton Randomized Clinical Trial of Behavioral and Nutrition Treatment to Improve Energy Intake and Growth in Toddlers and Preschoolers With Cystic Fibrosis Pediatrics, December 1, 2005; 116(6): 1442 - 1450. [Abstract] [Full Text] [PDF]

				N. Verma, A. Bush, and R. Buchdahl Is There Still a Gender Gap in Cystic Fibrosis? Chest, October 1, 2005; 128(4): 2824 - 2834. [Abstract] [Full Text] [PDF]

				B D Callaghan, A F Hoo, R Dinwiddie, I M Balfour-Lynn, and S B Carr Growth and lung function in Asian patients with cystic fibrosis Arch. Dis. Child., October 1, 2005; 90(10): 1029 - 1032. [Abstract] [Full Text] [PDF]

				R. Amin, J. Bean, K. Burklow, and J. Jeffries The Relationship Between Sleep Disturbance and Pulmonary Function in Stable Pediatric Cystic Fibrosis Patients Chest, September 1, 2005; 128(3): 1357 - 1363. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Peterson, M. L. Articles by Milla, C. E. Search for Related Content PubMed PubMed Citation Articles by Peterson, M. L. Articles by Milla, C. E. Related Collections Respiratory Tract

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2003 American Academy of Pediatrics. All rights reserved.