ORIGINAL

 

Association of nutritional status, plasma, albumin levels and pulmonary function in cystic fibrosis

Asociación entre el estado nutricional, niveles de albúmina plasmática y función pulmonar en pacientes con fibrosis quística

 

 

M. I. Souza dos Santos Simon¹, M. Drehmer², F. A. de Abreu e Silva³, A. Hoffmann⁴, C. Druck Ricachinewsky⁴, E. de Fonseca Andrade Procianoy⁴, I. Scattolin⁴ and S. Saldanha Menna Barreto⁵

¹Serviço de Nutrição e Dietética. Centro de Estudos em Alimentação e Nutrição. Hospital de Clínicas de Porto Alegre. Brazil.
²Departamento de Epidemiologia. Universidade Federal do Rio Grande do Sul. Porto Alegre. Brazil.
³Departmento de Pediatria. Universidade Federal do Rio Grande do Sul. Porto Alegre. Brazil.
⁴Unidade de Pneumologia Pediátrica. Hospital de Clínicas de Porto Alegre. Brazil.
⁵Departmento de Medicina Interna. Universidade Federal do Rio Grande do Sul. Porto Alegre. Brazil.

We are grateful to by the FIPE (Fundo de Incentivo a Pesquisa) and GPPG (Grupo de Pós-Graduação e Pesquisa) of the Hospital de Clínicas de Porto Alegre for their financial support.

Correspondence

 

 

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ABSTRACT

Background & aims: Malnutrition is related with pulmonary disease. The aim was to analyze the association of lung function respectively to nutritional status, identified pulmonary pathogens and socioeconomic condition of patients attending a pediatric CF reference center.
Methods: Cross-sectional study performed with CF patients aged 6 to 18 years attending a CF-Center in southern Brazil. Nutritional status, plasma albumin level and pulmonary bacterial colonization were assessed. The outcome studied was forced expiratory volume in 1 second (FEV₁).
Results: Eighty-five patients were included in this study. FEV₁ was significantly associated with body mass index (BMI) percentiles, plasma albumin level and methicillin resistant Staphylococcus aureus (MRSA) pulmonary colonization. Regression analysis showed that BMI below the 10^th percentile was associated with a 25.58% drop in FEV₁, and plasma albumin levels equal to or lower than 4.1 mg/dL was associated with 18.6% FEV₁ reduction. FEV₁ was 14.4% lower in the MRSA infected patients. Plasma albumin of 4.25 mg/dL predicted FEV₁ of 60% with 76.9% sensitivity and 72.2% specificity, and 85.7% accuracy. The socioeconomic status was not association with pulmonary function.
Conclusion: BMI below the 10^th percentile and albumin below 4.1 mg/dL were predictors of low FEV₁. Chronic MRSA infection was associated with lower FEV₁. Longitudinal studies may better complement these results.

Key words: Cystic fibrosis. Nutritional status. Pulmonary function.

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RESUMEN

Objetivos: Analizar la asociación entre la función pulmonar y tres factores: el estado nutricional, el estado de patógenos pulmonares y el estado socio-económico de pacientes en un centro de referencia en atención a pacientes pediátricos con fibrosis quística.
Métodos: Se realizó un estudio longitudinal en pacientes con fibrosis quística, de 6 a 18 años atendidos en un centro de fibrosis quística del Sur del Brasil. Fueron evaluados: estado nutricional, niveles de albúmina plasmática y colonización bacteriana pulmonar. El principal resultado estudiado fue el volumen espiratorio forzado en el 1 segundo (FEV₁).
Resultados: Fueron incluidos en este estudio 85 pacientes. El FEV₁ se mostró significativamente correlacionado con percentiles del Índice de Masa Corporal (IMC), albúmina plasmática y colonización pulmonar por Staphylococcus aureus resistente a meticilina (SARM). El análisis de regresión mostró que el IMC abajo del percentil 10 estuvo asociado con una disminución del 25,58% en el FEV₁, y que niveles de albúmina plasmática iguales o menores a 4,1 mg/dL se correlacionaron on una reducción de 18,6% del FEV₁. El FEV₁ fue 14,4% menos en los pacientes infectados por SARM. La albúmina plasmática de 4,25 mg/dL predijo un FEV₁ de 60% con una sensibilidad de 76,9% una especificidad de 72,2% y precisión de 85,7%. El estado socioeconómico no tuvo asociación con la función pulmonar.
Conclusiones: El IMC debajo del percentil 10 y albúmina plasmática menor que 4,1 mg/dL fueron predictivos de un bajo FEV₁ . La infección crónica de SARM mostró asociación con un menor FEV₁.

Palabras clave: Fibrosis quística. Estado nutricional. Función pulmonar.

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Introduction

Nutrition plays an essential role in the survival and quality of life of cystic fibrosis (CF) patients. Several factors, including pancreatic insufficiency, chronic suppurative pulmonary disease and anorexia may affect the energy balance, contributing to malnutrition. ^1,2,3,4 Malnutrition may affect lung growth and reduce lean body mass, leading to diminished force in the contraction of the diaphragm and other respiratory muscles^5,6. It may also be associated with reduced exercise tolerance, impaired immune response and antioxidant deficit, easing the way for the onset of infection and inflammation.^1,5,7

Pulmonary disease increases energy demands, diminishes appetite and increases respiratory work due to progressive air flow obstruction. Pulmonary inflammation and anorexia triggered by the inflammatory mediators, as well as recurrent infections, create a nega tive energy balance that leads to malnutrition.^1,6,8 Furthermore low socioeconomic status is associoated with significantly poorer outcomes in children with CF.⁹

Several studies performed in developed countries have shown a relationship between malnutrition and progression of pulmonary disease.^{1,3,6,10,11,12} In Brazil, however, there are no published data about this subject. The purpose of the present study was to analyze the association of lung function respectively to nutritional status, identified pulmonary pathogens and socioeconomic condition of patients attending a pediatric CF reference center in southern Brazil.

 

Materials and methods

A cross-sectional study was performed with CF patients, aged 6 to 18 years, recruited at a center of excellence of a tertiary care university hospital, Hospital de Clínicas de Porto Alegre/RS (HCPA), in southern Brazil. All patients were diagnosed by means of clinical history and by at least two sweat tests with chloride values equal to or higher than 60 mEq/l, or by the identification of two mutations in the CF gene who not displaying pulmonary exacerbation (requiring intravenous antibiotics).

The study was performed from July 2004 to December 2005, after approval by the Ethics and Research Committee at HCPA, and after obtaining the Free and Informed Consent of parents or guardians.

Nutritional evaluation

Weight and height were always determined by the same examiner using standardized techniques. Weight was assessed on a Filizola^® electronic scale (maximum capacity of 150 kg and 50 g variation), the patients wearing a standard gown. Height was measured on a wall-mounted stadiometer, with the patients barefoot and not wearing any hair ornaments. The patients had their heels joined together, their back to the anthropometer, and their arms relaxed along the body. They held their head in a vertical position and looked straight ahead. The horizontal cursor was lowered to the top of the patient's head during inspiration.

Mid arm circumference (MAC) was determined at the midpoint of the non-dominant arm, with a flexible, non-extensible Barlow^® measuring tape. Triceps skin fold (TSF) was measured at the midpoint of the nondominant arm, with a Harpenden skinfold caliper. Mid arm muscle area (MAMA) was calculated with the equation MAMA (cm) = MAC- (TSF mm x 0.314). All the values were compared to the criteria established by Frisancho (1981).¹³

The body mass index percentiles (BMIp) were calculated in the SAS (SAS Institute Inc., Cary, NC) software, using the reference values of the Center for Disease Control (Internet: http://www/cdc.gov/growthcharts). The nutritional parameters used were BMIp as recommended by the CF Pediatric Nutrition Consensus Report.¹⁴

Plasma albumin levels was measured same period of the nutritional evaluation and spirometry using the bromocresol green colorimetric method, were obtained from the patient's charts.

Assessment of pulmonary function

A flow-volume curve was performed in the Master Screen Jaeger^® spirometer (Wuerzburg, Germany), using the Zapletal table for the expected values.¹⁵ Spirometry was always performed by the same examiner and its quality was checked by the attending physician by analyzing the curves. Spirometry was done according to the guidelines for Pulmonary Function testing 2002.¹⁶ Forced expiratory volume at the first second (FEV1) was chosen for analysis, since it is the most widely used parameter in the literature to quantify the obstructive ventilatory damage characteristic of CF.^1,10,11

Other data

Bacterial examination of sputum specimens was done by primary seeding in the selective media chosen: mannitol Agar for Staphylococcus aureus detection, chocolate Agar for Haemophilus sp detection, McConkey Agar for detecting gram-negative rods, cetrimide Agar for detecting Pseudomonas aeruginosa, and the coagulase assay for Staphylococcus aureus. In vitro antibiotic sensitivity was tested according to Clinical and Laboratory Standards Institute, 2006.

The protocol used was based on data obtained from the charts, such as date of birth, sex, age, date of diagnosis, bacterial colonization, sweat electrolytes, genetic test and use of pancreatic enzymes. The Shwachmann Score (SS) was obtained by the physician and the nutritionist. ¹⁷ The parents/guardians informed the monthly family income and years of schooling of its members.

At each clinic (every two months) visit patients provided a sputum sample for culture. The bacterial colonization was considered when patients were infected in the last year. Co-infection could be present. There was no stratification by infective agent due to the small sample size at this CF center.

Statistical analysis

Sample size was calculated considering r = 0.40¹⁶ in the association between FEV₁ and BMI percentiles. Eighty-six cases were estimated based on a 1% level of significance, 95% confidence interval, and a statistical power of 90%.

The FEV₁ values were compared among the different dichotomic categorical variables using the Student t test and by analysis of variance when there were more than 2 groups. The relationship between FEV₁ and the quantitative variables was assessed by the Pearson correlation coefficient. A bivariate linear regression analysis was performed. The variables that showed P value up to 0.15 with the dependent variable (FEV₁) were included in the subsequent multivariate analysis. Multiple regression analysis was used to verify the independent association of the factors studied.

A Receiver Operating Characteristics (ROC) curve was used to determine the sensitivity and specificity levels to predict a FEV₁ of 60%.

The level of significance adopted was 0.05 and the analyses were performed with the Statistical Package for Social Sciences packet (version 12.0 SPSS Inc., Chicago, IL).

 

Results

Among eighty-six CF patients selected, one was excluded due to poor cooperation during spirometry performance. In the sample studied, 55.3% were male; the mean age was 11.2 years (± 3.2 years), and the age at diagnosis was 2.5 years (± 3.2 years). The nutritional, demographic, clinical and genetic characteristics, as well as the pulmonary pathogen status of the studied population, are shown in table I.

 

Regarding nutritional status, 77.7% of the patients were considered normal when the BMI cutoff point was above the 25^th percentile, according to the CF Consensus. ¹³ Mid Arm muscle area, an estimate of lean body mass, was below the 5^th percentile in 16.5% of the patients and above the 25^th percentile in 47% of them. By measuring the triceps skinfold, fat tissue depletion was found in 10.6%.

Regarding the socioeconomic situation of the families, 38.5% of the fathers and 34% of the mothers had not completed elementary school. The median monthly family income was U$ 454.54, i.e., 3.3 national minimum wages.

The DF508 homozygous and heterozygous patients presented FEV₁ of 79.11% and 78.48%, respectively; these values were significantly lower than those of patients with other mutations (96.15%) (P = 0.002). The mean values of % FEV₁ according to the pulmonary pathogen status of the studied CF population are shown in table II.

 

FEV₁ was significantly correlated with BMIp (r = 0.312, p = 0.004) (fig. 1), plasma albumin (r = 0.427, p = 0.000) (fig. 2) and mother's years of schooling (r = 0.229, p = 0.035). There was no correlation with father's years of schooling, age, time since diagnosis and age at diagnosis and body composition.

 

 

The variables showing an association with the dependent variable (FEV₁) P ≤ 0.15 in the bivariate regression analysis and that were thought to be clinically meaningful were included in the subsequent multivariate analysis. Plasma albumin levels were classified in quartiles for easier definition of which albumin levels were associated with FEV₁ reduction. The BMI was also classified in percentile for the same purpose.

The significant predictors for FEV₁ are depicted in table III, and 37.9% (R2 adjusted) of the variability observed in FEV₁ is statistically explained by this model. Regression analysis showed that BMI lower than the 10^th percentile was associated with a 25.58% drop in FEV₁, and plasma albumin lower than or equal to 4.1 mg/dL corresponded to a 18.6% reduction in FEV₁. MRSA chronic pulmonary infection was associated with 14.4% reduction in FEV₁. Pseudomonas aeruginosa colonization, gender, pancreatic insufficiency and mother's years of schooling were not statistically significant. Family income was not included in the model analysis, because it was associated with the parent´s years of schooling. The graph of residues and the normality test did not show any trend that would indicate that the analysis was inadequate.

 

 

The ROC curve for albumin to predict a FEV₁ of 60% showed an area of 0.79, 95% CI: 0.67-0.91, P = 0.001. The sensitivity for a cutoff point of 4.25 mg/dL was 76.9%, the specificity was 72.2% and the accuracy was 85.7%.

 

Discussion

In CF patients, nutritional status has a significant prognostic influence on the outcome of the disease^1,8. In the present cross-sectional study we associated nutritional status and pulmonary function of CF children, and studied the relationship with pulmonary pathogen status and socioeconomic conditions.

The association between nutritional status and pulmonary function found in this study has already been demonstrated in the literature. Based on the CF Foundation Patient Registry data set, a better FEV₁ status at about 80% predicted or above was associated with BMI percentiles at 50^th percentile and higher². Pedreira et al. (2005) found a significant association between BMI Z score and FEV₁ (r = 0.59, P = 0.0001) and between muscle mass and FEV₁ (r = 0.30, P = 0.03).¹¹ Hart et al. (2004) demonstrated the correlation between nutritional status and diaphragm strength.⁶ It has been reported that malnutrition causes loss of muscle mass, reduction in diaphragm performance, in strength and resistance of respiratory muscles, as well as the impairment of immune function. In addition, increased respiratory work and the interaction of the inflammatory and infectious processes increase energy demands, impairing pulmonary function even further.^1,5,7,8

The association of BMI in the 10^th percentile with FEV₁ enforced the use of this as the cut-off point for malnutrition, as stated by the CFF Pediatric Nutrition Consensus Report,¹⁴ providing a foundation to establish stricter cutoff points for CF. Stricter classification standard requires early detection of nutritional risk, enabling effective nutritional intervention which could diminish the prevalence of malnutrition and nutritional risk, improving survival and the quality of life of these patients.

Since the present study is a cross-sectional analysis, it only indicates associations, not allowing the establishment of cause-effect relationship between nutritional status and pulmonary function.

In the present study, plasma albumin was reasonably correlated to FEV₁. Other studies have shown the relationship between plasma albumin and the severity of pulmonary disease, considering it as a prognostic factor in patients with CF.^19,20 Albumin is a potent antioxidant, present in high concentrations in the extracellular fluid, and can prevent the deactivation of the a1-proteinase inhibitor.²¹ Albumin may be essential to maintain pulmonary gluthatione levels.²² Oxidatively modified albumin has been found in the sputum of patients with CF, and this may cause loss of its antioxidant function.²³

In a study that evaluated a model to predict CF patients life expectancy, plasma albumin levels were predictive of survival. The authors suggest that albumin is a more sensitive marker of survival than percentage of ideal body weight.²¹ Low plasma albumin was associated with higher morbidity and mortality in CF patients.²³

In this study, ROC curves showed that plasma albumin levels of 4.25 mg/dL were predictive of FEV₁ of 60% with good sensitivity, specificity and accuracy, possibly because it is a sensitive indicator of nutritional status and because of its interaction in the inflammatory reaction. Likewise, regression analysis showed that plasma albumin level lower than or equal to 4.1 mg/dL predicted a 18.6% fall in FEV₁. The albumin value of 4.1 mg/dL is the upper limit of the first quartile associated with a FEV₁ fall. These results show that only higher plasma albumin values are associated with better FEV₁ values.

The relationship between Pseudomonas aeruginosa colonization and pulmonary function deterioration is clearly established in the literature. Steinkamp and Wiedemann (2002) demonstrated that pulmonary function diminished in 56% of the adolescents with Pseudomonas aeruginosa and that pulmonary function of infected undernourished patients was worse than that of the non-infected ones³. In the present study, the presence of Pseudomonas aeruginosa was associated with lower FEV₁, however in the regression model this difference was non-significant, in contrast to what was found regarding MRSA colonization. The latter infection was associated with significantly reduced pulmonary function, and is one of the predictors of FEV₁. Co-infection by MRSA may possibly have an important impact in lung function, but studies that evaluate the effect of this bacteria separately are necessary to better understand its action.

A study with ten CF patients with MRSA concluded that MRSA infection did not significantly affect their pulmonary function, yet it affected their growth.²⁴ In the present study, infection was not correlated with BMIp, but only with FEV₁.

The socioeconomic situation of the families was consistent with the living conditions observed in a developing country, with low family income and low level of schooling. The variable years of maternal schooling was significantly correlated with FEV₁. Shechter et al. found that poorer patients with CF had a 3.65 fold higher risk of dying, and also presented deteriorated pulmonary function and nutritional status values.⁹ Another recent study demonstrated that the mortality risk of patients of a better socioeconomic level was 40% lower than that of patients of lower socioeconomic level.²⁵

A limitation of this study was that the patients' stages of pubertal development were not assessed. Delayed pubertal development is reported in CF and may affect the nutritional status. The reduced number of patients over 14 years of age (20% of population) also limited the conclusions concerning this age group. In addition, the patient's liver function tests, likely to interact with other variables, were not assessed.

This study contributes to a better understanding of the association of nutritional and lung function status of a CF population in a developing country. Based on these findings, the authors concluded that plasma albumin level lower than 4.1 mg/dl and BMI below the 10^th percentile are predictive factors for low FEV₁. Longitudinal studies may better complement these results, seeking to understand the association between plasma albumin, nutritional status and FEV₁ in similar populations.

 

Acknowledgements

We are indebted to the patients who accepted to collaborate with this study, to the Pediatric Pneumology Unit and the Nutrition and Dietetic Department of the Hospital de Clínicas de Porto Alegre (HCPA).

 

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Correspondence:
Miriam Isabel Souza dos Santos Simon.
Hospital de Clinicas de Porto Alegre.
Ramiro Barcelos, 2350.
ZIP 90035903 Porto Alegre - RS Brazil.
E-mail: mjsantos@hcps.ufrgs.br

Recibido: 11-V-2010.
1.^a Revisión: 23-II-2011.
Aceptado: 5-IV-2011.