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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.89 no.3 Santiago jun. 2018

http://dx.doi.org/10.4067/S0370-41062018005000303 

ORIGINAL ARTICLE

Spirometric caracterization of cystic fibrosis patients

Astrid PezoaA 

Pablo JorqueraB 

Ricardo MadridB 

Pamela MaturanaC 

Paola VivianiD 

Solange CaussadeE 

A Pediatric Division. School of Medicine. Pontificia Universidad Católica de Chile, Chile.

B Pediatric Service. Hospital Dr Sótero del Río, Chile.

C Pediatric Service. Chest Physioterapy. Hopital Dr Sótero del Río, Chile.

D Public Health Department. School of Medicine. Pontificia Universidad Católica de Chile, Chile.

E Cardiology and Pediatric Respiratory Department. School of Medicine. Pontificia Universidad Católica de Chile, Chile.

Abstract:

Introduction:

The prognosis of patients with cystic fibrosis (CF) has remarkably improved. The as sessment of the disease progression is based on the measurement of the FEV1 (Forced Expiratory Volume in one second).

Objectives:

1. To describe forced expiratory flows and volumes and com pare their interpretation according to different reference standards (Knudson, Gutiérrez, and multi ethnic GLI); 2. To describe bronchodilator response.

Patients and Method:

The medical records and spirometries of all patients with CF controlled at the Dr. Sotero del Rio Hospital were reviewed. Demographic background, sweat test results, genetic study , and bacteriological study were obtained. In addition, Forced Vital Capacity (FVC) was recorded as well as FEV1 and FEV1/FVC ratio.

Re sults:

Data from 14 patients, were analyzed, seven males, aged 6-24 years, median 15 years, median BMI 18.15 (range 14.6-23.3), median sweat chloride test 76 mEq/l (range 50,2-119 mEq/l), seven patients with at least one F508del mutation. Using multi-ethnic and Gutierrez predictive formulas, lung function involvement occurred previously in relation to the use of Knudson equations. None of the patients had a significant bronchodilator response.

Conclusion:

The group of patients descri bed mostly presents functional respiratory involvement and had no bronchodilator response. The interpretation of functional respiratory involvement varies according to the theoretical values used.

Keywords: Cystic fibrosis; spirometry; pulmonary function tests; FEV1

Introduction

Cystic Fibrosis (CF) is the most common autoso mal recessive lethal disease in Caucasians, caused by mutations in the gene that encodes the protein that regulates chlorine transport in the cell membrane1. In Chile, it is estimated a prevalence of approximately 1/8,000 to 1/10,000 live births2. It is a multisystemic disease in which pulmonary involvement represents 85% of mortality3.

Lung damage is caused by airway obstruction due to dehydration and thickening of secretions, resulting in endobronchial infection, and an exaggerated inflammatory response leading to the development of progressive bronchiectasis and obstructive and restric tive disease3. Lung function tests play a central role in the management and treatment of CF patients of all ages4-6. The measurement of FEV1 (Forced expiratory volume in one second) by spirometry is currently the essential parameter for monitoring lung function, as sessing its severity and progression7-12. On the other hand, the choice of reference standard may have a determinant effect on the interpretation of pulmonary function impairment and consequently on therapeutic measures11. Currently, in our country, reference equa tions of Knudson13, Gutiérrez14, and multi-ethnic from the Global Lung Initiative (GLI)15 are used. The objec tives of this study are 1. To describe forced expiratory volumes in cystic fibrosis patients and to compare their interpretation according to different reference stan dards, 2. To compare the evolution of FEV1 according to different reference standards, and 3. To describe the response to bronchodilator.

Patients and Method

Retrospective and descriptive study of CF patients controlled in the Pediatric Respiratory Care Unit of the Sótero del Rio Hospital. The clinical records were reviewed, recording the following data: age at diagno sis and date of the study, gender, anthropometry, nu tritional status according to body mass index (BMI), sweat test, present mutation, number of hospitaliza tions and exacerbations, and bacterial colonization to date. The following nutritional diagnoses according to BMI were considered: Obesity ≥ p95, overweight: ≥ p85 - ≤ 94, eutrophy: ≥ p10 - ≤ 84 and low weight: < p10, according to recommendations for this disease16,17.

In addition, the total spirometries of each pa tient were reviewed, recording Forced Vital Capacity (FVC), Expired Volume in one second (FEV1), FEV1/ FVC ratio, and Forced Expiratory Flows between 25 and 75% of FVC (FEF25-75). The spirometry was performed according to established standards18-20, meeting the criteria of acceptability and repeata bility required for schoolchildren and adolescents. The spirometer used was MedGraphics Breeze Suite 6.4.144SPA, 510 version, 2009, St Paul, Minnesota, USA. Knudson13, Gutierrez14, and multi-ethnic of GLI15 were used as reference values. The last spirome try recorded in each patient was interpreted, accor ding to Knudson and Gutiérrez using the fifth per centile as the lower limit (both using the lower limit in percent, which varies according to gender, height, and age), and for GLI 1 z-score (lower limit 1 z-score, -1.64 SD), analyzing FEV1, FVC and FEV1/FVC ratio. In order to establish the severity degree, a percentage of the real value of FVC and FEV1 was used with res pect to the theoretical value2.

The response to bronchodilator (salbutamol 400 ugr) was assessed, considering significant an increase of 12% in FEV 1( 19. The value of chlorine in sweat was obtained through the Gibson and Cooke method1.

In order to illustrate the progression of FEV1 over time and the theoretical curves of GLI, Knudson, and Gutiérrez, the free software R 3.3.1 version was used. This research was approved by the ethics committee of the Dr. Sótero del Río Hospital (waiver of informed consent).

Results

Out of the 17 patients controlled in this Unit, 14 had serial spirometry during a median follow-up time of nine years (range 1-17 years), seven men. The me dian age at the time of the study was 15 years (range 6 - 24 years), median weight 41 kg (range 19 - 61 kg). Table 1 shows the demographic characteristics, results of chlorine in sweat and genetic study.

Table 1 Clinical characteristics of the study group. 

Median follow-up time was ten years (range 1-17), exacerbations 12 (range 4-29). The median number of exacerbations calculated per year of follow-up was 1.8 (range 0.35 - 4/year) and hospitalizations 0.95 (range 0.14 - 3.5 / year). In three of our patients, no data were found due to the recent start of follow-up at our center.

Table 2 shows the interpretation of the last spiro metry of each patient, according to Knudson13, Gutiérrez14 and GLI15. Seven patients had normal spirometry according to Knudson, six of them according to GLI, and four according to Gutierrez parameters. In six pa tients there was no agreement on interpretation. According to GLI, there was a greater tendency to find restrictive patterns, and according to Gutierrez, obs tructive ones.

Table 2 Spirometric diagnosis according reference values. 

Table 3 shows the baseline values of FVC and FEV1 and the response to the administration of 400 ugr of salbutamol, observing that when interpreting according to guidelines19,20, no patient showed a significant increase (≥ 12% in relation to the baseline) in this va riable.

Table 3 Bronchodilator response. 

Figure 1 shows the evolution over time of the FEV1 percentage in each patient interpreted according to Knudson, GLI, and Gutierrez, and projects the average age at which 30% of the predicted FEV1 would be reached, being approximately 38 years if Knudson is used as a reference, and approximately 33 years using GLI and Gutierrez.

Figure 1 Percentaje of FEV1 evolution of Individual patients according Knudson, GLI and Gutiérrez reference values and its projection to 30% (arrows). FEV,: Forced Expiratory Volume in the first second. 

Discussion

In this series of 14 cystic fibrosis patients, our data indicate that the interpretation of functional respi ratory involvement varies according to the theoreti cal values used, diagnosing greater involvement with theoretical values GLI and Gutierrez, and reaching the critical level of FEV1 of 30% approximately five years earlier when using the latter as a reference compared to Knudson. In addition, there was no significant respon se to bronchodilator in any of the patients, consistent with the physiopathology of this disease1,3.

The implementation of the CF ministry program in Chile21,22 has contributed to the early diagnosis, highlighting the early diagnosis in our patients before the age of five in seven of them, and three before to the first year of life. It has also favored survival, which is why the current median age of our patients is 15 years.

The sweat test is the gold standard for the diagnosis of cystic fibrosis1, five patients had intermediate results (30-59 mmol/l)23 (Table 1). The patient with R117H and R1162X mutations have normal lung function, which would be consistent with the phenotypic pre valence of R117H, known to have mild manifesta tions23,24. In another patient, only one had F508del mu tation; it is assumed that the other mutation would be a mild phenotype since the patient is 22 years old and his lung function is normal. No mutation was identi fied in the remaining three patients. In two of them, lung function is impaired. Discrepancies between mu tations and expected clinical manifestations have been described25.

With respect to nutritional status, Barja et al26 re port a close correlation between nutritional status and FEV1 value. In our series, there were three overweight patients and one obese patient, due to the small number it is not possible to establish correlations. It is important to note that not only low weight but also overweight and excess fat mass are associated with im paired lung function, impaired metabolic function, and worse post-lung transplant outcomes27-29.

In Chile, predictive values of Knudson are still used13, which have been found to underestimate the results when interpreting spirometries30. The formulas of Gutierrez were obtained from healthy Chilean chil dren living in Valparaiso14. The predictive formulas of GLI15 were designed with data obtained from different countries and ethnic groups, with the great advantage of reflecting lung function as a continuum between the ages of two and 9511,31. In our series, there was a diffe rence in the interpretation of spirometry in six of the 14 patients, with greater involvement diagnosed using the Gutierrez and GLI formulas. This means that if we use Knudson as a reference, some CF patients would present results apparently in the ‘normal range’, and incorrect treatments could be determined. There were more restrictive limitations when interpreting with GLI, which would indicate that these formulas are more demanding for the FVC value, on the other hand, Gutiérrez would be for FEVi and FEVi/CVF.

FEVi is the most commonly used variable to assess the severity and progression of the disease. Its percentage with respect to the theoretical value is used to de cide on therapy changes, evaluate treatment efficacy, hospitalization decision, among others9,11,32. But in addition, the percentage of FEVi is related to the survival of CF patients; it was demonstrated that patients whose percentage of FEV1 is less than 30% compared to the theoretical one, have a mortality higher than 50% at two years7-10, and for this reason this is one of the criteria that is considered to decide the indication of lung transplantation4,7,8,18,28.

Figure 1 shows different evolutionary patterns, in cluding increased lung function in some patients. This could be explained by the known greater variability of spirometric parameters in these patients due to the permanent presence of bronchial secretions4,7,33. In our case, it is not due to the change in spirometric reference standards, as described in other cases31. A corre lation between significant variability of lung function during one year of evolution with greater deterioration of FEV1 fall has been seen, considering its variability a good predictor of disease progression4,7,9.

What is expected of a healthy child is an increase in lung volumes until the pubertal growth spurt ends6,34. Most CF patients have an unavoidable characteristic which is a progressive decrease in lung function over time10,11,34. To evaluate this evolution, FEV1 is used, des cribing a variable decrease between -0.65 and -2.52% per year according to various risk factors for loss of lung function, such as present mutation, pancreatic involvement, nutritional status, present infectious agent, number of annual exacerbations, etcétera7,25. In our patients, we see how the average percentage of FEV1 decreases with age, regardless of the reference standard used.

As a result of this study, it should be noted that the re is a relevant difference in the cut of FEV1 of 30% according to the different reference parameters. This occurs with up to five years difference between the Knudson values and the Gutierrez and GLI values. This leads to a delay in decision making which could have a negative impact on the evolution of patients.

In relation to therapy, CF patients frequently recei ve bronchodilators, but their use has not always been justified34-36. The pathogenesis of wheezing in this disease involves several overlapping mechanisms: edema of the bronchial mucosa due to chronic infection and inflammation, obstruction due to secretions, autonomic pathways stimulation, bronchial smooth muscle contraction, and dynamic collapse of the airway due to the destruction of its walls35. In this case, we see that following the guidelines for spirometric interpretation no patient showed a significant change in FEV1 with the use of bronchodilator, that is to say, FEV1 did not increase 12% or more from baseline19. These findings are similar to those found by Ziebach et al37 and Sán chez et al38. However, the latter authors report that a 6% increase over baseline FEV1, would suggest the presence of bronchial hyperreactivity in CF patients with 83% sensitivity and 100% specificity. If Table 3 is analyzed, only three patients would have a change equal to or higher than 6%. In any case, it is difficult to define a cut-off point to consider a significant chan ge due to the great variability that patients present of FEV1 and FVC, with figures of 15-20% spontaneously, even on the day of spirometry3. The authors of a Cochrane review39 suggest that prior to initiating perma nent bronchodilator therapy, the response to bron- chodilator should be assessed considering a reasonable increase in FEV1 of 10% after the administration of the drug. In relation to forced flows (FEF 25-75), we do not consider showing it since its variability has been seen to be even higher, and it is proposed to omit it in the spirometric report40, although other authors have found that these (FEF75) would serve as an early mar ker of small airway compromiso41.

We consider it a strength of this study to have had all the spirometries of each patient, which allowed to carry out functional respiratory follow-up for a considerable period of time, and thus define the individual trend of FEV1, determining its prognosis. In addition, these tests were always performed with the same spirometer, which meets the required characteristics for reliable results.

The weaknesses of the study are the low number of patients, which is not enough to assume a representation of the Chilean population nor to obtain correlations of lung function with clinical or other laboratory parameters.

Conclusion

Pulmonary function measurements are fundamen tal for making therapeutic decisions in CF patients, where FEV1 is the most commonly used variable to assess its severity and progression and to look for the presence of bronchial hyperreactivity.

We must be aware of the reference values used for spirometry since according to the chosen one, the respiratory functional diagnosis can be variable.

Ethical responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed according to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regulations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This docu ment is in the possession of the correspondence author.

Financial disclosure: Authors state that no economic support has been asso ciated with the present study.

Conflicts of interest: Authors declare no conflict of interest regarding the present study.

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Received: October 02, 2017; Accepted: January 15, 2018

**Correspondence: Dra. Solange Caussade solangecaussade@gmail.com.

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