Cystic fibrosis in adults clinical and spirometric aspects

Abstracts

INTRODUCTION: Cystic Fibrosis is usually diagnosed in childhood. In Brazil, few studies have approached CF diagnosed in adulthood. OBJECTIVE: The aim of this study was to describe demographic and clinical characteristics and spirometric data of patients with CF diagnosed in adulthood (over 16 years of age) in Bahia, Brazil. METHODS: Twenty-eight patients with cystic fibrosis diagnosed in adulthood were evaluated at the Reference Center of Cystic Fibrosis of the state of Bahia. Variables of interest were age, gender, race, body mass index (BMI), sputum culture, presence of sinusitis and bronchiectasis, spirometric tests with the best values performed for forced expiratory volume in the first second (% FEV1), forced vital capacity (FVC) and response to bronchodilators. RESULTS: Mean age of diagnosis was 31.1 ± 12.4 years. Of the patients, 53.4% were black and mulattos and the mean BMI was 18.7 ± 3.0 kg/m2. P. aeruginosa was present in 12 (43%) of the total patients. The mean percentages ± SD of FVC and FEV1 were 58.9 ± 21.6% and 44.1 ± 23%, respectively. In the group of patients with presence of P. aeruginosa in the sputum cultures mean of the spirometry parameters were lower than those of the P. aeruginosa-free group. However, this difference achieved a statistically significant difference (p = 0.0007) only in FVC. CONCLUSIONS: In agreement with many authors, this study strengthen the point of view that CF must be investigated in patients with recurrent infections, sinusitis and bronchiectasis even in adulthood. Values of the percentages of FVC and FEV1 in relation to those foreseen were lower in patients bearers of P.aeruginosa thereby showing a higher deterioration of the pulmonary function.

Cystic fibrosis; Adult; Spirometry

INTRODUÇÃO: A fibrose cística é diagnosticada usualmente na infância. No Brasil, poucos estudos abordam seu diagnóstico na idade adulta. OBJETIVO: Descrever as características demográficas, clínicas e os achados de espirometria dos pacientes com fibrose cística diagnosticados na idade adulta, na Bahia (Brasil). MÉTODO: Foram avaliados 28 pacientes com fibrose cística diagnosticada na idade adulta no Centro de Referência de Fibrose Cística do Estado da Bahia. As variáveis de interesse foram: idade, gênero, cor, índice de massa corpórea (IMC), cultivo do escarro, porcentagem do previsto da capacidade vital forçada (% CVF), porcentagem do previsto do volume expiratório forçado no primeiro segundo (% VEF1) e resposta ao broncodilatador. RESULTADOS: A média de idade dos pacientes foi de 31,1±12,4 anos. A proporção de negros e mulatos foi de 53,7%, e a média de IMC foi 18,7±3,0Kg/m2. Em doze pacientes (43%) foi confirmada P. aeruginosa no escarro. As médias ±DP dos percentuais do previsto da CVF e do VEF1 foram de 58,9±21,6% e 44,1±23% respectivamente. No grupo colonizado por P. aeruginosa as médias dos parâmetros espirométricos foram inferiores às do grupo não colonizado. Entretanto, somente em relação à CVF esta diferença alcançou significância estatística (p= 0,007). CONCLUSÃO: Concordante com a literatura, este estudo reforça que o diagnóstico de fibrose cística deve ser investigado em pacientes com infecções respiratórias de repetição, sinusite e bronquiectasias, mesmo na idade adulta. Os valores dos percentuais da CVF e VEF1 em relação ao previsto foram menores nos pacientes colonizados por P aeruginosa, evidenciando uma maior deterioração da função pulmonar.

Fibrose cística; Adulto; Espirometria

ORIGINAL ARTICLE

Cystic fibrosis in adults clinical and spirometric aspects ^*

Antônio Carlos M. Lemos^{(TE SBPT)}; Eliana Matos^{(TE SBPT)}; Rosana Franco^{(TE SBPT)}; Pablo Santana; Maria Angélica Santana^{(TE SBPT)}

^{Correspondence}

ABSTRACT

INTRODUCTION: Cystic Fibrosis is usually diagnosed in childhood. In Brazil, few studies have approached CF diagnosed in adulthood.

OBJECTIVE:The aim of this study was to describe demographic and clinical characteristics and spirometric data of patients with CF diagnosed in adulthood (over 16 years of age) in Bahia, Brazil.

METHODS: Twenty-eight patients with cystic fibrosis diagnosed in adulthood were evaluated at the Reference Center of Cystic Fibrosis of the state of Bahia. Variables of interest were age, gender, race, body mass index (BMI), sputum culture, presence of sinusitis and bronchiectasis, spirometric tests with the best values performed for forced expiratory volume in the first second (FEV₁), forced vital capacity (FVC) and response to bronchodilators.

RESULTS: Mean age of diagnosis was 31.1 ± 12.4 years. Of the patients, 53.4% were black and mulatto and the mean BMI was 18.7 ± 3.0 kg/m². P aeruginosa was present in 12 (43%) of the total patients. The mean percentages ± SD of FVC and FEV₁ were 58.9 ± 21.6% and 44.1 ± 23%, respectively. In the group of patients with presence of P. aeruginosa in sputum cultures, mean of the spirometry parameters were lower than those of the P. aeruginosa-free group. However, this difference achieved a statistically significant difference (p = 0.0007) only in FVC .

CONCLUSIONS: In agreement with many authors, this study strengthen the point of view that CF must be investigated in patients with recurrent infections, sinusitis and bronchiectasis even in adulthood. Values of the percentages of FVC and FEV₁ in relation to those foreseen were lower in patients bearers of P. aeruginosa thereby showing a higher deterioration of the pulmonary function.

Key words: Cystic fibrosis/diagnosis. Adult. Spirometry/methods.

Abbreviations used in this paper:

CF – Cystic fibrosis

BMI – Body mass index

FVC – Forced vital capacity

FEV1 – Forced expiratory volume in one second

SD – Standard deviation

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutation in the cystic fibrosis transmembrane conductance regulator gene. More than 1400 mutations have already been reported by the Cystic Fibrosis Genetic Analysis Consortium.⁽¹⁾

The incidence of CF ranges from 1/1200 to 1/400 in the Caucasian population and is considered rare in Asian and African populations.⁽²⁾ In Brazil, there are no comprehensive epidemiological studies or neonatal screening programs that would provide an estimate of the incidence of the disease. It is estimated that more than 90% of cases go undiagnosed every year.⁽³⁾

A diagnosis of CF is made based on clinical manifestations and confirmation of high sweat chloride levels (chloride concentrations equal to or greater than 60 mEq/L).⁽⁴⁾ The classic CF presentation is that of an obstructive suppurative pulmonary disease, and it may appear concurrently with exocrine pancreatic insufficiency or a history of CF within the family.⁽⁴⁾ Approximately 90% of patients present with exocrine pancreatic insufficiency.⁽⁴⁾ Most male patients present with obstructive azoospermia.⁽⁴⁾ The evolution of CF in patients presenting pancreatic sufficiency is milder, and such patients maintain better nutritional states and improved pulmonary function, often causing a delay in diagnosis.⁽⁵⁾ The variability of phenotypic expression of CF depends on factors such as gene mutations, genetic load, and environmental factors.⁽²⁾

The aim of this study, carried out at the Cystic Fibrosis Reference Center of the State of Bahia, was to describe clinical findings, demographic characteristics and spirometric data obtained from 28 patients diagnosed with CF in adulthood (defined as older than 16 years of age). This is one of the few studies on CF in adults in Brazil and is even more relevant if we consider the fact that the population in Bahia is ethnically diverse, with a higher degree of miscegenation than in other parts of the country.

Methods

In this study, 110 patients diagnosed with CF in adulthood were identified. Of these 110, 28 (24.1%) were monitored from 1991 to 2001 at a reference center in Salvador, Bahia (Brazil).

The criteria used for the diagnosis of CF were those recommended by the Cystic Fibrosis Foundation in 1999, namely: one or more of the classical phenotypic characteristics or family history, together with sweat chloride levels higher than 60 mEq/L in sweat samples of at least 100 mg.⁽⁶⁾ In all patients, 4 sweat samples were evaluated for chloride using the quantitative pilocarpine iontophoresis method.⁽⁷⁾ Diagnoses of sinusitis or bronchiectasis were based on clinical and radiologic correlations.⁽⁸⁾

The demographic variables recorded were age, gender and race. Clinical conditions such as nutritional state and body mass index (BMI) were also noted. Spirometric measurements included forced vital capacity (FVC; percentage of predicted value) and forced expiratory volume in one second (FEV₁; percentage of predicted value), both prior to and after administration of a bronchodilator. In addition, at least 3 sputum culture samples were obtained on different occasions and submitted to microbiological testing for P. aeruginosa.

To evaluate nutritional states using BMI, patients that presented with a BMI < 18.5 kg/m² were considered nutritionally deficient. All patients were submitted to spirometric determination of FVC and FEV₁, both prior to and after the use of inhaled bronchodilator (fenoterol, 400 µg). A Vitalograph spirometer (Vitalograph, Buckingham, UK) was used in accordance with the criteria established by the American Thoracic Society (ATS).⁽⁹⁾ The predictive values were calculated using the method described by Morris.⁽¹⁰⁾ Residual volume was not evaluated.

Data were analyzed using SPSS statistical software, version 9.0. Quantitative variables are expressed as means ± standard deviation (SD), and qualitative variables are described in percentages. The Mann-Whitney test was used to estimate the statistical significance of differences between means. All statistical tests were bicaudal and a significance of 5% was considered significant.

Results

The mean age of the patients studied was 31.1 ± 13 years (median, 28.5; range, 17–67). Of the 28 patients, 15 (53.7%) were black or mulatto. Sixteen (60.7%) of the patients were female. The mean BMI was 18.7 ± 3.0 kg/m², and the mean sweat chloride level was 97.1 ± 16.8 mEq/L (range, 71.4–136 mEq/L). In 26 (93%) of the patients, there was digital clubbing and clinical as well as radiological evidence of sinusitis and bronchiectasis. All but one patient had a history of pulmonary disease in childhood. Only one patient was diagnosed with cor pulmonale. One patient was taking enzyme supplements due to celiac disease. Of the 11 male patients, 6 (54%) were submitted to sperm count and 4 (67%) presented with azoospermia. None of the 7 patients tested presented DF508 mutation.

The following infectious agents were identified in sputum cultures (3 samples per patient): Pseudomonas aeruginosa in 12 samples (43%); Staphylococcus aureus in 5 samples (18%); Haemophilus influenzae in 1 sample (3%), and saprophytic bacteria in 9 samples (30%). In 1 of the 5 samples in which Staphylococcus aureus was isolated, Klebsiella pneumoniae was also isolated.

Spirometric data are summarized in Table 1. Means ± SD of the percentages of predicted values for FVC and FEV₁ were 58.9 ± 21.9% and 44.1 ± 23.0%, respectively. There was positive response to the bronchodilator in 8 patients (28.8%). No statistically significant differences in functional parameter means were found in relation to race, gender or BMI. When we considered the patients colonized with P. aeruginosa, the mean of the percentage of the predicted value for FVC was significantly lower when compared to the mean of the value in noncolonized patients (p = 0.007). The mean of the percentage of the predicted value for FEV₁ was lower in the group colonized with P. aeruginosa. However, the difference between colonized and noncolonized patients was not statistically significant (p = 0.092).

Discussion

Typically, CF is diagnosed in childhood. About only 8% of patients are diagnosed after the age of 10.⁽¹¹⁾ In such patients, CF presents a less severe phenotypic expression.⁽¹¹⁾ The prevalence of CF is higher in Caucasians than in blacks. In the United States, the prevalence is 1:3,200 in Caucasians and 1:17,000 in blacks. The smaller proportion of Caucasians among the patients evaluated in the present series can be attributed to the fact that the population of the state of Salvador is predominantly (77.5%) black and mulatto.⁽¹³⁾

This is one of the few studies of Brazilian CF patients diagnosed in adulthood. Gan et al.⁽¹⁴⁾ described a study of 143 patients with CF in which those diagnosed in adulthood (defined as older than 16 years of age) composed approximately 20% of the group. According to the authors, a delayed diagnosis is not necessarily the result of poor diagnostic methods. Rather, they postulated, it is the result of the distinct expression of a genotype within a group of patients presenting mild pulmonary disease and no gastrointestinal symptoms. It is possible that the patients in the present study, who are from a population with high levels of ethnic miscegenation (composed of descendants of African and Portuguese immigrants), may belong to a group of patients with a milder expression of the CF phenotype. We believe that the high proportion of late CF diagnoses in the present study (28/110; 24.1%) was related to a milder course of the disease during the early years of life, as well as to a lack of highly trained healthcare personnel able to diagnose and treat the disease. We would like to call the attention of physicians and pulmonologists to the fact that they should consider this diagnosis in adults, since the sweat test (for electrolytes) is inexpensive and easily performed.

In this study, the most common clinical manifestation was bronchorrhea (100%). The fact that only one patient needed enzyme supplements may represent a less pronounced expression of the phenotype in its gastrointestinal aspects. This milder type of manifestation has been described in patients with various DF508 mutations.⁽²⁾ In a study of Caucasian patients in the southern and southeastern regions of Brazil, Raskin et al.⁽¹⁵⁾ reported a 47.4% incidence of DF508 (the most common) mutation, a figure comparable to that seen in some Mediterranean peoples (namely Italians and Spaniards). This is not surprising, given that most people in those areas are of Italian or Spanish descent. The results of genotype studies in our cohort of patients may be in conflict with the findings of Raskin et al. In the southeastern Brazilian state of Minas Gerais, where ethnic miscegenation is at 50%,⁽¹⁶⁾ the prevalence of DF508 mutation within the African-Brazilian population is 10.5%.⁽³⁾ In the present study, 7 (25%) of the 28 patients were tested for DF508 mutations, and all 7 tested negative.

Spirometric results were compatible with moderate to severe obstructive lung disease. Even though residual volume was not measured, we can assume that the lower FVC values were due to airway obstruction and the consequent increase in residual volume.⁽¹⁷⁾ When we compare the means of the percentages of the predicted values for FVC (58.9%) and for FEV₁ (44.1%) with those reported in American patients (80.9% for FVC and 68.9% for FEV₁),⁽¹¹⁾ we observe that the patients in our series presented more severe conditions. In their study of Dutch patients, Gan et al. demonstrated that spirometric results are lower in patients diagnosed with CF before 16 years of age (FVC = 71.9% and FEV₁ = 52%) than in patients diagnosed later (FVC = 89.8% and FEV₁ = 72.5%). Both differences were statistically significant.⁽¹⁴⁾ These results were also higher than those observed in the present study. These discrepancies may be due to sampling differences, especially those related to ethnicity, socioeconomic status, treatment procedures and age at time of diagnosis. These variables influence the evolution of CF, and environmental factors, number and severity of respiratory infections, genetic load, nutritional state, delay in seeking medical treatment or misdiagnosis may determine the differences in lung function parameters.⁽²⁾

A lower percentage of the predicted value for FVC (p = 0.007) and a tendency toward lower percentages of the predicted value for FEV₁ (p = 0.092) were observed in patients colonized with P. aeruginosa. Fritz-Simmons et al. demonstrated that patients colonized with P. aeruginosa presented lower values for FEV1 (64.5% of predicted) than did noncolonized patients (87.7%).⁽¹¹⁾ The findings of those authors are in contrast with those recorded in the present study, in which lower FEV₁ values were observed. Again, this can be attributed to differences in sample size, ethnicity and socioeconomic status between the two populations studied. In agreement with other data in the literature, the present study reinforces the idea that a diagnosis of CF must be considered for patients with recurrent pulmonary infections, sinusitis and bronchiectasis, even in adulthood. Spirometric values demonstrate more severe respiratory involvement in patients colonized with P. aeruginosa.

References

Submitted: 02/05/2002.

Accepted, after revision: 10/10/2003.

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*

Study carried out in the Pulmonology Research Center (NUPEP) of the Bahia State Reference Center for Cystic Fibrosis, Octávio Mangabeira Specialty Hospital, Secretaria de Saúde do Estado da Bahia. Support: Pulmonology Department at FAMED/UFBA

Publication Dates

• Publication in this collection
  19 May 2004
• Date of issue
  Feb 2004

History

• Received
  02 May 2002
• Accepted
  10 Oct 2003