Cystic fibrosis is an autosomal recessive disorder seen worldwide, with typically a higher prevalence in Caucasians (13). A significant problem in developing countries is that CF patients have a shorter life expectancy with many patients diagnosed at a later time once symptoms of the disease, in particular, respiratory problems, have manifested (34). This study shows the average age of diagnosis of 9.2 years, with only 27% of patients diagnosed before the age of five. This later stage of diagnosis varies significantly across the world. In high-income countries, more than 95% of the patients are diagnosed during the first year of life (13,35).
For clinical evaluation, respiratory symptoms (cough, recurrent pneumonia, dyspnea on exertion and chest pain), followed by gastrointestinal symptoms (abdominal distention, increased frequency of stools, flatulence and steatorrhea) were typical expressions of the disease, as seen in similar reports from Latin America (29,36). As previously reported, BMI values are often low. In our cohort, young children have an average BMI of 16.6 kg/m2, being this number higher in girls (17.4 kg/m2) than in boys (15.8 kg/m2). Culhane et al. reported higher BMI values for girls being slightly lower (21 kg/m2) than boys (22 kg/m2(37). Despite the lateness of diagnosis, malnutrition was presented in only a quarter of patients. The Shwachman-Kulczycki scores arouse a ‘good’ or an ‘excellent’ score in more than 70% of patients, grade system used to track progress in this type of patients (38,39).
In terms of comorbidities, the diagnosis of asthma in CF patients is difficult due to the age of the patient and the respiratory parameters. Nevertheless, around 20 to 30% of the patients with CF can have a concomitant diagnosis of Asthma (40). Our results show that 1:3 patients had a concomitant and previously diagnosed with asthma, as reported elsewhere (41)
Pulmonary function test (FEV1 and FVC) were within the normal range in the majority of patients. It was found a mild-lower airway obstruction in all age groups, which is an interesting finding since lung function would have been expected to be lower in patients with a delayed CF diagnosis, a situation previously reported (39). Lung function at follow up showed a significant drop only at nine months. Besides this finding, follow-up guarantees an adequate assessment of the disease (42).
Prevention of complications is essential in managing this disease; periodical cultures had proven to be an important clinical step to perform an early treatment. Most common gram-positive germs were oxacillin susceptible and resistant S. Aureus. Age group analysis showed a decrease of positive Moraxella Catharralis, Haemophilus Influenzae cultures in older patients and an increase of positive S. Aureus and P. Aeruginosa cultures in elderly patients, homogenous finding as those reported (25). It has been suggested that finding Pseudomonas aeruginosa in patients with CF is a marker of the severity of the disease(43,44). This concomitant infection causes quicker deterioration in lung function and increases the cost of treatments(45,46). In our results, P. aeruginosa was detected in 12.5% of airway cultures and those patients were treated immediately with a double intravenous (IV) antibiotic therapy targeted to P. aeruginosa; the most common combination of antibiotics was tobramycin and ceftazidime.
Regarding molecular findings, as expected, F508del mutation was the most commonly reported (52.78% of tested patients). Around the world, this mutation accounts for an estimated 30%–80% of pathogenic variants, depending on the ethnic group (47). In addition, 78% of patients who had this mutation were heterozygous, which was also expected.
An important fact to note is the analysis of H609R mutation (caused by the transition of adenosine to guanine at nucleotide 1958 - exon 13), to our best knowledge, it has been carried out and documented only in Hispanic offspring (33,48–50). However, in this analysis, 13 patients (38.23%) had this mutation, two in a homozygous state, and six were compound heterozygous with F508del, which enhances the importance of this specific mutation in Ecuadorian population.
The other mutations had been previously described in Ecuadorian patients with CF (33,50). Nefzi et al. analyzed Latin American CF patients and found four common mutations: F508del (31.37%), G542X (1.96%), G85E (1.96%) and N1303K (1.96%), with 63.7% of Ecuadorian CF mutations remaining unidentified (42). In the second report, in order of frequency, the mutations reported were F508del (37.1%), G85E (8.9%), G542X (2.4%), N1303K (2.4%), with a detection rate of 53.22% of the total of CF patients studied. All four of these mutations were found in our tested patients in the following percentage: 52.77%, 5.56%, 11.11%, and 11.11%, respectively.
CFTR exhibits an important allelic heterogeneity, a situation in which different mutations in the same gene produce variations in clinical manifestations, with this heterogeneity well known to be related to ethnic origin. As we can clearly exemplify with H609R mutation, only reported in Hispanic offspring (33,48–50). As well as for the other common mutations: G542X, G85E and N1303K, all of them consistently found in Ecuadorian patients in different publications, and frequencies more prevalent than in Caucasian mutation panels.
In 7 of our patients, the polymorphism g.204099A>C was reported, all in homozygous state, three of them related to M470V homozygous polymorphism as described above and the others with the following features:
- F508del/ Gln685Thrfs/c.869+11C>T/g.204099A>C
- G970S /M470V/ g.204099 A>C.M470V
The polymorphism g.204099A> C has been reported only in Ecuadorian populations, establishing its role as a predisposing genetic factor in positive cases.
This study was carried out to understand better the demographics of those diagnosed with cystic fibrosis, as well as investigate the bacterial colonization of the airways and analyze the genetic mutations related to the disease found in the patients. The bacterial analysis showed microbial susceptibility to an array of available antibiotics, and this data could be useful in managing the therapies given to patients as well as monitoring the emergence of antibiotic resistance in the bacteria.