Introduction
Cystic fibrosis (CF) is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America and Australia. The disease is caused by mutations within the
CFTR gene that encodes a chloride-conducting transmembrane channel, the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance within airways [
1]. CF can cause abnormalities in respiratory, digestive, endocrine and reproductive systems, with patient prognosis depending largely on the extent of lung involvement. Early nutritional intervention and monitoring to detect respiratory and gastrointestinal disease in infants with CF are vital for improving long-term outcomes [
2]. Since 1938, when cystic fibrosis was first identified, more and more cases have been reported worldwide [
3]. However, epidemiological reporting of incidence rates has been limited in China until recently [
4]. Indeed, only about 113 Chinese cases of CF have been reported [
5], of whom most were diagnosed only within the past few years. The median age at CF diagnosis is currently 8.7 years in Chinese patients, according to results of a systematic review report [
5]. This median age at diagnosis is significantly delayed as compared to the median age at diagnosis of 0.5 years reported in European patients [
6] and of 3 months reported in American patients (according to the 2017 Patient Registry Annual Data Report). Here, factors underlying CF patient diagnostic delays and obstacles patients face in maintaining treatment compliance and achieving positive outcomes were investigated by retrospectively reviewing patient records in order to better understand challenges faced by children with cystic fibrosis in China.
Discussion
Our study analyzed treatment outcomes for a cohort of 46 Chinese children with CF who were monitored for 3 years on average. Generally, clinical phenotypes and the genotypic spectrum associated with Chinese pediatric CF cases differ from corresponding aspects of Caucasian cases [
15]. As compared to results of previous studies demonstrating diagnostic delays of 5.7 [
15] and 8.7 years [
5], here we found a 4.01-year diagnostic delay as evidence that underdiagnosis of CF patients still occurs in China. This issue is likely due to the lack of universal screening, whereby late diagnoses or misdiagnoses delay treatment initiation and delivery that can adversely impact patient prognosis [
16]. In one study of patients with delayed diagnoses, health of CF patients at time of diagnosis was significantly poorer than health of other patient groups due to their greater number of respiratory (
P < .0001), gastrointestinal (
P = .005) and failure-to-thrive manifestations (
P < .0001), with adverse effects on CF patient growth and respiratory function outcomes observed (FEV1% and
P. aeruginosa colonization) [
17]. Due to the greater diversity of genotypes and phenotypes observed in Chinese CF cases as compared to Caucasian cases, diagnostic delay and poor adherence to therapy, treatment responses and prognoses of Chinese CF patients are likely more variable than for Caucasian CF patients. In addition, we should further investigate both the spectrum of CFTR gene mutations and the range of CF phenotypes in the Chinese population and apply what we learn toward improving CF education delivered to doctors and patients.
Antibiotics are indispensable for achieving control of chronic pulmonary infections and acute exacerbations in CF patients. In one study [
18], annual FEV1% predicted rates of decline for 3 consecutive years were nearly 40% lower for patients using azithromycin as compared with matched controls. Azithromycin also reduced exacerbations and supported beneficial weight gain when administered for 6–12 months to CF patients in another open-label follow-up study [
19]. In our study, overall azithromycin treatment for roughly 2-years after initiation at 3 months post-diagnosis (on average) did not trigger obvious adverse reactions or drug resistance. Moreover, intravenous tobramycin treatment during acute exacerbations had a beneficial effect on bacterial clearance rate and expectorate quantity in our study. However, additional studies are needed to evaluate intravenous tobramycin treatment safety in pediatric CF patients.
In this study, as in some previous studies [
20,
21], treatment effectiveness has been undermined by low patient compliance with follow-up recommendations. Generally, treatment adherence of patients with chronic diseases rarely exceeds 80%, with adherence most often falling between 30 and 70% [
22]. CF is a relentless disease that, even with complete adherence, leads to declining health of survivors that continues even into adulthood [
23]. In addition, poor CF treatment adherence can lead to worse health outcomes and greater healthcare use and cost [
24]. CF guidelines recommend that patients receive at least 4 clinical visits per year, lung function testing every 6 months and yearly culture-based microbiological testing of respiratory tract secretions. Each visit should include a routine physical examination, pulmonary tests and collection of sputum or cough swab cultures for microbiological assessment as part of a multi-disciplinary approach to care. In a 2017 report from Cystic Fibrosis Foundation, more than half of patients with CF complied with recommendations relating to clinical visits, respiratory culture-based testing and lung function testing. However, in other studies only 40% of patients met care guidelines [
25]. Our patient compliance was still insufficient. Indeed, one study in France demonstrated that implementation of a tracking system significantly improved patient quarterly clinic visit attendance from 4.6 ± 2.3 in 2009 to 6.3 ± 4.6 in 2013 (
P < 0.0001) as one solution for patient non-compliance [
25]. Nevertheless, numerous obstacles to patient compliance exist, including long travel distances to health providers, financial issues, work and school conflicts and difficulties associated with clinical scheduling. Therefore, improved doctor-delivered patient education, regular follow-up reminders, specialized outpatient treatment and access to CF regional centers may be needed to improve patient compliance in China.
During follow-up we learned that 4 fatalities had occurred that have stemmed from severe illness, insufficient treatment adherence by some parents and the unavailability of pediatric lung transplantation in China for patients with chronic respiratory failure. Notably, 3 survivors remained stable without receiving long-term medication or daily airway cleaning that they might not have needed due to their mild disease severity. Conversely, CT findings in another 3 cases indicated worsening lung pathology at follow-up, although airway cleaning every day had led to reduced amounts of expectorated sputum and numbers of acute respiratory tract infections.
Pulmonary function testing is used to assess the severity of CF lung disease, with FEV
1 testing especially useful for this purpose [
10]. Failures of pediatric patients in completing pulmonary function testing were related to the lack of availability of such testing in some local hospitals and difficulties in completing such tests in very young patients. Regardless, no overall significant difference was observed between pulmonary function at diagnosis versus lung function at follow-up. However, improved pulmonary function observed in some patients were explained by timely treatment, shorter follow-up times or milder disease, emphasizing the fact that such testing should be used more frequently to monitor pulmonary function of the young CF patients. In fact, CT scans have been particularly valuable when used in combination with pulmonary function tests to monitor CF lung disease [
26,
27]. Moreover, 13.64% of children exhibited improvement of bronchiectasis in our study that was attributed to effective treatment delivery. Nonetheless, routine pulmonary infection testing of pharyngeal swabs or collected sputa should be conducted by outpatient clinics in China in order to improve treatment delivery and clinical status.
Importantly, lack of nutritional intake has been a major weakness of CF management efforts in China. Because CF patients rarely receive guidance from nutritionists, parents must often adjust patient diets themselves. As is well known, BMIs of pediatric CF patients and adolescents aged 2–18 years should be greater than 50% of BMIs of healthy children of the same sex within the same age range [
28]. However, only 11 children (29.72%) in this study received adequate nutrition, as recommended by accepted guidelines. Moreover, 10 children (27.03%) had BMIs lower than the fifth percentile of the same age group. These results reveal that malnutrition is a common and serious concern for pediatric CF patients in China that is tied to the lack of specialized nutritionists in China, lack of awareness by respiratory physicians of this issue, inadequate patient adherence [
29], and poor patient living conditions. Factors that aggravate patient malnutrition include repeated chronic infections, discontinuation of drugs, poor compliance, pancreatic exocrine dysfunction and poor basic nutritional status. Most notably, the number of patients with pancreatic malfunction of the total number of CF patients was 18 of 46 (39.13%) at baseline and 15 of 37 (40.54%) at follow-up. The poor overall outcomes may be due to insufficient PERT dosages and/or poor recovery of pancreatic function. More specifically, in patients with persistent symptoms and signs of exocrine pancreatic insufficiency (EPI), patients prescribed appropriate dosages of PERT may still fail to respond to PERT treatment due to missed doses, improper storage of enzymes, expired enzymes, mistiming of PERT administration (taking PERT after meals), destruction of enteric coating and comorbidities (non–EPI-related conditions) [
30]. Therefore, we advocate for inclusion of appropriate pancreatic enzyme replacement therapy within long-term treatment plans for these patients.
Our research had limitations. First, data were obtained from a single center and thus might not adequately represent all Chinese children with CF. Moreover, follow-up measures were not of sufficient quality or duration, while missing data prevented analysis of some variables. Nonetheless, our results highlight the need for improved CF patient quality of care and case management and should be confirmed in future investigations of larger patient cohorts to better understand challenges facing the Chinese CF population.
In conclusion, diverse CF severity, low patient compliance and insufficient long-term management by medical providers are challenges that CF patients currently face. Although we did not observe obvious deterioration of clinical status and lung function in our patients, malnutrition and low patient compliance should have received greater focus in this study and thus highlight the need for better systematic follow-up to improve pediatric CF patient management. We therefore recommend that greater efforts be made to deliver standardized and individual care management, strengthen education measures and provide comprehensive follow-up care beginning early in childhood to pediatric CF patients in China.
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