Our study analyzed treatment outcomes for a cohort of 46 Chinese children with CF who were monitored for three years on average. Generally, clinical phenotypes and the genotypic spectrum associated with Chinese pediatric CF cases differ from corresponding aspects of Caucasian cases [5]. To date, 51 genomically distinct mutations have been identified in Chinese cases, with c.2909G > A and c.1000C > T ranking highest in frequency (10.87%). Due to the greater diversity of genotypes and phenotypes observed in Chinese CF cases as compared to Caucasian cases, treatment responses and prognoses are likely more variable for Chinese CF patients than for Caucasians, but testing of this presumption awaits results of large-scale studies focused on Chinese CF patients.
Pulmonary function testing is used to assess the severity of CF lung disease, with FEV1 testing especially useful for this purpose [6]. Although 17 children in this study received regular follow-up care to maintain lung function, no overall significant difference was observed between pulmonary function at diagnosis versus that at follow-up. However, improved pulmonary function observed in some patients may be 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 youngest CF patients. With regard to pulmonary infection monitoring, of 27 patients who completed sputum culture examinations at diagnosis, 5 cases received additional sputum culture examinations at follow-up that showed they had effectively cleared Pa during the follow-up period. Moreover, 13.64% of children exhibited improvement of bronchiectasis symptoms that was attributed to effective treatment delivery that aligned with results of follow-up testing that revealed that Pa infections trended downward, although S. aureus detections trended upward. Nevertheless, 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.
Antibiotics are indispensable for achieving control of chronic pulmonary infections and acute exacerbations in CF patients. However, use of long-term oral antibiotics, including azithromycin and tobramycin, to control infection is not recommended, as shown in a study by Samson et al. Their results demonstrated that the beneficial effect of low-dose tobramycin treatment disappeared with prolonged administration beyond 12 months and thus did not outweigh potential risks associated antibiotic use [7]. Meanwhile, another clinical trial-based study was stopped in spite of a clinical benefit (increased time to first pulmonary exacerbation in the azithromycin-treated group), due to a lack of impact on patient microbiological outcomes that increased antimicrobial resistance risk [8]. In this study, overall azithromycin treatment of roughly 2-years duration after initiation at 3 months after diagnosis (on average) did not trigger obvious adverse reactions or drug resistance. Thus, we speculate that longer-duration treatments may be feasible if they are accompanied by intensive monitoring for side effects and antibiotic drug resistance.
Treatment of pediatric CF patients with inhaled tobramycin after first Pa detection has become standard practice during the past decade at most CF centers, since tobramycin use was not associated with detectable renal toxicity or ototoxicity in preschoolers with CF [9]. Here, intravenous tobramycin treatment during acute exacerbations seemed to have a beneficial effect on bacterial clearance rate and expectorate quantity in our study, but further studies are needed to evaluate safety of intravenous tobramycin treatment in pediatric CF patients.
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 [10]. However, only 11 children (29.72%) in this study received adequate nutrition, as recommended by accepted guidelines. Nevertheless, calculations based on CF patient data entered into the CF Foundation Annual Data Report 2014 indicated that the proportion of children aged 2–19 years old with acceptable BMIs was 55% [11]. 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 may be tied to the lack of specialized nutritionists in China, lack of awareness by respiratory physicians of this issue 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. Although the incidence rate of pancreatic malfunction was not very high, we advocate for inclusion of appropriate pancreatic enzyme replacement therapy within long-term treatment plans for these patients.
Another problem we faced was a low follow-up rate. Generally, treatment adherence of patients with chronic diseases rarely exceeds 80%, with adherence most often falling between 30% and 70% [12]. CF is a relentless disease that, even with complete adherence, leads to declining health of survivors that continues even into adulthood [13]. 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 study, more than half of patients with CF complied with recommendations relating to clinical visits, respiratory culture-based testing and lung function testing [14]. However, in other studies only 40% of patients met care guidelines, as reported by the Department of Pediatrics, St. Louis University School of Medicine in 2009 and 2010[15], although this percentage was greater than the 2002 rate of 24.6%. Similarly, although 24 patients in this study completely followed doctors’ prescriptions and engaged in regular follow-up visits, patient compliance was still insufficient. Thus, 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. 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[15].However, other challenges causing patient noncompliance may be related to long travel distances to health providers and insufficient recognition or understanding of CF disease that in China are of greater significance than in western countries. Moreover, financial issues, work and school conflicts and difficulties associated with clinical scheduling may be addition obstacles to patient compliance.
During follow-up we learned that 4 fatalities had occurred that may have stemmed from severe illness, insufficient treatment adherence by some parents and 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.
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. Nevertheless, 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. Nonetheless, our results highlight the need for better systematic follow-up to improve pediatric CF patient management. We thus 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.