The Importance of an Adequate Diet in the Treatment and Maintenance of Health in Children with Cystic Fibrosis

Abstract

This review focuses specifically on pediatric patients with cystic fibrosis. Cystic fibrosis (CF) is a serious inherited disease that affects the respiratory and gastrointestinal systems in children and adolescents, causing chronic inflammation, infections, and impaired nutrient absorption. A key component of patient care is monitoring nutritional status, particularly based on BMI, which correlates with lung function and life expectancy. This paper presents the latest guidelines for dietary therapy, including a high-calorie and fat-rich diet supported by pancreatic enzymes, as well as the importance of vitamin and mineral supplementation in the context of CF pathophysiology. The role of modern therapies that modulate CFTR function to improve patients’ quality of life and support antimicrobial therapy is discussed. Particular attention is paid to the role of the gut microbiota and the potential for its modulation by probiotics, highlighting their potential to alleviate inflammation and support the immune system. The conclusions underscore the need for a comprehensive, individualized approach to diagnosis and therapy, which is crucial for improving the quality of life and health prognosis of children with CF. New visual tools and a clinical case study enhance the practical applicability of current recommendations, while emerging areas such as microbiome-targeted interventions and treatment inequalities are also addressed.

1. Introduction

Cystic fibrosis (CF) is one of the most common life-threatening diseases inherited in an autosomal recessive manner among individuals of Caucasian descent, affecting approximately 48,000 people in Europe and 30,000 people in the United States [1]. This disease is caused by changes in a single gene, which result in functional alterations in the conductance of the respiratory epithelium (cystic fibrosis transmembrane conductance regulator, CFTR). A mutation in the CFTR gene promotes the occurrence of, among other things, intra-bronchial infections, pneumonia, and airway obstruction, leading to progressive lung disease and fibrosis. CF is characterized by persistent airway colonization, inflammation, and progressive pulmonary decline, primarily due to dysfunctional CFTR protein activity [2] The main nutritional problems for patients with CF are malnutrition and underweight. The significance of BMI and its role in nutritional evaluation are discussed in detail in Section 7 [3]. The updated 2024 ESPEN-ESPGHAN-ECFS guidelines highlight the key role of nutritional status in CF and provide new nutritional recommendations for patients of all ages, taking into account pregnancy, comorbidities, modulator therapies, and transplantation, among others [3]. The present review integrates updated clinical guidance, visual decision-making tools, a pediatric case scenario, and a discussion of emerging therapeutic areas such as microbiome modulation and CFTR modulators to provide a more comprehensive and practical resource for clinical care. To enhance the educational utility of the manuscript, visual tools such as flowcharts and comparative tables have been optimized with clear captions and design improvements.

Although the present review is based on the current ESPEN-ESPGHAN-ECFS guidelines, it also aims to highlight emerging research areas and address practical challenges, such as regional disparities in access to nutritional therapy, gaps in long-term data on high-fat feeding in patients receiving modulator therapies, and the ongoing debate surrounding probiotic supplementation in CF care [3].

2. Etiology

So far, over 2000 different variants of the CF transmembrane conductance regulator (CFTR), which plays a key role in the pathogenesis of CF, have been identified [4]. CF is a hereditary disease caused by mutations in the CFTR gene and inherited in an autosomal recessive manner [5]. Some CFTR mutations are associated with the occurrence of various disorders, while others do not seem to cause any disease symptoms [6,7]. The clinical features of CF are difficult to predict due to the episodic occurrence of most CFTR mutations, which are present in less than 0.5% of patients with this disease. This makes predicting disease symptoms challenging. To address this issue, the CFTR2 project was developed, which describes various genetic variants and their associated clinical features [8].

The defect in the CFTR protein that occurs in CF leads to changes in mucus production and function in the body [9]. The accumulation of thick and sticky mucus causes problems primarily in the respiratory and gastrointestinal tracts, such as difficulty breathing, chronic inflammation, and damage to organs, including the pancreas, liver, gallbladder, and intestines [10].

CF can manifest as meconium ileus, which occurs in approximately 20% of patients at birth [11]. Improper bicarbonate secretion in the case of CF leads to a decrease in pH in the intestines and the formation of an acidic and dehydrated environment. This, in turn, results in the production of thick, dehydrated mucus. The presence of high levels of albumin, as well as increased amounts of mineral components and carbohydrates bound to proteins, contributes to the formation of viscous meconium fragments, which physically block the distal part of the ileum [12].

CF is a complex monogenic disorder with over 2000 CFTR mutations, making clinical presentation highly variable and emphasizing the importance of genetic profiling for individualized care.

3. Cystic Fibrosis in the Gastrointestinal Tract

In approximately 80–85% of patients with CF, exocrine pancreatic insufficiency occurs [13]. Already in the womb, the presence of concentrated secretion in the pancreatic ducts leads to the deposition of proteins within them, resulting in blockage and dilation of these ducts. Unfortunately, this leads to gradual, irreversible damage and fibrosis of the pancreatic tissue. The resulting pancreas is severely impaired and fails to produce the enzymes needed for the digestion of carbohydrates, fats, and proteins [10]. Symptoms and complications associated with CF in the gastrointestinal tract may vary depending on the stage of the disease in the patient. In newborns and infants, the first symptom may be abnormal digestion and absorption of nutrients, leading to malnutrition and growth retardation. Frequent bloating, diarrhea, and weight maintenance issues may also occur. Vitamin deficiencies are frequent in CF and require proper monitoring and supplementation, as outlined in Section 9 [14]. Management of gastrointestinal complications in CF includes proper dietary strategies and enzyme supplementation. A detailed discussion on enzyme replacement is provided in Section 10 [15].

Alterations in gut microbiota in CF patients are significant and discussed extensively in Section 4. The use of antibiotics, a high-fat diet, and CFTR dysfunction in patients with CF lead to gut dysbiosis. This may also result from reduced secretion of pancreatic enzymes and insufficient bicarbonate to buffer acids in patients, leading to a decrease in pH in the intestinal environment. Additionally, the thick and dehydrated intestinal secretions create obstacles for flow through the intestines, exacerbating the problem. Consequently, changes in the microbiome may lead to the development of local inflammation, which negatively impacts the child’s development and quality of life. These changes are significant in the development of gastrointestinal complications and may initiate the onset of malignant tumors. Gut dysbiosis can trigger systemic inflammation and immunological disorders, which may lead to exacerbations of lung diseases through the gut–lung axis [16]. The gut microbiota of individuals with CF differs from that of healthy peers. The main issue is its low diversity [17]. In a study conducted by Nielsen et al. (2016), it was observed that even a fifteen-year-old child with CF does not achieve the same diversity in microbiota composition as a healthy one-year-old child [18]. Schippa et al. (2013) [19] demonstrated that patients with the homozygous F508 delta genotype have a more severe disruption of gut microbiota balance compared to other genotypes. In these patients, an excessive presence of Escherichia coli and a deficiency of Faecalibacterium prausnitzii and Bifidobacterium were observed in their intestines [19]. An important change in the microbiota is the reduction of species diversity, a modification related to inflammatory processes (nonspecific inflammatory bowel disease), metabolic disorders (obesity and type 1 and type 2 diabetes), or immune diseases (asthma) [20].

Pancreatic insufficiency and gastrointestinal manifestations in CF significantly impair nutrient absorption, emphasizing the need for early diagnosis and individualized enzyme and dietary therapy.

4. Probiotics

Building on the gastrointestinal complications described in the previous section, the role of probiotics in CF is now under increasing scientific scrutiny [21]. CF is associated with an early state of chronic dysbiosis, which can accentuate the gastrointestinal problems observed in individuals with CF [20]. Additionally, many treatment methods, such as recurrent or chronic use of antibiotics, can lead to the occurrence of dysbiosis. Dysbiosis, exacerbated by diet and antibiotic use, contributes to intestinal inflammation and systemic complications, making the gut microbiota a promising therapeutic target in CF [22]. The action of probiotics primarily involves improving gut motility, inhibiting the colonization of harmful bacteria, supporting the functions of the intestinal barrier, regulating metabolic processes, and enhancing the body’s immune response. As a result, patients with CF may experience relief from intestinal discomfort and an overall improvement in their health condition [23]. Administering probiotics (particularly Lactobacillus rhamnosus GG with one capsule daily and Lactobacillus reuteri with five drops daily on an ongoing basis) proves beneficial in reducing inflammatory markers in the gut, as indicated by decreased levels of calprotectin in the stool and nitric oxide in the rectum, although such interventions are not yet part of routine prescribing practices [20]. A recent study conducted by Asensio-Grau et al. (2023) highlighted that the supplementation of Lacticaseibacillus rhamnosus, Limosilactobacillus reuteri, and Lactiplantibacillus plantarum induces changes in the colonic microbiota, decreasing the levels of Proteobacteria and Bacteroidota while simultaneously increasing the abundance of Firmicutes [24]. In the observations by Madan et al. (2012), [25] conducted on seven patients with CF from birth to 9–21 months of age, connections between gut microbiota and lung condition were observed. Furthermore, it was noted that dietary changes also led to alterations in respiratory microbiota. This finding confirms a strong interrelationship between both systems and suggests the administration of probiotics to reduce exacerbations of lung diseases. Present at an early stage of life in clusters of gut bacteria, potential pathogens such as Enterococcus were later observed in the respiratory tract, highlighting the potential interconnection between these two systems and their microbiota [25]. In a study by Hoen et al. (2015), [26] 120 stool samples from 13 children with CF were analyzed, collected from birth to 34 months of age. The study found that greater diversity in the gut microbiota was associated with better health conditions. A significant relationship was discovered between the diversity of microorganisms in the gut and the delay of the first exacerbation of CF caused by the bacteria Pseudomonas aeruginosa. Therefore, long-term maintenance of a healthy gut flora could contribute to extending periods of health and improving the quality of life for individuals suffering from CF. A decrease in the number of two significant gut colonizers, Bacteroides and Bifidobacterium, was also observed in stool samples prior to the first exacerbation of CF and the initial colonization by P. aeruginosa [26]. A study conducted by Antosca and co-authors in 2019 analyzed the relationship between the composition of fecal microbiota and respiratory exacerbations in patients with CF. Fecal samples from 21 infants with CF were compared with data from 409 healthy children. The results showed a significant association between gut microbiota diversity and the severity of lung problems in the first year of life. It was observed that the level of Bacteroides bacteria, which play a role in modulating the immune system, was significantly reduced in infants with CF from 6 weeks of age through adulthood. Exposure of intestinal cells to Bacteroides metabolites reduces interleukin 8 production, suggesting that changes in gut microbiota may influence inflammation in CF. The findings of this study highlight the importance of gut microbiota composition in the context of pulmonary disease exacerbations in patients with CF, indicating the lowered levels of Bacteroides as a potential risk factor [27]. The species richness of bifidobacteria is positively correlated with the maturation of the mucosal immune system. This means that the greater the diversity of bifidobacteria, the better developed and more efficient the immune system. In children suffering from CF, a genetic disease, a reduction in the number of strains from the Bifidobacteria genus has been observed. Such a decrease in microbiome diversity can lead to extraintestinal disorders, making the body more susceptible to infections and respiratory tract inflammations [28]. However, at present, according to the ESPEN-ESPGHAN-ECFS guidelines, there is insufficient scientific evidence to support the efficacy of long-term use of probiotics or synbiotics in improving lung function, nutritional status, or quality of life in patients with CF, so their routine use is not recommended [3]. These microbial alterations are closely linked to nutrient malabsorption and fat-soluble vitamin deficiencies, highlighting the interdependence between microbiota health and nutritional interventions in CF.

Despite the potential therapeutic role of probiotics, their integration into clinical practice is limited by a lack of standardized protocols, regional variability in access, and heterogeneity in study populations. These uncertainties emphasize the need for further multicenter trials to assess long-term outcomes and to develop genotype- and age-specific supplementation strategies.

The interaction between the gastrointestinal and respiratory systems in cystic fibrosis has been increasingly recognized, particularly through the so-called gut–lung axis. This relationship is illustrated in Figure 1. This conceptual diagram helps clarify the systemic interplay between intestinal dysbiosis and pulmonary inflammation, emphasizing potential therapeutic targets.

5. Diagnostic Methods for Gastrointestinal Complications

The guidelines from the Cystic Fibrosis Foundation (CFF) recommend screening for liver diseases associated with cystic fibrosis (cystic fibrosis-associated liver disease, CFLD) in children. This includes abdominal examination (hepatosplenomegaly), biochemical assessment (bilirubin, AST, ALT, GGT, ALP, albumin, prothrombin time, and platelet count), abdominal ultrasound, and pulse oximetry (screening for hepatopulmonary syndrome) [29]. There are direct and indirect methods for assessing the exocrine function of the pancreas. In the pediatric population, direct tests are inappropriate because they require endoscopy, a costly and invasive procedure. However, their high specificity and sensitivity are considered the gold standard in evaluating exocrine pancreatic function. One such method is the secretin–cholecystokinin stimulation test, which assesses the amount of pancreatic enzymes and bicarbonate secreted. In the case of indirect tests, which are more commonly used, the effect is measured based on the absence of enzymes. These methods are preferred because they are non-invasive, cheaper, and less time-consuming [30]. The most commonly used test for assessing the need for pancreatic enzyme replacement therapy is the measurement of elastase concentration in the stool. This test is easy and quick to perform, and it is also more specific and sensitive compared to other methods, such as measuring the fat absorption coefficient or the concentrations of chymotrypsin and lipase. This makes it a better tool for evaluating pancreatic function and the potential need for enzyme therapy [31]. PPERT is essential for the treatment of pancreatic insufficiency in CF and allows for adequate digestion and nutrient absorption. Section 10 includes a full overview of enzyme formulations, dosing, and evidence-based recommendations [3]. Studies suggest that PERT may have an impact on complications associated with CF—an association with distal bowel obstruction syndrome has not been observed, while a small RCT suggests that PERT may reduce postprandial hyperglycemia by affecting incretins and gastric emptying rate [32,33]. A study by Declercq et al. [32] analyzed the association between dietary intake and pancreatic enzyme therapy and the first episode of small intestinal obstruction (DIOS) in patients with CF. Twelve CF patients were diagnosed with a first DIOS, and during this episode, their diet and pancreatic enzyme intake were analyzed 3 days before the attack, compared with data from 1 year ago and a control group. The results showed that only fat and enzyme intake were higher during the episode, but when enzyme units per gram of fat are taken into account, the differences disappeared. Overall, there is no evidence of an effect of diet or enzymes on the occurrence of the first DIOS, suggesting that these factors do not play a major role in its development [32]. In contrast, a randomized crossover study by Perano et al. [33] involving 14 adolescents with pancreatic insufficiency in the course of CF showed that the administration of PERT (50,000 IU. lipase) after a high-fat meal significantly reduced postprandial hyperglycemia (p = 0.0002), slowed gastric emptying (p = 0.003), and normalized GLP-1 and GIP incretin secretion (p < 0.001), without affecting insulin levels, compared with the placebo and the control group [33].

Recommendations for the care of people with CF emphasize the importance of checking liver and pancreatic function early and using appropriate PERT. These enzymes play a key role in the treatment of exocrine pancreatic insufficiency, and their use enables better absorption of nutrients. In addition, they may influence complications such as postprandial hyperglycemia, although their importance in the context of the development of DIOS syndrome has not been confirmed.

6. Cystic Fibrosis Pharmacotherapy

CFTR modulator therapy is very effective and is therefore currently an integral part of the standard care provided to most individuals with CF [34]. Access to these medications is limited in several countries due to their high cost. Patients receiving CFTR modulator therapy still experience exacerbations related to the lungs, which have been documented in scientific studies; however, starting modulator therapy at an early age may minimize the risk of lung infections [35]. So far, there is no evidence that individuals with CF can interrupt or change their current treatment regimen (antibiotics, physiotherapy, mucolytics, macrolides, etc.) while using CFTR modulators, especially since chronic infections are common in CF and may not subside during treatment with CFTR modulators [36]. Restoring CFTR function in the airways of patients with CF may enhance the effectiveness of antibiotics through several mechanisms. First, it improves the quality of airway surface liquid (ASL), which aids antibiotic action. Second, it influences pH balance, which is crucial for a healthy microenvironment and fighting infections. Third, the modulation of airway microbiota resulting from CFTR repair may support the immune response. Fourth, restoring CFTR function may enhance the eradication of pathogens through the activation of defensins. The combination of these factors contributes to a synergistic effect with antibiotics, which may lead to more effective infection control [37]. A study by Durfey et al. (2021) [38] showed that patients with CF who received ivacaftor, an effective modulatory therapy, had a lower number of pathogens. The aim of the study was to evaluate whether the combination of ivacaftor with an intensive 3.5-month antibiotic therapy treats chronic pulmonary infections caused by Pseudomonas aeruginosa or Staphylococcus aureus in patients with the R117H-CFTR mutation. The results indicate that ivacaftor improves CFTR function, lung function, and reduces inflammation within 48 h, as well as leads to approximately a tenfold reduction in the number of pathogens within a week [38].

Despite the transformative effect of CFTR modulators, their efficacy remains limited to specific classes of mutations, while patients with class I or V mutations still do not receive significant therapeutic benefit [39]. Additionally, even in individuals with the F508del mutation, the clinical response can be variable, indicating the influence of additional factors such as the microbiome, environmental interactions, and other genetic modifiers [40]. Increasing attention is therefore being paid to novel approaches such as modulation of the microbiome (e.g., using probiotics or bacteriophages) [41], RNA-based therapies, and stem cells, which can complement or provide an alternative to classical modulators [42]. At the same time, inequalities in access to modulator treatment—whether due to high drug costs, limited infrastructure, or lack of reimbursement—are a significant barrier to implementation, particularly in resource-limited countries [43]. Current clinical guidelines do not adequately address this complexity—both biological and systemic—highlighting the need to update them with advancing research, regional differences, and the need to individualize care.

While CFTR modulators show promising clinical outcomes, their high cost (USD ~300,000/year in the U.S.) raises questions of affordability, especially in low-and middle-income countries (LMICs). Similarly, long-term use of specialized high-calorie diets and enzyme supplements imposes financial burdens on families [44]. Cost-effectiveness studies suggest that early aggressive nutritional interventions may reduce hospitalizations and improve lung function, potentially offsetting long-term costs. However, such data remain sparse and geographically limited [45].

In light of evolving evidence, there is an urgent need for dynamic clinical guidelines that integrate emerging data on CFTR modulators, microbiome interventions, and region-specific feasibility. Implementing modular guidelines—adjusted for age, genotype, and local infrastructure—could bridge the gap between innovation and real-world care.

In many LMICs, access to PERT and high-quality nutritional supplements remains sporadic due to cost, lack of reimbursement systems, and weak supply chains. Access to CFTR modulators such as ivacaftor and elexacaftor–tezacaftor–ivacaftor (ETI) is even more limited, often due to prohibitive pricing and absence of national reimbursement agreements [46]. Only 12% of the global CF population currently receives modulator therapy, with near-universal access confined to high-income countries. Even within wealthier nations, socioeconomically marginalized groups experience diagnostic delays and suboptimal care due to systemic inequality and lack of tailored mutation panels [47].

7. The Role of an Appropriate Diet in the Treatment of Cystic Fibrosis in Children

Nutritional status has a significant relationship with the long-term evolution of lung diseases, as it is linked to the quality of life and survival of patients [48]. In the 1960s, a low-fat diet was recommended for the treatment of fatty liver; however, it turned out to cause severe malnutrition and stunted growth. In one of the studies conducted, a high-fat diet was introduced in combination with aggressive PERT therapy. This innovative approach suggested a significant improvement in growth and survival prognosis for patients [49,50]. Therefore, long-term use of a high-calorie and high-fat diet, supported by PERT preparations, began to be practiced to increase body mass and elevate BMI values [51]. However, despite initial optimism, it was noted that consuming nutrient-poor foods carries serious negative consequences. Such food typically contains a higher amount of saturated fats, sugars, and salt, which raises concerns. A society that relies on low-quality food products is at risk of deficiencies in essential nutrients, which are linked to chronic diet-related diseases, particularly cardiovascular diseases and metabolic syndrome [52].

A high-calorie, high-fat, and protein-rich diet tailored to age and disease severity is essential in pediatric CF, and regular monitoring of growth parameters is necessary to detect undernutrition or excess weight gain early.

8. Dietary Recommendations

Dietary recommendations for CF are developed based on the latest available scientific evidence and are the result of consensus among experts in the field. Nutritional needs differ significantly between infants, young children, and adolescents. Infants require close monitoring of weight gain and formula or breast milk supplementation. Toddlers often experience appetite fluctuations and need tailored feeding strategies. Adolescents face additional challenges due to growth spurts, hormonal changes, and increased independence in dietary choices, which can impact adherence to nutritional recommendations [51]. High caloric intake is essential for most patients with CF due to increased metabolism and absorption issues. This recommendation aligns with the American Cystic Fibrosis Foundation guidelines, which also recommend an energy intake of 110% to 200% of the estimated average requirement for healthy individuals [53]. While both North American and European recommendations align in emphasizing elevated caloric intake, implementation can be challenging in lower-resource settings due to limited access to specialized food products, supplements, and PERT. Moreover, differences in dietary culture and local food composition require flexible, context-sensitive adaptations of these guidelines.

Despite the clarity of current international dietary guidelines, their practical implementation in resource-limited settings remains highly challenging [54]. Barriers include the limited availability of enzyme preparations and high-quality supplements, inadequate infrastructure for regular nutritional monitoring, and cultural dietary habits that may conflict with high-fat dietary prescriptions [55]. Moreover, there is often a lack of trained dietitians specialized in cystic fibrosis care. Without systemic support and local adaptations, even evidence-based interventions remain inaccessible to many patients globally [56].

Increased energy intake for children with CF is necessary to ensure proper growth and development. A higher consumption of high-calorie foods may result in deficiencies of certain nutrients [57]. Among children with CF, lower microelement intake is observed compared to healthy individuals. Reduced intake of microelements leads to the occurrence of chronic conditions often associated with CF, such as impaired bone structure and diabetes [58]. The diet should contain an appropriate amount of calories, proteins, fats, and salt, tailored to individual needs. Whenever possible, patients should strive to consume balanced meals from various sources to meet their macro- and microelement requirements [59]. Patients with CF have higher energy requirements compared to the general population. This is mainly due to the pathophysiology of the disease, which is related to, among other factors, an increased resting energy expenditure caused by enhanced work of the respiratory muscles, impaired exocrine pancreatic function, and the presence of inflammation in the body. The daily energy requirement for patients with CF ranges from 120% to 150% of that for a healthy individual [60]. American guidelines suggest similarly high energy intake (110% to 200% of the energy requirement for healthy individuals) to promote weight gain [53]. The daily diet of a patient with CF should contain 35–40% fats, 20% proteins, and 40–45% carbohydrates. The optimal protein requirement in CF is significantly higher than in other chronic inflammatory diseases. Individuals suffering from CF experience an imbalance between anabolic and catabolic protein reactions, which can lead to muscle mass loss. Adjusting the diet, including protein and pancreatic enzymes, can be crucial in preventing muscle mass loss among those suffering from this disease [61].

Since the publication of new guidelines in 2020, the nutritional status in CF has changed dramatically. Especially in developed countries, the number of malnourished patients has significantly decreased [62]. This shift has led to a growing number of patients presenting with overweight or obesity, especially in regions with access to advanced therapies. Obesity poses a new challenge, as excessive fat intake can increase the risk of cardiovascular complications, insulin resistance, and reduced lung function. Therefore, while high-calorie diets remain crucial, they should be balanced with nutrient-dense choices and monitored regularly to avoid excess weight gain [63]. Over the past twenty years, an increase in overweight and obesity has been recorded, estimated to be between 6% and 33% among patients with CF [64]. There is a significant difference between developed and developing countries regarding malnutrition rates and the number of individuals affected by CF. In developed countries, the malnutrition rate is 4–19% of the total CF patients, while in developing countries, this rate reaches 25–50% [65]. Although for many years the elimination of malnutrition among CF patients relied on a high-calorie and high-fat diet combined with PERT therapy (see Section 10) and vitamin supplementation (see Section 9), the current trend toward healthier dietary alternatives is becoming standard practice, which helps to avoid obesity [66]. This emerging shift from malnutrition to overweight and obesity in developed regions underscores a critical need to revisit universal high-calorie recommendations. A growing number of experts now call for more personalized dietary strategies that account for regional access to modulator therapies, baseline nutritional status, and long-term metabolic risk [67,68].

Nutritional requirements in children with cystic fibrosis vary considerably by age, growth rate, and disease severity.

Table 1. Summary of age-specific nutritional recommendations for children with cystic fibrosis. The table presents recommended ranges for caloric intake, macronutrient distribution, and fat-soluble vitamin supplementation, adapted from ESPEN-ESPGHAN-ECFS 2024 guidelines. It serves as a quick-reference tool to support nutritional planning across pediatric age groups [3].

Age Group	Energy Needs (% RDA)	Fat (%)	Protein (%)	Carbohydrates (%)	Vitamin A (μg/d)	Vitamin D (IU/d)	Vitamin E (IU/d)	Vitamin K (μg/d)
Infants (0–12 m)	110–120%	35–40%	10–15%	45–55%	400–500	400–800	50	0.3–1.0
Toddlers (1–3 y)	120–140%	35–40%	10–20%	40–50%	300–400	600–1000	100	1–5
Children (4–8 y)	130–150%	35–40%	15–20%	40–45%	400–500	800–1200	200	5–10
Adolescents (9–18)	140–200%	35–40%	20%	40–45%	600–700	1000–2000	400	10

summarizes current European and North American recommendations for caloric intake, macronutrient distribution, and fat-soluble vitamin supplementation in pediatric CF patients. In order to support clinicians in applying nutritional recommendations, Figure 2 presents a simplified diagnostic and therapeutic flowchart. This visual guide outlines the key steps in managing nutritional care in pediatric CF patients, including BMI assessment, evaluation for pancreatic insufficiency, and appropriate interventions such as enzyme replacement and vitamin supplementation.

This case exemplifies how evidence-based recommendations can be effectively tailored and implemented in daily pediatric CF care, bridging theory and practice.

Clinical Case Example: Nutritional Approach in Pediatric Cystic Fibrosis

A 9-year-old boy diagnosed with cystic fibrosis (homozygote F508del) in infancy by newborn screening presented with weight deficiency (BMI at the 12th percentile), frequent respiratory infections, and symptoms of gastrointestinal discomfort. Despite enzyme therapy (PERT), fat-soluble vitamin supplementation, and a high-fat diet, the patient’s features of mild malnutrition and recurrent abdominal bloating persisted.

Dietary analysis showed an inadequate intake of total energy, particularly of high biological value protein. Elevated fecal calprotectin levels confirmed mild intestinal inflammation. The multidisciplinary team implemented an individualized dietary plan, increasing the calorie content of the diet to 140% of requirements and emphasizing nutrient-rich foods. Pancreatic enzyme dosage was adjusted according to current ESPEN-ESPGHAN-ECFS recommendations. Due to persistent gastrointestinal symptoms and parental interest, probiotic supplementation (Lactobacillus rhamnosus GG, one capsule daily) was also introduced as a therapeutic trial.

After six months of follow-up, there was an improvement in BMI to the 25th percentile, a reduction in gastrointestinal complaints, and less frequent respiratory exacerbations. This case highlights the importance of individualizing nutritional strategies, regular assessment of caloric and enzymatic needs, and the potential role of supportive probiotic therapy in the care of children with cystic fibrosis.

A visual summary of the case scenario is presented in Figure 3, combining a simplified clinical flowchart with a BMI percentile trajectory, to highlight the progression and response to individualized nutritional interventions in a pediatric CF patient.

9. Supplementation of Vitamins and Minerals

In parallel with dietary recommendations, targeted supplementation of micronutrients plays a critical role in managing nutritional deficits in CF [69]. Vitamin and mineral deficiencies are common among patients with CF, especially when accompanied by pancreatic insufficiency. Contributing factors also include fat malabsorption and comorbid conditions such as short bowel syndrome, liver disease, and non-compliance with PERT therapy recommendations. Annual monitoring of vitamin and mineral levels is recommended, along with adjusting supplement doses [70].

The disrupted mechanism of fat absorption due to pancreatic insufficiency can lead to deficiencies of fat-soluble vitamins (A, E, D, and K) in individuals with CF and exacerbate health issues [71]. Vitamin K deficiency can result in the formation of bruises due to a lack of the vitamin, which leads to clotting disorders. Vitamin E deficiency may cause ataxia and peripheral neuropathy. In contrast, vitamin A deficiency can lead to night vision disturbances and xerophthalmia (dryness and irritation of the cornea). Additionally, vitamin D deficiency can manifest as muscle cramps, osteomalacia (weakening and deformity of bones), and osteoporosis [72].

Low levels of vitamin A can negatively affect lung function and increase the frequency of lung disease exacerbations. Supplementation with vitamin A is recommended, but monitoring its concentration during treatment with modulators is essential (Rana et al. 2014) [73]. Vitamin A is important for vision, epithelial differentiation, and resistance to infectious diseases, as well as for its antioxidant properties [74]. Low serum vitamin A levels are associated with poorer clinical status, lung function abnormalities, bronchial mucosal dysfunction, and increased frequency of pulmonary exacerbations [75]. The ESPGHAN guidelines confirm that a daily dose of beta-carotene (1 mg/kg body weight/day for 12 weeks, followed by a maintenance dose of up to 10 mg/day) is effective and safe for children aged 6 to 18 years with CF [76].

Vitamin D deficiency remains a problem among patients with CF, even in those receiving supplements. One cause of vitamin D deficiency is poor fat absorption. However, other factors such as higher geographical latitude, low dietary intake, limited sun exposure, improper hydroxylation of vitamin D, and non-adherence to dosing recommendations can also contribute. Vitamin D plays a crucial role in maintaining calcium homeostasis and bone health, so its deficiency can lead to skeletal complications like osteopenia and osteoporosis in CF patients [77]. It is essential to adjust doses based on age and weight. For instance, vitamin D recommendations range from 400 IU/day in infants to 1000–2000 IU/day in older children and adolescents, depending on serum levels [78]. According to European guidelines from 2016, the minimum level of 25(OH)D in serum for CF patients should be 20 ng/mL. However, the American Cystic Fibrosis Foundation suggests that vitamin D levels are sufficient when the level of 25(OH)D is above 30 ng/mL. Both documents emphasize the importance of maintaining adequate vitamin D levels for bone mineralization in individuals with CF [51,79].

Vitamin E deficiency can lead to severe clinical consequences, such as hemolytic anemia, neuromuscular disorders, retinal damage, and impaired cognitive function. Proper dosing of vitamin E is crucial for lung health and maintaining adequate antioxidant levels in the body [80]. Given that vitamin E is primarily transported in blood lipoproteins, its serum level depends on the amount of circulating lipids in the body. Patients with CF often have low lipid levels, which can affect serum vitamin E concentrations [81]. According to European guidelines on nutrition for children and adults with CF, regular supplementation of vitamin E is recommended. For individuals over 12 months old, a vitamin E dose of 100 to 400 IU/day is suggested, while for infants under 12 months, the recommended dose is 50 IU/day. The supplementation goal is to maintain an α-tocopherol to cholesterol ratio in serum above 5.4 mg/g, which is critical for CF patients [51].

Vitamin K deficiency can negatively impact blood coagulation and bone health. However, there are no specific biochemical indicators to determine vitamin K levels in the body. Particular attention should be given to individuals with CF, especially those with liver dysfunction related to CF [73]. Symptoms of vitamin K deficiency may present as gastrointestinal bleeding, hematuria, nosebleeds, or subcutaneous bleeding. Additionally, a deficiency of vitamin K can affect bone health by disrupting the remineralization process and leading to weakened bones [82]. In a study by Dougherty et al. (2010) [83], it was found that children and young adults with CF on protease inhibitor therapy typically had vitamin K levels below the optimal range, despite regular use of formulations specifically designed for those with CF. Only individuals taking high doses of vitamin K (1000 μg/day) reached levels similar to those of healthy individuals. These studies suggest that to ensure optimal vitamin K levels in this population, supplementation with high doses of vitamin K should be integrated [83]. The ESPGHAN recommendations for vitamin K supplementation vary depending on the patient’s age. For infants, a daily dose of 0.3 to 1.0 mg is recommended, while for older children and adults, a dose of 1 to 10 mg daily is suggested. In cases of prolonged antibiotic therapy, higher doses of vitamin K may also be considered [79].

Children and adolescents with CF may be at increased risk of sodium deficiency, which can lead to growth disorders and electrolyte imbalances, particularly in infants. Breast milk (<7 mmol/L) and infant formulas (<15 mmol/L) contain relatively low sodium levels [84]. It is essential for individuals with CF to have an adequate salt intake to meet their needs. According to the Cystic Fibrosis Foundation guidelines, routine salt supplementation is recommended [85], while ESPGHAN recommends assessment and supplementation as needed. It is crucial to monitor serum and/or urine sodium levels in children and adolescents with CF. In the absence of fever, heat, or intense physical exertion, a Western diet should provide sufficient salt, particularly in older children and adults [51]. Therefore, it is important for each patient to receive personalized recommendations for salt supplementation to ensure adequate and optimal body functioning [86].

Children with CF also have a high risk of iron deficiency. Chronic inflammation and iron absorption issues result from pancreatic insufficiency. The prevalence of iron deficiency among CF patients is high and is estimated to range from 33% in children to over 60% in adults [87,88]. According to a 2016 World Health Organization (WHO) report, iron deficiency is one of the most common nutritional disorders globally, affecting both children and adults. The WHO recommends that ferritin levels should not be <12 mg/L in children under five years of age and <15 mg/L in older children. Iron deficiency can lead to anemia, growth and development disorders, and weakened immune function. Therefore, it is essential to regularly monitor ferritin levels in the blood of children and adjust dietary intake to prevent iron deficiencies [89]. This means that in patients with CF, conventional iron level markers can be misleading, as higher values do not necessarily indicate adequate iron levels. Elevated ferritin may suggest increased inflammatory activity [90].

Patients with CF frequently exhibit decreased bone mineral density caused not only by deficiencies of vitamins D and K but also by a negative calcium balance [91,92]. The occurrence of fractures may indirectly hinder effective chest physiotherapy and lead to a decline in lung function [79]. ESPGHAN recommends annual evaluation of calcium intake to identify potential dietary deficiencies. To prevent bone demineralization, attention should be paid to consuming adequate amounts of calcium-rich foods, such as dairy products [51].

Zinc is an essential trace element that participates in various metabolic processes as a catalytic, regulatory, and structural component [93]. Zinc is important for human health and disease due to its key roles in growth and development, bone metabolism, the central nervous system, immune function, and healing processes [94,95]. Zinc deficiency increases susceptibility to pathogenic bacteria, viruses, and fungi [96]. Screening studies have shown that zinc concentrations (<40 mg/dl) occur in approximately 30% of infants with CF [97]. Maqbool et al. (2006) reported that low serum zinc levels range from 0% to 40% among infants, children, and adolescents with CF [98]. Patients with CF should be recommended zinc supplementation. Retrospective analysis of clinical data suggests that zinc supplements improved appetite, nutritional status, and lung function [82]. High-dose supplementation (5 mg zinc/kg/day) positively influenced lung function and promoted greater growth [99]. The ESPGHAN guidelines recommend zinc supplementation for individuals with CF but only for those at risk of zinc deficiency [100].

Despite standard supplementation protocols, fat-soluble vitamin deficiencies—particularly of vitamins D and K—remain common in CF, underlining the need for individualized dosing and consistent biochemical monitoring.

Table 2. Common nutrient deficiencies in pediatric cystic fibrosis and recommended interventions. Adapted from ESPEN-ESPGHAN-ECFS 2024 guidelines [3]. ↑ = need to increase supplementation in specific clinical situations (e.g. during antibiotic therapy for vitamin K).

Nutrient	Clinical Manifestations	Recommended Monitoring	Supplementation/Intervention
Vitamin A	Night blindness, xerophthalmia, epithelial dysfunction	Serum retinol levels	1 mg/kg/day β-carotene (max 10 mg/day); monitor levels with modulators
Vitamin D	Osteopenia, rickets, muscle cramps, poor bone mineralization	Serum 25(OH)D	400 IU/day (infants) to 1000–2000 IU/day (older children/adolescents)
Vitamin E	Neuropathy, ataxia, hemolytic anemia	α-tocopherol to cholesterol ratio	50 IU/day (infants), 100–400 IU/day (older children)
Vitamin K	Coagulation disorders, bleeding, impaired bone health	Prothrombin time (indirect), INR	0.3–1.0 mg/day (infants); 1–10 mg/day (older children); ↑ during antibiotics
Sodium	Growth disturbances, hyponatremia, muscle weakness	Serum/urine sodium, clinical assessment	Routine salt supplementation individualized by age and sweat loss
Iron	Anemia, growth delay, reduced immunity	Ferritin (consider inflammatory markers)	1–2 mg/kg/day elemental iron; monitor ferritin and CRP
Zinc	Growth retardation, poor immunity, poor appetite	Serum zinc levels	Supplement if deficient; doses up to 5 mg/kg/day in severe cases
Calcium	Osteoporosis, bone fractures, poor mineralization	Dietary intake + bone density (DEXA)	Dietary enrichment + ensure adequate vitamin D + K status

summarizes the most frequent micronutrient deficiencies in pediatric CF, their clinical relevance, and evidence-based supplementation strategies.

10. Enzyme Replacement Therapy

Enzyme replacement therapy with pancreatic enzymes is the standard treatment for CF, aimed at maintaining proper nutritional status [101]. PERT is a process that involves the oral administration of exogenous pancreatic enzymes, such as lipase, amylase, and protease, to aid in the digestion of fats and proteins in the intestines. PERT is required in 80–90% of patients with CF. Pancreatic enzymes are administered in the form of capsule preparations containing microspheres with enteric coatings, which protect them from gastric acid and allow their activation in the alkaline environment of the duodenum with a pH above 5.0–5.5 [102]. Regardless of the type of CFTR mutation present, PERT should be initiated if there are clear signs of malabsorption or confirmed pancreatic insufficiency (low levels of elastase-1 in the stool) [103]. Recommendations for pancreatic enzyme dosing in the latest ESPEN-ESPGHAN guidelines vary based on the child’s age. For infants up to 12 months of age, it is recommended to administer 2000–4000 units of lipase per 120 mL of milk or per gram of dietary fat consumed. Children aged between one and four years should receive 2000–4000 units of lipase per gram of dietary fat. In contrast, children over four years old may receive 500 units of lipase per kilogram of body weight per meal. The dose should be gradually increased, reaching a maximum daily dose of 10,000 units of lipase per kilogram of body weight per day, or 1000–2500 units per kilogram per meal, or 2000–4000 units per gram of dietary fat. This is crucial to ensure proper digestion and absorption of fats [79]. Routine assessment of nutritional status and body weight allows for monitoring whether the patient is receiving an adequate amount of pancreatic enzymes, which can affect weight gain. Regular evaluations enable quick responses to any potential issues related to enzyme therapy and appropriate adjustments to the treatment [102].

Pancreatic enzyme replacement therapy (PERT) is a cornerstone of nutritional management in CF patients with pancreatic insufficiency.

Table 3. Recommended pancreatic enzyme (lipase) dosing for children with cystic fibrosis, stratified by age. Adapted from ESPEN-ESPGHAN-ECFS guidelines (2024).

Age Group	Recommended Lipase Units per Meal	Maximum Daily Dose	Notes
Infants (0–12 m)	2000–4000 U per 120 mL milk	≤10,000 U/kg/day	Based on volume of milk or formula
Toddlers (1–4 y)	2000–4000 U/g fat	≤10,000 U/kg/day	Dosing adjusted to fat content
Children (4–8 y)	500 U/kg/meal	≤2500 U/kg/meal	Titrate based on stool consistency and weight gain
Adolescents (9–18)	500–1000 U/kg/meal	≤10,000 U/kg/day	Higher doses may be split across meals/snacks

provides general dosing recommendations according to age and weight, based on ESPEN-ESPGHAN 2024 guidelines.

11. Summary

CF is a hereditary disease caused by mutations in the CFTR gene, primarily affecting the respiratory and digestive systems. This updated version incorporates newly discussed areas, including access disparities, microbiome modulation, and the evolving role of CFTR modulator therapies, ensuring the review reflects both current standards and future directions in CF care. Malabsorption, pancreatic insufficiency, and increased energy expenditure place patients at high risk for protein-energy malnutrition. Maintaining an appropriate BMI is strongly associated with better pulmonary function and survival. European guidelines recommend a high-calorie, high-fat diet supported by PERT, alongside fat-soluble vitamin supplementation. Advances in therapy, including CFTR modulators and probiotic use, have further influenced nutritional management by improving gut health and systemic inflammation. Figure 4 illustrates the evolving trends in nutritional status among CF patients over the past two decades, with a decline in malnutrition but a rising prevalence of overweight and vitamin deficiencies. Despite progress, several challenges remain. There is limited evidence on the long-term effects of high-fat diets in the modulator era, especially regarding metabolic risks. Access to nutritional therapies varies globally, and cultural dietary norms may affect adherence. Few studies have addressed the cost-effectiveness of early intensive nutrition strategies. Future research should focus on personalized approaches and sustainable, equitable models of care to optimize outcomes across diverse patient populations. In light of evolving evidence, there is an urgent need for dynamic clinical guidelines that integrate emerging data on CFTR modulators, microbiome interventions, and region-specific feasibility. Implementing modular guidelines—adjusted for age, genotype, and local infrastructure—could bridge the gap between innovation and real-world care.