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Special Article

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

Thomas Lahiri, Sarah E. Hempstead, Cynthia Brady, Carolyn L. Cannon, Kelli Clark, Michelle E. Condren, Margaret F. Guill, R. Paul Guillerman, Christina G. Leone, Karen Maguiness, Lisa Monchil, Scott W. Powers, Margaret Rosenfeld, Sarah Jane Schwarzenberg, Connie L. Tompkins, Edith T. Zemanick and Stephanie D. Davis
Pediatrics April 2016, 137 (4) e20151784; DOI: https://doi.org/10.1542/peds.2015-1784
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Abstract

Cystic fibrosis (CF) clinical care guidelines exist for the care of infants up to age 2 years and for individuals ≥6 years of age. An important gap exists for preschool children between the ages of 2 and 5 years. This period marks a time of growth and development that is critical to achieve optimal nutritional status and maintain lung health. Given that disease often progresses in a clinically silent manner, objective and sensitive tools that detect and track early disease are important in this age group. Several challenges exist that may impede the delivery of care for these children, including adherence to therapies. A multidisciplinary committee was convened by the CF Foundation to develop comprehensive evidence-based and consensus recommendations for the care of preschool children, ages 2 to 5 years, with CF. This document includes recommendations in the following areas: routine surveillance for pulmonary disease, therapeutics, and nutritional and gastrointestinal care.

  • Abbreviations:
    ACT —
    airway clearance therapy
    BAL —
    bronchoalveolar lavage
    CF —
    cystic fibrosis
    CFTR —
    cystic fibrosis transmembrane conductance regulator
    CT —
    computed tomography
    FEV1 —
    forced expiratory volume in 1 second
    HS —
    hypertonic saline
    LCI —
    lung clearance index
    MBW —
    multiple-breath washout
    OP —
    oropharyngeal
    PCP —
    primary care provider
    PERT —
    pancreatic enzyme replacement therapy
    PI —
    pancreatic insufficiency
    PICO —
    population, intervention, comparison, outcome
    PS —
    pancreatic sufficiency

    • Early nutritional intervention and monitoring for respiratory and gastrointestinal disease in infants with cystic fibrosis (CF) is vital to improve long-term outcomes. Clinical care guidelines specific to infants with CF,1 and nutrition and pulmonary guidelines for children > 6 years of age have been published by the CF Foundation.2,3 However, a gap exists in clinical care recommendations pertaining to preschoolers with CF, children ages 2 to 5 years.

    In addition to typical developmental milestones, preschoolers with CF and their families face complex, time-consuming treatment regimens to maintain lung health and achieve optimal growth. It is well established that airway inflammation, infection, airway obstruction, and structural damage exist during preschool years in children with CF, often in the absence of overt respiratory symptoms.4–7 For families of preschoolers with CF, it can be challenging to institute appropriate mealtime behaviors, which can lead to poor nutritional outcomes8–10 and decreased survival at age 18 years when weight-for-age is ≤10th percentile for age and gender at age 4 years.11 Supporting preschoolers with CF and their families is critical to establish habits that promote normal growth and development and an active lifestyle (ie, exercise) to prevent pulmonary decline.

    Methods

    In January 2014, the CF Foundation convened a committee of 16 CF pediatric experts and parents to develop clinical care guidelines for preschool-aged children with CF. The treatment of this population has become increasingly important, as earlier diagnoses are made, primarily through newborn screening. Committee members participated in 1 of 3 workgroups. Each group developed population, intervention, comparison, and outcome (PICO) questions,12 which were reviewed and approved by the wider committee. Dartmouth College investigators conducted a Medline literature search using PICO questions and additional medical search headings provided by the committee. Committee members conducted hand searches for additional literature and existing guidelines.

    In May 2014 the committee convened to review draft recommendation statements and supporting evidence. Unfortunately, the evidence is lacking for most treatments and monitoring tools in the 2- to 5-year-old age group. Whenever possible, statements were developed and graded by using the US Preventive Services Task Force grade definitions (Supplemental Table 1). The committee decided to make recommendations for CF care that would guide both CF clinicians and primary care providers (PCPs). Therefore, questions for which evidence was limited or absent were then presented and discussed by committee members. Use of existing evidence from older children and adults, as well as clinical experience, was then used as the basis for consensus recommendations. An 80% approval by the committee was agreed on a priori, and required for all statements. Revisions and voting were managed by using an online survey. All recommendations were approved by the committee, and had a final consensus rate of at least 87.5%.

    A draft manuscript was distributed by the CF Foundation to all accredited care centers for a 2-week public comment period. Feedback was collected by using an online survey and the guidelines were revised accordingly. The committee recognizes the limitations of these guidelines, which are the first step in standardization of preschool CF care. We fully expect these recommendations to evolve over time, as randomized controlled trials in these younger patients may provide evidence in favor of or against consensus recommendations.

    Results

    In total, 10 427 articles were retrieved. Review articles, case reports, letters, nonhuman studies, and studies not related to the PICO questions were removed. A total of 344 articles were retained for review. Additional details on the review process can be found in the Supplemental Information. Guideline recommendations are summarized in Table 1.

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    TABLE 1

    Recommendation Statements

    Discussion

    Health Maintenance

    Preschoolers with CF should receive routine well-child care from a PCP. Collaboration among the family, PCP, and a CF Foundation accredited care center is essential, and information about CF and the child’s CF care should be provided to the PCP.1 Children should receive age-appropriate immunizations and annual seasonal influenza vaccination along with family members and caregivers.13–15 They should receive the first dose of pneumococcal polysaccharide vaccine (PPSV23), given at least 8 weeks after the last pneumococcal conjugate vaccine (PCV13) dose. Environmental tobacco smoke exposure should be avoided; providers should routinely assess for environmental smoke exposure and offer caregivers information about smoking cessation and interventions to limit exposure.16 Table 2 outlines routine monitoring care for preschoolers with CF including primary care visits. Table 1: Recommendations 1–5.

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    TABLE 2

    Routine Monitoring and Care

    Caregiver Engagement

    Parenting a preschooler with CF can be demanding and stressful. Families can face significant obstacles accessing CF care, including the high cost of insurance and prescription medications, and delays in, or denial of, coverage. Families may need guidance to model behaviors to handle refusals to take medications and to navigate mealtime struggles. To promote normal growth and development, it is essential to institute and maintain CF care routines in partnership with families, especially during preschool-age development. Parents and CF providers should collaborate to develop individualized treatment goals and plans that address barriers to care. Supplemental Table 2 lists some risk factors for poor adherence and Supplemental Table 3 outlines questions and topics to help caregiver engagement with treatment adherence. Table 1: Recommendation 6.

    Surveillance for Pulmonary Disease

    Pulse Oximetry

    Few studies have evaluated oxygen saturation levels in CF. In older children and adolescents with CF, correlations between nocturnal O2 saturation and lung function indices, chest computed tomography (CT), and chest radiograph scores have been reported17,18; hypoxia during sleep has been demonstrated to be associated with low forced expiratory volume in 1 second (FEV1).19 In infants and preschoolers, no significant difference was observed in nocturnal O2 saturation in those with CF versus controls.20 Given the paucity of data in preschoolers with CF, the committee concluded that there is insufficient evidence to recommend for or against routine use of pulse oximetry as an adjunctive tool to detect lung disease. Table 1: Recommendation 7.

    Spirometry

    Spirometry is the most important and widely used tool to assess lung function in CF. Several studies have demonstrated that spirometry is feasible in preschoolers with CF, and has the potential to detect pulmonary exacerbations and airway obstruction despite minimal symptoms.6,21,22 In a cross-sectional, multicenter study, FEV in 0.5 second and flow-related volumes were found to be more sensitive than FEV1 for identifying abnormal lung function in asymptomatic, preschool-aged children.23 Another study demonstrated improvement of spirometric indices in both school-aged children and 10 preschoolers who were treated for pulmonary exacerbations.24 Because there is no risk to performing spirometry in preschool-aged children, and they benefit from practicing with technicians, the committee concluded that spirometry should be attempted as early as 3 years of age, depending on the child’s developmental level. Table 1: Recommendations 8–9.

    Bronchodilator Responsiveness

    Three articles demonstrated bronchodilator responsiveness in <20% of children with CF. Bronchodilator responsiveness may be associated with certain polymorphisms.25–27 Although there is insufficient evidence to recommend for or against routine monitoring of bronchodilator responsiveness, evaluation may be considered if there are concerns or symptoms suggestive of airway hyperreactivity. Table 1: Recommendation 10.

    Multiple-Breath Washout

    Multiple-breath washout (MBW) testing measures regional ventilation heterogeneity and appears to be more sensitive than spirometry in detecting pulmonary function abnormalities in young children with CF. Two prospective studies that included preschool-aged children reported that MBW indices, specifically lung clearance index (LCI), was more sensitive than spirometry in detecting abnormal lung function5,28 and was generally abnormal in preschoolers with CF compared with healthy controls.20 The utility of MBW in the clinical setting and what constitutes a clinically significant change in the LCI has not yet been determined. The committee concluded that there is currently insufficient evidence to recommend for or against the routine use of MBW in CF. Table 1: Recommendation 11.

    Chest Radiographs

    Chest imaging can be performed at all ages and can identify structural changes that may be regional, early, and presymptomatic. Chest radiographs are relatively insensitive and nonspecific compared with CT scans, but require less radiation exposure, expense, and patient cooperation. Chest radiographs have been shown to detect the existence and progression of CF lung disease in infants,29 and preschool-aged30 and school-aged children.31 Chest radiographs demonstrate a higher correlation than FEV1/forced vital capacity with Pseudomonas acquisition in young children with CF.32 Chest radiograph scores are superior to FEV1 in detecting concurrent abnormalities on chest CT scans,33 and in predicting future FEV1 and chest radiograph scores.34 To monitor disease progression, chest radiographs should be obtained at a minimum of every other year following a baseline radiograph at diagnosis. Use of a scoring system, such as Brasfield,35 Chrispin-Norman,36 or Wisconsin37 scores, should be considered to monitor changes over time. Chest radiographs also should be considered in preschoolers with CF with a change in respiratory status that does not respond to appropriate interventions. Table 1: Recommendation 12.

    Chest CT

    Chest CT is a sensitive tool for monitoring early CF lung disease, as it detects early airway wall thickening, bronchiectasis, and gas trapping in infants and preschoolers,4,38,39 without symptoms or abnormal pulmonary function.40,41 Bronchiectasis in this age group often persists or progresses.42 The rate of structural lung disease progression on CT in preschoolers with CF is not well defined; however, CT scans have revealed progressive bronchiectasis in older children over a 2-year period, despite stable pulmonary function testing.40 In children <4 years of age experiencing a pulmonary exacerbation, CT detected regional differences in airway inflammation and scores improved after treatment.43 Although the carcinogenic risk of radiation exposure is small and continues to decrease with technological innovations,44 concerns remain regarding the risk of radiation exposure and expense. Controversy also persists regarding the significance of early changes seen on CT45 and the preferred methodology and reproducibility of scoring systems, especially in early or mild disease.46 There are currently no valid surrogates to replace CT. In a cohort of patients 5 to 19 years of age, a normal LCI almost excluded CT abnormalities41; in a younger cohort (mean age 7.8 years), LCI and high-resolution CT had similar sensitivity to detecting CF lung disease but provided complementary information.47 If routine monitoring is performed, it should replace chest radiographs, be performed every 2 to 3 years, and use the lowest radiation dose possible needed to obtain diagnostic-quality images. If used, consideration should be given to using a scoring system to standardize interpretation of repeated scans over time. Table 1: Recommendation 13.

    Microbiology

    Quarterly respiratory cultures are the standard of care for patients with CF.48 For infants1 and other nonexpectorating patients, an oropharyngeal (OP) swab is the usual respiratory sample, despite limited diagnostic accuracy compared with bronchoalveolar lavage (BAL).49 BAL is the only means by which to directly sample the lower respiratory tract and provides measures of lower airway inflammation that may have important prognostic value,4 but is invasive and costly. A randomized controlled trial in infants and preschoolers with CF50,51 found no difference in outcome at age 5 years when therapy was directed by OP culture as opposed to BAL. Induced sputum may have greater yield than OP culture,52–54 but it is time-consuming and impractical in standard clinic settings. Respiratory microbiology monitoring by OP cultures should be performed at least quarterly and routine airway monitoring by bronchoscopy is not recommended. However, bronchoscopy with BAL should be considered in patients with a change in respiratory status that does not respond to antibiotics directed toward pathogens isolated from OP swabs. Table 1: Recommendations 14–15.

    Pulmonary Therapeutics

    Pulmonary Exacerbations

    Based on our current understanding of early disease progression, the association of pulmonary exacerbations with worse outcomes, and evidence of improvement with antibiotic treatment,43,55–66 the recommendation for preschoolers with CF experiencing an exacerbation is oral, inhaled, and/or intravenous antibiotic treatment. Defining a pulmonary exacerbation is beyond the scope of this article; however, Fig 1 outlines the recommended approach to preschool-aged children with increased respiratory symptoms. There are no randomized clinical trials of pulmonary exacerbation treatment in preschool-aged children with CF; thus, these guidelines for management were based on consensus recommendations, and management decisions should be individualized. Oral antibiotics targeting bacteria detected on airway cultures are recommended for mild to moderate pulmonary exacerbations, whereas intravenous antibiotics are recommended for moderate to severe pulmonary exacerbations or mild exacerbations unresponsive to oral antibiotics. Inhaled antibiotics are recommended based on standard guidelines for treatment of new and chronic Pseudomonas aeruginosa infection.2,67 Table 1: Recommendation 16.

    FIGURE 1
    FIGURE 1

    Approach to preschool-aged children with increased respiratory symptoms.

    Airway Clearance Therapy

    Airway clearance therapy (ACT) is an important maintenance treatment and is recommended for all individuals with CF.1,68 With early airway disease noted in the youngest population, ACT has the potential to prevent development of irreversible disease. Continuing ACT through preschool years will encourage maintenance throughout childhood. An active lifestyle consisting of vigorous physical activity and exercise, important components of maintaining lung health, should be encouraged and initiated in this age group. In preschoolers with CF, daily ACT is recommended and increased frequency and/or duration is recommended during pulmonary exacerbations. Table 1: Recommendations 17–18.

    Bronchodilators

    No studies were found that address bronchodilator efficacy in the absence of asthma or bronchial hyperresponsiveness in CF; therefore, the evidence is insufficient to recommend for or against the chronic use of inhaled bronchodilators in preschoolers. However, viral-triggered wheezing or asthma in preschoolers may respond to bronchodilator therapy. Table 1: Recommendation 19.

    Hypertonic Saline

    Several studies have demonstrated safety and tolerability of 7% hypertonic saline (HS) in infants and young children.69–71 Unlike a study in older individuals with CF,72 a randomized controlled trial of 344 children <5 years failed to show a reduction in the primary endpoint of pulmonary exacerbation rate.73 However, in 2 small studies that were part of this larger trial, infant lung function and the LCI did demonstrate improvement in subjects receiving 7% HS.73,74 Given these findings, the CF Foundation recommends that HS be offered to patients based on individual circumstances, either for chronic use or during acute pulmonary exacerbation. Further studies may alter this recommendation. Table 1: Recommendation 20.

    Dornase Alfa

    Routine use of dornase alfa is associated with reduced pulmonary exacerbations, improved lung function, and decreased rate of lung function decline among older children and adults with CF.75–81 Dornase alfa has been shown to have positive effects on CT changes and LCI82–84 and improved health-related quality-of-life scores in children >6 years.85 Safety and tolerability of dornase alfa has been demonstrated in children ages 3 months to 5 years.86,87 Potential benefits include its effect on mucous plugging, air trapping, and lung health in CF that may result in delayed pulmonary disease progression. Based on moderate evidence that dornase alfa is safe and effective, and the potential benefit is at least small, the CF Foundation recommends that dornase alfa be offered to patients based on individual circumstances, either for chronic use or during acute pulmonary exacerbation. Further studies may alter this recommendation. Table 1: Recommendation 21.

    Systemic and Inhaled Corticosteroids

    With the exception of treatment of allergic bronchopulmonary aspergillosis, systemic corticosteroids are not recommended for routine use in children with CF, as potential harm outweighs any benefit. Inhaled corticosteroids are not recommended for management of CF lung disease, as no clear benefit has been identified.2 Table 1: Recommendation 22–23.

    Ibuprofen

    High-dose ibuprofen is recommended for chronic use in individuals with CF older than 6 years with mild lung disease.2 We found no prospective trials that support its use in children younger than 6 years and conclude there is insufficient evidence to recommend for or against its use in preschoolers with CF. Table 1: Recommendation 24.

    Leukotriene Modifiers

    In the absence of comorbid conditions, such as asthma or recurrent wheezing, there is insufficient evidence to recommend for or against the chronic use leukotriene modifiers for preschoolers with CF. Table 1: Recommendation 25.

    Azithromycin

    Routine use of azithromycin is recommended for individuals with CF >6 years with persistent P aeruginosa infection.2 Azithromycin is safe, reduces lower airway inflammation and exacerbations, and improves lung function and weight gain in older children with mild CF lung disease.88,89 There are conflicting data regarding the potential for higher nontuberculous mycobacterial infection rates in individuals with CF on chronic azithromycin.60,90–92 There is insufficient evidence to recommend for or against the chronic use of azithromycin in preschoolers with CF. Table 1: Recommendation 26.

    Chronic P aeruginosa Infection

    The use of cycled inhaled tobramycin for the management of infants, children, and adults with persistent P aeruginosa infection has been previously recommended.1,2 Additional inhaled antibiotics, such as aztreonam, also have been effective and safe in improving lung function and reducing exacerbations outside of the infant and preschool age range.93–96 Microbiologic efficacy and safety of inhaled tobramycin has been demonstrated in infants and young children.97–100 The use of alternate-month inhaled antipseudomonal antibiotics for preschoolers with persistent P aeruginosa infection is recommended. Table 1: Recommendation 27.

    Staphylococcus aureus Prophylaxis and Eradication

    In keeping with previous guidelines,4,42,43,101 the prophylactic use of oral antistaphylococcal antibiotics is not recommended given the risk of increased P aeruginosa isolation.2,102–106 Several studies have addressed the utility of eradication attempts after first acquisition of S aureus, particularly methicillin-resistant isolates, but none have been randomized or focused on young children with CF.107–110 Prophylactic use of oral antistaphylococcal antibiotics is not recommended; evidence is insufficient to recommend for or against attempts to eradicate S aureus and for chronic use of oral antistaphylococcal antibiotics in preschoolers with CF who persistently culture S aureus. Table 1: Recommendations 28–30.

    Ivacaftor

    Ivacaftor has been shown to improve lung function, sweat chloride values, weight gain, and quality of life in people 6 years and older with at least 1 copy of the G551D mutation.2,111–113 This therapy has recently been approved for use in patients with additional cystic fibrosis transmembrane conductance regulator (CFTR) gating mutations: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, and R117H. A forthcoming study in preschoolers has demonstrated safety of ivacaftor in the preschool-aged child.114,115 The availability of oral granules now allows for appropriate dose adjustment in young children. Monitoring of liver function abnormalities will be important. Based on data in older subjects, forthcoming safety data, and recent Food and Drug Administration approval for this age group, the use of ivacaftor for preschoolers with specific gating mutations and R117H is a consensus recommendation of this committee. Table 1: Recommendation 31.

    Clinical and Behavioral Nutrition and Gastrointestinal Care

    Nutrition

    Normal ranges of weight-for-age, height-for-age, and BMI percentile are associated with better pulmonary function, height closer to the 50th percentile for age and gender, and survival.3 A recent study demonstrated that weight-for-age ≥10th percentile for age and gender at age 4 years was associated with superior survival at 18 years.11 Therefore, it is recommended that weight-for-age of preschoolers with CF be maintained at ≥10th percentile. Table 1: Recommendation 32.

    Measurement of height and weight, with calculation of BMI percentile using Centers for Disease Control and Prevention growth charts, should be performed to assess weight-for-stature.116,117 Weight-for-height and BMI must be evaluated in the context of the child’s height. Stunting is a risk in CF and can obscure nutritional risk in a child. Preschoolers with CF should maintain a BMI ≥50th percentile. Recommended monitoring of growth and nutrition in this age group is found in Table 3. Table 1: Recommendations 33.

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    TABLE 3

    Routine Monitoring and Nutritional Care of Preschoolers with CF

    Energy and protein requirements should be assessed in preschoolers with CF.118,119 Energy and protein recommendations of ≥90 to 110 kcal/kg per day, and protein intake based on dietary reference intakes120 and dietary guidelines recommend ≥13 g protein per day for children aged 2 to 3 years and ≥19 g protein per day for children aged 4 to 5 years to meet optimal nutritional thresholds. Table 4 outlines general energy guidelines by age and gender for preschoolers with CF. Table 1: Recommendation 34.

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    TABLE 4

    General Calorie Guidelines for Age and Gender: The Recommendations Are a Consolidation of 3 References118–120

    Nutritional Risk

    Nutritional risk is defined as a BMI <50th percentile, or rate of weight gain <50th percentile expected for age (≥6 g per day), or weight-for-age <10th percentile, or inappropriate weight loss. Families of preschoolers with CF at nutritional risk and CF health care professionals should establish a multifaceted care plan that addresses medical, behavioral, and nutritional issues and schedule more frequent follow-up to ensure rapid establishment of normal growth. Interventions to improve nutritional status can be guided by the algorithm in Figs 2A, 2B, 2C, and 2D. Collaboration with a PCP or a visiting nurse to obtain weight and height measurement is an option for preschoolers needing more frequent evaluation. Table 1: Recommendations 35–36.

    FIGURE 2A
    FIGURE 2A

    Nutrition algorithm: Tier One Initial Evalutaion.

    FIGURE 2B
    FIGURE 2B

    Nutrition algorithm: Tier Two Consultation and In-depth Diagnostic Evaluation.

    FIGURE 2C
    FIGURE 2C

    Nutrition algorithm: Tier Three Consideration of G-Tube.

    FIGURE 2D
    FIGURE 2D

    Nutrition algorithm: BMI and Weight for Age.

    Increased energy intake results in improved weight gain3; however, fewer data support improved height with increased energy intake.121,122 There is conflicting evidence regarding the use of nutritional supplements to increase energy intake.122,123 Oral supplements may be beneficial to preschoolers with CF at nutritional risk. Supplements may increase protein and energy at a time when eating behaviors may interfere with daily food intake. The use of supplements should be integrated with other nutritional and behavioral approaches for this age group. Families and CF health care professionals should be aware of the substantial impact of behavior on optimal nutrition.124–127 Children who continue to be at nutritional risk despite having addressed pulmonary, social, and dietary factors should be referred to pediatric gastroenterologists, endocrinologists, and behavioral specialists for further evaluation and management. Gastrostomy tube feedings have been shown in older children and adults with CF to improve weight and pulmonary function.128–131 Table 1: Recommendations 37–40.

    Vitamins

    CF-specific multivitamins are recommended, in a form that the child will best accept, and at recommended doses based on manufacturer guidelines.1 Patients with low serum levels of a specific fat-soluble vitamin(s) should continue to receive CF-specific multivitamins in addition to supplementation of the specific fat-soluble vitamin associated with low serum levels. Serum levels should be remeasured to ensure adequate response to therapy. Frequency of remeasurement should depend on the level of deficiency, the dose used for treatment, and the risk associated with deficiency or toxicity of the vitamin. Specific CF guidelines for vitamin D management are published132; there has been limited evaluation of the efficacy of these guidelines.133 Table 1: Recommendations 41–43.

    Salt

    Preschoolers with CF are advised to continue a high-salt diet, especially in the summer, and for those who live in warmer climates. For those who may not select foods with a high salt content, supplementation with at least one-quarter teaspoon of salt per day (581 mg sodium) may be necessary. Caregivers should be advised to avoid overuse of salt.134 Table 1: Recommendation 44.

    Pancreatic Enzyme Replacement Therapy

    For preschoolers with CF who are pancreatic insufficient (PI), consistent administration of the appropriate doses of pancreatic enzyme replacement therapy (PERT) is essential. Recommendations for PERT follow previous guidelines to ensure adequate digestion and avoid risk of fibrosing colonopathy.135 Evaluation of PERT dose and adherence should occur at each visit (Supplemental Table 4). Table 1: Recommendation 45.

    Behavior

    To meet growth goals, families of preschoolers with CF and health care professionals should establish individualized energy-intake goals and routinely monitor progress.10,136–139 Table 1: Recommendation 46.

    In multiple studies, families consistently reported challenges with mealtime energy-intake goals due to demanding mealtime behaviors, leading to significant stress.8,9,124–127 These mealtime behavioral challenges can predict calorie intake and weight gain.140 Regular assessment for mealtime behavior challenges should be performed and proactive behavioral assistance should be provided when needed Table 5.10,136,137,141–143 Table 1: Recommendation 47.

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    TABLE 5

    Behavioral Assessment and Management of Mealtimes

    CF health care professionals with appropriate training should provide behavioral therapy for preschoolers with CF at nutritional risk, exhibiting challenging mealtime behaviors, or not meeting energy-intake goals. Behavioral and nutrition treatment can lead to improvements in attaining energy-intake goals.10,136–140,143,144 Table 1: Recommendation 48.

    Gastrointestinal

    Conditions associated with abdominal pain may contribute to malabsorption, impaired quality of life, reluctance to perform airway clearance therapies, and loss of appetite in children with CF. In a large retrospective study of children with CF, abdominal pain frequency in children <6 years of age was no different from the general population.145 Abdominal pain should not be attributed to pancreatic enzyme dosing.145 If pain persists after assessment for common causes of abdominal pain in CF, or “red flag” symptoms, listed in Supplemental Table 5, are present, refer to pediatric gastroenterology. Studies of preschoolers with CF have shown that constipation,146 distal intestinal obstruction syndrome,147 gastroesophageal reflux disease,148 small bowel overgrowth,149 and celiac disease150 can occur. Providing parents with a questionnaire directed at gastrointestinal symptoms can assist in detecting disease.151,152 CF health care professionals unfamiliar with the diagnosis and management of these conditions should refer the child to a pediatric gastroenterologist. Table 1: Recommendations 49–50.

    Children with CF who are pancreatic sufficient (PS) do not necessarily have normal pancreatic function.153 Over time, they may develop PI. Diarrhea is an unreliable indicator of PI. Poor weight gain or growth may be a late indicator of PI, and micronutrient deficiency may be present. Fecal elastase, 72-hour stool for fecal fat, and cholecystokinin/secretin-stimulated pancreatic function testing may be used to diagnose PI. Fecal elastase is the simplest, most available screening test. Table 1: Recommendation 51.

    Children with PS and CFTR mutations associated with milder disease are at risk for acute pancreatitis, which may lead to episodes of acute, recurrent, or chronic pancreatitis.154 Specific CFTR mutations cannot reliably predict which children will get pancreatitis.155 Acute pancreatitis is a potentially life-threatening disease associated with severe pain, nausea, and vomiting. Although infrequent in preschoolers, providers should be aware that pancreatitis can occur in preschoolers who are PS. Table 1: Recommendation 52.

    Vitamin B12 is absorbed exclusively in the terminal ileum. Individuals with resection of the terminal ileum will become vitamin B12 deficient, which may take 1 to 3 years to develop.156,157 These individuals should be screened by using serum B12 levels or urinary methylmalonic acid. Providers should not wait for the development of hematologic signs to screen for deficiency. Table 1: Recommendation 53.

    Unanswered Questions

    With few clinical trials evaluating monitoring, therapeutics, and nutritional care, determining care pathways for preschoolers with CF is challenging. Additional research on monitoring for lung disease in preschoolers to advance early detection and potentially improve outcomes is needed. MRI and other imaging modalities that avoid radiation exposure may hold promise for evaluation of early CF lung disease. MBW, after further validation, may become incorporated into clinical care. Therapeutic trials evaluating efficacy of chronic respiratory medications, including dornase alfa and HS, are important; increasing treatment complexity with additional therapies must be weighed against the potential of preventing irreversible damage. CFTR modulators are a potentially life-changing therapeutic strategy for CF. The recent approval of ivacaftor for preschoolers will hopefully allow for early disease prevention. As modulators and correctors are developed for other mutations, it is important to recognize the substantial benefits for the youngest patients. Gaps in nutritional, behavioral, and gastrointestinal studies in this age group remain. Additional research on timing of nutritional interventions and of the conversion from PS to PI is needed. Determining the prevalence of key gastrointestinal disorders is needed to assist providers with testing and diagnostic decisions.

    Conclusions

    The care of the preschool-aged child with CF includes complex, time-consuming treatment regimens and overcoming behavioral challenges common in this age group to maintain lung health and optimize growth. We hope that these guidelines will help CF care teams and families make informed decisions regarding care of the 2- to 5-year-old children with CF.

    Acknowledgments

    The authors acknowledge Elaine Skopelja, Indiana University, for her assistance with the literature review.

    Footnotes

      • Accepted December 29, 2015.
    • Address correspondence to Thomas Lahiri, MD, Director, Pediatric Pulmonology, University of Vermont Children’s Hospital, Smith 571, 111 Colchester Ave, Burlington, VT 05401. E-mail: Thomas.Lahiri{at}uvmhealth.org

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: Funding was provided by the Cystic Fibrosis Foundation.

    • POTENTIAL CONFLICT OF INTEREST: Dr Cannon's institution has received funding from Vertex Pharmaceuticals, Gilead Sciences, Insmed, and Novartis Pharmaceuticals for running the studies supported by Cystic Fibrosis Therapeutics funds. Dr Cannon is an inventor on a patent for an antimicrobial licensed to Akron Research Commercialization Corporation, DBA Nebusil. Dr Guillerman has consulted for PTC Therapeutics, Inc, received funding from the Cystic Fibrosis Foundation Therapeutics, Inc, and compensation from Vertex Pharmaceuticals. Dr Rosenfeld has received grant funding from Vertex Pharmaceuticals. Dr Davis has served as a board member for Vertex Pharmaceuticals and served as an unpaid consultant for Eli Lilly. The other authors have indicated they have no potential conflicts of interest to disclose.

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    Pediatrics
    Vol. 137, Issue 4
    1 Apr 2016
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    Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis
    Thomas Lahiri, Sarah E. Hempstead, Cynthia Brady, Carolyn L. Cannon, Kelli Clark, Michelle E. Condren, Margaret F. Guill, R. Paul Guillerman, Christina G. Leone, Karen Maguiness, Lisa Monchil, Scott W. Powers, Margaret Rosenfeld, Sarah Jane Schwarzenberg, Connie L. Tompkins, Edith T. Zemanick, Stephanie D. Davis
    Pediatrics Apr 2016, 137 (4) e20151784; DOI: 10.1542/peds.2015-1784
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