|Year : 2020 | Volume
| Issue : 1 | Page : 1-7
Elements of Treatment Adherence in Children with Cow’s Milk Protein Allergy
Fatih Ozdener1, Feza Kirbiyik2, Anil Akşit2, Ali Evrim Doğan2, Arzu Baygül3, Nermin Güler4, CAAAD Study Group5
1 Department of Pharmacology, School of Medicine, Bahcesehir University, Istanbul, Turkey
2 Medical Department, Nutricia, Advanced Medical Nutrition, Istanbul, Turkey
3 Department of Biostatistics and Medical Informatics, School of Medicine, Beykent University, Istanbul, Turkey
4 Department of Pediatric Allergy and Immunology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
5 The Academy of Pediatric Allergy and Asthma Association (CAAAD), Istanbul, Turkey
|Date of Submission||23-Oct-2019|
|Date of Decision||21-Nov-2019|
|Date of Acceptance||27-Nov-2019|
|Date of Web Publication||25-Feb-2020|
MD, PhD Fatih Ozdener
Department of Pharmacology, School of Medicine, Bahcesehir University, Sahrayı Cedit mah. Batman sok. No: 66-68, Yenisahra-Kadıkoy, Istanbul
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Adherence with treatment is critical for a successful outcome in cow’s milk protein allergy (CMPA). Determination of the factors associated with non-adherence will enable us to develop effective approaches to increase the adherence rates, thus better cost-effectiveness of the treatment. The aim of this study was to identify the main factors associated with non-adherence with treatment for CMPA in children through the view of the physicians. Materials and methods: This focus-group study involved 51 pediatricians. Data were obtained using face-to-face surveys and subsequent discussions with the physicians. Results: Based on the treating physician’s opinion, adherence to treatment was 65.7%. Of the patients, 55.4% and 29.3% were treated with an amino-acid-based formula (AAF) and an extensively hydrolyzed formula (eHF) with the tolerability rates of 77.4% and 77.2%, respectively. Remaining patients were treated with elimination diet. For patient-related factors, CMPA severity and the existence of underlying morbidities, of family-related factors, the education level of the family and their confidence in the treatment, and of product-related factors, product taste/aroma and formula choice were most strongly associated factors with treatment adherence. Conclusions: The main obstacles in treating CMPA in clinical practice were intolerability or incorrect use of the formula, dislike of its flavor and odor, and difficulties in implementation of elimination diet by parents. Determination of the factors associated with non-adherence is important in order to develop effective strategies to increase the adherence rates which will in turn improve the outcome and cost-effectiveness of the treatment.
Keywords: Amino acid formula, cow’s milk protein hypersensitivity, elemental formula, extensively hydrolyzed formula, treatment adherence
|How to cite this article:|
Ozdener F, Kirbiyik F, Akşit A, Doğan AE, Baygül A, Güler N, CAAAD Study Group. Elements of Treatment Adherence in Children with Cow’s Milk Protein Allergy. Int J Nutr Pharmacol Neurol Dis 2020;10:1-7
|How to cite this URL:|
Ozdener F, Kirbiyik F, Akşit A, Doğan AE, Baygül A, Güler N, CAAAD Study Group. Elements of Treatment Adherence in Children with Cow’s Milk Protein Allergy. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2020 Dec 1];10:1-7. Available from: https://www.ijnpnd.com/text.asp?2020/10/1/1/279180
CAAAD Study Group collaborators:
ÜLKÜ AYBERK, ESRA KEZER, İLKAY EVRİM ÖZDEN, PINAR ATILGAN, NAZLI ERCAN, SEVGİ SIPAHİ, MUZAFFER SİVRİ, ÜNAL ULUCA, EMEL CAN ÇOMU, HASAN KAPAKLI, CEMİL KAYA, AHMET KAN, HÜSEYİN ÜSKÜL, SADIK ERHAN ÖZAYDIN, YUNUS EMRE BAYSAL, MERVE ATEŞOĞLU, NESRİN GÖKTAŞ, ZERRİN TEKINKUŞ, MEHMET SUAT GÜRKAN, MEHTAP FIRAT ATA, ŞEYDA EREN, EMİNE EREN, AYÇA BİLGE SÖNMEZ, EMİNE ECE ÖZDOĞRU, ADİLE YÜKSEL, AYNUR KARACA, LATİFE DEMİRELLİ, FULYA ÇELİKTÜRK, AYŞE AVRANBUL, ALİ GÜNYAZI, SADIYE DEMIRCIOĞLU, SERTAÇ ÖZALP, MÜGE KUZU AVCI, YUNUS TURGUT, ERDAL KESEOĞLU, NURAY KESEOĞLU, AYŞE YARAMAZ, SULTAN D. MERAL, DEMET BALCI, EROL GÜNALP, SERDAR AL, OSMAN EZSÜRER, AYCAN ÖNER, FADIME SÜMER, NURCAN BASIT, FATMA DUKSAL, DEMET HAFIZOĞLU, PINAR UYSAL, FULYA TAHAN
| Introduction|| |
Cow’s milk protein allergy (CMPA) is defined as an adverse reaction to cow’s milk protein (CMP) and is the most prevalent nutritional allergy in infants and children under 3 years of age.,, Although the overall prevalence of CMPA has been estimated to range from 1.9% to 4.9% among children in cohort studies and several meta-analyses, there is a peak prevalence of 2–3% during the first year of life decreasing to <1% in children 6 years or older.,,,
CMPA can be immunoglobulin E (IgE)- or non-IgE-mediated and is usually associated with atopic reactions including urticaria, eczema, rhinitis, and/or asthma in the former and with gastrointestinal symptoms including vomiting, constipation, and gastroesophageal reflux in the latter.,, These symptoms may occur in a few minutes after cow’s milk ingestion up to 2 hours (immediate reactions) mostly in IgE-mediated CMPA and after several days (delayed reaction) mostly in non-IgE-mediated CMPA. CMPA usually manifests before the one month of the life and often within the first week after ingestion of CMP-based formula. Most infants with CMPA have at least two symptoms from at least two organ systems.,
The main strategy in CMPA is strict avoidance of CMP as an elimination diet which necessitates the use of alternative hypo- or non-allergenic products to meet the nutritional requirements of the child., Allergic reactions to complementary foods such as egg and soy may occur in infants with CMPA and should be avoided during dietary elimination until proper diagnosis. Infants with CMPA can be fed by a number of cow’s milk-based formulae such as extensively hydrolyzed formula (eHF) or amino acid formula (AAF) which is also known as elemental formula. Extensively hydrolyzed soy and rice formulae may also be utilized in place of eHFs as they are considered as hypoallergenic formulae. eHFs are well tolerated by infants and children when used to treat or prevent the CMPA due to the removal of allergenic epitopes during hydrolysis. On the other hand, AAF is recommended to overcome the problem of hypersensitivity due to the residual proteins found in eHF, particularly in severe cases with enteropathy and multiple allergies., Non-hypoallergenic formulae such as partially hydrolyzed formulae (pHF) of soy, rice, or casein may be considered as dietary intervention by some practitioners in the case of prevention of allergic symptoms but may be avoided in the case of severe allergic reactions. Infants with CMPA should not be fed with CMPA-containing foods for at least 6 months or until the age of 1 year in Turkey.
In this context, adherence with treatment is critical for a successful outcome in infants with CMPA. It is well-known that non-adherence is higher with long-term versus short-term treatment regimens with an adherence rate of only 50–55% reported for long-term used medications. Non-adherence to the treatment can negatively influence the health of the patient and overall cost of the treatment and even the results of clinical trials. There may be patient-related, family-related, and product-related factors associated with the treatment adherence for children with CMPA. Patient- and family-related factors may include demographic variables such as age and gender and socioeconomic status such as educational level and family composition. On the other hand, there may be several product-related factors including taste, adverse effects, price, and dosing regimen.
Determination of these factors will enable us to develop effective approaches in order to increase the adherence rates which will in turn improve the outcome and cost-effectiveness of the treatment in these children.
Several researchers showed the importance of physician–patient relationship and health beliefs of the patients for several diseases  but there are a limited number of studies focused on physician perceptions about the causes and consequences of the treatment non-adherence. In their earlier study, Rapoff and Christophersen have suggested that physician-reported adherence rates are better than that reported by patients and/or family. On the other hand, patient- and/or family-reported assessments usually overestimate the adherence rates mostly because of memory problems or misinformation. Although there are many studies on the diagnosis and management of CMPA in children from different ages, to our knowledge, there are only a few reports in the literature on the patient- or family-reported but no physician-reported treatment adherence rates in children with CMPA.,
The aim of this study was to identify the main factors associated with non-adherence with treatment for CMPA in children not from the patient and/or family reports but in the view of the physicians prescribing the cow’s milk-based formulae.
| Materials and Methods|| |
This was a focus-group study involving 51 pediatric specialists from different geographical regions of Turkey. The study was approved by the ethics committee of Bahcesehir University Medicine Faculty.
Data were obtained using face-to-face surveys and subsequent manually recorded discussions with the physicians. Pediatricians were instructed to answer the questions based on their observations on the treatment of CMPA patients in their respective region. For patient flow data compliance rates presented in [Table 1] and [Figure 1]a, physicians were asked to respond by providing a numerical answer for each question and answers were collectively analyzed with respect to frequency distribution. For factors associated with adherence to CMPA treatment presented in [Table 1], physicians were provided a list of known factors for each category and were asked to prioritize them by numbering (the highest priority is 6, the lowest priority is 1 for [Figure 1]b, and the highest priority is 8, the lowest priority is 1 for [Figure 1]c and 1d). Frequency distribution and mean has been calculated and listed from high to low. The answers to open questions ([Figure 1] and [Figure 2]) were categorized according to the percent frequency of the responses obtained from the group. To the best of our knowledge, this is the first report on patients with CMPA using a novel data acquisition approach combining the scoring of the physicians, analysis of the scores, and discussion of the results simultaneously in the same meeting.
|Figure 1 CMPA treatment compliance rates and related factors. (a) Compliance rates for CMPA treatment. Focus group physicians were provided with questions regarding preferences, intolerance rates and adherence rates regarding CMPA treatment modalities and asked to give numerical answer for each question. Results shown are the averages of numbers from 51 physicians taking part in the focus group. (b) Patient-related treatment adherence factors. (c) Family-related treatment adherence factors. (d) Product-related treatment adherence factors. Focus group physicians were provided a list of known factors for each category and were asked to prioritize them by numbering. Frequency distribution and average have been calculated and listed from high to low.|
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|Figure 2 Main obstacles in treating CMPA in clinical practice. In an open question, focus group physicians were asked to write main obstacles that they observe in the treatment of CMPA in clinical practice. The answers were categorized and listed according to percent frequency of the responses obtained from the group.|
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Statistical analysis was performed using the MedCalc statistical software. The normality of continuous variables was investigated by Shapiro-Wilk’s test. Descriptive statistics were presented using mean and standard deviation for normally distributed variables and median (and minimum-maximum) for the non-normally distributed variables. The chi-squared test was used for categorical variables, which are expressed as counts and percentages.
| Results|| |
Since workload of the physicians is one of the major determinants for high-quality management for chronic diseases, we determined the daily patient loads and characteristics for patients diagnosed as CMPA by the physicians. The mean number of pediatric patients examined per day by each pediatrician was 45.2±24.0; 7.3% of whom were diagnosed with CMPA. The mean age at diagnosis of CMPA was 5.9±4.0 months, with a 2.6± month delay between symptom onset and diagnosis. Of all patients diagnosed with CMPA, 81.8% started on an elimination diet and 62.9% received CMPA-specific medical nutrition. Of these children 80.5% were followed up by the same physician [Table 1].
Of the patients, 55.4% were started on an AAF and 29.3% on an eHF; the tolerability rates were 77.4% and 77.2%, respectively. Remaining patients were treated with elimination diet. In view of the physicians the overall rate of adherence with CMPA treatment was 65.7% [Figure 1]a.
Then, we tried to identify the most important patient-, family-, and product-related factors in treatment adherence. In terms of patient-related factors, CMPA severity and the existence of underlying morbidities (e.g. multiple nutritional allergy, anaphylaxis, or enteropathy) were most strongly associated factors with treatment adherence [Figure 1]b. Among family-related factors, the education level of the family and their confidence in the treatment modality were most strongly associated factors with treatment adherence [Figure 1]c. Regarding product-related factors, product taste and/or aroma was the main factor for treatment adherence and formula choice (amino acid-based or extensively hydrolyzed) was another strongly associated factor [Figure 1]d.
Subsequently, we examined how the diagnosis of the CMPA was made. In daily practice, CMPA was mostly diagnosed based on physical examination (96%), medical history (94%), and the results of laboratory tests (74%). The lack of a specific diagnostic test and the difficulty in convincing the family about the benefits of an elimination diet and follow-up represented the major obstacles to diagnosis of CMPA.
Lastly, since it can be helpful in the selection of intervention methods for improving the treatment adherence, we asked the physicians about their opinions on the main obstacles in treating CMPA in clinical practice. The pediatricians indicated that main obstacles in treating CMPA in clinical practice were intolerability or incorrect use of the formula, dislike of its flavor and odor, and parents not being able to implement elimination diet [Figure 2].
Discussion Non-adherence is higher with long-term versus short-term treatment regimens with an adherence rate of only 50–55% reported for long-term treatments in pediatric population. Non-adherence to the treatment can negatively influence the health of the patient and overall cost of the treatment and even the results of clinical trials. In addition, studies of the adherence with treatment in pediatric population differ from that in adults because of sharing the responsibility of adherence with the parents. Furthermore, the problem of non-adherence in pediatric population is more complicated because of timing and supply of the medications and solid foods, developmental constraints, nutritional habits, and influence of family members.
CMPA is the most prevalent nutritional allergy in infants and children under 3 years of age with an overall prevalence ranging from 1.9% to 4.9% among children in cohort studies and several meta-analyses.,,, In our study, a higher rate of 7.3% is perceived for the frequency of CMPA in Turkey with a mean age at diagnosis being 5.9 months. This may reflect the greater awareness of physicians about CMPA in children and particularly in suspected cases or the over-diagnosis of the CMPA in children with nonspecific symptoms. Based on the physician opinions, adherence to treatment is estimated to be 65.7% among children with CMPA in Turkey which is slightly higher from the adherence rate of 50–55% reported for long-term treatments in pediatric population.
Physicians report that, of the CMPA-diagnosed children, 81.8% starts on an elimination diet and 62.9% receives CMPA-specific enteral nutrition. On the other hand, 55.4% and 29.3% of the patients are treated with an AAF and an eHF with the tolerability rates of 77.4% and 77.2%, respectively while applying an elimination diet to the remaining patients. The relatively high tolerability of formulae may be due to the simplicity of the treatment for CMPA. Tolerability has been suggested to be inversely associated with the complexity of treatment regimen with increasing adherence rates reported with decreasing number of treatments.
In terms of patient-related factors, CMPA severity and the existence of underlying morbidities (e.g. multiple nutritional allergy, anaphylaxis, or enteropathy) were most strongly associated factors with treatment adherence based on the opinion of the physicians. As mentioned above, multiple treatment regimens may decrease the adherence rates to CMPA treatment because of the complexity of the treatment resulting in forgetting or confusing the formulae. On the other hand, one can assume that adherence rates would be higher in patients with more frequent and severe symptoms. However, there are contradictive results in the literature about the association between disease severity and treatment adherence in pediatric populations with some studies reporting lower adherence rates seen in children with higher disease severity , and others reporting higher adherence rates with increasing disease severity. Because the disease severity acknowledged by patient and/or family members may be more strongly associated with the adherence than that of the physician, the stronger association of CMPA severity with treatment adherence may be resulted from the greater efforts of the pediatricians to tell the family the benefits of the treatment. It is important to tell the potential risks and negative outcomes of the disease in detail to the parents who have the major role in the treatment of children.
Among family-related factors, the education level of the family and their confidence in the treatment modality were scored by the physicians as the most strongly associated factors with treatment adherence. Lower socioeconomic status and particularly the lower parental education level were found to be associated with treatment non-adherence in children with chronic illnesses., In a study on children with celiac disease, when the parents had a higher level of education and informed adequately about the disease, they were more distressed about the adverse effects of the treatment. Moreover, the education of patients in groups has been shown to increase treatment adherence among patients with osteoporosis. The factors associated with treatment adherence can be divided as modifiable such as nutritional habits, confidence in treatment and several product-related factors that can be used to improve the adherence and as unmodifiable such as disease severity, educational level, and income level that may be only useful in identifying at-risk patients. On the other hand, increased perception and confidence of the family about the efficacy of the treatment have been associated with higher adherence rates for several chronic diseases in children., Because parents are those responsible for the consistency of treatment in CMPA, if they do not believe in the benefits of the treatment, the regimen will most likely be discontinued. Therefore, parents should be clearly informed about the efficacy and limitations of their treatment. However, according to the results of present study, approximately 45 patients are examined by pediatricians per day which means that a pediatrician can spent only 10–15 min for a patient. Hence, it will be more feasible to instruct the patients in groups rather than individually which will make possible to explain the parents the details of treatment modality including the duration, dose, and benefits of the treatment adequately in an attempt to increase the treatment adherence.
Regarding product-related factors, product taste and/or aroma were the main factors for treatment adherence with formula choice (amino acid-based or extensively hydrolyzed) being another strongly associated factor with adherence to the CMPA treatment. Tastes of the different types of formulas including cow’s milk, AAF, and eHF differ vastly. In fact, until the age of 18–24 months, children prefer the products without any aroma whereas they prefer a variety of aromas in the products or recipes thereafter. Breast-feeding infants may initially reject the different taste of the formulae, however they can begin to consume different flavors over time.
The pediatricians included in this study reported that CMPA was mostly diagnosed based on physical examination (96%), medical history (94%), and the results of laboratory tests (74%). When an infant with symptoms suggestive of CMPA is examined in the clinic, a differential diagnosis including family/medical history and physical examination is needed. Although physical examination and medical history usually indicate and an elimination diet confirms the diagnosis of CMPA, laboratory tests may be also needed for an accurate diagnosis in these children. However, the laboratory tests including specific IgE testing and atopy patch test have limited role in confirming the diagnosis of CMPA., In this context, pediatricians suggested that the major obstacles to the diagnosis of CMPA are the lack of a specific diagnostic test and the difficulty in convincing the family about the benefits of an elimination diet and follow-up.The pediatricians also indicated that main reasons for non-adherence to CMPA treatment are the low tolerability, incorrect use of the formula, and dislike of its taste and odor in general. In order to select an effective intervention method for improving the treatment adherence, pediatricians should know the degree and reasons of the non-adherence. For the patients with major adherence problems, a greater effort is needed to improve the adherence. On the other hand, reasons of the non-adherence will determine the type of intervention needed which includes parental education, organizational interventions such as simplifying the treatment regimen, or improving physician-family communication and/or behavioral interventions., Frequent outpatient visits may help to increase the treatment adherence and enable the pediatrician to learn the major treatment-related problems encountered at home-based setting. On the other hand, emerging technologies such as the Web and hand-held devices such as cell phones and PDAs can also be used to improve the adherence. These technological interventions offer some advantages such as making possible accessing the adherence interventions from home at any time and making the family more attractive about adherence interventions, they also have a cost to develop and use, and development of them necessitates a multidisciplinary team including a variety of health-care professionals other than pediatricians., Because the time spent on cell phones is very high in Turkey, particularly in some geographical regions and urban areas, mobile phone applications and text message reminders may be also effective in improving the adherence among children with CMPA.
| Conclusion|| |
In conclusion, the pediatricians from Turkey reported that the frequency of CMPA and non-adherence rates to the CMPA treatment are slightly higher in Turkey. They thought that the adherence to CMPA treatment is associated with low tolerability, incorrect use of the formula, and dislike of its taste and odor which should be kept in mind in determining the individual intervention method needed to improve the treatment adherence among these children.
Ethics approval and consent to participate
The authors state that they have obtained appropriate institutional review board approval from ethics committee of Bahcesehir University Medicine Faculty, Turkey.
Consent for Publication
Consent for publication is present and included in the ethics approval package.
Availability of Data and Materials
The dataset supporting the conclusions of this article is included within the manuscript.
This study was supported by Nutricia Advanced Medical Nutrition, Turkey. Feza Kirbiyik, Ali Evrim Dogan, and Anil Aksit are employees of Nutricia Advanced Medical Nutrition, Medical Department, Turkey.
Financial support and sponsorship
Conflicts of interest
The authors declare that there is no conflict of interest.
Fatih Ozdener contributed to conception and design, acquisition of data, analysis, interpretation, and drafting the article. Feza Kirbiyik, Ali Evrim Dogan, Arzu Baygul, and Nermin Guler contributed to the conception and design, acquisition of data, analysis, interpretation, and revising it critically for important intellectual content. CAAAD study group* investigators contributed to acquisition of data and interpretation. All authors read and agreed the final version to be submitted.
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[Figure 1], [Figure 2]