Expert panel on practice patterns in the management of cow’s milk protein allergy and associated economic burden of disease on health service in Turkey

Abstract

Aims: To evaluate practice patterns in the management of cow’s milk protein allergy (CMPA) and associated economic burden of disease on health service in Turkey.

Materials and methods: This study was based on experts’ views on the practice patterns in management of CMPA manifesting with either proctocolitis or eczema symptoms and, thereby, aimed to estimate economic burden of CMPA. Practice patterns were determined via patient flow charts developed by experts using the modified Delphi method for CMPA presented with proctocolitis and eczema. Per patient total 2-year direct medical costs were calculated, including cost items of physician visits, laboratory tests, and treatment.

Results: According to the consensus opinion of experts, 2-year total direct medical cost from a payer perspective and societal perspective was calculated to be $US2,116.05 and $US2,435.84, respectively, in an infant with CMPA presenting with proctocolitis symptoms, and $US4,001.65 and $US4,828.90, respectively, in an infant with CMPA presenting with eczema symptoms. Clinical nutrition was the primary cost driver that accounted for 89–92% of 2-year total direct medical costs, while the highest total direct medical cost estimated from a payer perspective and societal perspective was noted for the management of an exclusively formula-fed infant presenting either with proctocolitis ($US3,743.85 and $US4,025.63, respectively) or eczema ($US6,854.10 and $US7,917.30, respectively). The first line use of amino acid based formula (AAF) was associated with total direct cost increment $US1,848.08 and $US3,444.52 in the case of proctocolitis and eczema, respectively.

Limitations: Certain limitations to this study should be considered. First, being focused only on direct costs, the lack of data on indirect costs or intangible costs of illness seems to be a major limitation of the present study, which likely results in a downward bias in the estimates of the economic cost of CMPA. Second, given the limited number of studies concerning epidemiology and practice patterns in CMPA in Turkey, use of expert clinical opinion of the panel members rather than real-life data on practice patterns that were used to identify direct medical costs might raise a concern with the validity and reliability of the data. Also, while this was a three-step study with six experts included in the first stage (developing local guidelines for diagnosis, treatment, and follow-up of infants with CMPA in Turkey) and 410 pediatricians included in the second stage (a cross-sectional questionnaire-survey to determine pediatricians’ awareness and practice of CMPA in infants and children), only four members were included in the present Delphi panel, which allows a limited discussion. Third, lack of sensitivity analyses and exclusion of indirect costs and costs related to alterations in quality of life, behavior of infants, and general well-being of infants and their parents from the cost-analysis seems to be another limitation that may have caused under-estimation of relative cost-effectiveness of the formulae. Fourth, calculation of costs per local guidelines rather than real-life practice patterns is another limitation that, otherwise, would extend the knowledge achieved in the current study. Notwithstanding these limitations, the present expert panel provided practice patterns in the management of CMPA and an estimate of the associated costs, depending on the symptom profile at initial admission for the first time in Turkey.

Conclusions: In conclusion, in providing the first health economic data on CMPA in Turkey, the findings revealed that CMPA imposes a substantial burden on the Turkish healthcare system from both a payer perspective and societal perspective, and indicated clinical nutrition as a primary cost driver. Management of infants presenting with eczema, exclusively formula-fed infants, and first line use of AAF were associated with higher estimates for 2-year direct medical costs.

Keywords:

• Cow’s milk protein allergy
• practice patterns
• proctocolitis
• eczema
• cost-analysis
• expert panel
• Turkey

Introduction

Cow’s milk protein allergy (CMPA) is a clinically abnormal immune reaction to cow’s milk protein (CMP)¹. CMPA presents with food protein-induced proctocolitis, food protein-induced enterocolitis, enteropathy and eosinophilic disorders, atopy with or without atopic eczema, and allergic rhinitis and/or asthma, depending on the type of (i.e. immediate, delayed, or mixed) immune reaction^2,3.

Diagnosis is based on detailed history taking and medical examination, followed by an elimination diet, and is confirmed by a standardized oral challenge test or double blind placebo controlled food challenge (DBPCFC) after documentation of significant improvement on the diagnostic elimination, which leads to a definitive diagnosis as well as symptomatic treatment plan^2,4,5. An appropriate diagnostic approach is crucial to minimize the risk for both over- and under-diagnosis, and to enable the introduction of an appropriate diet and, thus, maintenance of normal growth and development^5,6.

Awareness of CMPA, alongside appropriate diagnosis and management, is important, given that CMPA poses a considerable burden on patients and their families, and a substantial economic burden on the health service^7,8.

Although evidence-based guidelines and consensus reports on the diagnosis and management of CMPA are available^{1,3,5,7,9–11}, there is a need for region-specific recommendations considering local experiences and challenges for the prevention, diagnosis, and treatment of CMPA in Turkey⁴.

Accordingly, a three-step intervention study was designed, aiming to (a) develop local guidelines for diagnosis, treatment, and follow-up of infants with CMPA in Turkey, (b) determine pediatricians’ awareness and practice of CMPA in infants and children, and (c) determine expert panel-based practice patterns and related costs in management of CMPA in Turkey. Data on the first two steps are presented elsewhere⁴. This expert panel study was designed to identify daily practice patterns for the management of CMPA presenting either with proctocolitis or eczema symptoms and, thereby, to estimate the 2-year direct medical cost for the management of infants with CMPA from a payer perspective and societal perspective for the first time in Turkey.

Methods

Design

This expert panel study was aimed at identifying practice patterns in daily clinical practice and estimating 2-year total healthcare costs associated with the management of CMPA from public and societal perspectives in Turkey. Practice patterns in the diagnosis, treatment, and follow-up of CMPA in Turkey were determined based on consensus opinion of the expert panel selected from pediatric gastroenterology and pediatric allergy/immunology specialists with experience on CMPA management. Patient flow charts were developed by experts using a modified Delphi method¹² for two separate clinical presentations of a 2-month old pediatric patient with CMPA including proctocolitis and eczema, with respect to diagnosis, treatment, and follow-up of patients consistent with the current management algorithms applied in their daily clinical practice. Cost-analysis was performed with respect to the price of formula [average price, lowest price, and first-line amino acid based formula (AAF) prescription] and type of clinical nutrition (exclusively breast-fed, non-exclusively breast-fed, exclusively formula-fed) separately in cases presenting with proctocolitis or eczema.

Expert panel

A total of four experts from tertiary centers located in Ankara and Istanbul provinces were selected based on their clinical practice and scientific background. All experts were informed about the study via e-mail by the sponsor and then participated in the three consecutive meetings conducted between March 2015 and December 2015 for (a) developing local guidelines for diagnosis, treatment, and follow-up of infants with CMPA in Turkey, (b) reviewing findings from a cross-sectional questionnaire-survey conducted among 410 pediatricians in Turkey on pediatricians’ awareness and practice of CMPA in infants and children, and (c) determining a practice patterns algorithm for the management of CMPA, based on data collected from guideline development and physician survey stages of the study.

Accordingly, the present study included an analysis of economic burden of CMPA in Turkey, based on third expert panel meeting results on practice patterns algorithms for the management of an infant with CMPA presenting with proctocolitis or eczema.

Cost analysis

Per patient total 2-year direct medical costs were calculated based on cost items including physician visits (primary care, secondary care, tertiary care), laboratory tests (routine hemogram, blood biochemistry, serum, and stool immunology), and treatment (with respect to formula and clinical nutrition type), both from a payer perspective (only direct medical costs using prices of the imbursement authority “Social Security Institution (SSI)” in Turkey) and a societal perspective (only direct medical costs using resale prices). For drugs, retail prices from the updated price list and updated institution discount list of SSI for May 2016 were taken into account in calculation of the unit costs. Costs related to nutritional and other non-pharmacological treatments and tests were calculated considering the Health Implementation Notification by SSI, while nutritional treatment costs were calculated as weighted for weekly energy requirement and infant distribution percentage. Physician/dietician visit costs were calculated using unit prices, also based on the same SSI notification. The time horizon of analysis was 2 years. Monetary results were converted by using the 2.97 $US/TL May 2016 exchange rate.

Total direct medical costs were also calculated based on recommended clinical nutrition scenarios without being weighted for ongoing treatment percentage, while direct non-medical costs of different origin (e.g. transfers of patient and caregivers for examinations and/or hospitalization, home care, etc.) and indirect costs were not included in the cost analysis.

Statistical analysis

Descriptive statistics were used to summarize results on practice patterns for the CMPA management. Expenses related to diagnosis, treatment, and follow-up of CMPA were the main cost-analysis related parameters of the study. The cost model was based on the following equation:

Results

Physician visits cost item

According to expert panel consensus on practice pattern algorithms and unit costs, the 2-year cost of physician visits item was calculated to be $US165.58 in an infant presenting with proctocolitis, and to be $US157.44 in an infant presenting with proctocolitis, both from payer and societal perspectives (Table 1).

Table 1. Cost of physician visits recommended by expert panel in the management of an infant with CMPA presenting with proctocolitis or eczema.

Physician visits	Visit count^a		Unit cost (USD)	2-year cost (USD)^a
	Proctocolitis	Eczema		Payer perspective		Social perspective
				Proctocolitis	Eczema	Proctocolitis	Eczema
Primary care (Family physician, general practitioner)	1.0	1.0	6.73	6.73	6.73	6.73	6.73
Secondary care (General pediatrician)	1.0	2.0	8.02	8.02	16.04	8.02	16.04
Tertiary care (Pediatric gastroenterologist)	10.7^b	0.0	13.46	144.07	0.00	144.07	0.00
Tertiary care (Pediatric allergists)	0.5	8.0^b	13.46	6.73	107.72	6.73	107.72
Dietitian	0.0	2.0	6.73	0.00	13.47	0.00	13.47
Total physician visit cost (USD)				165.58	157.44	165.58	157.44

^a Weighted for the percentage of infants subjected for tolerance test and additional follow-up.

^b Tolerance test and additional follow-up for those failed to develop tolerance in 12 months.

Laboratory tests cost item

According to expert panel consensus on practice pattern algorithms and unit costs, the 2-year cost of laboratory tests item was calculated to be $US17.24 (from a payer perspective) and $US32.32 (from a societal perspective) in an infant presenting with proctocolitis, while it was $US103.43 and $US105.59, respectively, in an infant presenting with eczema (Table 2).

Table 2. Cost of laboratory tests recommended by expert panel in the management of an infant with CMPA presenting with proctocolitis or eczema.

Laboratory tests	Procedure count^a		Unit cost (USD)	2-year cost (USD)^a
	Proctocolitis	Eczema		Payer perspective		Social perspective
				Proctocolitis	Eczema	Proctocolitis	Eczema
Serum alkaline phosphatase	1.0	2.0	0.37	0.00	0.00	0.37	0.74
Serum phosphorus	0.5	3.0	20.20	0.00	0.00	0.34	0.67
Serum calcium	1.0	2.0	0.34	0.00	0.00	0.37	0.74
Skin tests	1.0	2.0	0.37	10.10	60.61	10.10	60.61
Serum specific IgE	0.5	3.0	14.28	7.14	42.83	7.14	42.83
Complete blood count	2.0	NA	1.01	0.00	NA	2.02	NA
Stool culture	1.0	NA	1.01	0.00	NA	1.01	NA
Stool pH	2.0	NA	0.44	0.00	NA	0.88	NA
Stool microscopy	3.0	NA	1.72	0.00	NA	5.15	NA
Fecal occult blood test	3.0	NA	1.18	0.00	NA	3.54	NA
Fecal reducing substances test	2.0	NA	0.34	0.00	NA	0.67	NA
Fecal fat test	1.0	NA	0.74	0.00	NA	0.74	NA
Total laboratory tests cost (USD)				17.24	103.43	32.32	105.59

IgE, immunoglobulin E; NA, not applicable.

^a Weighted for the percentage of infants subjected to the procedure.

Direct medical costs with respect to formula prices

Unit cost of formulae (cost per kcal) calculated based on average formula prices, as weighted for weekly energy requirement and infant distribution percentage, were $US0.010/kcal and $US0.011/kcal for extensively hydrolyzed formula (eHF), while they were $US0.016/kcal and $US0.021/kcal for aminoacid based formula (AAF) from payer and societal perspectives, respectively (Table 3).

Table 3. Unit cost (per kcal) of formulae used for calculation of clinical nutrition cost item.

	Total kcal per package	Payer perspective		Societal perspective
		Price ($US)	Cost per kcal ($US)*	Price ($US)	Cost per kcal ($US)*
Extensively hydrolyzed formula (eHF)
Similac Alimentum	2,100	23.62	0.011	26.54	0.013
Bebelac Pepti Junior	2,259	19.84	0.009	22.29	0.010
Lowest price			0.009		0.010
Average price			0.010		0.011
Aminoacid based formula (AAF)
Aptamil pregomin AS	2,000	35.11	0.018	50.16	0.025
Neocate	1,932	29.4	0.015	33.37	0.017
Lowest price			0.015		0.017
Average price			0.016		0.021

* Cost per kcal values are rounded to three decimals.

In an infant with CMPA presenting with proctocolitis, 2-year total direct medical costs from payer and societal perspectives were $US2,116.05 (treatment items costed $US1,933.23) and $US2,435.84 (treatment item costed $US2,237.94), respectively, based on average formula prices, whereas they were $US3,302.72 (treatment items costed $US3,119.90) and $US4,283.92 (treatment item costed $US4,086.02), respectively, based on first line use of AAF. As compared with average formula prices, first line use of AAF was associated with incremental total direct medical costs of $US1,186.67 and $US1,848.08 from payer and societal perspectives, respectively (Table 4).

Table 4. The 2-year total direct medical costs related to management of an infant with CMPA presenting with proctocolitis with respect to formula prices

	Cost-payer perspective ($US)			Cost-societal perspective ($US)
	Year-1	Year-2^a	Total	Year-1	Year-2^a	Total
Physician visits	161.54	4.04	165.58	161.54	4.04	165.58
Laboratory tests	17.24	0.00	17.24	32.32	0.00	32.32
Treatments
Average formula prices	1,348.04	585.19	1,933.23	1,572.45	665.49	2,237.94
Lowest formula prices	1,184.11	514.97	1,699.07	1,382.72	581.29	1,964.01
First line use of AAF	2,183.63	936.27	3,119.90	2,873.77	1,212.26	4,086.02
Total
Average formula prices	1,526.82	589.23	2,116.05	1,766.31	669.53	2,435.84
Lowest formula prices	1,362.89	519.01	1,881.89	1,576.58	585.33	2,161.91
First line use of AAF	2,362.41	940.31	3,302.72	3,067.63	1,216.30	4,283.92
Incremental cost^b	835.59	351.08	1,186.67	1,301.32	546.77	1,848.08

Costs are weighted for the percentage of infants who are exclusively breast-fed or breast-fed and formula combination, or exclusively formula fed.

^a After the 12 month control visit, symptoms were considered to persist in 15% of infants.

^b Incremental cost: difference between first line use of AAF and average formula prices.

In an infant with CMPA presenting with eczema, 2-year total direct medical costs from payer and societal perspectives were $US4,001.65 (treatment items costed $US3,698.20) and $US4,828.90 (treatment item costed $US4,291.51), respectively, based on average formula prices, whereas they were $US6,213.41 (treatment items costed $US5,909.96) and $US8,273.42 (treatment item costed $US7,736.03), respectively, based on first line use of AAF. As compared with average formula prices, first line use of AAF was associated with incremental total direct medical costs of $US2,211.76 and $US3,444.52 from payer and societal perspectives, respectively (Table 5).

Table 5. The 2-year total direct medical costs related to management of an infant with CMPA presenting with eczema with respect to formula prices.

	Cost-payer perspective ($US)			Cost-societal perspective ($US)
	Year-1	Year-2^a	Total	Year-1	Year-2^a	Total
Physician visits	117.04	40.40	157.44	117.04	40.40	157.44
Laboratory tests	36.94	66.49	103.43	37.71	67.88	105.59
Treatments
Average formula prices	1,348.04	2,350.16	3,698.20	1,572.45	2,719.06	4,291.51
Lowest formula prices	1,186.59	2,084.26	3,270.85	1,391.00	2,420.23	3,811.23
First line use of AAF	2,183.63	3,726.33	5,909.96	2,873.77	4,862.27	7,736.03
Others^b	23.65	18.92	42.58	152.42	121.94	274.36
Total
Average formula prices	1,525.67	2,475.97	4,001.65	1,879.62	2,949.28	4,828.90
Lowest formula prices	1,364.22	2,210.07	3,574.30	1,698.17	2,650.45	4,348.62
First line use of AAF	2,361.26	3,852.14	6,213.41	3,180.94	5,092.49	8,273.42
Incremental cost^c	835.59	1,376.17	2,211.76	1,301.32	2,143.21	3,444.52

Costs are weighted for the percentage of infants who are exclusively breast-fed, non-exclusively breast-fed, or exclusively formula fed.

^a After the 12 month control visit, symptoms were considered to persist in 80% of infants.

^b Other treatments included mometasone furoate, moisturizing cream, and baby cleansing products.

^c Incremental cost: difference between first line use of AAF and average formula prices.

Direct medical costs with respect to clinical nutrition recommendations

In an infant with CMPA presenting with proctocolitis, 2-year total direct medical costs from payer and societal perspectives were $US501.68 (treatment item costed $US318.87) and $US707.82 (treatment item costed $US509.92), respectively, in an exclusively breast-fed infant, $US1,963.33 (treatment item costed $US1,780.52) and $US2,289.31 (treatment item costed $US2,091.41), respectively, in a non-exclusively breast-fed infant, and $US3,743.85 (treatment item costed $US3,561.04) and $US4,025.63 (treatment item costed $US3,827.73), respectively, in an exclusively formula-fed infant (Table 6).

Table 6. The 2-year total direct medical costs related to management of an infant with CMPA presenting with proctocolitis with respect to expert panel clinical nutrition recommendations.

	Cost-payer perspective ($US)			Cost-societal perspective ($US)
	Year-1	Year-2^a	Total	Year-1	Year-2^a	Total
Physician visits	161.54	4.04	165.58	161.54	4.04	165.58
Laboratory tests	17.24	0.00	17.24	32.32	0.00	32.32
Treatments
Exclusively breast-fed	0.00	318.87	318.87	66.03	443.89	509.92
Non-exclusively breast-fed	1,416.87	363.65	1,780.52	1,664.79	426.62	2,091.41
Exclusively formula-fed	2,833.74	727.30	3,561.04	3,003.66	824.07	3,827.73
Total
Exclusively breast-fed	178.77	322.91	501.68	259.89	447.93	707.82
Non-exclusively breast-fed	1,595.64	367.69	1,963.33	1,858.65	430.66	2,289.31
Exclusively formula-fed	3,012.52	731.34	3,743.85	3,197.52	828.11	4,025.63

Calculated based on recommended clinical nutrition without being weighted for ongoing treatment percentage.

^a After the 12 month control visit, symptoms were considered to persist in 15% of infants.

In an infant with CMPA presenting with eczema, 2-year total direct medical costs from payer and societal perspectives were $US588.82 (treatment item costed $US284.77) and $US1,009.26 (treatment item costed $US471.87), respectively, in an exclusively breast-fed infant, $US3,355.54 (treatment item costed $US3,052.09) and $US4,139.07 (treatment item costed $US3,601.68), respectively, in a non-exclusively breast-fed infant, and $US6,854.10 (treatment item costed $US6,550.65) and $US7,917.31 (treatment item costed $US7,379.92), respectively, in an exclusively formula-fed infant. The contribution of non-nutritional treatments including mometasone furoate, moisturizing cream, and baby cleansing products to total direct cost was $US42.58 and $US274.36 from payers and societal perspectives, respectively (Table 7).

Table 7. The 2-year total direct medical costs related to management of an infant with CMPA presenting with eczema with respect to expert panel clinical nutrition recommendations.

	Cost-payer perspective ($US)			Cost-societal perspective ($US)
	Year-1	Year-2^a	Total	Year-1	Year-2^a	Total
Physician visits	117.04	40.40	157.44	117.04	40.40	157.44
Laboratory tests	36.94	66.49	103.43	37.71	67.88	105.59
Treatments
Exclusively breast-fed	0.00	284.77	284.77	66.03	405.84	471.87
Non-exclusively breast-fed	1,264.37	1,787.72	3,052.09	1,494.60	2,107.08	3,601.68
Exclusively formula-fed	2,528.74	4,021.91	6,550.65	2,857.15	4,522.76	7,379.92
Others^b	23.65	18.92	42.58	152.42	121.94	274.36
Total
Exclusively breast-fed	177.63	410.58	588.22	373.20	636.06	1,009.26
Non-exclusively breast-fed	1,442.00	1,913.53	3,355.54	1,801.77	2,337.30	4,139.07
Exclusively formula-fed	2,706.37	4,147.72	6,854.10	3,164.32	4,752.98	7,917.31

Calculated based on recommended clinical nutrition without being weighted for ongoing treatment percentage.

^a After the 12 month control visit, symptoms were considered to persist in 80% of infants.

^b Other treatments included mometasone furoate, moisturizing cream, and baby cleansing products.

Discussion

Being the first health economic study on CMPA in Turkey, our findings revealed the considerable economic burden of CMPA in an infant presenting with proctocolitis ($US2,116.05 from a payer perspective and $US2,435.84 from a societal perspective) or eczema ($US4,001.65 from a payer perspective and $4,828.90 from a societal perspective), based on average formula prices in Turkey. Management of CMPA in an infant presenting with eczema as compared with proctocolitis was associated with higher 2-year total direct medical costs in terms of average formula prices and nutritional treatment recommendations.

Our findings revealed a high economic burden of CMPA on health economics in Turkey. This seems to be in agreement with data from past studies which indicated an association of CMPA with an estimated 12-monthly healthcare cost of €11.28 million in The Netherlands¹³, 6-monthly cost of AU$6.5 million in Australia¹⁴, 12-montly cost of €202.0 (private sector) and €89.0 (public sector) in South Africa¹⁵, 12-monthly cost of £1,853 and £3,161 per patient in the eHF and AAF groups, respectively, in the UK¹⁶, and 12-monthly cost of £1,381 per patient and annual cost of £25.6 million in the Health Improvement Network (THIN) Database¹⁷.

Clinical nutrition preparations were the primary cost driver in our study that accounted for 89.0–92.0% of total 2-year direct medical costs, based on average formula prices. Likewise, clinical nutrition preparations were reported to account for 91% of the total 12-monthly cost in The Netherlands¹³, 62% of the total 6-monthly cost in the Australian database¹⁴, and 37% and 54% of total 12-monthly cost of managing patients with CMPA in the eHF and AAF groups, respectively in the UK¹⁶.

Managing an exclusively formula-fed infant presenting either with proctocolitis ($US3,743.85 from a payer perspective and $US4,025.63 from a societal perspective) or eczema ($US6,854.10 and $US7,917.31, respectively) was associated with the highest estimates of direct medical costs in our analysis.

Besides, when compared to average formula prices, use of AAF as a first-line treatment was associated with cost increments of $US1,186.67 (56.0%) from a paper perspective and $US1,848.08 (76.0%) from a societal perspective in proctocolitis, and cost increments of $US2,211.76 (55.0%) from a payer perspective and $US3,444.52 (71.0%) from a societal perspective in eczema groups. This seems consistent with past studies from Brazil, Spain, Italy, the UK, and the US, which indicated initial dietary management with an eHF instead of an AAF to afford more cost-effective use of healthcare resources in the management of CMPA^16,18–21.

The total incremental 12-monthly health service cost of starting treatment with an AAF instead of an eHF was estimated to be £1,308 in the UK¹⁶, while authors considered starting treatment with an eHF as the cost-effective strategy, given the similar clinical outcomes between two groups¹⁶. Additionally, the cost-effectiveness of an eHF relative to an AAF was reported to be very sensitive to the time to symptom resolution and the acquisition cost of the formulae, while it was less sensitive to the number of GP visits, outpatient visits, and hospital admissions¹⁶. Similarly, expected costs of managing CMPA in The Netherlands were reported to be most sensitive to the acquisition costs of eHF and AAF, whereas they were insensitive to changes in the number of physician visits¹³.

However, sensitivity analysis in the Australian CMPA database revealed a similar 6-monthly cost (AU$7.1 million) of prescribing first-line eHF or AAF, along with a reduced likelihood of follow-up visits to pediatric immunologists/allergists and pediatric gastroenterologists among infants prescribed with first-line AAF than eHF due to the lower probability of a need for switching diet in the former group¹⁴.

Cost-analysis for the physician visits item in the present study was based on expert consensus estimated visit numbers required up to (three visits for proctocolitis, two visits for eczema) and after consulting with a pediatric gastroenterologist or pediatric allergists/immunologists (11 visits for proctocolitis, sixvisits for eczema). This seems notable, given that analysis of the THIN database revealed a higher number of follow-up visits with a mean 14.0 general pediatrician visits (once in every 3 weeks) for CMA after the diagnosis and identified physician visits as the major cost driver (44%) followed by clinical nutrition (38%)¹⁷.

Notably, 60% of all infants were initially treated with soy, 18% with an eHF, and 3% with an AAF in the THIN CMPA database¹⁷, while the acquisition costs of the clinical nutrition preparations as well as soy intolerance were indicated to have an impact on expected costs in a study from South Africa, in which the primary cost driver in the management of CMPA was also reported to be physician visits¹⁵.

Hence, identification of clinical nutrition as the primary cost driver in our study might also be associated with the fact that soy is not considered amongst the recommended options for clinical nutrition for infants aged <6-months with CMPA in Turkey⁴.

The second-step of our study (presented elsewhere) was based on a questionnaire-survey conducted among 410 pediatricians in Turkey, and revealed that practice patterns in the management of exclusively breast-fed infants with CMPA were in accordance with the European Society of Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines⁵. Overall, 95.4% of physicians considered CMPA to be able to develop in an exclusively breast-fed infant, and 79.4% identified continuation of breast feeding via elimination of CMP containing products from the maternal diet to be the treatment of choice in this group. AAF was the most commonly selected formula by pediatricians for infants presenting with anaphylaxis (58.8%), enterocolitis (40.7%), or multiple food allergies (52.0%), and in at-risk infants with no chance of exclusive breastfeeding (40.2%). However, inappropriate practice patterns were noted among physicians considering the first-line treatment among non-exclusively breast-fed infants with use of AAF (45.8%) rather than eHF (23.2%). This seems notable, given the recommendation of eHF in this group^5,7,22,23, due to its lower cost and higher efficacy in inducing tolerance than AAF^16,24. Notably, pediatric gastroenterologists had more appropriate practice patterns in CMPA with respect to evidence-based therapeutic formula selection when compared to pediatric allergists/immunologists who had a higher tendency to prescribe AAF as a first-line treatment, possibly due to the higher likelihood of encountering cases with anaphylaxis than proctocolitis in their clinical practice.

It should also be noted that first line AAF was prescribed only in 20% of all newly-diagnosed infants with CMA aged <6 months, while the other 80% started treatment with an eHF in the THIN database¹⁶. Also, acquisition of eHF was reported to be the primary cost driver accounting for 72% of the total cost (ranged from €8.68–€14.21 million), while acquisition of AAF accounted for 19% of the total cost (ranged from €9.50–€19.84 million) in The Netherlands¹³.

Conversely, AAF regimens comprise ∼80% of the current formula market in Turkey, based largely on their safety, particularly in cases presenting with eczema, despite the fact that they should be reserved for those infants with eHF intolerance or failure or severe symptoms¹⁶. Given the cost increments associated with first-line use of AAF, the tendency for over-prescribing AAF among Turkish physicians seems to contribute to a high economic burden of disease on health economics, as well as higher direct medical costs associated with managing an infant presenting with eczema rather than proctocolitis symptoms. This emphasizes that practice patterns in use of formula-based therapy of infants with CPMA in clinical practice in Turkey should be improved in terms of compatibility with therapeutic indications specified for each formula.

Our findings are in agreement with data from other countries in terms of identification of clinical nutrition preparations as the key cost driver^13,14,16, as well as cost-effectiveness of using eHF rather than AAF as a first-line treatment^16,18–21. Nonetheless, it should be noted that, given the considerable heterogeneity in experiences from different countries regarding practice patterns in the management of CMPA including responsible clinicians, referral patterns, diagnostic and therapeutic strategies, comparison of findings between countries has been considered to be difficult¹⁷.

Certain limitations to this study should be considered. First, being focused only on direct costs, lack of data on indirect costs (loss of productivity due to the illness), or intangible costs of illness (costs of suffering for the patient and his/her family) seems to be the major limitation of the present study, which likely results in a downward bias in our estimates of the economic cost of CMPA. Second, given the limited number of studies concerning epidemiology and practice patterns in CMPA in Turkey, use of expert clinical opinion of the panel members rather than real-life data to obtain practice patterns that were used to identify direct medical costs might raise a concern with the validity and reliability of the data. Also, while this was a three-step study with six experts included in the first stage (developing local guidelines for diagnosis, treatment, and follow-up of infants with CMPA in Turkey) and 410 pediatricians included in the second stage (a cross-sectional questionnaire-survey to determine pediatricians’ awareness and practice of CMPA in infants and children), only four members were included in the present Delphi panel, which allows a limited discussion. Third, lack of sensitivity analyses and exclusion of indirect costs and costs related to alterations in quality-of-life, behavior of infants, and general well-being of infants and their parents from the cost-analysis seems to be another limitation which may have caused under-estimation of the relative cost-effectiveness of the formulae. Fourth, calculation of costs per local guidelines rather than real-life practice patterns is another limitation which otherwise would extend the knowledge achieved in the current study. Notwithstanding these limitations, the present expert panel provided practice patterns in the management of CMPA and an estimate of the associated costs, depending on the symptom profile at initial admission, for the first time in Turkey.

Conclusions

In conclusion, providing the first health economic data on CMPA in Turkey via expert consensus on practice patterns in management of CMPA, our findings revealed that CMPA imposes a substantial burden on the Turkish healthcare system from both a payer perspective and a societal perspective. Clinical nutrition was the primary cost driver; while remarkably higher costs were noted in the case of managing an exclusively formula-fed infant, as well as managing an infant presenting with eczema rather than proctocolitis symptoms. Along with a tendency for prescribing AAF rather than eHF as a first-line treatment in infants with CMPA among pediatricians, use of AAF as a first-line treatment was associated with a remarkable increase in the total cost.

Transparency

Declaration of funding

This study was supported by Abbott Nutrition Turkey. Abbott Nutrition Turkey did not have any role in the study design, data collection, analysis, and interpretation of data, or in the writing of the article and the decision to submit it for publication.

Declaration of financial/other relationships

OS is an Abbott employee. BES declares that he has no conflict of interest.

Acknowledgments

We thank Professor Aydan Kansu, MD, from Ankara University School of Medicine and Professor Buket Dalgic, MD, from Gazi University School of Medicine for their significant contributions to the identification of the management algorithms in an infant with CMPA in the daily clinical practice, which provided a basis for the present cost-analysis. We thank Cagla Ayhan, MD, and Professor Sule Oktay, MD, PhD, from KAPPA Consultancy Training Research Ltd, Istanbul, who provided editorial support, and Mehmet Berktas, MD, MICR, from KAPPA Consultancy Training Research Ltd, Istanbul, who performed modeling and pharmacoeconomic analysis funded by Abbott Nutrition Turkey.