Neglected Children with Cystic Fibrosis due to War (Turkey Profile of Refugee Patients)

doi:10.21203/rs.3.rs-3564095/v1

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Neglected Children with Cystic Fibrosis due to War (Turkey Profile of Refugee Patients)

https://doi.org/10.21203/rs.3.rs-3564095/v1

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published 24 Jan, 2024

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Introduction: Since the outbreak of the Syrian civil war in 2011, the population of Arab refugees in Turkey has rapidly increased. While cystic fibrosis (CF) is believed to be rare among Arabs, recent studies suggest it is underdiagnosed. This study aims to present the demographic, clinical, and genetic characteristics of CF patients among Arab refugees in Turkey. Additionally, a comparison is made between the findings in the National CF Registry 2021 in Turkey (NCFRT) and the refugee CF patient group.

Materials and Methods: The study included refugee patients between the ages of 0 and 18 years who were diagnosed with CF and received ongoing care at pediatric pulmonology centers from March 2011 to March 2021. The study examined demographic information, age at diagnosis, age of diagnosis of patients through CF newborn screening (NBS), presenting symptoms, CFTR mutation test results, sputum culture results, weight, height, and body mass index (BMI) z score. Their results were compared with the NCFRT results.

Results: The study included 14 pediatric pulmonology centers and 87 patients, consisting of 46 (52.9%) boys and 41 (47.1%) girls. All of the patients were Arab refugees, with 80 (92%) being Syrian. The median age at diagnosis of patients was 22.33 (1-258) months. The median age of diagnosis of patients through NBS was 4.2 (1–12) months. Parental consanguinity was observed in 52 (59.7%) patients. The most frequently found mutation (22.2%) was F508del, found in 32 out of 144 alleles. There was a large number of genetic variations. Compared to NCFRT, refugee patients were diagnosed later and long-term follow-up of refugee CF patients had significantly worse nutritional status and pseudomonas colonization.

Discussion: Although refugee CF patients have equal access to NBS programs and CF medications as well as Turkish patients, the median age at diagnosis of patients, the median age of diagnosis of patients through NBS, their nutritional status, and Pseudomonas colonization were significantly worse than Turkish patients, which may be related to the difficulties of living in another country and poor living conditions. The high genetic heterogeneity and rare mutations detected in the refugee patient group compared to Turkish patients. Well-programmed NBS programs, thorough genetic studies, and the enhancement of living conditions for refugee patients in the countries they relocate to can have several advantages such as early detection and improved prognosis.

children

cystic fibrosis

refugee

war

Cystic fibrosis (CF) is an autosomal recessive chronic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The CFTR protein affects the ion channel function on the apical surface of epithelial cells, causing a change in mucus rheology and producing mucus with a thick sticky consistency that is difficult to clear. This leads to obstruction in the channels, and high susceptibility to infections develops. CF is distributed worldwide and is most common (1 in 2500 Caucasians) in Northern Europeans and 1 in 2270 Ashkenazi Jews [1]. CF has been included in the newborn screening (NBS) program in Turkey since January 1st, 2015. It is thought to be rare in the Arab population, but its exact prevalence is not known. In Arabs, CF is often not properly diagnosed because the symptoms resemble those of malnutrition, which is common in societies with low socioeconomic status. Furthermore, the occurrence of CF may be higher in this population due to the high rate of consanguinity.

One of the most important problems today is regional wars and pandemics. The number of refugees, who constitute a minority in Turkey, has witnessed a rapid increase following the onset of the civil war in neighboring Syria in 2011. Millions of adults, children, and older individuals have migrated, particularly to neighboring countries, such as Turkey, Lebanon, Jordan, Iraq, and Egypt. It has now been 13 years since the political crisis began in Syria. As stated in the 2023 report by the United Nations Refugee Agency (UNHCR), 64.5% of Syrian refugees are currently residing in Turkey. Unfortunately, 51% of these refugees are minors aged under 18 years [2]. Challenges related to vaccination, protection against infectious diseases, and the psychological impact of war make children the most vulnerable group in times of conflict. Children with chronic diseases need to be able to access and administer their medicines on time because this has an impact on their life expectancy. The Turkish Government has been addressing the fundamental requirements of refugees, which include housing, healthcare, and food. All newborn refugees have benefited from the NBS program that was implemented in Turkey. These patients can be examined free of charge in health institutions and have access to medical treatment. The Turkish Disaster and Emergency Management Presidency offers assistance for regular education and basic daily necessities. Although there is a minority group residing in tent cities, the majority of refugees prefer to settle in areas near the Syrian border and in major cities [3, 4].

This study aimed to present the demographic, clinical, and genetic characteristics of refugee patients with CF in Turkey. To understand the problems experienced by refugee patients (access to health resources, medication, and how their clinical status is affected in this process), we also compared the results in the National CF Registry in Turkey 2021 (NCFRT) report [5–6].

Data collection/patient population

This was a retrospective, multicentre study. The study included refugee children aged 0–18 years with CF who were monitored in pediatric chest disease clinics in Turkey from March 2011 to March 2021. All pediatric CF centers were invited to participate in the study, covering various regions of Turkey (with a focus on Gaziantep, Şanlıurfa, and Istanbul) that had the highest number of refugee patients. Patient information was electronically scanned from patient files. The study examined demographic information, age at diagnosis, age at diagnosis after NBS implementation in Turkey, symptoms at presentation, results of CFTR mutation tests, results of sputum cultures, weight, height, body mass index (BMI) z scores (for ages 2–18 years) calculated using the World Health Organization software (specifically the January 2011 anthropometric calculator). The findings of the CFTR and Multiplex ligation-induced probe amplification (MLPA) analysis for the patients were noted. The protocol used for CF screening in NBS in Turkey is immunoreactive trypsinogen (IRT)/IRT.

Definitions

According to the Geneva Refugee Convention, a refugee is defined as an individual who has a well-founded fear of persecution based on their race, religion, nationality, membership in a particular social group, or political opinion. This fear leads them to leave their country and either not return or not want to return due to this fear [1, 7]. The status of being a refugee is recognized under the law, and Turkey became a signatory to this convention in 1961. However, immigrants and asylum-seekers were not considered in the study.

Patients who were diagnosed as having CF according to the consensus report created by the American Cystic Fibrosis Foundation were included in the study. It has been stated that if one or more typical CF findings are present, along with a history of a sibling with CF or a positive newborn screening, CF can be diagnosed by demonstrating CFTR anomalies under laboratory conditions. This can be done by observing an increased chloride concentration in sweat tests, two mutations in the CFTR gene, or abnormal nasal epithelial ion transport. The most commonly known mutation is F508del [8]. Approval was obtained from the Necmettin Erbakan University Faculty of Medicine Ethics Committee (2021/3502).

Statistical analysis

Analyses were performed using the SPSS 25.0 package program. The variables were investigated using visual (histogram, probability plots) and analytic methods. The Kolmogorov–Smirnov/Shapiro–Wilk test was used to determine whether data were normally distributed. Descriptive analyses are presented using proportions, means, and standard deviation (SD), medians, minimum, and maximum values as appropriate. In the study, a one-sample t-test was used to analyze the difference between the measurement values of the two groups. Chi-square test analysis was used for proportional comparisons. In the study, p-values less than 0.05 were considered statistically significant.

A total of 87 patients from 14 CF centers participated in the study. Out of these, 46 (52.9%) were boys and 41 (47.1%) were girls. All of the patients were Arab refugees, and 80 (92%) were Syrian nationals. The median age at diagnosis was 22.33 (range, 0.7–258) months. Thirty-one (35.6%) refugee patients were born after 2015 and all were diagnosed through the NBS. The median age of diagnosis of patients through NBS was 4.2 (range, 1–12) months. When looking at the admission symptoms, 32 (34.4%) had recurrent lower respiratory tract infections, eight (9.1%) had growth retardation, eight (9.1%) had pseudo-Bartter's syndrome, and eight (9.1%) had meconium ileus. Parental consanguinity was present in 52 (59.7%) patients. Additionally, 23 (26.4%) had a sibling with a history of CF. Pancreatic insufficiency was present in 77% of patients. The mean initial immunoreactive trypsinogen (IRT) value of patients who came from the NBS was 155.21 ± 52.58 (minimum = 87, maximum = 280) ng/mL, and the second mean IRT value detected was 132.09 ± 51.51 (minimum = 70, maximum = 273) ng/mL. The mean sweat test in patients with chloride demonstrated results of 85.09 ± 25.18 (minimum = 6, maximum = 147) mmol/L. The median follow-up period was 46.6 (range, 2.5–82) months. Table 1 provides further demographic and clinic information.

Table 1

Demographic and clinic information of the refugee patients
	Refugee patients (n = 87)
Males n (%)	46 (52.9)
Famales n (%)	41 (47.1)
Median age at diagnosis (months)	22.33 (0.7–258)
Median current age (months)	66,7 (4-252)
Median follow-up period (months)	46.6 (2.5–82)
Number of patients diagnosed through NBS n (%)	31 (35.6)
Median age at diagnosis of patients through NBS (months)	4.2 (1–12)
Parental consanguinity n (%)	52 (59.7)
Pancreatic insufficiency n (%)	77 (88,5)
The initial IRT value ng/mL	155.21 ± 52.58
Second IRT value ng/mL	132.09 ± 51.51
The mean sweat test mmol/L	85.09 ± 25.18
Staphylococcus aureus colonization (MSSA + MRSA) n (%)	25 (29,2)
Pseudomonas aeruginosa colonization n (%)	32 (36,8)
rhDNaz n (%)	58 (66,7)
Pancreatic enzyme n (%)	76 (87,5)
Multivitamin n (%)	77 (88,5)
IRT: immunoreactive trypsinogen, NBS: newborn screening, MSSA: Methycilline Sensitive Staphylococcus Aureus, MRSA: Methycilline Resistance Staphylococcus Aureus

The mean vitamin D level was measured at 24.5 ± 3.1 (range, 3-51.2) nmol/L in the patients. The mean height, weight, and BMI score follow-ups of the patients at the time of admission and their last visit are presented in Table 2.

Table 2

The height, weight, and body mass index (BMI) score follow-ups of the refugee patients at the time of admission and at their last visit
z score	First Admission	Last control
Mean weight (min, max.)	-1.65 ± 1.85 (-6.22, 3.51)	-1.8 ± 1.6 (-5.7, 1.36)
Mean height (min, max.)	− 0.13 ± 4.2 (-5.75, 12.92	-1.7 ± 1.5 (-4.6, 1.9)
Body mass index (min, max.)	-1.26 ± 1.95 (-5.15, 4.75)	-0.4 ± 4.4 (-3.5, 18.9)
min: minimum, max: maximum

A total of 41 different variants were found. Homozygous mutations were found in 59 patients. The most commonly found variant, F508del, accounted for 22.2% of the total alleles (32 out of 144). There was a total of 20 patients identified as heterozygous and homozygous for this mutation. The second most common mutation was CFTRdel2-3, which accounted for seven cases (9.7%) (four of whom were siblings), and CFTRdel12-18 was found in one patient. Other variants that were detected included 2043delG, R352Q, 1677delTA, N1303K, L997F, I175V, S1118F, S1235R, 2184delA, 3121-1G > A, CFTRdel12-18, R352Q, Y1424Y, 2043delG, and I506V. Y1424Y and c.1911del variants were not found in NCFRT but were only detected in the refugee patient group. CFTR genotyping could not be conducted for 12 patients. These patients had high sweat tests and their genetic mutations could not be determined due to a lack of data. The most frequently occurring genetic variants are presented in Table 3.

Table 3

The most common frequency occurrence of genetic variants in refugee patients
	Heterozygous gene variant n (%)	Homozygous gene variant n (%)	Total n (%)
F508del	8 (10,6)	12 (16)	20 (22.2)
Exon 2–3 deletion	0	7 (9,3)	7 (9,7)
1898 + 3A- >G	2 (2,6)	3 (4)	5 (5,5)
W1282X	2 (2,6)	2 (2,6)	4 (4,1)
2183AA->G	0	3 (4,1)	3 (4,1)
c.1911del	0	3(4)	3 (4,1)

A comparison of demographic characteristics, the most common two mutations in CFTR, and the treatments used between refugees and NCFRT are given in Table 4.

Table 4

Comparison of refugee patients and NCFRT
	Refugee patiens n = 87	NCFRT n = 1948	P value
Median age at diagnosis (months) ***	22.33 (1-258)	3 (0.9–492)	0.01*
Median current age (months) ***	66,7 (4-252)	100 (0.9–552)	0.01*
Median age of patients diagnosed through NBS (months) ***	4.2 (0.7–18)	1 (0.9-3)	0.01*
Median weight (z score) ***	-1.8 (-5.7, 1.36)	-0.82 (-8.19-6,17)	0.01*
Median height (z score) ***	-1.7 (-4.6, 1.9)	-0.74 (-8.14-6)	0.01*
Body mass index (z score) ***	-0.4 (-3.5, 18.9)	-0.54 (-3,65 − 7,5)	0.55
Staphylococcus aureus colonization (MSSA + MRSA) ** n (%)	25 (29,2)	529 (27.2)	0.86
Pseudomonas aeruginosa colonization** n (%)	32 (36,8)	311 (16.1)	0.01*
rhDNaz** n (%)	58 (66,7)	1694 (87,7)	0.01*
Pancreatic enzym** n (%)	76 (87,5)	1663 (85,4)	0.56
Multivitamin** n (%)	77 (88,5)	1558 (80,7)	0.13
F508del ** n (%)	20 (22.2)	486 (24)	0.91
Exon 2–3 deletion n (%) **	7 (9,7)	29 (1.5)	0.01*
NCFRT: National CF Registry in Turkey, MSSA: Methycilline Sensitive Staphylococcus Aureus, MRSA: Methycilline Resistance Staphylococcus Aureus
*One sample t test. Chi-square test. *Significant difference at 0.05 level

The purpose of this study was to assess the demographic information and CFTR mutations of refugee children with CF in Turkey and compare the findings with those of patients in the NCFRT. Refugee children were also successfully included in the NBS program in Turkey, a program that has not yet been introduced in any Arab country. Even though refugee newborns had the same access to NBS as Turkish newborns, the diagnosis of refugee patients occurred at a later stage compared with Turkish patients. Though both groups had similar access to CF medications, we noticed a higher instance of pseudomonas colonization and poorer nutritional status in refugee patients during long-term follow-up. Additionally, the CFTRdel2-3 mutation, which is less common in NCFRT, was found to be the second most prevalent mutation in refugee patients. Furthermore, we observed two rare mutations in refugee patients that were not present in NCFRT.

Awareness of CF is low in Middle Eastern and Asian countries and there is currently no known incidence [9, 10]. The high rate of consanguineous marriage particularly among Arabs may contribute to a higher prevalence of CF. Among Arabs, the rate of consanguineous marriage is 50% in the general population but rises to 85% in families with CF. As a result, the frequency of rare mutations also increases [11]. In our study, the rate of consanguineous marriage was very high at 59%, and based on our data, the estimated incidence of CF among refugee Arab patients is 1/33,000. However, because our study did not include adult patients with CF and unregistered refugees, this information may not fully represent the CF population among refugee Arabs.

Compared with Western countries, CF survival is lower in Middle Eastern countries due to the availability of NBS programs, the introduction of promising drugs such as modulatory therapies, and improvements in care conditions [12]. Due to the lack of a NBS program and the low awareness among physicians, the average diagnosis is around age 3 years [10, 13]. Currently, no NBS program for CF is available in any Arab countries. Although the median age of diagnosis for patients was significantly higher compared to NCFRT; patients born after 2015, who are eligible for the NBS program, were diagnosed more quickly. We hypothesized that this difference might be attributed to the challenges of living in and adjusting to a new country. However, implementing a well-structured NBS program in Arab countries could result in early identification of these patients, leading to improved prognosis and increased survival rates.

Most patients did not have any issues with their follow-up appointments or treatment adherence. Multivitamin and pancreatic enzyme use rates of refugee patients were similar to NCFRT, only rhDNaz use was found to be significantly lower in the refugee patient group. This outcome might be related to the significantly higher median age at the current age in the NCFRT group compared with the refugee patient group. Modulator treatments are not yet reimbursed for any patients with CF in Turkey. The Ministry of Health covers all healthcare expenses, except for modulator treatment, so accessing medicine is not a problem for refugee patients [14]. However, we observed that refugee patients with CF had lower height and weight z scores, as well as a higher rate of P. aeruginosa colonization, during their follow-up. Compared with NCFRT, the nutritional status and P. aeruginosa colonization of refugee patients with CF were found to be significantly worse. We believe that these results may be attributed to the challenging social living conditions faced by refugee patients, such as crowded family living, housing problems, and cultural differences.

In many studies conducted in Arab ethnic groups such as Jordan, Lebanon, Palestine, and Tunisia, F508del was found to be the most common mutation, with rates varying between 34–56% [15–18]. This rate was 80.3% in the 2021 European Cystic Fibrosis Registry [19]. Similar to reference studies, in our study, F508del was the most frequently detected mutation in the refugee patient group with a rate of 22%. Global investigation showed that the frequency of the F508del mutation decreases from northern Europe, with Denmark having a rate of 87.2%, to southern Europe. Based on geographic factors, it is expected that the frequency of F508del in Syria would be lower or equal to its frequency in Turkey [20]. Similar to this study, the most frequently detected F508del mutation in the 2021 NCFRT was reported as 24% [5].

In our study, we found that there was a high level of variants in CF mutations within the patient population. The second most common mutation was the deletion of exons 2–3. Interestingly, the frequency of this specific mutation in our study was significantly higher than the NCFRT and worldwide average [5, 21]. We also discovered that almost all patients who carried this deletion in both copies of the gene experienced severe respiratory problems, Pseudomonas infection, pancreatic insufficiency, liver cirrhosis, a lower BMI, and more frequent failure to thrive. Additionally, they had high sweat test results and were diagnosed as having CF before the age of 1 year. These findings suggest that the presence of exon 2–3 deletions in this population may be indicative of a common, founder mutation among Syrian patients.

In another study conducted on Iranian patients with CF, the most prevalent mutation was R334W, which was found at a rate of 40.74%, followed by F508del at a rate of 22% [22]. Another study conducted on patients with CF in the United Arab Emirates (UAE) revealed that the most common mutation was S549R, accounting for 28% of cases. Additionally, it was reported that nearly half of the patients received a diagnosis after the age of 10 years, and a significant number of them exhibited high P. aeruginosa colonization, reaching 82%. It is believed that this situation has a negative effect on the prognosis and life expectancy of these patients [23]. In a comprehensive study that examined 72 studies conducted in 22 countries, a total of 5481 Arab patients with CF were analyzed for CFTR genetic mutations. The study reported that the most frequently observed mutation was F508del, except for Iraq, Sudan, and Qatar. Furthermore, in Saudi Arabia, the most common mutations are c.3700A > G, 3120 + 1G > A, c.3909C > G, and c.1657C > T, whereas in Bahrain, the common mutations are c.2043delG, c.548A > T, c.4041C > G, and F508del. The c.3700A > G mutation is particularly prevalent among Gulf Cooperation Council (GCC) countries [11]. The results indicate that it is important to consider a different approach to molecular genetics diagnostic strategies in Arabic countries. Therefore, knowing the frequency and distribution of CF mutations in each population can be beneficial for managing the disease, developing diagnostic tools, and conducting prenatal diagnosis. Each ethnic group may have its own unique frequency of CFTR mutations. The unexpectedly high prevalence of certain mutations may be explained by factors such as high consanguineous marriage rates. In our study population, which consisted mostly of Syrian Arab refugees, there was a distinct distribution of CFTR mutations. As a result, we suggest conducting whole-gene sequencing as the initial step in mutation analysis for CF. If patients show clinical symptoms but no mutations are detected in the CFTR panel, we strongly recommend MLPA analysis [24–26].

The strength of this study is that it implemented the NBS program for the first time in Arab refugee patients, leading to early diagnosis. However, despite free access to CF medications, no improvement in their malnutrition was observed during long-term follow-up. This study has some limitations. The high genetic heterogeneity made it impossible to establish the genotype-phenotype relationship of the patients. Language differences and communication difficulties were major obstacles in the follow-up and treatment of refugee patients [27]. Patients who were seeking asylum and immigrants could not be included in the study, so we may not have been able to reach all patients. Another limitation was the lack of data due to the retrospective nature of the study.

In conclusion, we found that the patients were diagnosed shortly after NBS was successfully used on Arab refugees. Despite there being no issues with accessing CF medications, we noticed that their nutritional status was worse, and that pseudomonas colonization increased during follow-up. We discovered significant genetic diversity and uncommon mutations in these refugees. Therefore, it is important to implement NBS for CF in Arab countries to enable early diagnosis and treatment. Furthermore, enhancing the living conditions for refugee individuals with CF in the countries they relocate to will have a positive impact on the prognosis of the disease.

Conflict of interest: The authors declare that they have no conflict of interest.

Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approved by Necmettin Erbakan University Faculty of Medicine Ethics Committee ((2021/3502).

Consent to participate: Written informed consent was obtained from the parents.

Funding: There was no funding declaration

Availability of data and materials: Available upon request to the corresponding author.

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No competing interests reported.

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Neglected Children with Cystic Fibrosis due to War (Turkey Profile of Refugee Patients)

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