Cystic fibrosis: Saudi arabia current situation and perspectives

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Cystic fibrosis (CF) is an autosomal recessive disease of the exocrine glands with multiple serious complications. It was reported that the incidence of CF in  Saudi Arabia is 1 case in every 4243 of the population in 1986. Around 2000 mutations were listed in the CF Mutation Database, among them only the 32  were considered as common mutations. In Saudi Arabia, 1548 delG is the most common mutation among CF cases. The main problems of CF in Saudi Arabia  are the delay in diagnosis, lake of awareness and the economic burden of treatment of CF cases especially with late diagnosis and multiple complications.  However, recently, more attention is paid to CF with more specialized diagnosis facilities and more awareness, however further large scale and longitudinal  studies should be done to determine Saudi CFTR mutation patterns which could be needed during a screening of CF in Saudi Arabia.

Introduction

Cystic fibrosis (CF) is an autosomal recessive disease of the exocrine glands that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients []. Pulmonary involvement occurs in 90% of patients surviving the neonatal period and end-stage lung disease is the principal cause of deaths [2]. Once limited largely to infants and children, the immediate prognosis has changed drastically over the last three decades so recently, the majority of patients survive into adolescence, and nearly 80% live beyond their twentieth birthdays [].

Cystic fibrosis had been well known in European folklore since the middle ages. It was defined as woe, which was manifested as a child who tastes salty from a kiss on the brow, for he is cursed, and soon must die [4]. Cystic fibrosis was first recognized as a separate disease entity and was distinguished from celiac disease in 1938 in the pancreas during postmortem dissection of malnourished infants and termed as “cystic fibrosis of the pancreas” [5], while the causative gene mutation was first discovered in 1989. Since then, research was expanding to highlight the underlying molecular abnormalities [6].

Epidemiology of CF:

Cystic fibrosis is the most common life-shortening autosomal recessive disease of whites, which affects approximately 1 in 3,500 live births [1,2]. Cystic fibrosis was estimated to affect 60,000 individuals worldwide. It was observed primarily in individuals of European Caucasian descent with an incidence ranging from 1 in 2,000 to 1 in 4,000 [7]. In the United States of America, the number of CF cases registered in CF Foundation Patient Registry had increased from 21000 to 26000 cases between 2000 and 2010. Their median age increased from 14.3 to 16.7 years with adjusted mortality lowered by 1.8% per year and increased median survival of children born with CF to be 37 years for females and 40 years for males. Hence, its lifespans are expected to increase with continuously lowered mortality rates [8].

A more recent study in 2017 compared CF survival between the United States of America and Canada revealed that based on the available data collected from 2009 to 2013, the median age of survival in Canada was 10 years longer than the United States (50.9 vs. 40.6 years, respectively) [9]. Cystic fibrosis is much less common in native African and native Asian populations [7].

In China, there are no definite data about CF statistics and only 38 cases were reported from 1974 until 2018. This under-reporting of cases in China may be due to more difficult diagnosis caused by low awareness, atypical clinical symptoms, and a lack of testing facilities in most hospitals [10].

There is no definite data regarding the prevalence of CF in the Middle East countries including Saudi Arabia [11]. The first Middle East reported case of CF was from Lebanon in 1958 [12] while the first reported case in Saudi Arabia was in 1986 [13]. It was reported that the incidence of CF in Saudi Arabia is one case in every 4243 of the population in 1986 [13]. However, it is roughly estimated that at least 800-1000 cases may have CF in Saudi Arabia. This estimated number is expected to increase in reality due to high rates of consanguinity [11]. Cases reported from Saudi Arabia are shown in Table 1.

King Faisal Specialist Hospital, the main referral center for CF cases in Saudi Arabia, reported that 183 cases were diagnosed as CF from 1985 to 2003. They were diagnosed as CF by their typical clinical picture and two consecutive positive sweat tests. Their ages were around 4.3 ± 3.3 years with no significant difference of prevalence between both genders. Their follow-up period ranged from 0.01 to 18 years [14]. Unfortunately, the median survival for CF cases in Saudi Arabia was estimated to be up to 20 years of age [11-15] due to delayed diagnosis caused by low awareness and decreased specialized medical facilities for CF. In addition to poor follow up of the diagnosed cases, delayed diagnosis caused by a lack of parents’ awareness.

Pathogenesis of CF:

Cystic fibrosis is an autosomal recessive disease caused by abnormalities in the cystic fibrosis transmembrane regulator [CFTR] gene, which encodes for a protein that functions as chloride and bicarbonate channels and also regulates the flow of other ions across the apical surface of epithelial cells [6]. In 1989, the CF locus was localized through linkage analysis to the long arm of human chromosome 7 [22]. Thus far, 1893 CFTR mutations have been identified [23].

Around 2000 mutations are listed in the Cystic Fibrosis Mutation Database [10]. Among them, only the 32 were considered as common mutations and included in the recommended CFTR gene mutation screening panel [24]. The most common mutation is named as p.F508del, which was reported in about 70% of diagnosed Caucasian CF cases [25]. Half of affected individuals of northern European descent are homozygous for the p.F508 mutation, another 25%-30% have one copy of ΔF508 plus another mutation, however, the p.F508del variant is not common among reported Asian CF cases. [10]

CFTR mutations result in abnormalities of cAMP-regulated anion transport across epithelial cells on mucosal surfaces. The failure of chloride and sodium conductance of epithelial cells and associated water transport abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear and predispose to the colonization of pathogens and repeated infections with excessive neutrophils infiltrates and cytokines secretion [26]. Microbiology studies reveal a fairly typical evolution of pathogens with respiratory viruses, Haemophilus influenzae and Staphylococcus aureus, predominant at an early age. With time, more problematic and resistant pathogens develop, including, Pseudomonas aeruginosa and other gram-negative bacteria e.g. Burkholderia cepacia, Stenotrophomonas maltophilia [27].

Based on molecular and structural defects, CF-causing mutations are classified into five classes [28].  Classes I, II, and III are generally more severe causing “classic CF.” While Classes IV and V are usually milder. Also, other genes called modifier genes can affect a person’s symptoms and outcome. A sixth class has also been proposed but this class has not been well described yet (Table 2) [29]. Unfortunately, this classification is not correlated well with the clinical findings regarding disease severity and recommended guide counseling [30].

Atypical CF was described as a milder form of the CF caused by mutations of the CFTR gene. These cases usually have 1 severe mutation and 1 less common mutation or abnormality of trinucleotide repeats on their other CFTR gene [31]. Cases with atypical CF might only have dysfunction in a single organ system [32].

In Saudi Arabia, CF cases report data regarding CFTR mutations detection showed that 89% of CFTR alleles have been identified (Table 1) [18-21]. F508del constitutes 12% of CFTR mutation. 1548 delG is the most common Saudi CFTR mutation identified (20%). 1548 delG, F508del, I1234V, 3120 1G > A, H139L, 711 1G > A, N1303K, S549R, 2043delG, 1507del 9 are the most common CFTR mutations of Saudi ethnic origin (80%) [11]. Screening for the previously mentioned 10 mutations would identify 80% of C.F. alleles

Clinical features of CF:

Cystic fibrosis is characterized by chronic sinopulmonary and gastrointestinal involvement [33]. Most body organs are involved (Table 3). Mostly the progressive pulmonary disease leads to death in the majority of patients (about 90% of CF mortalities) [2]. Abdominal symptoms (AS) of CF are a hallmark of the multi-organ disease CF. However, the abdominal involvement in CF is insufficiently understood and still receives little scientific attention than the pulmonary manifestations [7]. Pancreatic CF is rare in children. Malnutrition, diarrhea, and abdominal pain are its main clinical manifestations [34].

Diagnosis of CF:

Diagnosis is based on a panel of screening test, clinical and laboratory data which are shown in Table 4. Late diagnosis is a limiting factor for proper treatment in the majority of cases due to minimal early manifestations which mimic other diseases. Lack of training and awareness among healthcare physicians are among other important issues in the delayed diagnosis. Additionally, a limited number of CF-specialized testing center s in the Middle East and Saudi Arabia is another crucial cause for delay in diagnosis. Sweat test remains the standard test for diagnosis [36].

Management of patients with cystic fibrosis:

A problem in the treatment of CF patients is that very mild cases can also rapidly deteriorate after viral infections or due to other unrecognized factors, implying that once the diagnosis has been made, the preparedness to treat mild symptoms is important. Monthly check-up for CF cases is recommended. It is also well recognized that a center should be organized as a team consisting of a doctor, nurse, physiotherapist, dietician, social worker, psychologist, secretary, and technical assistant for sweat tests [38]. The management lines of cases with CF are shown in table [5]. The most attention has been given to the treatment of airway symptoms since pulmonary disease is responsible for 95% of the mortality from CF. Although all strategies rely on a combination of mucus – dissolving agents, passive or active physical activities and antibiotics, success varies greatly between centers and countries [2].

According to King Faisal Specialist hospital guideline, published by Banjar (2003) [14], sputum or nasopharyngeal aspirate cultures are taken routinely from all cases of CF on initial diagnosis and at every follow-up visit. Prophylactic broad-spectrum antibiotics are prescribed for the first 1 to 2 years if cases show tachypnea, wheezing and excessive sputum as recommended by Weaver et al. (1994) [42] and McCaffery et al. (1999), [43] such as amoxicillin, cephalexin monohydrate, or trimethoprim/ sulfamethoxazole (Bactrim). After 2 years of prophylaxis, anti-microbials are given during acute attacks and selected according to the bacterial cultures. Resistant infections are admitted for therapy for further evaluation and treated with intravenous third-generation cephalosporin and an aminoglycoside according to their culture and sensitivity results [44-45]. For pancreatic insufficiency pancreatic enzymes are given, according to Cystic Fibrosis Foundation recommendations [46], in combination with supplementation of fat-soluble vitamins (A, D, E, and K).

Cystic fibrosis current situation in Saudi Arabia:

All over the kingdom and over the last 3 decades, a lot of articles and case reports were published about CF in Saudi Arabia. The number of reported cases was increasing in the successive publications. This means that CF came to the focus of the healthcare services plans and staff. However, more efforts are required especially more cases are expected with the very high rates of consanguinity all over the kingdom.

The main problem in CF in Saudi Arabia is the delay in diagnosis. Most cases start with mild symptoms and their proper diagnosis mostly is overlooked. This problem is multifactorial. Firstly, a lack of awareness of the healthcare staff is a major limiting obstacle in the way of early diagnosis. Additionally, a limited number of specialized centers for CF diagnosis is another problem. These centers should be properly distributed all over the kingdom and should be equipped with the required facilities and properly trained staff for the genetic diagnostic workup.

The second problem is a lack of public awareness of the disease. This leads to a lack of adherence to the long-life follow-up visits, which are crucial in improvement of the disease complications and increasing the median survival of the diagnosed cases. Also, this incompliance of the patients and their families may be due to the limited number of the specialized centers. Hence lots of time, money, and efforts are spent in the long follow-up programs. Also, the outcomes of cases are mostly not satisfactory for patients and their families with terminal cases that mostly thought to be not-treatable and hopeless in cases of CF. This concept makes them desperate to continue the follow-up program.

The third important issue is related to the economic burden of treatment of CF cases especially with late diagnosis and especially to continuously deteriorated lung function and prolonged colonization of resistant pathogenic microbial stains. Specific gene therapy potentiators and correctors are highly expensive and only available for big specialized centers. All Saudi people are covered by the umbrella of the government insurance and all services for CF cases are unpaid, but this should not force us to ignore that CF cases survival is strongly affected by social factors and mortalities are more common among cases of the low social class [47].

Mortality among cases of CF in Saudi Arabia is a multi-factorial issue. Delayed diagnosis and delayed onset of nutritional replacement were suggested to play a major role. Also, resistant pseudomonas and methicillin-resistant staph aureus MRSA infections are related to early deaths. Additionally, high hematocrit with low red blood cells indices was shown to be related to CF poor prognosis and mortalities [14].

Finally, the extending publications from Saudi Arabia in the era of CF are promising, however further large scale and longitudinal studies should be done to determine Saudi CFTR mutation patterns which could be needed during screening of CF in Saudi Arabia. Internationally, more researches should be conducted to investigate the long-term effects of the emerging novel CF genetic and functional treatment modalities.

Scientific Responsibility Statement

The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.

Animal and human rights statement

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.

Conflict of interest

None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.

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Additional Info

  • Recieved: 16.12.2018
  • Accepted: 14.01.2019
  • Published Online: 16.01.2019
  • Printed: 01.11.2019
  • DOI: 10.4328/ACAM.6130
  • Author: Shehab Ahmed Alenazi
  • Identifier: DOI: 10.4328/ACAM.6130
  • Index Page: 775-80
  • How to Cite: Alenazi SA. Cystic fibrosis: Saudi arabia current situation and perspectives. Ann Clin Anal Med 2019;10(6): 775-80
  • Running Title: Cystic fibrosis in Saudi Arabia
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