Local Prevalence

In a study of year 2000, the reported frequency of the AF508 mutation in Pakistani children with CF is lower than the reported frequency among the Western Caucasian population (JPMA 50:217, 2000). Frossard et al. (1998) who had the opportunity to study Pakistanis in the United Arab Emirates reported a frequency of 86% in Pakistanis of Balochi origin. Previous studies on Pakistani children and families with CF in UK and elsewhere have also failed to show the AF508 mutation and a variety of other mutations have been described (Bowler IM et al 1993; Schwartz Ml et al 1990; Curtis A et al 1993). The Delta F508 mutation is present in 70-100 % of CF patients of Caucasian origin, was found in only 33% of the Pakistani patients according to study done in 2000 (Bhutta Z et al 2000).

The prevalence of the disease in the Pakistani population, which comprises individuals of diverse ethnic backgrounds, is unknown. Since phenotypic expression of the disease is related to genotype, elucidation of these mutations would be critical for its understanding and management in this population.

According to study conducted in 2004, 80.6% of the patients presented with pulmonary problems while 91.6% had failure to thrive. The most frequently isolated pathogen in 41.3% of the patients was Pseudomonas aeruginosa. There was a history of consanguinity in 41.7% of cases and 75% of the patients died in the first year of life (Shah, U. et al 2004).

 

Global Prevalence

Whilst DF508 frequency is 87% in Northern Europe, it is only 28% in Asia and the Middle East with a combined worldwide frequency of 66% (Cystic Fibrosis Mutation Database 2008). In the United States, the number of people who carry a CFTR gene mutation which causes cystic fibrosis (CF) is about:

• 1 in 29 Caucasian-Americans
• 1 in 46 Hispanic-Americans
• 1 in 65 African-Americans
• 1 in 90 Asian-Americans

More than 30,000 people in USA are living with cystic fibrosis (more than 70,000 worldwide).

The incidence of cystic fibrosis (CF) varies by ethnicity. CF is most common in Caucasian populations with one out of every 3,500 newborns diagnosed with CF. It is less common in other ethnic groups, affecting about 1 in 7,000 individuals in the Hispanic population and 1 in 17,000 African Americans. CF is most common among people of Northern European ancestry and affects about one out of every 3,000 newborns. About one in 25 people is a carrier. It is least common in Africans and Asians.

According to literature review done during a study in 2015 – The incidence rate of CF among the immigrant Asians residing in Canada, United Kingdom (UK) and United States is documented as 1 in 9200, 1 in 10 000 and 1 in 40 000 respectively. However, there is a remarkable variation in the incidence rates of CF reported among native Asians. For example, CF incidence in Jordan is 1 in 2500 live births, followed by 1 in 5000 in Bahrain; which is comparable with the incidence of CF between 1 in 2000 and 1 in 4000 in Caucasians. In contrast, incidence rate of CF in Japan is as low as 1 in 350 000 live births. Furthermore, fewer than 30 CF cases have been reported over the last two decades from China. The factors that may have contributed to the wide range of CF incidence reported from Asian countries include (but are not limited to) under-diagnosis, under-reporting, lack of national registries and variability in the frequency of CF mutation carriers. For example, mutation carrier frequency of CF in India is 1 in 238 compared with 1 in 25 to 1 in 60 in Arabian countries (Singh, M. et al, 2015).

 

What is Cystic Fibrosis?

Signs and symptoms

Early signs of CF include:

• Salty sweat; many parents notice a salty taste when kissing their child
• Poor growth and weight gain (failure to thrive)
• Constant coughing and wheezing
• Thick mucus or phlegm
• Greasy, smelly stools that are bulky and pale colored

Signs and Symptoms	Approximate number of patients (when available)
Biliary cirrhosis	Very frequent (present in 80%-99% of cases)
Decreased antibody level in blood	Very frequent (present in 80%-99% of cases)
Exocrine pancreatic insufficiency	Very frequent (present in 80%-99% of cases)
Immunodeficiency	Very frequent (present in 80%-99% of cases)
Malabsorption	Very frequent (present in 80%-99% of cases)
Pulmonary fibrosis	Very frequent (present in 80%-99% of cases)
Recurrent respiratory infections	Very frequent (present in 80%-99% of cases)
Dehydration	Occasional (present in 5%-29% of cases)
Hepatomegaly	Occasional (present in 5%-29% of cases)
Asthma	–
Autosomal recessive inheritance	–
Bronchiectasis	–
Chronic lung disease	–
Cor pulmonale	–
Elevated sweat chloride	–
Failure to thrive	–
Hypercalciuria	–
Male infertility	–
Meconium ileus	–
Rectal prolapsed	–
Recurrent bronchopulmonary infections	–
Recurrent pneumonia	–

Table 1: Symptoms and their frequencies in CF

 

Causes

Individuals with cystic fibrosis (CF) are unable to move chloride ions and water throughout their body. As a result, the lungs, pancreas, and other organs produce mucus that is unusually thick and sticky. This mucus is unable to protect the body. Therefore, mucus clogs the body’s airways and glands and reduces its ability to fight infections.

 

Figure 1: Symptoms, CFTR Activity and Pathogenesis in CF

Testing and Follow-Up

Testing

All babies should be tested within 24 to 72 hours of birth via heel-prick test. If the results are positive for CF, the IRT Mutation analysis is done to confirm the result.

Confirmatory tests

A 2009 study discovered that the PCR was not accurate, as several positive results could not be confirmed by sequencing. This was an important discovery, as PCR results are frequently used to diagnose CF in Pakistan (Shah, U., Frossard, P. and Moatter, T. 2009)

1. Sweat Test:

In the first part of the test, a chemical that causes sweating is put on a small area of skin (usually on the arm or leg). An electrode is then put over that spot to make the area sweat. This will not cause your baby any pain, although he or she may feel tingling or warmth in the area. In the second part of the test, the sweat will be collected on a piece of filter paper or gauze and sent to a hospital laboratory for evaluation. If the sweat test is inconclusive, your baby’s doctor may order genetic testing for CF to further investigate the reason for the out-of-range screen result.

• AFIP Rawalpindi offers the sweat test!

 

2. Immunoreactive Trypsinogent Test (IRT):

It checks the levels of a chemical made by the pancreas called immunoreactive trypsinogent, or IRT. IRT is normally found in small levels in the body. In people who have CF, IRT levels tend to be high but IRT levels can also be high if a baby is premature or had a stressful delivery or for other reasons. Some states only test IRT levels on the first blood test. These are called IRT-only states. Other states conduct both an IRT and a DNA test. These are called IRT-DNA states.

Conditions for confirmation:

1. Babies with two CF gene mutations are very likely to have CF. However; a sweat test should be used to confirm a diagnosis of CF.
2. Babies with only one gene mutation found on a newborn screening result probably do not have CF. A high IRT level sometimes occurs when a baby is a carrier of CF.

• Not all CF carriers (people who have only one CF gene mutation) will be found with the blood test that measures IRT. Most CF carriers will have normal IRT levels, and will not be identified by newborn screening.

1. Babies with no CF gene mutations but who have very high IRT levels are unlikely to have CF. As a precaution, the health care provider might ask parents to bring the baby to a CF Foundation-accredited care center for a sweat test.
2. If the sweat test confirms that your baby does not have CF, he or she may have CFTR-related metabolic syndrome (CRMS).

 

1. CFTR-related metabolic syndrome CRMS:

Although the future health of someone diagnosed with CRMS remains unclear, there is a higher risk of experiencing problems in the airways, sinuses, intestines, pancreas or the reproductive system.

 

You should see your regular doctor — and possibly a CF specialist — if you or your child has any of these symptoms:

• No weight gain
• Loose stools, very bad gas or constipation that last more than 2 weeks
• Very bad stomach aches
• Coughing or wheezing that last more than 2 weeks

 

How to Survive with CRMS?

• If you or your child experience symptoms related to CRMS, the best thing to do is to have regular checkups with a CF specialist at a CF Foundation-accredited care center so that any health changes or problems can be found early and treated quickly.
• As is true for everyone, people with CRMS should not be around tobacco smoke. All people 6 months of age and older should receive an influenza vaccine every year in the fall.

 

3. Genetic/Mutation Analysis Tests:

A CF gene mutation panel may be ordered for a test:

• When you or your partner are planning to become pregnant
• During the first trimester of pregnancy or the first prenatal visit
• When someone has a close relative who has been diagnosed with cystic fibrosis
• For an infant, soon after birth
• When a person has had a positive CF screening test such as a sweat chloride conductivity test or IRT test
• When a person has signs and symptoms of CF

 

Diagnosis Availability

• Agha Khan Laboratory: IRT Testing: They are only testing single and the most common mutation which is DeltaF508.
• Excel Lab: IRT Testing: They cover 97 Mutations for Cystic Fibrosis.
• AFIP Rawalpindi: Sweat test.

For more details on this, call the ZBF Islamabad office: 051 5732124

Outcomes

Research shows that children who receive CF care early in life have better nutrition and are healthier than those who are diagnosed later. Early diagnosis and treatment can:

• Improve growth
• Help keep lungs healthy
• Reduce hospital stays
• Add years to life

 

 

Treatment

The Agha Khan Hospital suggests that there are also surgical procedures available with them that can help with cystic fibrosis. These include:

• Nasal polyp removal: Your doctor may recommend surgery to remove abnormal growths of tissue that obstructs breathing.
• Endoscopy: In this process a long thin tube (known as an endoscope) is inserted through your nostrils to remove mucus from your airways.
• Feeding tube: A feeding tube can be used to help your child absorb nutrients the right from.
• Bowel surgery: Surgery is an option to remove a severe bowel blockage.
• Lung transplant: If your child’s breathing problems are very severe, lung transplantation may be a possible option to help relieve breathing function.

Dietary Limitations and Supplements:

• A high-calorie diet – Some children with cystic fibrosis (CF) need more food for healthy growth and development.
• Pancreatic enzymes – Your baby may need to take pancreatic enzymes before eating to properly digest food. These enzymes can help your baby gain weight and grow at a healthy rate.
• Vitamin supplements – Your baby’s body may also have trouble getting vitamins from food. The doctor may prescribe vitamin supplements to ensure proper nutrition.

 

Medications:

• Some children need special medications to treat the lung problems associated with CF. The baby’s doctor may prescribe one or more of the following:
• Mucus-thinners – These drugs are usually inhaled, and they help make mucus thinner and easier to cough up.
• Bronchodilators – These inhaled drugs open up the airway to make breathing easier.
• Anti-inflammatories – These drugs can help reduce lung swelling.
• Antibiotics – Children with CF tend to have frequent lung infections, which may require treatment with antibiotics.

 

• Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Inhaled antibiotic therapy helps lung function by fighting infection, but also has significant drawbacks such as development of antibiotic resistance, tinnitus, and changes in the voice.
• Inhaled levofloxacin may be used to treat Pseudomonas aeruginosa in people with cystic fibrosis who are infected. Antibiotics by mouth such as ciprofloxacin or azithromycin are given to help prevent infection or to control ongoing infection. The aminoglycoside antibiotics (e.g. tobramycin) used can cause hearing loss, damage to the balance system in the inner ear or kidney failure with long-term use. To prevent these side-effects, the amount of antibiotics in the blood is routinely measured and adjusted accordingly.

 

 

Therapies

Airway Clearance Therapy (ACT)

• Airway Clearance Therapies (ACT) are treatments that help people with CF loosen thick, sticky lung mucus so that it can be cleared by coughing. This will help your child stay healthy and breathe more easily. There are a number of ways to perform ACT. Your baby’s doctor will help you choose the most effective technique for your baby.
• Pulmonary rehabilitationas a management of CF continues throughout a person’s life, and is aimed at maximizing organ function, and therefore the quality of life. At best, current treatments delay the decline in organ function. Because of the wide variation in disease symptoms, treatment typically occurs at specialist multidisciplinary centers and is tailored to the individual.
• Targets for therapy are the lungs, gastrointestinal tract (including pancreatic enzyme supplements), the reproductive organs(including assisted reproductive technology), and psychological support.^[61]
• The most consistent aspect of therapy in CF is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections. Mechanical devices and inhalation medications are used to alter and clear the thickened mucus. These therapies, while effective, can be extremely time-consuming.

 

Chest Physiotherapy

• A respiratory therapist percusses an individual’s chest by hand several times a day, to loosen up secretions. Chest physiotherapy is beneficial for short-term airway clearance.
• Devices that recreate this percussive therapy include the ThAIRapy Vestand the intrapulmonary percussive ventilator. Other methods such as biphasic cuirass ventilation, and associated clearance mode available in such devices, integrate a cough assistance phase, as well as a vibration phase for dislodging secretions. These are portable and adapted for home use.
• Ivacaftoris a medication taken by mouth for the treatment of CF due to a number of specific mutations. It improves lung function by about 10%; however, as of 2014 it is expensive.

 

Lung Transplantation

Lung transplantation is considered when lung function declines to the point where assistance from mechanical devices is required or someone’s survival is threatened.

 

References

• Bowler IM, Estlin Fi, Littlcwood iM. Cystic fibrosis in Asians. Arch. Dis. Child.. 1993:68:120-22.
• Schwartz Ml, Simper M, Walfis C, et al. Delta F508 testiiig of the DNA baitk of the Royal Manchester Children’s Hospital. Hum. Gcnct., 1990:85:428-30.
• Curtis A, Richardsomm RJ, Boohene 3, ct al. Absence of cystic fibrosis mutations in a large Asian population sample and occurrence of a Itoitiozygoiis S549N mutation itt an inbred Pakistani family. 3. Med. Genet., 1993;30:164-66.
• Shah, U., Frossard, P. and Moatter, T. (2009), Cystic fibrosis: defining a disease under-diagnosed in Pakistan. Tropical Medicine & International Health, 14: 542–545. doi:10.1111/j.1365-3156.2009.02253.x
• Bhutta Z, Moatter T, Shah U. Genetic Analysis of Cystic fibrosis in Pakistan: a preliminary report. J Pak Med Assoc 2000;50(7): 217-9
• Aziz, D.A., Billoo, A.G., Qureshi, A., Khalid, M. and Kirmani, S., 2017. Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan.
• Singh, M., Rebordosa, C., Bernholz, J. and Sharma, N., 2015. Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next‐generation treatments. Respirology, 20(8), pp.1172-1181.
• Janssens, S., De Paepe, A. and Borry, P., 2014. Attitudes of health care professionals toward carrier screening for cystic fibrosis. A review of the literature. Journal of community genetics, 5(1), p.13.
• Shah, U., Moatter, T., Bhutta, Z. and Frossard, P., 2004. P0277 Cystic Fibrosis In Pakistani Patients: The Tip Of The Iceberg?. Journal of Pediatric Gastroenterology and Nutrition, 39, p.S163.