Review question: In infants, children, young people and adults (including those that have undergone new-born screening) when should cystic fibrosis be suspected?
5.1. Introduction
Today, most people with cystic fibrosis will be diagnosed at birth as part of the national Newborn Screening Programme using the blood spot immunoreactive trypsin test. Screening was introduced UK-wide in 2006 and so there remains a cohort of young people and adults with cystic fibrosis who have not been screened and yet have been diagnosed through a clinical assessment. Although highly successful, the Programme is not able to screen for all cystic fibrosis associated genetic variants and so some infants will inevitably remain undiagnosed. It should be noted that over 2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. Many of these variants are rare and have not been shown to lead to clinical disease and therefore their clinical significance can be unclear. Of these 2,000 variants, around 200 have been shown to lead to cystic fibrosis disease. Although only common disease-associated variants are tested for as part of the Newborn Screening Programme.
Additionally, infants may not undergo newborn screening due to parent’s wishes or if newborn screening is not carried out in the country of birth. People with atypical manifestations of cystic fibrosis can reach adulthood undiagnosed and therefore untreated when clinical intervention would beneficial.
Given the potential for people with cystic fibrosis to remain undiagnosed at all stages in life this review aims to determine what symptoms may indicate a possibility of cystic fibrosis and so warrant further investigation.
5.2. Description of clinical evidence
The aim of this review was to support health care professionals in identifying cystic fibrosis even in people who have been through new-born screening.
In this review, our index test were clinical symptoms and signs, including:
Respiratory features (including recurrent infection, chest x-ray evidence of chronic disease)
Faltering growth
Symptoms of malabsorption
Azoospermia
Acute pancreatitis
Meconium ileus (in infants).
The committee agreed DIOS is known to be a symptom unique to cystic fibrosis, and therefore there was not need to include it in the review. We looked for prospective or retrospective cohort studies to identify diagnostic or prognostic factors, but no relevant studies were found. Therefore we looked for observational studies that reported the prevalence of cystic fibrosis among people presenting with one of the symptoms of interest.
As no diagnostic or prognostic data were finally included in the review, a GRADE approach (as specified in the protocol) was no longer deemed appropriate. Therefore for this review, the quality appraisal of the evidence has been conducted by study, and not by outcome.
For full details of the protocol see Appendix D.
5.2.1. Respiratory symptoms
Four observational studies were identified, 2 prospective (Ooi 2012, Seer 1997) and 2 retrospective (Hubert 2014, Grimaldi 2015).
Sample sizes ranged from 72 to 601, and the studies were conducted in Canada (Ooi 2012, Seer 1997) and France (Hubert 2014, Grimaldi 2015).
5.2.2. Faltering growth
No studies were identified.
5.2.3. Symptoms of malabsorption
No studies were identified.
5.2.4. Azoospermia
One observational study was identified (Ooi 2012).
Sample size was 92 and it was conducted in Canada.
5.2.5. Acute pancreatitis
Two observational studies were identified (Lucidi 2011, Ooi 2012).
Sample sizes ranged from 44 to 78, and the studies were conducted in Canada (Ooi 2012) and Italy (Lucidi 2011).
5.2.6. Meconium ileus
No studies were identified.
A summary of the included studies is presented in Table 19. See also study selection flow chart in Appendix F, excluded studies list in Appendix H, and study evidence tables in Appendix G.
Table 19
Summary of included studies and results.
5.3. Summary of included studies and results
A summary of the studies that were included in this review and the results is presented in Table 19.
5.4. Clinical evidence profile
See summary of results in Table 19.
5.5. Economic evidence
This review question is not relevant for economic analysis because it does not involve a decision between alternative courses of action.
No economic evaluations to identify the clinical manifestations suggestive of cystic fibrosis were identified in the literature search conducted for this guideline. Full details of the search and economic article selection flow chart can be found in Appendix E and F, respectively.
5.6. Evidence statements
5.6.1. Respiratory symptoms
Very low quality evidence from 1 prospective observational study showed that among 81 children with a history >3 months of productive cough 1.23% (n=1) had a diagnosis of cystic fibrosis (by means of sweat test, thresholds not reported). The study does not report whether these children had undergone newborn screening.
Very low quality evidence from 1 retrospective observational study showed that among 502 infants and children (age range: 1 month to 10 years) who had a negative cystic fibrosis newborn screening presenting respiratory symptoms:
0.3% (n=1; N=358) of the children presenting with asthma had a diagnosis of cystic fibrosis (sweat test ≥60 mmol/l)
1.5% (n=4; N=263) of the children presenting with a chronic cough had a diagnosis of cystic fibrosis (sweat test ≥60 mmol/l)
1.8% (n=4; N=212) of the children presenting with lower airway infections had a diagnosis of cystic fibrosis (sweat test ≥60 mmol/l)
5.7% (n=2; N=35) of the children presenting with bronchiectasis had a diagnosis of cystic fibrosis (sweat test ≥60 mmol/l).
Very low quality evidence from 1 retrospective observational study showed that among 601 adults (mean age: 31 years) referred for diffuse bronchiectasis:
6.16% (n=37) had confirmed diagnosis of cystic fibrosis (sweat test >60 mmol/l)
1.50% (n=9) had borderline diagnosis of cystic fibrosis (sweat test 40 to 60 mmol/l).
The study does not report whether these people had undergone newborn screening, but seems unlikely as newborn screening was implemented in France in 2003.
Very low quality evidence from 1 prospective observational study showed that among 72 children, young people and adults (mean age; range: 34.8 years; 9.9 to 66.7 years) with idiopathic chronic sinopulmonary disease:
19.4% (n=14) had a diagnosis of classic cystic fibrosis based on sweat test (European Consensus Recommendations)
4.2% (n=3) had a CFTR abnormality (based on extensive CFTR genotyping, and according to European Guidelines). This is also known as non-classic or atypical cystic fibrosis
1.4% (n=1) had an inconclusive diagnosis.
The study does not report whether these people had undergone newborn screening.
5.6.2. Faltering growth
No evidence was found for this sign.
5.6.3. Symptoms of malabsorption
No evidence was found for this symptom.
5.6.4. Azoospermia
Very low quality evidence from 1 prospective observational study showed that among 92 adult men (mean age; range: 34.8 years; 25.4 to 56.6 years) with infertility due to obstructive azoospermia:
20.7% (n=19) had a diagnosis of classic cystic fibrosis based on sweat test (European Consensus Recommendations)
22.8% (n=21) had a CFTR abnormality
9.8% (n=9) had an inconclusive diagnosis.
The study does not report whether these men had undergone newborn screening.
5.6.5. Acute pancreatitis
Very low quality from 1 retrospective observational study with 78 infants, children and young people (age range: 4 months to 18 years) affected by acute pancreatitis:
1.3% (n=1) had a diagnosis of cystic fibrosis based on sweat test (thresholds not reported)
9% (n=7) had a borderline diagnosis of cystic fibrosis based on sweat test (thresholds not reported);
39.6% had a single CFTR mutation on genetic testing
n=1 had a diagnosis of cystic fibrosis based on the detection of 2 cystic fibrosis-causing mutations (the study included 78 children and young people, but it is unknown for how many of them genetic testing was available)
The study does not report whether these people had undergone newborn screening.
Very low quality evidence from 1 prospective observational study showed that among 44 children, young people and adults (mean age; range: 24.3 years; 7.9 to 59.9 years) with idiopathic recurrent, acute or chronic pancreatitis:
4.5% (n=2) had a diagnosis of classic cystic fibrosis based on sweat test (European Consensus Recommendations)
13.6% (n=6) had a CFTR abnormality
2.3% (n=1) had an inconclusive diagnosis.
The study does not report whether these people had undergone newborn screening.
5.6.6. Meconium ileus
No evidence was found for symptoms in infants.
5.6.7. Economic evidence statements
No evidence on cost-effectiveness in people with cystic fibrosis was available for this review.
5.7. Evidence to recommendations
The aim of this review was to support health care professionals in identifying cystic fibrosis even in people who have been through new-born screening.
The committee chose clinical diagnosis of cystic fibrosis as a critical outcome for this evidence review. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio were rated as important outcomes.
5.7.1. Consideration of clinical benefits and harms
The committee agreed that a definition of cystic fibrosis was needed in order to emphasise that cystic fibrosis is a syndrome rather than a disease.
There are a number of investigations (such as sweat test or genetic test) that can be done in the event that cystic fibrosis is suspected, but there is no gold standard as such. These tests are useful in confirming cystic fibrosis, but they cannot completely exclude it. Ultimately, in rare cases, the diagnosis can be made based on the clinical signs and symptoms alone, even if tests results are negative. The committee discussed the emotional implications of being diagnosed with cystic fibrosis with a negative sweat test and cystic fibrosis gene mutations that have been conclusively shown to be disease causing.
The committee discussed the limitations of the available evidence. None of the studies reported diagnostic accuracy data. They agreed the usefulness of prevalence data reported in the studies was very limited as these studies did not adequately define the population and the analysis did not control for confounders. Due to this, they concluded it was not very useful in informing their recommendations and these were based on their clinical experience.
The committee discussed the relevance of each sign and symptom included in the evidence review. The committee agreed that infants (children under 1 year of age), children and young people and adults, required separate recommendations depending on the pertinence of the symptoms for each subgroup.
The committee noted that the presence of meconium ileus in infants was considered a highly suggestive sign of cystic fibrosis that should lead to further investigation. This is because meconium ileus is a unique feature of cystic fibrosis.
Likewise, the suspected diagnosis of DIOS in children, young people and adults (which is the equivalent to meconium ileus in infants) is also a well-known factor suggestive of cystic fibrosis that should also lead to further investigations of cystic fibrosis.
In relation to respiratory symptoms, the committee emphasised that one single respiratory event should not necessarily lead to further investigation. The committee considered recurrent lower respiratory tract infections, chronic lung disease or chest X-ray with persistent changes as reasons for referral in infants. Similarly, chronic sinus disease and chronic wet or productive cough should also be considered as reasons for referral in children, young people and adults. They noted that children do not produce sputum and agreed to use the term wet cough. In adults, they agreed it was more appropriate to use productive sputum instead of wet cough, as adults are more aware of having sputum. Finally, they noted the presence of chronic or repeated chest infection regardless of species may raise the possibility of cystic fibrosis. They agreed not to specify pathogens causing chest infection as people with cystic fibrosis may become colonised or chronically infected with many different opportunistic infections and so highlighting any individual species is likely to confuse diagnosis.
The committee discussed that people with cystic fibrosis often show signs of bronchiectasis due to recurrent inflammation and infection. Additionally, people with cystic fibrosis may present with asthma-like symptoms, such as wheezing, coughing, chest tightness and shortness of breath due to inflammation and infection of the airways.
The committee acknowledged that cystic fibrosis is known to cause pancreatitis. Approximately 10–15% of people with cystic fibrosis are exocrine pancreatic sufficient and so do not show malabsorption symptoms or diabetes mellitus, however, these patients do show a high incidence of attacks of pancreatitis.
The committee agreed that cystic fibrosis can also be suspected if there are signs of faltering growth in infants and pre-school children or undernutrition in older children, young people and adults. They noted that in young people, undernutrition can lead to delayed puberty but agreed not to include it as a sign where cystic fibrosis should be considered as there are other reasons that can lead to delayed puberty. They noted that in adults with cystic fibrosis undernutrition normally goes in association with other symptoms, such as pancreatitis and malabsorption.
The committee stressed that malabsorption should be separated from undernutrition as malabsorption, such as steatorrhea, may be indicative of pancreatic insufficiency, a common complication of cystic fibrosis (as discussed above), whereas undernutrition has a variety of non-cystic fibrosis causes.
The committee highlighted that azoospermia showed an important association with a diagnosis of cystic fibrosis. They noted that this was consistent with previous findings, as it is estimated 99% of men with cystic fibrosis are infertile. They also noted that some men can produce sperm, but they are still infertile. They discussed whether this symptom applied to young people too, but agreed that generally it will not be apparent to people under 18 years. It was also discussed that women may present with sub-infertility, but agreed that this is rather unusual and that clinically it is not possible to use the term subinfertility.
The committee also discussed other signs and symptoms not included in the review protocol, such as congenital intestinal atresia, DIOS, rectal prolapse, pseudo-Bartter syndrome and diabetes mellitus.
The committee noted congenital intestinal atresia is a rare condition that leads to the complete occlusion of the intestinal lumen in neonates. It has been associated with the presence of cystic fibrosis.
As highlighted in the protocol, DIOS is considered a symptom of cystic fibrosis. Therefore, the committee agreed that the suspected diagnosis of DIOS in children, young people and adults (which is the equivalent to meconium ileus in infants) should lead to further investigations of cystic fibrosis.
They noted that rectal prolapse can be a sign that health care professionals should be aware of. However, this sign does not present on its own and it is associated with pancreatitis.
Cystic fibrosis may present as Pseudo-Bartter Syndrome, dehydration and salt depletion due to dysregulation of salt homeostasis in cystic fibrosis. But this is rare in the UK and more common in warmer climates.
They also discussed whether the presence of diabetes mellitus in young people could be a sign of cystic fibrosis. However, they agreed not to include it in the recommendations as cystic fibrosis-related diabetes is diagnosed in the presence of other symptoms related to cystic fibrosis.
In addition to the signs and symptoms mentioned above, the committee noted that family history could also prompt an assessment for cystic fibrosis.
The committee agreed that a sweat test should be recommended in infants, children and young people. If the test was positive or borderline, the person should be referred for further investigations at a specialist cystic fibrosis centre.
Furthermore, the committee were concerned about carrying out genetic testing in a child carrier to determine their carrier status (for example if the child is heterozygous), as they cannot give consent. Thus, they agreed that genetic testing should only be considered when sweat tests results are uncertain. In adults, however, the sweat test is less reliable and cystic fibrosis gene testing is preferred.
With regards to gene testing, the committee noted that over 2000 variants in the CFTR have been identified but at present only around 10% of these have been linked to the development of cystic fibrosis. At present genetic tests only return results for the most common variants associated with the disease. Clinicians should be aware this means results from genetic tests cannot rule out a diagnosis of cystic fibrosis.
The committee discussed how the results of genetic testing results related to the obligation of clinicians to refer people to a specialist cystic fibrosis centre. They agreed that a gene test revealing 1 or more cystic fibrosis mutations was a reason for referral. It was also decided that due to the possibility that negative results do not entirely rule out cystic fibrosis, a referral should be based on the clinician’s judgement in light of gene test results and apparent symptoms (as discussed above).
The committee noted that these recommendations are consistent with the NHS Service Specifications for cystic fibrosis.
5.7.2. Consideration of economic benefits and harms
The committee advised that their recommendation to offer a sweat test or gene test follows current clinical practice to identify the clinical manifestations of cystic fibrosis and its complications. The committee also added that this was reflected in the Guidelines for the Performance of the Sweat Test for the Investigation of Cystic Fibrosis in the UK 2nd Version 2014. Overall, the committee agreed their recommendations promoted a cost-effective use of resources as those tests would subsequently inform the patient’s management which may potentially improve their health-related quality of life and outweigh the relatively cheap cost of those tests.
Moreover, knowing what clinical manifestations suggest a diagnosis of cystic fibrosis and the complications of cystic fibrosis may lead to better identification. This may result in more timely management and therefore has potentially important resource implications, albeit indirectly. Therefore, it was important those manifestations and complications were included in the committee’s recommendations.
5.7.3. Quality of evidence
Prospective and retrospective observational studies were included in the review. The quality of evidence as assessed per individual studies was very low. The main sources of bias in the studies were:
Selection bias: It was noted that most studies do not indicate whether children had undergone newborn screening. Although committee members were able to assume that in some of the studies it was likely the participants were not assessed based on the date of the study and the country (Hubert 2004 - France).
Prognostic factor of interest or outcome of interest not defined: It was noted that some studies did not adequately define the symptom evaluated. Other studies did not provide details about how sweat test was conducted or the thresholds used for diagnosis.
Lack of control of potential confounders: Studies did not indicate if the people included in the studies presented with other sign or symptoms suggestive of cystic fibrosis. This was considered a very serious limitation.
Due to all these limitations, the committee considered that the usefulness of prevalence data reported in the studies is very limited.
None of the studies reported diagnostic accuracy data or enough data to calculate diagnostic outcomes.
5.7.4. Other considerations
No equality issues were identified by the committee for this review question.
The committee agreed there was no need to prioritise a research recommendation for this topic. They noted that a universal screening programme is in place in the UK since 2006. In addition, they agreed their clinical experience and expertise was sufficient to draft recommendations regarding the clinical features that should lead to investigation of cystic fibrosis.
The committee noted that there are useful publications on diagnosing cystic fibrosis that health care professionals can refer to, such as the Guidelines for the Performance of the Sweat Test for the Investigation of Cystic Fibrosis in the UK, 2nd Version, by the Royal College of Paediatrics and Child Health (2014); and the supporting publications by Public Health England (2012) on the newborn blood spot screening programme in relation to cystic fibrosis, which are available online.
5.7.5. Key conclusions
The committee concluded that cystic fibrosis is a clinical syndrome that is diagnosed based on clinical presentation. This diagnosis can be confirmed by sweat test and a genetic test. In infants, children, young people and adults that have not been previously diagnosed with cystic fibrosis, including those who had a negative newborn screening test, cystic fibrosis can be suspected based on family history or if one or more of the following signs or symptoms are present: meconium ileus or DIOS, respiratory symptoms, pancreatitis, faltering growth or malnutrition, symptoms of malabsorption, rectal prolapse or pseudo-Bartter syndrome.
5.8. Recommendations
- 1.
Be aware that cystic fibrosis can be diagnosed based on:
positive test results in people with no symptoms, for example infant screening (blood spot immunoreactive trypsin test) followed by sweat and gene tests for confirmation or
clinical manifestations, supported by sweat or gene test results for confirmation or
clinical manifestations alone, in the rare case of people with symptoms who have normal sweat or gene test results.
- 2.
Assess for cystic fibrosis and, when clinically appropriate, perform a sweat test (for children and young people) or a cystic fibrosis gene test (for adults) in people with any of the following:
family history
congenital intestinal atresia
meconium ileus
symptoms and signs that suggest distal intestinal obstruction syndrome
faltering growth (in infants and young children)
undernutrition
recurrent and chronic pulmonary disease, such as:
recurrent lower respiratory tract infections
clinical or radiological evidence of lung disease (in particular bronchiectasis)
persistent chest X-ray changes
chronic wet or productive cough
chronic sinus disease
obstructive azoospermia (in young people and adults)
acute or chronic pancreatitis
malabsorption
rectal prolapse (in children)
pseudo-Bartter syndrome.
- 3.
Refer people with suspected cystic fibrosis to a specialist cystic fibrosis centre if:
they have a positive or equivocal sweat test result
their assessment suggests they have cystic fibrosis but their test results are normal
gene testing reveals 1 or more cystic fibrosis mutations.
FAQs
Diagnosis of cystic fibrosis? ›
A sweat test checks for high levels of chloride in your sweat. The sweat test is the standard test for diagnosing cystic fibrosis. It may be used if you have symptoms that may indicate cystic fibrosis or to confirm a positive diagnosis from a screening of your newborn baby.
How is cystic fibrosis diagnosed? ›Cystic Fibrosis Diagnosis
Most people are diagnosed with CF at birth with newborn screening, or before 2 years of age. A doctor who sees the symptoms of CF will order a sweat test or a genetic test to confirm the diagnosis. A sweat test is the most common test used to diagnose CF. It is a painless test.
Diagnosing CF is a multistep process. A complete diagnostic evaluation should include a newborn screening, a sweat chloride test, a genetic or carrier test, and a clinical evaluation at a CF Foundation-accredited care center.
What is the most specific test for cystic fibrosis? ›A “sweat test” is thought to be the most reliable way to tell if someone has CF. It checks the amount of salt in your sweat. People with CF have higher levels of chloride, a compound in salt. This test can be done on people of any age.
What are the tests and screening for cystic fibrosis? ›Doctors diagnose cystic fibrosis using a blood test that looks for the CF gene. There is also a sweat test, which looks for saltier-than-normal sweat, another symptom of cystic fibrosis. Doctors may use other tests, such as a chest x-ray or upper GI series, to check for lung and bowel problems caused by CF.
What is the first test for cystic fibrosis? ›Every state's CF newborn screening program begins with a blood test from the baby to check the levels of a chemical made by the pancreas called immunoreactive trypsinogen (IRT). IRT is normally found in small levels in the body.
What is one of the first signs of cystic fibrosis? ›Call your provider if an infant or child has symptoms of CF, and experiences: Fever, increased coughing, changes in sputum or blood in sputum, loss of appetite, or other signs of pneumonia. Increased weight loss. More frequent bowel movements or stools that are foul-smelling or have more mucus.
What is the gold standard for diagnosing cystic fibrosis? ›A well-performed and well-interpreted sweat test is the gold standard for accurately diagnosing cystic fibrosis.
What test is the gold standard for diagnosing CF? ›The sweat test (ST) measures chloride levels in sweat and is considered the gold standard for the diagnosis of cystic fibrosis (CF).
Which test is the gold standard for diagnosing cystic fibrosis? ›The sweat test is considered the most reliable for diagnosing cystic fibrosis. Sweat tests should be done at a CF Foundation-accredited care center, where guidelines are used to help ensure accurate results.
How is CF diagnosed in adults? ›
A person with cystic fibrosis generally has more salt in his or her sweat. A genetics test can also be used to diagnose. Other tests may be required, including a blood test, sputum (mucus) test, and a lung function test to measure how well you are breathing.
What is the workup for cystic fibrosis? ›Requirements for a CF diagnosis include either positive genetic testing or positive sweat chloride test findings (>60 mEq/L) and 1 of the following: Typical chronic obstructive pulmonary disease. Documented exocrine pancreatic insufficiency. Positive family history (usually affected sibling)
Can lung function test detect cystic fibrosis? ›Pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions, such as asthma and cystic fibrosis (CF), in children over 6 years of age.
Can cystic fibrosis go undetected? ›However, not every case of CF presents with meconium ileus in the newborn, failure to thrive, or severe lung disease. Atypical CF is characterized by a milder form of the disease usually remaining undiagnosed for years, even into late adulthood [2].
Can cystic fibrosis be diagnosed later in life? ›While most cystic fibrosis patients are diagnosed by the time they are two years old, and others are diagnosed in adulthood. It's important to recognize that there are more than 1,800 mutations in the cystic fibrosis gene, which may complicate the diagnosis.
Can you see cystic fibrosis on a CT scan? ›Chest or abdominal computed tomography (CT) scan: These exams use special x-ray equipment and computers to produce detailed images of the inside of the lungs or intestines. These images can help determine the severity of cystic fibrosis by looking for abnormal mucus and for dilated airways in the lungs.
What is the life expectancy of a person with CF? ›Just three decades ago, the average person with cystic fibrosis would live only to the age of 30, but now 50 years is typical, and some patients with CF live into their 80s. This means they live long enough for other health concerns to surface.