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Draft Genetic Test Review

Cystic Fibrosis
Clinical Utility
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CLINICAL UTILITY

Question 26: What is the natural history of the disorder?
Question 27: What is the impact of a positive (or negative) test on patient care?
Question 28: If applicable, are diagnostic tests available?
Question 29: Is there an effective remedy or acceptable action, or other measurable benefit?
Question 30: Is there general access to that remedy or action?
Question 31: Is the test being offered to a socially vulnerable population?  
Question 32: What quality assurance measures are in place?
Question 33: What are the results of pilot trials?
Question 34: What health risks can be identified for follow-up testing and/or intervention?
Question 35: What are the financial costs associated with testing?  
Question 36: What are the economic benefits associated with actions resulting from testing?
Question 37: What facilities/personnel are available or easily put in place?  
Question 38: What educational materials have been developed and validated, and which of these are available?
Question 39: Are there informed consent requirements?
Question 40: What methods exist for long term monitoring?  
Question 41: What guidelines have been developed for evaluating program performance?


CLINICAL UTILITY

Question 26:  What is the natural history of the disorder?

Summary 

  • In the year 2000, the median age at death for individuals with cystic fibrosis is 24 years

  • The projected median age for survival in the year 2000 is 32.2 years

  • Respiratory morbidity is the most frequent cause of death, and liver disease is the second most  frequent cause

  • Improved survival time in recent years can be largely attributed to more effective management, delivered by specialized centers

  • Examples of newer treatments include enzymes to digest mucus and lung transplantation

  • Research is ongoing to develop strategies for gene therapy

Respiratory morbidity is the most frequent cause of death among individuals with cystic fibrosis.  The highly viscous mucus secretions in the respiratory tract cannot be adequately cleared.  This provides an ideal habitat for bacterial colonization and subsequent lung infection.  This, in turn, results in chronic bronchial and lung inflammation.  Bacterial infections associated with a marked inflammatory response occur frequently in untreated infants under three months of age (Armstrong et al., 1995; Khan et al., 1995).  Some primary lung changes may precede postnatal lung infection (Ornoy et al., 1987).  Occasionally, inflammatory responses have been seen even in the absence of positive bacterial cultures, suggesting that some intrinsic factor, such as the biochemical defect itself, may act as a trigger (Khan et al., 1995).  The severe inflammatory response is responsible for progressive tissue damage which eventually results in destruction of the bronchial passages and, together with plugging of the airways, leads to respiratory failure.  Airway obstruction, caused by abnormal secretion, inflammatory exudate and epithelial debris, results in further hyperinflation or collapse.  Chronic hypoxia is a major factor causing pulmonary hypertension and cor pulmonale.  Pneumothorax and hemoptysis are common complications in those with advanced disease.

Cystic fibrosis related liver disease is the second most common cause of mortality after lung disease.  The incidence increases with age from about 0.3 percent before the age of 5 years to a peak of 8.7 percent in those aged 16-20 years (Scott-Jupp et al., 1991).  The exact pathogenesis of the disease is unknown; however, recent evidence suggests that defective CFTR chloride channel function may cause abnormal biliary secretions resulting in mucus plugging of intrahepatic bile ducts (Grubman et al., 1995).  This, in combination with other factors such as increased levels of toxic bile acids and inflammatory cytokines, has been implicated in the development of portal hypertension and associated cirrhosis (Maurage et al., 1989; Tanner, 1992).

Severe gastrointestinal disease in the form of intestinal obstruction caused by meconium ileus is the first clinical manifestation in 10-18 percent of newborns with cystic fibrosis (Rescorla et al., 1989; Littlewood 1992).  Meconium ileus is frequently associated with peritonitis, volvulus and atresia.  Because of the severity of these complications, mortality in the first month of life is higher when meconium ileus is present.  Thereafter, the clinical course is similar whether or not meconium ileus was present (Coutts et al., 1997), although those with meconium ileus may have a higher risk of developing liver complications (Padoan et al., 1997).

Many of the subsequent clinical manifestations related to the gastrointestinal tract are due to malabsorption, the main cause of which is insufficient pancreatic enzyme and bicarbonate activity.  In the absence of pancreatic enzyme secretion, protein and fat malabsorption occurs, leading to bulky, frequent malodorous stools with an abnormally high fat (steatorrhea) and nutrient content (Murphy et al., 1991).  Approximately 60 percent of neonates diagnosed with cystic fibrosis through neonatal screening already suffer from pancreatic insufficiency and require dietary pancreatic enzyme supplements (Waters et al., 1990).  By 12 months, the frequency of pancreatic insufficiency has risen to 92 percent (Bronstein et al., 1992).  Most of those who develop pancreatic insufficiency will do so before the age of 10 years (Cooper et al., 1992).    The prevalence of pancreatic insufficiency in adults with cystic fibrosis exceeds 85 percent (Gaskin et al., 1982) and is probably closer to 95 percent.  Further complications of pancreatic dysfunction include impaired glucose tolerance, leading to diabetes mellitus.  As adults, cystic fibrosis patients are approximately six times more likely than unaffected individuals to develop digestive tract cancers (Neglia et al., 1995; Schöni et al., 1996).  As with digestive tract cancer, the prevalence of diabetes is increasing in cystic fibrosis patients because of improved survival.  In a recent study performed over a 5-year period, the average annual incidence was 3.8 percent, and prevalence increased from 11 percent to 24 percent, overall.  In those aged over 20 years, the annual incidence was 9.3 percent, and the prevalence rose from 25 percent to 53 percent (Lanng et al., 1994).  Reports of microvascular complications such as retinopathy, nephropathy and neuropathy among cystic fibrosis patients with diabetes are also increasing.

Esophageal problems include frequent gastroesophageal reflux, peptic esophagitis or esophageal varices.  Approximately 25 percent of cystic fibrosis patients aged 5 years or more have gastroesophageal reflux (Malfoot et al., 1991).  In the small intestine, viscous mucin leads to obstruction of the goblet cells, Brunner cells and even the lumen.  Clinical problems include rectal prolapse, distal intestinal obstruction syndrome, intussusception and volvulus.  More recently, fibrosing colonopathy leading to colonic strictures has been observed as a rare complication of high lipase pancreatic enzyme treatment.

Lung transplantation was introduced as a therapeutic modality for cystic fibrosis in 1988; three of those procedures were performed for that reason in 1988, and the number rose steadily on an annual basis until 1995, when 136 transplantations were carried out.  The number leveled off, thereafter (Cystic Fibrosis Foundation, 2000).  In the year 2000, 161 lung transplants of various types were carried out (bilateral 134, heart-lung 1, lobar-cadaveric 10, lobar-living related donor 11, lobar-unrelated donor 5).  In addition, 18 liver transplants and 6 "other" transplants were performed.  Patients with cystic fibrosis now account for an important portion of lung transplants done annually in the United States. Kurland and Orenstein [2001] wrote a commentary explaining the difficulties encountered by families in this situation.  This article highlighted the psychological, social, medical and financial costs faced by patients, families, and caregivers, over and above the traditional stresses associated with managing this chronic, progressive disorder.  Even in the absence of transplantation, patients with cystic fibrosis often face increasing psychosocial, as well as medical, difficulties as they reach adulthood.  One young woman with cystic fibrosis recently described her day-to-day struggles (Hillyard, 2001).  One important hope for the future is gene therapy, and research currently focuses on how this treatment might be effectively delivered to the lungs of affected individuals (McCray, 2001).  Although promising, this treatment modality has not yet proven successful.

References

Armstrong DS, Grimwood K, Carzino R, Carlin J, Olinsky A, Phelan PD.  1995.  Lower respiratory tract infection and inflammation in infants with newly diagnosed cystic fibrosis.  BMJ  310:1570-1572.

Bronstein MN, Sokol RJ, Abman SH, Chatfield BA, Hammond KB, Hornbridge KM, et al.  1992.  Pancreatic insufficiency, growth and nutrition in infants identified by newborn screening as having cystic fibrosis.  J Pediatr  120:533-540.

Coutts JAP, Docherty JG, Carachi R, Evans TJ.  1997.  Clinical course of patients with cystic fibrosis presenting with meconium ileus.  Br J Surg  84:555.

Gaskin KJ, Gurwitz D, Durie P, Corey M, Levison H, Forstner G.  1982.  Improved respiratory prognosis in patients with cystic fibrosis and normal fat absorption.  J Pediatr  100:857-862.

Grubman SA, Fang SL, Mulberg AE, Perrone RD, Rogers LC, Lee DW, et al.  1995.  Correction of the cystic fibrosis defect by gene complementation in human intrahepatic biliary epithelial cell lines.  Gastroenterology  108:584-592.

Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DWH.  1995.  Early pulmonary inflammation in infants with cystic fibrosis.  Am J Respir Crit Care Med  151:1075-1082.

Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiøtz, Koch C.  1994.  Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications.  Acta Paediatr  83:72-77.

Littlewood JM.  1992.  Gastrointestinal complications in cystic fibrosis.  J R Soc Med  85 (suppl 18):13-19.

Malfoot A, Dab I.  1991.  New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow-up.  Arch Dis Child  66:1339-1345.

Maurage C, Lenaerts C, Weber AM, Brochu P, Yousef I, Roy CC.  1989.  Meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis.  J Pediatr Gastroenterol Nutr  9:17-20.

Murphy JL, Wooton SA, Bond SA, Jackson AA.  1991.  Energy content of stools in healthy normal controls and patients with cystic fibrosis.  Arch Dis Child  66:495-500.

Neglia JP, FitzSimmons SC, Maisonneuve P, Schöni MH, Schöni-Affloter F, Corey M, et al.  1995.  The risk of cancer among patients with cystic-fibrosis.  N Engl J Med  332:494-499.

Ornoy A, Arnon J, Katznelson D, Granat M, Caspi B, Chemke A.  1987.  Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis.  Am J Med Genet  28:935-947.

Padoan R, Marzano MT, Colombo C, Genoni S, Corbetta C, Seia M, et al.  1997.  Genotype prognosis and clinical follow-up of cystic fibrosis patients with meconium ileus or neonatal intestinal obstruction [abstract].  Proceedings 21st European Cystic Fibrosis Conference (EWGCF), 157.

Rescorla FJ, Grosfield JL, West KJ, Vane DW.  1989.  Changing pattern of treatment and survival of neonates with meconium ileus.  Arch Surg  51:34-48.

Schöni MH, Mainsonneuve P, Schöni-Affloter F, Lowenfels AB.  1996.  Cancer risk in patients with cystic fibrosis: The European data.  J R Soc Med  89 (suppl 27):38-43.

Scott-Jupp R, Lama M, Tanner MS.  1991.  Prevalence of liver disease in cystic fibrosis.  Arch Dis Child  66:698-701.

Waters DL, Dorney SFA, Gaskin KJ, Grauca MA, O’Halloran M, Wilken B.  1990.  Pancreatic function in infants identified as cystic fibrosis in a neonatal screening program.  N Engl J Med  322:303-308.


CLINICAL UTILITY  
Question 27:  What is the impact of a positive (or negative) test on patient care?

Summary

When both partners have an identifiable mutation, genetic counseling is provided to advise the couple of the risk that the fetus is affected (1 in 4) and possible options

When one partner has an identifiable mutation but the other does not there are two possibilities depending on the screening model employed

  • With the two-step (sequential) and expanded one-step (concurrent) models, the couple is notified and counseled that there is an increased risk over background, but no further testing is recommended  

  • With the one-step (couple) model, the couple will be classified as having a negative test result and not counseled.

When the first, or both, partners have a negative test, the couple receives a negative test result and no further testing is recommended.

Screening models
The initial impact of prenatal screening for cystic fibrosis on patient care depends upon which of three published models is being used.  

The two-step (sequential) model, the pregnant woman's sample is collected and analyzed.  If a mutation is identified, the woman is made aware of this finding, counseled, and her cooperation sought in obtaining a sample from her partner for DNA analysis.  Approximately 1 in 30 screened non-Hispanic Caucasian women will require counseling in this model.  When the partner is also identified as having a mutation, the couple will then be provided with more intensive counseling, given the 1 in 4 risk that the fetus will be affected by cystic fibrosis.  Approximately 1 in 900 screened pregnancies will fall into this category.  The uptake of diagnostic testing and decision-making about termination of affected fetuses found in pilot trials is summarized in Question 33, Table 4-3.

The one-step model, samples are collected from both the pregnant woman and her partner at the outset.  DNA analysis is then performed on the woman's sample, but the partner's sample is tested only if a mutation is identified in the woman.  Notification of a positive screening result is made only when both partners are found to carry a mutation (unless the woman specifically requests a report of her carrier status).  In this model, more effort is required initially to obtain samples from both partners, but the need for counseling is reduced; being restricted to the 1 in 900 couples who will need to make decisions about diagnostic testing. 

The modified one-step model, has been recommended by the American College of Medical Genetics (Grody et al., 2001).  It calls for samples to be collected at the outset from both partners (as in the one-step model, above).  DNA testing is then performed on all of the samples from both partners.  Notification is made when a mutation is found in either partner, and counseling is provided.

If all couples with positive screening results for cystic fibrosis were to choose diagnostic testing, this would lead to one additional amniocentesis (or CVS) for every 900 couples screened.  The impact on prenatal diagnostic testing services is relatively small, in comparison to demands incurred by other prenatal screening tests.  For example, if a woman's age of 35 is used as a screening test for Down syndrome, 100 amniocenteses would be performed for every 1,000 women screened.  Even with more efficient serum screening tests for Down syndrome, between 30 and 50 amniocenteses would be indicated for every 1,000 screened women.

Other data indicate that during the two-step process, the women identified as being carriers of a CF mutation usually experience some anxiety while awaiting the partner’s results.  However, this worry usually resolves when the partner is found not to carry and identifiable mutation (Miedzybrodzka et al., 1995; Mennie et al., 1992; Grody et al., 1997).  In both the two-step and modified one-step process, couples will be identified where one partner is a carrier and the other is not.  These couples are at a higher risk than background (Question 23), but no definitive testing is available to provide diagnostic testing for their fetus.

References

Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ.  2001.  Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.  Genet Med  3:149-154.

Grody WW, Dunkel-Schetter C, Tatugawa ZH, Fox MA, Fang CY, Cantor RM et al.  1997.  PCR-based screening for cystic fibrosis carrier mutations in an ethnically diverse pregnant population.  Am J Hum Genet  50:935-947.

Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, Whyte DA, Brock DJH.  1992.  Prenatal screening for cystic fibrosis.  Lancet  340:214-216.

Miedzybrodzka ZH, Hall MH, Mollison J Templeton A, Russel T et al.  1995.  Antenatal screening for carriers of cystic fibrosis: randomised trial of stepwise v couple screening.  BMJ  310:353-357.


CLINICAL UTILITY

Question 28:  If applicable, are diagnostic tests available?

The purpose of prenatal screening for cystic fibrosis is to determine whether or not that disorder is present in the fetus.  The diagnostic test is DNA testing for cystic fibrosis mutations in fetally derived cells obtained via amniocentesis, or chorion villus sampling (CVS).  If two disease-causing mutations are identified, the couple is counseled that the fetus will have the disorder.


CLINICAL UTILITY  

Question 29:  Is there an effective remedy, acceptable action, or other measurable benefit?

There is no effective treatment in utero for cystic fibrosis identified in the fetus.  However, the pregnant woman and her partner can choose to terminate the pregnancy and thus avoid the birth of an affected child.  For couples who choose to terminate an affected pregnancy, there is an assumption of benefit, although little research exists on the psychological sequelae of this decision.  The couple might also choose to continue the pregnancy and plan for initiating treatment immediately after birth.  There is little information about the psychological sequelae of this decision, either.  The couple might want to consider alternatives for future reproductive planning, including adoption and preimplantation genetic testing. Some couples identified as carriers might be unwilling to undergo further testing in their current pregnancy but might, nevertheless, alter their reproductive behavior in future pregnancies.  There are some studies that suggest that carriers misunderstand the implications of carrier status for their own health and for the health of their children. 

References

Grody WW, Dunkel-Schetter C, Tatugawa ZH, Fox MA, Fang CY, Cantor RM et al.  1997.  PCR-based screening       for cystic fibrosis carrier mutations in an ethnically diverse pregnant population.  Am J Hum Genet  50:935-947.

Loader S, Caldwell P, Kozyra, Levenkron JC, Boehm CD, Kazazian HH, Rowley PT.  1996.  Cystic fibrosis carrier population screening in the primary care setting.  Am J Hum Genet  59:234-247.

Marteau T, Dundas R, Axworthy D.  1997.  Long-term cognitive and emotional impact of genetic testing for carriers of cystic fibrosis: the effects of test result and gender.  Health Psych  16:51-62.

Miedzybrodzka ZH, Hall MH, Mollison J Templeton A, Russel T et al.  1995.  Antenatal screening for carriers of cystic fibrosis: randomised trial of stepwise v couple screening.  BMJ  310:353-357.

Witt DR, Schaefer C, Hallam P, Wi S, Blumberg B, Fishbach A et al.  1996.  Cystic fibrosis heterozygote screening in 5,161 pregnant women.  Am J Hum Genet  48:823-835. 


CLINICAL UTILITY

Question 30:  Is there general access to that remedy or action?

Pregnancy termination before the third trimester is legal through federal statute, but access is limited by two factors.  First, there are areas of the country where health care practitioners providing this service are scarce.  Secondly, there are many states in which pregnancy termination is not a reimbursable service; this affects access by women with limited economic resources.  For couples choosing to continue the pregnancy, resources for treating the infant and child exist throughout the United States.


CLINICAL UTILITY

Question 31:  Is the test being offered to a socially vulnerable population?

Pregnant women are considered a medically vulnerable population, and a case can be made for their being psychosocially vulnerable, as well.  There is often a time-related urgency involved in medical decisions during pregnancy, which can foreshorten time to carefully consider options.  In addition, data have shown that women’s motivation to do whatever they can to protect the health of their fetus can lead to overestimates or misunderstandings of the benefits of prenatal testing.  Offering screening for cystic fibrosis early in pregnancy (at the first prenatal visit between 8 and 12 weeks’ gestation) allows for more time to consider further testing if both members of the couple are found to be carriers.  Carefully constructed and validated patient informational materials will also be important (Question 38).  It may be helpful to develop strategies for educating the public about this testing to alleviate the burden of ‘learning’ at the time of pregnancy.

 

Updated on August 13, 2004