Early Diagnosis of Cystic Fibrosis: To Screen or Not To Screen—An Important Question

(1)

LETTERS TO THE EDITOR

115

9. Anonymous. Azarcon use in Los Angeles County-Survey

results. Los Angeles County, Department of Health Services.

Public Health Letter, Vol 4, No. 8, August 1982 10. Trotter R: Preliminary report of survey findings concerning

azarcon and greta use for empacho. Presented at US/Mexico

Cross Border Health Association meeting in Albuquerque,

NM, June 14, 1983

Early

Diagnosis

of Cystic

Fibrosis:

To Screen or Not To Screen-An Important

Question

To the Editor.

-Cystic fibrosis (CF) is one of the most complex

disor-ders faced by pediatricians and continues to be not only a challenge but an enigma for both physicians and

re-searchers. Although there is no cure for the pulmonary disease associated with CF, a variety of clinical ob-servationsl3 strongly suggest that early recognition and aggressive treatment can have a beneficial effect on the course of the disease. Thus, there has been considerable interest in the possibility of routine neonatal diagnosis by screening. Because of the absence of knowledge con-cerning the molecular pathogenesis of CF, diagnostic tests for CF have been dependent upon detection of secondary abnormalities. Of the organ system disturb-ances that might be evaluated in a screening test, only the pancreatic lesion has proved useful due to the lack of satisfactory sweat production in newborns and the

nor-mat pulmonary status at birth. Although the first neo-natal screening approach studied, namely meconium

analysis for protein, proved unsatisfactory when

rigor-ously investigated, a new test involving immunoreactive trypsinogen (IRT) analysis on dried neonatal blood spots

has generated worldwide enthusiasm. In fact,

develop-ment of the IRT analysis was cited as a major advance

in CF research during the past decade when a Delphi survey of practitioners and scientists was conducted by the National Institutes of Health.4

Recently, the Cystic Fibrosis Foundation convened a Task Force on Neonatal Screening to review data on the

IRT test and make recommendations for its use. Their report5 is informative and commendable in

recommend-ing further research before establishment of generalized mass screening. Because of its shortcomings, however, further exploration of relevant issues is needed.

First of all, it is extremely difficult to evaluate in a

fair, objective manner research projects that are currently

in progress, such as the investigation of Hammond and associates in Colorado. Conclusions about the

character-istics of the test and the screening system must await

further research. In fact, even more encouraging infor-mation about the IRT method was presented at the

Second International Congress on Pediatric Laboratory Medicine which met more recently. Statements such as

“the elevated IRT values fall rapidly”, and “there may be a delay of several weeks from initial screening until

diagnosis,” and the resulting “large number of sweat

tests” which could overwhelm “accredited laboratories” all represent judgments about problems that are unlikely

to occur. The implications that CF neonatal screening

will be dependent upon physician interest and that

fam-ilies will be indifferent because this is “a disease for which

there is no specific therapy” are also unlikely to be true,

in my opinion. Although more research is certainly

needed on the benefits and risks of neonatal screening for CF by IRT analysis, there may eventually be

compel-ling reasons to perform neonatal screening in some states

because of the following:

1. The IRT test is inexpensive (about $1 per newborn),

technically satisfactory, and probably will improve fur-ther with development of standardized antibody and quality control measures for routine use.

2. The yield of the IRT test in terms of numbers of

patients with CF diagnosis during neonatal period will be

relatively large because of the high CF gene frequency.

For instance, approximately a tenfold greater number of

patients with CF would be detected by neonatal screening programs compared with number ofpatients with

phenyt-ketonuria.

3. The IRT test has a sound basis and theoretically should have a high degree of specificity because of the

unique presence of pancreatic ductule obstruction at birth

in the majority of patients with CF. Despite the presence of the pancreatic lesion, the respiratory system (which generally determines prognosis) appears normal in neo-nates with CF.

4. The incidence of false-positive IRT tests appears to be acceptable, despite the Task Force report; figures as low as 0.1% and 0.3% were reported by investigators from Colorado and England, respectively, at the Second Inter-national Conference on Pediatric Laboratory Medicine.

5. The diagnosis of CF can be readily confirmed by a

pilocarpine iontophoresis sweat test. New technology has eliminated the problem of evaporative loss of sweat and

has reduced the volume needed for precise determination

of sodium and chloride concentrations. Another issue that was raised in the report concerning costs of sweat

testing is only a minor concern since the test is not

particularly expensive.

6. Implementation of a neonatal screening program

can be readily accomplished in most states using IRT

analysis coupled to sweat tests for confirmation of diag-nosis. All of the necessary elements currently exist

in-cluding methods for collection and processing of dried neonatal blood spots, reagent kits for the analysis per se, established CF centers in every region of the United

States for confirming the diagnosis, and teams of

dedi-cated caregivers to provide education and treatment. 7. Diagnosis in early infancy through centralized screening programs linked to CF centers will facilitate,

in fact accelerate, referral of patients to CF centers. As a result, the network of centers established by the Cystic

Fibrosis Foundation would be better utilized. This poten-tial benefit may be increasingly important for CF patients

because of the development of health maintenance

orga-nizations that will likely discourage referral to tertiary

care centers for comprehensive evaluation and treatment

programs.

at Viet Nam:AAP Sponsored on September 7, 2020

www.aappublications.org/news

(2)

1 16

PEDIATRICS

Vol. 73 No. 1 January1984

8. The IRT test would offer the opportunity to reduce

the number of missed cases and “lost” CF patients. This would clearly be advantageous since population statistics suggest that many patients with CF die without their disease ever having been diagnosed.6 Since CF is poten-tially lethal in early childhood, the benefits of the IRT test to some individuals would be critically important (in fact, life-saving).

9. With successful implementation of newborn

screen-ing by IRT analysis, genetic counseling could be im-proved, in fact optimized, since the first affected child could be identified, allowing an informed choice for future

family planning. Although the Task Force has correctly

pointed out that uncertainty exists regarding the impact

of neonatal screening relative to future reproductive

de-cision-making, the important point is that identifying the

index case of CF will give individual parents the

oppor-tunity to have genetic counseling at the earliest possible time and make an informed decision. The anguish

suf-fered by families who have multiple children whose

con-dition has been diagnosed as CF following recognition of

disease in the index case (eg, oldest sibling) convinces one of the great potential benefits of neonatal screening for individual families. The population impact will not be determined until this issue has been properly studied.

10. Early determination of CF, ie, avoiding delays in diagnosis, will improve the delivery of care, help avoid

part of the disease’s morbidity (eg, malnutrition), and even prevent some deaths. Currently, delayed diagnosis is common in many states. Rosenstein et a!7 reported

that there was a mean diagnostic delay of 15.4 months in 194 patients with CF seen at The Johns Hopkins Hospital from 1971 to 1981, and an average interval of 22 months

between the onset of steatorrhea with pulmonary disease

and eventual diagnosis of CF. The delay is likely to be

longer at CF centers serving a largely rural population as

evidenced by an average age of 45 months in the 42 most recently diagnosed cases of CF at the University of Wis-consin CF Center in Madison. Our experience and that

of other centers’ indicates that many patients already have advanced lung disease and irreversible

bronchopul-monary injury at the time of diagnosis. Although

pro-spective trials of aggressive treatment in neonatally

di-agnosed cases of CF have not been performed, there is a

good indication of potential benefits from a study of 16 sibling pairs by Orenstein et a!2 and from the spectacular

survival statistics reported by the Toronto CF Center,3 in which approximately 90% of the CF diagnoses are made before 1 year of age (H. Levison, personal commu-nication).

11. Research will be enhanced by the identification of a large population of presymptomatic CF patients. This

will allow complete epidemiologic investigation, better characterization of the natural course of the disease, and identification of subclinical abnormalities such as bio-chemical malnutrition which may in the long run have important clinical ramifications. Neonatal diagnosis by

screening could help eliminate many of the “bai’riers” to progress in research identified in the Delphi survey.4 For

instance, the pulmonary benefits of early aggressive

treat-ment regimens involving chest physiotherapy and

anti-biotics cannot be adequately studied unless early

diag-nosis is accomplished before secondary respiratory

corn-plications become established.

As the Task Force pointed out, there are several po-tential problems and negative features to neonatal screening for CF by IRT analysis including the following:

1. There will probably always be false-negative CF

neonatal screening tests with methods that detect pan-creatic abnormalities. Although the IRT test is imperfect,

it should be emphasized that: (a) a minority of patients are missed (10% to 25%); (b) catastrophic results such as irreversible brain damage in “missed cases” of

phenylke-tonunia or hypothyroidisms should not occur; (c) the

course of CF is milder in patients with malabsorption, ie, those with “intact” pancreatic function8; and (d) many more years of research may be needed before a better test can be advised allowing detection of the elusive metabolic

defect in CF.

2. Psychological damage may result in cases of

false-positive IRT tests and even in patients for whom the CF diagnosis is accurate (the “stigmatization” phenomenon). Although the former problem can be managed by a good screening program with effective communication and ed-ucation, the latter issue needs to be investigated. Never-theless, it can be argued that the psychological damage of delayed diagnoses and unnecessary anxiety in families with sick children will offset this concern.

3. The IRT test may not be cost effective unless the patients derive clinical benefit with amelioration of symptoms, reduced morbidity, fewer hospitalizations, etc.

This issue remains to be studied and will require many years of research. Because state governments may require

neonatal screening programs to pay for themselves in the future, it is important to evaluate the cost effectiveness of all neonatal screening tests.

4. CF centers will be required to do more sweat tests on infants than in the past. This is a minor problem,

however, because of the apparently low incidence of

false-positive IRT tests results. Calculations based on data from Colorado applied to our Center indicate that we would only increase our number of sweat tests by 30% per year, which would be readily manageable.

5. Physicians may “dismiss consideration of CF based on normal screening results”, ie, not respond appropri-ately to symptomatic patients. This concern could be overcome by appropriately educating primary care phy-sicians who are already well aware of the potential for inaccurate tests from their experience with other inborn errors of metabolism.

6. Litigation might result from inaccurate tests or from ineffective communication (eg, misunderstood ge-netic counseling). This problem also applies to neonatal screening for other metabolic disorders, and it remains to be determined whether a CF test would cause medi-colegal confrontations.

From this discussion of positive and negative aspects of neonatal screening, it can be readily appreciated why enthusiasm has developed around the world for the IRT

test. A large number of pediatric practitioners and

re-searchers are optimistic that this approach will offer

significant advantages for both care and future research.

(3)

LETTERS TO THE EDITOR

117

Therefore, it is important that the Cystic Fibrosis Foun-dation’s Task Force Report be interpreted properly as a

caution against immediate establishment of mass

screen-ing for CF in general and as a call for “extensive

re-search ... determining the value of early treatment . ..the reliability and validity of the screening method ... and

the benefits and risks of early detection.” It must be recognized that ultimately the decision “to screen or not to screen” will be made by individual states on the basis of regional considerations.

REFERENCES

PHILIP M. FARRELL, MD, PHD Department of Pediatrics

University of Wisconsin Medical School

Madison, WI 53706

1. Wood RE, Boat TF, Doershuk CF: State of the art: Cystic fibrosis. Am Rev Respir Dis 1976;113:833

2. Orenstein DM, Boat TF, Stern RC, et at: The effect of early diagnosis and treatment in cystic fibrosis. Am J Dis Child

1977;131:973

3. Corey ML: Longitudinal studies in cystic fibrosis, in Stur-gess (ed): Perspectives in Cystic Fibrosis, Proceedings of the 8th International Cystic Fibrosis Congress, 1980, p 245

4. A Ten Year Evaluation of Pediatric Pulmonary Diseases.

Washington, DC, Government Printing Office, in press 1984

5. Ad Hoc Committee Task Force on Neonatal Screening, Cystic Fibrosis Foundation: Neonatal screening for cystic fibrosis: Position paper. Pediatrics 1983;72:741

6. Warwick WJ: Undiagnosed patients with cystic fibrosis. J Chron Dis 1980;33:685

7. Rosenstein BJ, Langbaum TS, Metz SJ: Cystic fibrosis: Diagnostic considerations. Johns Hopkins Med J 1982;150:1 13

8. Gaskin K, Gurwitz D, Durey P, et al: Improved respiratory prognosis in patients with cystic fibrosis with normal fat

absorption. J Pediatr 1982;100:857

Uses

Higher

Level

To the

Editor.-Watchko and Oski’s one act play about yellow fever among pediatricians was deeply appreciated (Bilirubin 20 mg/dL = vigintiphobia Pediatrics 1983;71:660-663). I

note they cite several of the Acta Paediatrica Scandinczv-ica articles for their references but fail to cite my favorite by Bengtsson and Verneholt (Acta Paediatr Scand

1974;63:70-80). In this article 108 Coombs negative term

infants were reported and followed from ages 6 to 13 years, all of these infants had a peak bilirubin >20 mg/

dL. Five (all boys) of this group of 108-one of whom

had bilirubin of 51 mg/dL-had some neurologic deficit. One of this group of five had a peak bilirubin of 24 (for

seven of the first ten days of life it was >21). Bengtsson

“concludes” that a bilirubin of 25 should thus be our upper limit and that’s where I’ve sat since. Rarely have I been feverish.

WILLIAM D. COCHRAN, MD

Beth Israel Hospital

330 Brookline Ave

Boston, MA 02215

Who

Has Bugs?

To the

Editor.-Recently, a 26-month-old female child was brought

into our emergency service by her mother who claimed that the child had “bugs.” An extensive search for head lice, scabies, or any other evidence of infestation revealed nothing.

When the mother was questioned again about where the bugs were, she pointed to the child’s skin and tried to demonstrate that she

too

had them, by vigorously

“rubbing” them out of her palms and forearms, again to no avail. It was then noticed that the mother was slightly tremulous and diaphoretic while obviously intensely

con-cerned about the “bugs.” Further questioning revealed

that the mother was a chronic cocaine abuser and that

she had been experiencing these visual and tactile hallu-cinations for weeks.

We feel this case exemplifies one of the problems that can be seen when evaluating the child of a cocaine-abusing parent: a projection of symptomatology onto the child, thereby including the child in the hallucination. Cocaine bugs (Magnan’s sign) or tactile hallucinations, are well known in chronic cocaine abusers’ as a manifes-tation of altered tactile perception.

Even in the absence of objective signs of infestation,

this child might have been treated for scabies or lice

empirically if the mother’s history had been considered

accurate. This case emphasizes the importance of a good

history (including drug utilization and dependency) and

physical examination in families manifesting cutaneous symptomatology without physical corroboration. At times this diagnosis may be very difficult, as the subcu-taneous crawling sensation may lead to self-excoriation and even excoriation of the child’s skin with a potential

“pseudoscabitic” appearance. Awareness of the mother’s

medical problem made possible the correct diagnosis,

obviated the need for such treatment, and avoided the potential risk of single or multiple exposures to a

scabi-cide in a 26-month-old child. In addition we were able to

direct social agency support to this family.

REFERENCE

ALAN KULBERG, MD

Pediatric Emergency Service

LEwIs GOLDFRANK, MD Emergency Medical Services Bellevue Hospital Center

New York, NY 10016

1. Goldfrank LR, Lewin N, Weisman RS: Cocaine, in

Toxico-logic Emergencies: A Comprehensive Handbook in Problem

Solving. New York, Appleton-Century-Crofts, 1982, pp

179-188

Biostatistics in Pediatrics

To the

Editor.-I read with great interest the recent article by Hayden’ concerning the expanding use (and misuse) of

(4)

1984;73;115

Pediatrics

PHILIP M. FARRELL

Question

An Important

−−