Topics in Chronic Granulomatous Disease

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LETTERS TO THE EDITOR 183 pered by the sensitivity of development to the

environ-rnent (which may itself change) and also by the fact that

different domains attain prominence at different times

(eg, language and academic skills).7’2 To address prob-lems in prediction, child development specialists and the American Academy of Pediatrics recommend repeating measurements through time (whether it be screening or diagnostic tests) rather than extrapolating from admin-istration of a single test.’3 Most intervention programs

deal effectively with the problem of prediction by

reas-sessing young children usually within 6 months after

admission. Children who then perform within normal

limits may be dismissed to more typical and less

expen-sive forms of stimulation, such as day care or parent

training. Thus, it seems less than crucial for screening tests to include indicators of predictive validity.

The criteria we used to select tests for review are clearly stated in our article. We included tests for differ-ent age groups because Public Law 99-457 extends public

school services to 3- to S-year-olds, as well as to infants

and toddlers. Because it is difficult for practicing pedia-tricians to give multiple screening tests, we selected meas-ures which, according to the test authors, assessed a variety of developmental domains. Although these selec-tion criteria excluded most single-domain screens (such as those of language or school readiness), we found that,

on occasion, authors’ descriptions of what tests measured

and what panelists thought tests measured varied sub-stantially. It is our ratings of test content, not the authors, which are reflected in the table.

The panelists’ ratings on the quality of standardization were based on: (a) information in the test manual on construction (eg, age, gender, race, geographic residence,

and socioeconomic status) and; (b) peer reviewed research

for information on validity, sensitivity, and specificity,

etc. Some authors include copies of journal articles in

their test manuals or refer to published studies. In the

absence of either, there is no choice but to depend on the

authors’ descriptions of his or her own research. Disa-greements among panelists were resolved in one of two ways: by taking the consensus response or by assigning

numbers to ratings and using the mean.

In summary, our paper makes an important

contribu-tion to the literature on developmental screening by

informing pediatricians about various tests, by helping

establish criteria by which a quality measure can be

identified, and by evaluating the relative merits of a

number of tests. Pediatricians should be able to use the criteria described in the article to evaluate the many new

and revised tests which have entered the market since

our paper was submitted for publication.’4’7 Although no

test is perfect, some are clearly superior to others. Crucial decisions which significantly affect the lives of families

and young children are made on the basis of screening

tests. In fact, children’s eligibility for intervention

serv-ices often is established by screening, even if services

only extend to providing further testing. As Drs Felt and Stancin suggest, there is clearly a need for a comprehen-sive screening process which includes the context of

children’s lives. However, as long as the measurement of

development is a part of the process, there is a need to

use quality screening tests which are known to be accu-rate.

REFERENCES

FRANCES PAGE GLASCOE, PHD

Child Development Center

Department of Pediatrics

Vanderbilt University

2100 Pierce Avenue

Nashville, Tennessee 37232

1. Glascoe FP, Martin ED, Humphrey S. A comparative review

of developmental screening tests. Pediatrics. 1990;86:547-554

2. American Psychological Association. Standards for

Educa-tional and Psychological Tests. Washington, DC: American Psychological Association; 1985

3. Lichtenstein R, Ireton H. Preschool Screening: Identifying Young Children with Developmental and Educational Prob-lems. Orlando, FL: Grune & Stratton; 1984

4. Barnes KE. Preschool Screening: The Measurement and

Prediction of Children at Risk. Springfield, IL: Charles C

Thomas Publisher; 1982

5. Meisels SJ. Developmental Screening in Early Childhood: A

Guide. Washington, DC: National Association for the

Edu-cation of Young Children; 1985

6. Wolery M. Child find and screening issues. In: Baily DB,

Wolery M, eds. Assessing Infants and Preschoolers With

Handicaps. Columbus, OH: Merrill Publishing Co; 1989;1

19-143

7. Gallagher JJ, Ramey CT. The Malleability of Children. Bal-timore, MD: Paul H. Brookes Publishing Co., 1987

8. Aylward GP. Environmental Influences on the

Develop-mental Outcome of Children at Risk. Infants and Young

Children. 1990;2:1-9

9. Infant Health and Development Program. Enhancing the

outcomes of low-birth weight, premature infants. JAMA.

1990;263:3035-3042

10. Meisels SJ, Wasik BA. Who should be served? Identifying

children in need of early intervention. In: Meisels SJ, Shon-koff JP, eds. Handbook of Early Childhood Intervention.

Cambridge, MA: Cambridge University Press; 1990;605-632

11. Aylward GP, Gustafson N, Verhulst SJ, et al. Consistency

in diagnosis of cognitive, motor and neurologic function over the first three years. J Pediatr Psychol. 1987;12:77-98 12. Bell RQ. Age-specific manifestations in changing

psycho-social risk. In: Farran DC, McKinney JC, eds. Risk in

Intellectual and Psychosocial Development. Orlando, FL: Ac-ademic Press, Inc; 1986

13. Committee on Children with Disabilities. Screening for

de-velopmental disabilities. Pediatrics. 1986;78:526-528

14. Frankenburg W, Dodds J, Archer P, Bresnick B, Shapiro H.

The Denver II: revision and restandardization of the DDST. AJDC. 1990;144:446

15. Ireton H, Thwing E. Minnesota Child Development Inven-tories-Revised. Minneapolis, MN: Behavior Science Sys-tems; in preparation

16. Harrison PL, ed. Early Screening Profile. Circle Pines, MN:

American Guidance Service; 1990

17. Glascoe FP. Developmental screening: rationale, methods

and application. Infants and Young Children. In press

Topics

in Chronic

Granulomatous

Disease

To the

Editor.-Such phagocytic cells as neutrophils and macrophages

are crucial elements in the host defense against bacterial

at Viet Nam:AAP Sponsored on September 2, 2020

www.aappublications.org/news

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TABLE. Types of Chronic Granulomatous Disease

184 LETTERS TO THE EDITOR

Types Inheritance Incidence,*

%

Factors of NADP H Oxidase System

Cytochrome b Cytosolic Proteins

91 kd 22 kd 67 kd 47 kd

X- (classic) X-Linked recessive 52 (-) (-) (+) (+)

A (type II) Autosomal recessive 38 (+) (+) (-) (-)

A (rare) Autosomal recessive S (+) (-) (+) (+)

X± (rare) X-Linked recessive S (+)11 (+) (+) (+)

* Reference 9.

1: Twelve percent of A type are missing the 67-kd protein.9 § Eighty-eight percent of A type are missing the 47-kd protein.9

#{182}Missense mutation of 9i-kd protein produces cytochrome b,,9 dysfunction.”

and fungal infections. Microbicidal activity depends to a

large extent on NADPH oxidase system, which can be

activated by stimuli (bacteria, fungi) and which generates

the superoxide anion and other highly reactive forms of

reduced oxygen.’2 The neutrophil NADPH oxidase

sys-tern is composed functionally of membrane-bound

cata-lytic components (which consist of at least two

constit-uents, the low potential cytochrome b,,,’ and

flavoprotein’) and soluble cytosolic components6’7 which

participate as either catalytic or regulatory elements.

Among the membrane components, cytochrome b,,8 has

been shown to be a heterodimer with subunits of 91 and

22 kd.’4 It has been found recently that cytosolic oxidase

components consist of at least two constituents including

67-kd and 48-kd proteins.5

In chronic granulomatous disease (CGD), in which the

NADPH oxidase system fails to generate superoxide, it

recently has become apparent that the phenotype of CGD

can result from genetic lesions affecting one or another

of the four proteins noted, the two (91 and 22 kd)

cyto-chrome b proteins and the two (67 and 47 kd) cytosolic

proteins in the oxidase system9’2 (Table). X type CGD (classic X-linked/cytochrome b-negative), which is the most common form of CGD, is associated with a defect

in the gene encoding of the 9i-kd subunit and absence of

the 22-kd subunit, but it has normal amounts of both the

67-kd and 47-kd cytosolic oxidase components.9 In

addi-tion, in some cases of classic X type CGD, a deficiency

of flavoprotein in the oxidase system has been reported.”

In A type CGD (type II autosomal/cytochrome

b-posi-tive) which is present in 38% of all patients with the

disease, the 91-kd and 22-kd proteins of cytochrome b

are normal, but 88% of these patients lack the 47-kd

cytosolic protein and the rest are missing the 67-kd

cytosolic component.9 In a rare A type CGD (autosomal/

cytochrome b-negative), there are normal amounts of the

two cytosolic oxidase components,9 but cytochrome b is

not expressed in neutrophil membranes because of a

defect in the gene encoding for the 22-kd protein of

cytochrome b.’ In another rare X type CGD (X-linked/

cytochrome b-positive), which appears in 5% of CGD

cases, a missense mutation at amino acid residue 415 in

the 9i-kd cytochrome b component occurs,” but there

are normal amounts of the cytosolic proteins of 67 and

47 kd.9

An extensive series of investigations recently have

been undertaken to define the nature of the phagocyte

NADPH oxidase system and its molecular basis in the

pathophysiology of CGD. The availability of gene probes

should permit an even more detailed characterization of the multiple genetic lesions capable of interrupting the

phagocyte NADPH oxidase system in CGD patients.

REFERENCES

SHIGENOBU UMEKI, MD

Division of Respiratory Diseases

Department of Medicine

Kawasaki Medical School

577 Matsushima, Kunashiki

Okayama 701-01, Japan

1. Malech HL, Gallin JI. Neutrophils in human diseases. N

Engi J Med. 1987;317:687-694

2. Babior BM. The respiratory burst oxidase. Trends Biochem Sci. 1987;12:241-243

3. Parkos CA, Allen RA, Cochrane CG, et al. Purified cyto-chrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weight of 91,000 and 22,000. J Clin Invest. 1987;80:732-742 4. Segal AW. Absence of both cytochrome b_24 subunits from

neutrophils in X-linked chronic granulomatous disease.

Na-ture. 1987;326:88-91

5. Gabig TG, Lefker BA. Catalytic properties of the resolved flavoprotein and cytochrome bcomponents of the NADPH-dependent 02-generating oxidase from human neutrophils. Biochem Biophys Res Commun. 1984;118:430-436

6. Babior BM, Kuver R, Curnutte JT. Kinetics of activation

of the respiratory burst oxidase in a fully soluble system

from human neutrophils. J Biol Chem. 1988;263:1713-1718

7. Umeki S. Human neutrophil cytosolic activation factor of

the NADPH oxidase: characterization of activation kinetics. J Biol Chem. 1990;265:5049-5054

8. Volpp BD, Nauseef WM, Clark RA. Two cytosolic

neutro-phil oxidase components absent in autosomal chronic

gran-ulomatous disease. Science. 1988;242:1295-1297

9. Clark RA, Malech HL, Gallin JI, et al. Genetic variants of

chronic granulomatous disease: prevalence of deficiencies of

two cytosolic components of the NADPH oxidase system.

N Engl J Med. 1989:321:647-652

10. Parkos CA, Dinauer MC, Jesaitis AJ, et al. Absence of both the 91 kd and 22 kd subunits of human neutrophil cyto-chrome b in two genetic forms of chronic granulomatous

disease. Blood. 1989;73:1416-1420

11. Dinauer MC, Curnutte JT, Rosen H, et al. A missense

mutation in the neutrophil cytochrome b heavy chain in

cytochrome-positive X-linked chronic granulomatous dis-ease. J Clin Invest. 1989;84:2012-2016

12. Segal AW. The electron transport chain of the microbicidal oxidase of phagocytic cells and its involvement in the

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LETTERS TO THE EDITOR 185

lecular pathology of chronic granulomatous disease. J Clin

Invest. 1989;83:1785-1793

13. Ohno Y, Buescher ES, Roberts R, et al. Reevaluation of cytochrome b and flavin adenine dinucleotide in neutrophils

from patients with chronic granulomatous disease and

de-scription of a family with probable autosomal recessive

inheritance ofcytochrome b deficiency. Blood. 1986;67:1132-1138

Exercise

for Children

To the

Editor.-The urgently needed commentary by the Committee

on Sports Medicine entitled “Risks in Distance Running

for Children” exemplifies the alarming deficiency in

exercise prescriptions for our children. Clearly, we need

metabolic studies of children, particularly in risk groups,

ie, those with hypercholesteremia (cholesterol greater

than 200 mg/dL), those with chronic disease, those with

various degrees of overweight or obese status as well as

those who are otherwise healthy, but poorly conditioned,

to determine precise prescriptions for exercise.

We have studied more than 500 children being seen in

a private pediatric practice and/or high school

partici-pation physicals for exercise asthma with an incidence of

10% as determined by exercise testing. Strunk et al2 have

outlined standardized tests for functional endurance,

body fat composition, flexibility, and abdominal strength

as determined by The American Alliance of Health,

Phys-ical Education, Recreation and Dance Health-Related

fitness test (HRFT) to ascertain fitness of children with asthma. Earlier work by Fitch’ has indicated the positive effects of swimming training, and Nickerson4 has

deter-mined that swimming may improve physical fitness of

asthmatic children without inducing unnecessary

bron-chospasm. These are examples of well-conducted studies

attempting to find appropriate exercise for risk groups.

This clearly needs to be done for our otherwise healthy

pediatric patients, for example, who are seen for their

annual school physical. With the incidence of poorly

conditioned children and the rising incidence of

over-weight and obese status in our children with declining

guidance from school settings, it is our responsibility as

physicians to begin offering concise prescriptions for

exercise for all of our children. These groups need to be

identified, metabolic studies need to be conducted to

determine tolerance levels and appropriate limits to

ex-ercise, and then prescriptions may be offered by the

general practicing pediatrician. These studies involve use

of a standard exercise bike with measures of maximum

oxygen consumption and other cardiopulmonary indices

as defined by the Academy of Pediatrics in its exercise

testing protocol.

Until we have performed these studies for these defined

risk groups, particularly for our otherwise healthy

pedi-atric population, we have not met our responsibility as

pediatricians for the physical fitness of children.

REFERENCES

CHRISTOPHER RANDOLPH, MD

Allergy/Immunology/Pediatrics

60 Westwook Avenue

Waterbury, CT 06708

1. Committee on Sports Medicine. Risks in distance running for children. Pediatrics. 1990;86:799-800

2. Strunk RC, Rubin D, et al. Determination of fitness in

children with asthma. AJDC. 1988;142:940

3. Fitch KD, Morton AR, Blanksby BA. Effects of swimming

training on children with asthma. Arch Dis Child. 1976;61:1/

90

4. Nickerson BG, Bautista DB, Namey MA, Richards W,

Keens TG. Distance running improves fitness in asthmatic

children without pulmonary complications or changes in

exercise-induced bronchospasm. Pediatrics.

1983;71:147-152

Questioning

Asthma

Treatment

Study

To the

Editor.-The article “Methylprednisolone Therapy for Acute

Asthma in Infants and Toddlers: A Controlled Clinical

Trial” by Tal et al’ is interesting, but it does have some

weak areas which perhaps the authors can address. First

of all, the outcome which seems to be most emphasized

in the study, ie, percent admitted, is a fairly weak outcome

measure when compared with other more objective

meas-ures such as changes in pulmonary function. Note that

the decision to discharge was made by the senior resident

in charge of the emergency department. Although it is

not possible to demonstrate a systematic bias in this

study, certainly we all recognize that different physicians

have different levels of threshold for discharging patients

from the emergency department; and, although the

pul-monary index score in this study was done by one

phy-sician, we presume the decision to discharge was made

by several physicians. The differences in discharge rates

look impressive as raw percentages, but these are based

on fairly small numbers (as evidenced by the fact that

the Fisher’s exact test was used).

Pulmonary index score is perhaps more objective than

the discharge rate as an outcome, but it is not possible

from the article to know the statistical method used. A

nonparametric test may be indicated in statistical

analy-sis of this kind of score.

One question raised by the difference in discharge rates

ofthe 7- to 14-month-old age group is whether a relatively

higher dose of salbutamol for this group (because the

same dose was given to all patients) might have caused a

greater effect in the intervention in this group.

One wonders also why a third treatment group was not

included which involved treatment with salbutamol and

theophylline. This might be particularly important

be-cause it seems that the combination of salbutamol and

aminophylline might be more likely to give a difference

in effect at 3 hours than salbutamol simply given at 0

and 30 minutes, which was done in this study.

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1991;88;183

Pediatrics

SHIGENOBU UMEKI