COMNIENTARIES 68:3
(hieing the need for hospital-based
pediatri-(IUI1S and expensive pediatric services.
Bal-aticed against this has been the increased
use of I)ediatricians in the health centers, in
areas of communities where previously
there were none.
EFFECTIVENESS OF HEALTH SERVICES
Finally, with society recognizing that the
provision of health services alone does not
increase health as much as we have
thought, and with third party payers
in-creasingly critical of what benefits they are
l)uying for their health dollar, there may
well be a decreased willingness to pay for
national health services. Such services as
the recommended 10 or 12 well child visits
in the first year of life for all children may
come under increasing attack as
unneces-sary, because they yield little increase in
health for the investment. Such a move will
also decrease the need for pediatricians.
NEW ROLES
Counter-balancing all of these factors
ducing the demand for pediatricians, the
major opposing factor ‘ill be those needs
of children never yet adequately met-the
consequences of developmental, behavioral, and social problems. Today, pediatricians
are being asked to serve in entirely new
roles: as consultants not onI’ to schools but also to the head start programs, drug crisis centers, and mental health proj’cts. \Vliik’ l
cannot predict the mans- future changes
that will similarly increase tlit’
respotisihuli-ties of tomorrow’s pediatricians, I wouki
confidently speculate that we do not need
more pediatricians than we are currently
producing,
if
they contiiiue to do what they have been doing in the past.if,
however, their distribution is changed by encourage-ment to settle in areas with low pediatrician to children ratios, andif
they take oii sonic of the new roles society is asking of them,we may not only need more but we will
certainly need new kinds of pediatricians.
ROBERT
J.
HAGGRTY, Ml).Department of Pediatrics University of Rochester
Rochester, New York
REFERENCES
1. Schonfeld, FL. K., Heston, j. F., and Falk, I. S.: Numbers of physicians required for primary medical care. New Eng. J. Med., 286:571, 1972.
2. Child Health Services and Pediatric Education: Report of the American Academy of
Pediat-rics, The Commonwealth Fund, New York,
1949 survey.
3. Mason, H. R.: Manpower needs by specialty. JAMA, 219:1621, 1972.
PLASMA
INFUSION
THERAPY
FOR
HURLER’S
SYNDROME
E
VER since the first report from Houstonof the “plasma infusion” approach to
modification of the Hurler’s syndrome
pic-ture’ there has been a wide popular feeling
that the beginnings of a “treatment” were at
hand for this group of inborn error diseases. Intriguing data on alteration of the pattern
of urinary mucopolysaccharide excretion,
and, to some extent, of the children’s
clini-cal manifestations, opened a real hope that
a substantial mechanism existed for
render-ing more normal the skewed metabolism of
these patients. In addition, the authors
commented that “human plasma infusions
seemed to fit the recommendations”
given in a previous Pr.inAllucs
Comnien-tary2 for theoretically useful therapeutic tri-als of new materials in patients with inborn error syndromes.
If indeed one assumes that most of these
hereditary conditions can be accepted as
the expression of a deficient specific
lysoso-mal hydrolase activity, then the most
pri-mal therapy would be in the area of
“re-placement” by some broad means. And
since virtually all such enzymes are
detect-able in normal plasma, this medium could
684 THERAPY FOR HURLER’S SYNDROME
concentration, replacement source. Other
possible enzyme supplements, in a more
di-rected high concentration, could be sought,
of course, in various tissue extracts or
ly-ophilization products, cell suspensions,
or-gan transplants, or plant and bacterial
preparations.3 The recent work of Neufeld’s
group4 has provided encouraging insights
about the widespread distribution of
“cor-rective factors” in normal human tissues
and body fluids which are active in allevia-tion of intracellular mucopolysaccharide accumulation; it has been shown that
incor-poration of these factors from the media is
accomplished efficiently by fibroblasts grow-ing in tissue culture.
The use of blood or plasma to deliver
special support to ailing patients, beyond
simple supplementation of a lowered
sup-ply of hemoglobin or of the major plasma
proteins, has a long clinical tradition.
Transfusions, often planned to be with
blood as fresh as possible, have been given
without controlled observations at the time
of surgery or severe infection in many
in-born error patients. Specific programs,
how-ever, are of more recent vintage. A trial of
large whole blood transfusions (with the
blood less than one hour old), and of
weekly “fresh frozen plasma” infusions, was
reported in 1958 for patients with
Nie-mann-Pick disease, with no discrete benefi-cial effects detected. In the instance of
de-tailed studies with patients with Fabry’s
disease, it has been shown that large
infu-sions of normal plasma can indeed produce
the appearance of transiently restituted
cer-amide-trihexosidase levels in involved
pa-tients. This results, in fact, in an enzyme
concentration greater than expected per
plasma dosage considerations (so-called
“enhancement”) 6 No useful clinical effects
could be documented, however. Frequent
plasma infusions have also been used to
passively transfer a supply of the enzyme
“lecithin-cholesterol acyltransferase” in pa-tients with “LCAT” deficiency.
Observations on the effects of plasma
therapy in the various
mucopolysacchari-dosis syndromes are handicapped by the
in-complete identification of relevant
enzy-matic parameters. In only two of the
dis-eases have apparently specific enzyme
defi-ciencies been claimed
(
sulfatase B inMaroteauxe-Lamy, and
alpha-acetylglucos-aminidase in Sanfilippo type B
),
and theserequire tissue specimens for demonstration.
Neufe1d has commented that, based on
“correction factor” bioassays, the usual type
of large volume plasma infusion trials
cur-rently being given to
mucopolysaccharido-sis patients would be as much as three
or-ders of magnitude too small to provide
enough factor from which one could expect
any notable amount of tissue effect in the
intact patient. Beyond that one must again
seek “activation” or “enhancement”
hy-potheses to explain any noted activity.
Per-tinent delivery of intravenously
adminis-tered enzyme to an intracellular neuronal
locus seems a particularly poor prospect.8
Many workers have now attempted to
re-peat the provocative preliminary
observa-tions recorded by DiFerrante et al.1 by
seeking laboratory or clinical changes in
mucopolysaccharidosis patients during and
after their receiving plasma infusions.
Informal reports from a half-dozen or so
centers have all spoken of irregular and
un-impressive shifts in urinary mucopolysac-charide excretion, and no detectable clinical effects (favorable or otherwise). This issue
of Piminucs includes the specific results of
Dekaban et al. and Erickson et al.b0 in this
regard; neither
group
of authors is able tofind support for recommendation of the
presently practiced type of plasma
“ther-apy.” It is to be hoped that eventually a
critically valuable form of enzyme
replace-ment will be available for children with
Hurler’s disease and related conditions.
Un-less ongoing research uncovers special
an-cillary metabolic determinants, this will
most probably be accomplished by the use
of tissue factor concentrates or perhaps
or-gan transplants.
Aim C. CRoc1un, M.D.
Developmental Evaluation Clinic
Children’s Hospital Medical Center
COMMENTARIES 685
REFERENCES
1.DiFerrante, N., Nichols, B. L., Donnelly, P. V.,
Neri, G., Hrgovcic, R., and Bergiund, R. K.: Induced degradation of glycosaminoglycans
in Hurler’s and Hunter’s syndromes by
plasma infusion. Proc. Nat. Acad. Sci., 68: 303, 1971.
2. Crocker, A. C.: Therapeutic trials in the inborn errors; an attempt to modify Hurler’s
syn-drome. PEDIATRICS, 42:887, 1968.
3. Crocker, A. C., and Farber, S.: Therapeutic approaches to the lipidoses. In Aronson, S. M., and Volk, B., eds.: Cerebral
Sphingo-lipidoses. New York: Academic Press, p. 421, 1962.
4. Neufeld, E. F.: Mucopolysaccharidoses: the
biochemical approach. Hosp. Practice, 7: 107, 1972.
5. Crocker, A. C., and Farber, S.: Niemann-Pick disease: A review of 18 patients. Medicine,
37:1, 1958.
6. Sweeley, C. C., Mapes, C. A., Anderson, R. L.,
Desnick, R. J., and Krivit, W.: Fabry’s dis-ease: Chemical and enzymatic abnormalities
and a pilot study of enzyme replacement. In
Bernsohn, J., and Grossman, H. J., eds..:
Lipid Storage Diseases: Enzymatic Defects
and Clinical Implications. New York: Aca-demic Press, p. 165, 1971.
7. Norum, K. R., Glomset, J. A., and Gjone, E.:
Familial lecithin: cholesterol acyl transferase deficiency. In Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, D. S., eds.: The Met-abolic Basis of Inherited Disease, ed. 3. New York: McGraw-Hill Book Company, p. 531,
1971.
8. Greene, H. L., Hug, C., and Schubert, W. K.: Metachromatic leukodystrophy; treatment
with arvlsulfatase-A. Arch. Neurol., 20:147, 1969.
9. Dekaban, A. S., Holden, K. R., and
Constanto-poulos, C.: Effects of fresh plasma or whole
blood transfusions on patients with various
types of mucopolysaccharidosis. PEDIATRICS, 50:688, 1972.
10. Erickson, R. P., Sandman, R., Robertson, W. van B., and Epstein, C. J.: Inefficacy of
fresh frozen plasma therapy of
mucopolysac-charidosis II. PEDIATRICS, 50:693, 1972.
FROM FANCY TO FACT
ECOGNITION of a given symptom, sign,
or abnormal laboratory finding
repre-sents the start of a long, often tortuous path.
The trail soon broadens, as combinations of
findings coalesce into syndromes. Blind
alleys, thick forests, and divergent roads
beguile and confuse the traveler. One may
stumble onto the main route by application of rational, physiologic patterns of thought. Charting a discrete map to finite understand-ing and effective therapy is dependent upon
delineation of underlying cellular
mecha-nisms.
Similar parables have often been utilized to indicate the applicability and essentiality of studies of cellular and intercellular
pro-cesses in relation to human physiology and
disease. Perhaps they have also been used to
help the investigator, caught in the complex
web of laboratory data, to believe in the
relevance of his efforts. The impact of such
parables is clearly discernible when one
ex-amines the clinical problem of
hypogly-cemia.
The concentration of blood glucose is a
re-sult of two interacting and interdependent processes: peripheral glucose utilization and hepatic glucose production. Characteriza-tion of the cause of hypoglycemia requires clarification of those factors which regulate
or control each of these fundamental
pro-cesses. The history of hypoglycemia in
in-fancy and childhood mimics the “tortuous
path,” for the majority of affected children are still classified according to syndromes, and therapy is usually empirical and
proble-matic.’ Methodologic advances have
facili-tated delineation of enhanced rates of
glu-cose utilization caused by increased insulin secretion or decreased output of hormones
which inhibit insulin-mediated glucose
transport. The study of glycogen storage
dis-eases has indicated that the availability of
readily retrievable carbohydrate stores is,
on occasion, necessary for the maintenance
of normoglycemia. On the other hand,
meta-bolic dissection of the physiology of
starva-tion has placed appropriate emphasis on the
synthesis of new glucose from
