Journal of Pediatric Gastroenterology and Nutrition

39:S711S716 June 2004 Lippincott Williams & Wilkins, Philadelphia

Persistent and Chronic Diarrhea and Malabsorption: Working

Group Report of the Second World Congress of Pediatric
Gastroenterology, Hepatology, and Nutrition
Zulfiqar A. Bhutta (Coordinator), Fayez Ghishan, Keith Lindley, Iqbal A. Memon, Santosh Mittal,
and J. Marc Rhoads
Commonwealth Association of Paediatric Gastroenterology and Nutrition (Z.A.B., S.M.); North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition (F.G., J.M.R.); European Society for Paediatric Gastroenterology, Hepatology, and
Nutrition (K.L.); and Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (I.A.M.).

Research
1. Assessment of mucosal immuno-pathology and molecular and cellular biology of
persistent diarrhea in representative populations in developing countries.
2. Studies of small bowel microbiology in PD, especially in at-risk populations e.g.,
malnourished children and HIV endemic areas.
3. Evaluation of the link of micronutrient deficiencies with PD and their relationship with
intestinal repair mechanisms.
Intervention
1. Improved facility-based approaches and algorithms for the nutritional management of PD
and malnutrition.
2. Diagnosis and management of PD in public health system and primary care (including
domiciliary) settings.
3. Scaling-up environmental control measures and safe water and hygiene strategies.
Education
1. Continuing medical education strategies to educate medical students and physicians in the
recognition, management and prevention of PD.
2. Education of nursing and paramedical personnel in the recognition and management of
PD in ambulatory and health system settings.
3. Community and public health education strategies for increased awareness of the
prevention of PD and optimal management of acute and prolonged diarrheal episodes.

Diarrheal disorders form a continuum, the majority of

cases resolving within the first week of the illness. However, a smaller proportion of diarrheal illnesses may fail
to resolve and persist for >2 weeks. Persistent diarrhea
(PD) may be defined as the passage of 3 watery stools
per day for >2 weeks in a child who either fails to gain
or loses weight. PD identifies children with a substantial
diarrhea-related morbidity and accounts for between
36% and 54% of all diarrhea-related deaths (4). Many
infants and toddlers in developing countries may have
frequent recurrent episodes of acute diarrhea or PD, resulting in nutritional compromising and/or predisposing
these children to PD.
The bulk of epidemiological data on the relationship
between acute diarrheal disorders and PD are from studies undertaken > 10 to 15 years ago. There is a paucity of
recent data on this subject, especially from nonHIVendemic areas. However, chronic enteropathy and PD
have been increasingly recognized as manifestations of
advancing HIV infection and AIDS.

INTRODUCTION
Despite considerable advances in the understanding
and management of diarrheal disorders in childhood,
they are still responsible for an estimated 2.2 million
childhood deaths worldwide (1). In 1980, the World
Health Organization calculated that there were >700 million episodes of diarrhea annually in children <5 years of
age in developing countries (excluding China), with >4.6
million deaths (2). More recent reviews indicate that although global mortality has decreased, the incidence remains unchanged at >3.2 episodes per child-year (3).
These findings indicate the continuing need to focus on
the prevention and management of acute and chronic
diarrhea in children in developing countries.

Address correspondence and reprint requests to Dr. Bhutta (e-mail

zulfiqar.bhutta@aku.edu).

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ETIOLOGY

Broadly speaking, the origins of diarrhea may lie primarily within the small intestine, large intestine, or accessory digestive organs (pancreas and hepatobiliary
tract). Disorders of the large intestine usually cause diarrhea through defective water salvage, whereas disorders of the small intestine can be either secretory or
osmotic (in association with malabsorption). Secretory
and osmotic processes may be present concurrently (eg,
with rotavirus enteritis).
Protracted diarrhea may arise from a large number of
conditions. Globally, the most important trigger for PD is
an acute diarrheal episode caused by an enteric infection.
In areas in which HIV infection is endemic, chronic infection of the gastrointestinal tract (eg, cryptosporidiosis)
is an important cause. In the absence of an infective
etiology, other specific disease entities associated with
PD in children should be sought. The most common are
dietary protein intolerances, celiac disease, and secondary disaccharide (lactose) intolerance. In a large historical series in Europe, these diagnoses accounted for 56%
of cases of PD in infancy (5). In these infants with severe
PD, 24% had other diagnoses, but in 30%, no specific
diagnosis was reached despite extensive investigation.
Now, the subgroup of children with PD and no identifiable diagnosis accounts for <2% of cases in large European centers (K. Lindley, unpublished data, 2003).
It is useful to have a diagnostic algorithm as an aid to
diagnosis that (in a necessarily arbitrary and mutually
nonexclusive fashion) categorizes PD either by age of
onset (in utero, neonatal, infantile, or older) or into
congenital/inherited and acquired disorders. It is also
useful to group the patients into those with secretory
diarrhea and those with predominantly osmotic diarrhea
on the basis of response to fasting and of stool electrolytes. Although from a global public health perspective
these cases of protracted diarrhea are not important, an
understanding of their underlying cellular and genetic
mechanisms may provide invaluable insight into enterocyte pathophysiology, with potential implications for
therapy. The diagnosis and management of these disorders, however, will not be discussed in depth in this
report.
Risk Factors and Pathophysiology for PD in
Developing Countries
The most important epidemiological risk factor for PD
is malnutrition. Zinc deficiency, lack of breastfeeding,
male sex, infection with enteropathogenic or enteroaggregative Escherichia coli or Cryptosporidium, and a
history of intrauterine growth retardation are other important associated conditions. A recent acute diarrheal
episode (within the past 2 months) is common in PD.
Also important is immune status. Children with abnor-

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

mal delayed-type hypersensitivity reactions and specific

immune deficiencies such as HIV infection and severe
combined immunodeficiency are particularly prone to PD.
Diarrheal disease is closely related to malnutrition, but
the causal nature of this association has been challenged.
The relationship between PD and malnutrition is less
controversial because it is commonly associated with
significant malnutrition. In a verbal autopsy study of diarrheal deaths in Bangladesh, almost half the deaths were
in malnourished children with PD, and the relative risk of
dying of PD and severe malnutrition was 17-fold higher
than in children with lesser degrees of malnutrition (6).
There is a wealth of experimental and clinical evidence
that improved nutrition hastens recovery from protracted
diarrheal diseases.
There are several reasons why malnutrition should
both predispose to and follow PD. These range from
achlorhydria with increased risk of small bowel contamination, systemic immune deficiency, intestinal and pancreatic enzyme deficiency, and altered intestinal mucosal
repair mechanisms after an infectious insult. An independent relationship has also been demonstrated between
cutaneous anergy and the subsequent risk of PD (7).
There has been much interest in the possibility that such
transient immune deficiency may be a marker of concomitant micronutrient deficiency (8,9). The most striking example of the critical role that the immune system
plays in the pathogenesis of PD is the relationship between HIV/AIDS and PD. This is exemplified by the
plethora of studies linking PD with cryptosporidiosis
(10) and other parasitic infections in Africa and Asia.
Poor intestinal repair is regarded as a key component
of the abnormal mucosal morphology. However, the factors underlying this ineffective repair process and continuing injury are poorly understood. The result of this
mucosal derangement is poor absorption of luminal nutrients and increased permeability of the bowel to abnormal dietary or microbial antigens. Alterations of intestinal permeability in early childhood may reflect changes
in intestinal mucosal maturation and may be affected by
concomitant enteric infections.
Key micronutrient deficiencies may contribute to poor
intestinal repair. Recent meta-analyses of zinc supplementation in diarrheal illnesses indicate a significant reduction in the duration and severity of diarrheal illnesses
(11). Thus, zinc deficiency may significantly contribute
to the prolongation of mucosal injury and delayed intestinal repair mechanisms. Given the close relationship between diarrheal disorders and malnutrition, it is not surprising that PD is widely recognized as a nutritional disorder and that optimal nutritional rehabilitation is
considered the cornerstone of its management (12).
A clear understanding of alterations in intestinal morphology and molecular mechanisms underlying the
pathophysiology of PD in developing countries is crucial
for the development of interventional strategies. However, in contrast to the progress made in understanding

PERSISTENT AND CHRONIC DIARRHEA AND MALABSORPTION

the hereditary disorders causing protracted or intractable
diarrhea in infancy, there has been little progress in understanding the pathophysiology of this problem in developing countries beyond descriptive studies.
Priority Goals in Research
Appropriate and well-directed research is required to
clarify the pathogenesis of PD and to develop sound
public health preventive and treatment strategies. Among
the several aspects of PD that merit further in-depth research, the following emerge as priority issues for the
immediate future.
1. Assessment of mucosal immunopathology in PD and
its relationship with malnutrition and malabsorption.
These studies need to be undertaken in both HIVinfected children and noninfected children. We need
to understand the interactions between specific pathogens and altered mucosal repair mechanisms. Suitable
animal models to assess prolonged diarrheal episodes
do not exist, and the models available have been used
largely to assess the interaction between malnutrition
and intestinal function. A clear understanding of the
elements that underlie persistent mucosal injury is
fundamental to the development of prevention and
intervention strategies. There is a need to better define
the inflammatory process within the lamina propria in
tissues obtained at intestinal biopsy. In addition to
research initiatives, this should facilitate accurate diagnosis and, when diagnosis is indeterminate, permit
a logical approach to therapy. Mucosal immunopathology research should go beyond a simple description of inflammatory infiltrate and should clarify the
basis of the inflammatory process (ligands involved,
etc). Important areas of research are the interaction
between innate and acquired immune responses in
intestinal inflammation, the effects of inflammation
on (enterocyte) gene expression and digestive/absorptive apparatus, and intestinal neuroimmune interactions.
2. Studies of small bowel microbiology in PD. Although
PD has been associated with specific pathogens, eg,
enteroaggregative E. coli, there is no consensus on this
issue. Up to two thirds of children with PD have small
bowel bacterial overgrowth, but it is not known
whether small bowel bacterial overgrowth is a cause
of PD or the result of impaired immunity and/or contaminated water. Several other pathogens have been
associated with PD, especially in HIV-endemic populations. A wealth of data demonstrate that the innate
immune response to bacteria and bacterial products is
an important trigger in the pathogenesis of autoimmune and other gut diseases (13). Thus, studies of
small bowel bacterial overgrowth and host-pathogen
interactions at the molecular and cellular levels in the
gut should be high priority in the quest to understand
the origins of protracted diarrheal disease.

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3. Evaluation of the link between micronutrient deficiencies and PD. Although the causal relationship between PD and micronutrient, especially zinc, malnutrition is well recognized, little is known about the
mechanisms underlying this process. Nor is it known
how micronutrients affect intestinal mucosal repair
and recovery patterns. Zinc deficiency may well be a
key factor in the widespread prevalence of PD in zincdeficient populations, and research should be undertaken to evaluate the magnitude and the mechanisms
of action of this effect.
Priority Goals for Medical Interventions
Although parenteral nutrition has been occasionally
life-saving in selected cases in developing countries, it is
clearly an impractical option for most of the developing
world. There is now clear evidence supporting the enteral
route for nutritional rehabilitation of malnourished children with PD (4,12). Starvation has been shown to have
deleterious effects on the intestinal mucosa, thereby
causing a reduction in the nutritive transporters for glutamine and arginine. It is thus imperative that malnourished children with PD receive enteral nutrition during
their rehabilitation. Continued breastfeeding is universally accepted and recommended during diarrhea, and
the disorder is frequently seen in the wake of lactation
failure or after weaning. The choice of an appropriate
diet or feeding regimen for these children is much debated because the diet offered must be well tolerated and
of a sufficient nutritional quality to ensure adequate absorption without an osmotic penalty.
Regardless of the cellular mechanisms and structural
alterations in malnourished children with PD, the result
is one of altered brush border and luminal enzymes and
consequent malabsorption. Despite the aforementioned
alterations in digestive and absorptive mechanisms,
analysis of metabolic balance studies in children with PD
indicates that satisfactory carbohydrate, protein, and fat
absorption can take place on a variety of diets (14).
Postinfectious cases of PD can usually be managed by
dietary measures, including provision of dietary complex
carbohydrates, eg, cereals such as rice, maize, lentils, or
legumes, bananas, vegetable oil, and milk as a source of
protein (human or cows milk, the former being preferable). Soy formulas may be acceptable but are significantly more expensive and in some studies were less
effective than the cereal-lentilbased diets (4). Generally, the goal is to provide at least 150 kcalkg1d1
enterally. Research is underway to determine which
complex carbohydrate is optimal for enhancing absorption (colonic) and bowel repair in PD. Candidates are
maize, green banana fibers, pectin, and guar gum. Other
potentially effective treatments are L-glutamine, which
provides intestinal fuel, nucleotides for proliferating enterocytes, corticosteroids for children with protein-losing

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BHUTTA ET AL.

enteropathy and bowel inflammation, preparations containing growth factors for ostensible intestinal trophic
effects, and immunoglobulins (eg, bovine colostrum or
bovine serum concentrate) for their antirotavirus effects.
When this is unsuccessful, replacement of milk with another protein source, eg, egg white or chicken, is often
effective.
Most nutritional rehabilitation protocols for the treatment of PD in developed countries entail the administration of specialized enteral formulations, mainly
lactose-free formulations or semielemental diets. However, these are beyond the reach of health resources in
developing countries. They are also frequently unpalatable, require continuous administration, and thus are not
appropriate in ambulatory settings. Because most PD
cases occur in the community and parents frequently
hesitate to seek help, the challenge is to develop a form
of dietary therapy using inexpensive, home-available,
and culturally acceptable ingredients. Recent data indicate that it may be entirely feasible to do so in community settings (15).
The key role of micronutrients, especially zinc, in the
treatment and prevention of PD is also well recognized.
However, zinc supplementation is not included in public
health programs in developing countries. Zinc supplementation during acute episodes has been shown to reduce the duration and severity of diarrhea (16), and when
administered as part of a community treatment package
for diarrhea, it reduces mortality and the rates of prescribing antimicrobials (17).
As stated earlier, the biggest public health challenge is
the development and widespread implementation of
evidence-based strategies to treat PD. However, these
must be based on information from intervention protocols in other settings. Too much emphasis is placed on
developing new strategies when the technology and information needed to prevent most child deaths resulting
from diarrhea are widely available (18).
1. Improved facility-based approaches and algorithms
for the nutritional management of PD and malnutrition. Good nutrition is central to rapid and complete
recovery from PD. Thus, the development and assessment of cost-effective enteral multinutrient formulations for the nutritional rehabilitation and therapy of
children with PD and malnutrition remain a priority.
These formulations need to be based on our understanding of the gut absorptive capacity and the critical
nutrients required for repair and should consist of an
appropriate balance of macronutrients and micronutrients. Although past dietary approaches have included soy formulations and elemental diets, they
have not been shown to be superior to other diets or
combinations validated in facility settings in developing countries. Oral antibiotics, either singly or in combination, have not been proven useful, but antimicrobial therapy is required for proven Clostridium diffi-

J Pediatr Gastroenterol Nutr, Vol. 39, Suppl. 2, 2004

cile enterocolitis, cryptosporidial enteritis, and

giardiasis. The role of antibiotics in the treatment of
associated systemic infections that are seen in almost
30% to 40% of children with PD is poorly appreciated. Management protocols designed for facility settings in developing countries (4) need to be widely
disseminated and used. Efforts should be made to
devise agreed-on and appropriate diagnostic algorithms that reflect contemporary management strategies, ie, the place of parenteral nutrition, the place of
specific therapies, and the place/timing of intestinal
transplantation in intractable early-onset severe diarrheal diseases.
2. Diagnosis and management of PD in public health
system and primary care (including domiciliary) settings. Although the fundamental principles of nutritional rehabilitation of PD are well recognized, optimal dietary treatment modalities for poor communities remain a challenge, especially for health system
and primary care settings. These include the development of algorithms for management in ambulatory
care, especially domiciliary settings, where referral to
facility settings may not be possible. Although further
research is needed to develop optimal, cost-effective
strategies for the prevention and treatment of PD in
children in such settings in developing countries,
enough is known to design interventions, especially
preventive strategies. However, these strategies need
to be evaluated in large effectiveness studies. As
noted, the early and unhygienic introduction of milk
other than mothers milk and poorly managed recurrent acute diarrheal episodes are important predisposing factors for PD and should be prevented if possible. Thus, promotion of exclusive breastfeeding for
at least 6 months, avoidance of formula feeding, and
timely and adequate weaning with hygienic nutritious
foods will help to prevent episodes of postinfectious PD.
3. Scaling-up of environmental control measures and
safe water and hygiene strategies. Both macroenvironmental measures (provision of a safe and adequate
water supply, hygienic waste disposal, etc) and microenvironmental measures (hand washing, hygienic
storage and use of water, avoidance of stale/coldstorage infant foods in tropical environments) will
help to prevent acute diarrhea and consequently PD.
Although the benefit of hand washing strategies for
the prevention of diarrhea is well recognized (19), the
challenge is to introduce these measures on a scale
that is meaningful and sustainable. In addition, rational and prompt management of acute diarrheal episodes, including use of oral rehydration solution,
avoidance of unnecessary antimicrobial agents, early
and adequate feeding during and after the episode of
diarrhea, and possibly micronutrient supplementation
(11,20), will contribute to early recovery from acute
diarrheal episodes. These measures will also help to

PERSISTENT AND CHRONIC DIARRHEA AND MALABSORPTION

prevent diarrhea-associated malnutrition and the occurrence of PD.
It is beyond the scope of this report to evaluate how these
basic needs can be met within public health and diarrheal
disease control programs, but they require a combination
of appropriate resources for public health and basic
needs, staff training, and community mobilization.
Priority Goals for Medical Education
Information about potential preventive and intervention strategies for the reduction of the burden of PD
should be incorporated into medical education programs.
This should not be limited to medical and pediatric training curricula but should be extended to large-scale continuing medical education initiatives for the training of
health professionals and workers. In addition, there must
be commensurate moves toward public education so that
a combination of push and pull strategies can be used.
The priorities are the following:
1. Continuing medical education strategies. The important role that pediatricians play in child health notwithstanding, family physicians and public health officers represent the backbone of most primary care
health services. Development of standardized education modules for the training of primary care physicians and health workers in the prevention, recognition, and management of PD and malnutrition is a
priority. These educational strategies can thus consist
of development of continuing medical education on
the prevention and treatment of malnutrition and diarrheal diseases in childhood by colleges and professional societies, articles on clinical care and practice
in journals devoted to standard general practice and
family medicine, and manuals with simplified diarrhea prevention and treatment protocols for healthcare
professionals at different levels. These should include
simplification and improvement of the current World
Health Organization/United Nations Children Fund
integrated management of the sick child modules that
concern the recognition, resuscitation and treatment
of the malnourished child with PD.
Web-based training modules are an excellent vehicle for
spreading information. Some of these materials should
be targeted to medical students and pediatric trainees
and should focus on the recognition, management, and
prevention of PD and malnutrition. They should consist of Web-based self-learning and educational materials, CD ROMs of background material and guidelines for treatment and prevention, and publication of
standard case definitions and problems (vignettes or
representative cases and photographs) in core pediatric
texts and materials.
2. Education of nursing and paramedical personnel in
ambulatory and health system settings. Given the in-

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creasing role of nursing and paramedical personnel in

service delivery and health systems, it is important
that they be well versed in the recognition and management of diarrhea, including PD. Development of
protocols for the integrated management of the sick
child in public health and community settings offers
an important opportunity for training. These educational opportunities can also be extended to community health workers, given their increasing role in primary care settings.
3. Community and public health education strategies are
important in educating families and parents in the
recognition and management of diarrhea. They should
be based on social marketing strategies for improved
breastfeeding practices, domiciliary hygiene, and
home-based management of diarrheal illnesses and
should be reinforced through the mass media. Simple
messages on diarrhea prevention, appropriate management, and early recognition of complicated diarrhea and PD may yield considerable dividends. Empowering parents and families with the skills for
prompt recognition of problems and care seeking will
lead to improved outcomes in children with recurrent
diarrhea and PD.
CONCLUSIONS
In summary, PD is still a major cause of morbidity and
mortality in the developing world and usually follows
acute infectious diarrhea. Despite considerable progress
in the understanding of the basic mechanisms and pathophysiology of prolonged diarrhea in infancy and related
syndromes in the developed world, not even a fraction of
comparable research has taken place in the developing
world, where it is needed most. Thus, the challenge is to
develop appropriate research, management, and education strategies to prevent and manage PD.
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