Much has been learned about the epidemiology of acute diarrheal disease
since the folk conceptualization of a syndrome caused by "food indigestion."
Despite early recognition of shigellosis, salmonellosis, giardiasis, and amebiasis
as distinct clinical entities, there has been difficulty in the recent past in accepting
that the remaining diarrheas were of an infectious nature. Furthermore,
the appearance of diarrhea with the onset of weaning in many animal species
and in man (18) and the systematic failure to find pathogenic agents in the
majority of the diarrheas in the general population, contributed to questions
of its infectious etiology.
During studies in the 1950s and 1960s, investigators recognized the importance
of the diarrheal diseases that occur when infants are shifted from
exclusive breast-feeding to a mixed diet (5,7). The recognition of this "weanling
diarrhea" has focused attention on the causes and prevention of diarrhea during
this critical period in the infant's life.
Dr. Suskind: In the last community you referred to, what were the specific measures
you took to achieve such a dramatic change?
Dr. Mata: This is a long-term study of a large, typical rural population with a very
active rural health program and a good water supply. In addition, we have initiated an
intervention program in the hospital where most of the women deliver their babies.
The custom in that hospital was to separate the infant from the mother. We did change
that. We put the mother and infant together. We tried to promote breast-feeding by
placing a psychologist in the hospital to work with the mothers and teach them how
to breast-feed. We have been very successful with this program of inducing breastfeeding
to the extent that more than 85% of the infants are breast-fed exclusively for
at least 2 months. Further, a rural health program of immunization assures that every
child is vaccinated. After 4 years of field work, 1,700 infants have been vaccinated
against the usual diseases of childhood—measles, whooping cough, and so forth, and
we have not had any deaths due to diarrhea either in 3 years.
Recently, viruses or virus-like particles have been detected by electron microscopic
examination in stools from patients with acute diarrhea; they are
considered the causative agents of acute diarrhea (3). Among them, the human
rotavirus has been recognized as a most important pathogen of acute diarrhea
in infants and young children in many parts of the world. However, these
viruses associated with acute diarrhea have been identified mainly on the basis
of their morphological and immunological features. Although a great deal of
effort has been directed to adaptation of these viruses to continued propagation
in cell cultures, only several animal viruses, including rotavirus strains, have
been adapted to grow efficiently to high titer in cell culture (13). The difficulties
in propagating human enteric viruses, particularly rotavirus in conventional
cell culture systems, have hampered rapid progress in virological, serological,
and epidemiological studies on viral diarrheal diseases.
The recent elucidation of etiologic agents of infantile diarrhea has markedly
improved our understanding of the pathophysiology and epidemiology of acute
nonbacterial gastroenteritis. In addition, the study of these agents has led to
the formulation of potential strategies for the prevention and treatment of
these infections. The agent of nonbacterial gastroenteritis in children which
has received the most attention is human rotavirus. This agent is responsible
for a large percentage of the serious cases of diarrhea which occur in children
living in both developed and developing countries (3,8). However, in spite of
the importance of this agent, it is clear that there are numerous episodes of
serious diarrheal disease which cannot be explained by infection with rotavirus
or with known bacterial agents.
Following the important discovery by Bishop and her colleagues in 1973
(1) that reovirus-like particles in duodenal biopsies of children with diarrhea
had an etiologic relationship to their enteritis, the study of rotaviruses and
the disease they produce has been intense. While the inability to cultivate
human rotavirus in vitro retarded some studies, the availability of animal
models in which species-specific rotaviruses produced nearly an identical disease
were an obvious advantage (2,3,4,9). One prominent similarity between
rotavirus-induced enteritis in humans and other mammals was the age restriction
of serious disease to the young. In human infants the peak age appears
to be 8 to 16 months; in mice it is 5 to 10 days. This age restriction is not well
Dr. Kapikian: Recently, Dr. Masutto has been able to grow twenty out of twentyfour
field isolates in cell cultures directly, and he has been able to show that these
possibly fall into three sera types. This finding appears to show that there are perhaps
a finite number of rotavirus sera types as in the rhinovirus field where there are over
a hundred at present. Thus, the hopes of developing a vaccine are more plausible now
because there are not literally hundreds of sera types.
The number of enteric bacteria recognized as causing acute diarrheal disease
has increased rapidly during the past 10 years. Not only have new organisms
been described, but new mechanisms of pathogenesis, including enterotoxinmediated
secretion, have been elucidated. Whereas previously very few
(~20%) cases of acute diarrhea could be diagnosed etiologically, now that
figure is closer to 80%, a large share being viral agents which have been discussed
Dr. Sack has masterly summarized the present state of knowledge on the
etiology of acute diarrhea, making it possible to concentrate on some aspects
that I consider relevant.
Dr. Levine: Dr. Sack mentioned data in animals showing that strains that have lost
their toxins but still contain adhesion colonization factor can cause diarrheal disease
in neonatal animals. Also he raised the question as to whether that phenomenon is
relevant or occurs in man. I would like to mention some instances where we think we
have seen it occurring.
The physical growth of poor children in developing countries often falls far
below the standards of more affluent children in these countries, or of children
in developed countries. The growth of many children in developing countries
may be limited from reaching its full genetic potential by outside factors, such
as inadequate nutrient intake and morbidity from specific diseases.
Microorganisms have played a prominent role in the evolutionary development
of the gastrointestinal tract of vertebrates. Through eons, the human
intestinal mucosa has evolved in intimate association with myriads of bacteria,
and with viruses and parasites, to such an extent that the majority of microbial
species are "indigenous" or "autochthonous" to the human host (10). There
are several microbial habitats in the intestinal milieu (Fig. 1); the lumen and
interplical spaces (virtual or filled with pabulum) apparently are of similar
nature, unless proof of existing difference is contributed (17).
Dr. Klish: I was fascinated to find out, from Dr. Black's data, that E. coli was
responsible for causing growth failure, in contrast with rotavirus. I would have expected
the opposite, since rotavirus seems to produce a disease that causes relatively severe
malabsorption of at least the carbohydrates, and E. coli tends to produce a disease
more attuned to cholera, causing massive malabsorption of fluid and electrolytes but
not so much of other nutrients.
Most physicians who treat children with diarrheal illnesses intuitively recognize
that diarrhea exerts a profound impact on their nutritional status. These
observations are not new. In 1897, L. Emmett Holt (5) wrote in his textbook
Diseases of Infancy and Childhood: "In infants malnutrition often depends
upon some previous acute disease, especially of the stomach and intestines,
and sometimes of the lungs."
Dr. Suskind: If we look at the changes that occur in the host as a result of infection,
we see two factors that are playing a role in their nutritional depletion.
One is the effect of the infectious process and the other is the effect of gastroenteritis
in terms of malabsorption of nutrients. The combination of the two leads to the clinical
and metabolic changes that have been discussed previously.
In the etiology of acute diarrhea in infancy, bacterial and viral agents play
an equally important role (L. Mata, this volume). It seems essential to develop
adequate measures for the prevention and treatment of these infections.
The superiority of human milk for the nutrition of the newborn and young
infant is not only based on its well-balanced composition by which the infant's
nutritional requirements are met, but also on the presence of various immune
and nonimmune factors (Table 1) that contribute to build up—ex alimentatione—
infant resistance against infectious diseases and/or allergic disorders.
Dr. Bellanti: I would like to ask Dr. Hilpert whether in the preparation of his material,
the bacterial extracts were injected intramuscularly or were they given locally into the
Dr. Hilpert: It was a combined immunization, locally into the udder and intramuscularly.
The association between famine and pestilence has been recorded in ancient
history. Puranic literature and biblical references cite observations that suggest
an increase in the prevalence and severity of infection among starved individuals
and populations. Besides these historic observations, several types of
evidence may be marshalled to support causal links between malnutrition,
impaired immunity, and infectious illness.
This chapter examines how immune defects may participate in the nutritioninfection
interaction in terms of enteric disease susceptibility. The relationship
between diarrhea, malnutrition, and immunological defenses is a complex
scheme of interactions.
An excellent review has been presented describing how immune defense
mechanisms may participate in nutrition-infection interaction, with special
emphasis on the diarrheic syndrome (F. Koster, this volume).
Dr. Edelman: I should like to ask Dr. Chandra whether there is a relationship between
antibody affinity and malnutrition. I do not remember him discussing whether there
are any changes in the type of antibody that is produced in malnourished individuals.
For about 200 million years, mammals have been feeding their babies with
their own milk. Humans have been the only species to interrupt the practice
by making milk products for artificial feeding. Formulas based on cow's milk
became available in many countries, without knowing enough about the consequences
of their use.
This chapter reports chiefly on our epidemiological studies that have been
conducted over the last 14 years in the lowest socioeconomic classes of our
Latin American communities.
Dr. Pierce: I think there is now a rather large body of evidence, from a variety of
animal species and also from humans, to indicate that parental immunization, even
in the instance of prior enteric priming is clearly a two-edged sword.
The subject of oral therapy's nutritional effects is still somewhat controversial
due to apparent inconsistencies between findings of different investigators
and even of the same investigators in different studies. Moreover, the
complex and costly nature of longitudinal studies of nutritional impact has
permitted completion of relatively few such studies to date.
As discussed by Dr. Nalin (this volume) many questions remain unanswered
in the area of nutrition related to oral therapy. The magnitude of the problem
related to diarrheal disease mortality and morbidity has been pointed out by
a number of authors in this volume. An example of the diarrheal disease
morbidity is shown in Table 1.
Dr. Klish: It's always been my bias, as well as other people's, that the oral rehydration
solutions that are on the market now need not be as nutritionally deficient as they are.
The presence of glucose in these solutions is largely based on studies done in the late
1960s that showed that glucose enhances the absorption of sodium through the coupling
effect in the gut mucosa. More recently, it has also been shown that the same coupling
exists with amino acids.
The World Health Organization published data in 1977 (41) showing that
diarrhea still ranks among the leading causes of death and illness in developing
countries; mortality rates in some regions continue to be as high as those of
the industrial nations 80 years ago, when 4,000 per 100,000 infants died with
The prevention of acute diarrhea, particularly in childhood, is a world challenge
(14). As happens with most socially induced health problems resulting
from inequity and poverty, its root causes are difficult to overcome, and its
prevention is not a straightforward and easy task.
Dr. Robbins: I would like to make some unrelated comments about the problem of
vaccines designed to prevent diarrheal disease. The first comment comes from our
experience with the use of pneumococcal vaccine to treat pneumonia. We are entering
an age where the diseases that we are going to prevent are caused by a variety of agents.
We no longer have vaccines with high degrees of specificity, such as against diphtheria
in gastroenteritis, 39-42
prevention of, 209
Aeromonas hydrophila, 59
Age distribution, 11, 29
Anorexia, 13, 86, 101
Antibiotic therapy, 62; see also specific