Management of Children With

Infection-Associated Persistent Diarrhea

Theresa J. Ochoa, MD,* Eduardo Salazar-Lindo, MD,† and Thomas G. Cleary, MD*

Diarrhea is the leading cause of death in children younger than 5 years of age; persistent
diarrhea accounts for 30 to 50 percent of those deaths in developing countries. Malnutri-
tion, immunosuppression, young age, and an increase in the preceding diarrhea burdens
are risk factors for the development of persistent diarrhea. Although many viruses, bacteria,
and parasites can produce persistent diarrhea, enteropathogenic Escherichia coli, entero-
aggregative E. coli, Giardia, Cryptosporidium, and Cyclospora are the most important of
these agents. With currently available tests, identifying a specific cause usually is difficult.
Newer sensitive molecular tests must be used for studying the epidemiology of persistent
diarrhea in children. Management includes rehydration, adequate diet, micronutrient sup-
plementation, and antimicrobials. Persistent diarrhea seriously affects nutritional status,
growth, and intellectual function. Meeting these challenges is profoundly important, par-
ticularly in developing countries.
Semin Pediatr Infect Dis 15:229-236 © 2004 Elsevier Inc. All rights reserved.

D iarrheal disease is still one of the most important public

health problems in developing countries, despite ad-
vances in understanding and management that have oc-
curred during recent years. Diarrhea is the leading cause of
death in children younger than 5 years of age, accounting for
3 to 4 million deaths each year worldwide.1,2
Persistent diarrhea is defined as diarrhea that lasts for more
than 14 days. As improvements in treating children with
acute diarrheal disease (particularly oral rehydration ther-
apy) have decreased morbidity and the rate of mortality in
developing countries, persistent diarrhea has emerged as a
common cause of death. Although persistent diarrhea in a
young child may be caused by a variety of noninfectious
causes (eg, celiac disease, intolerance to cow’s milk, allergic
colitis, intolerance to various carbohydrates), persistent diar-
rhea is an infection-induced illness in much of the world.
Persistent diarrhea can result from multiple consecutive in-
fections, an unresolved infection, secondary malabsorption
(mainly lactose), or the postgastroenteritis syndrome.3,4 Post-
gastroenteritis syndrome is a poorly understood clinical en-
*Department of Pediatrics, Division of Infectious Diseases, University of
Texas Medical School, Houston, TX.
†Departamento de Pediatría, Universidad Peruana Cayetano Heredia, Lima,
Perú.
Address reprint requests to: Theresa J. Ochoa, MD, University of Texas
Medical School at Houston, Department of Pediatrics, Pediatric Infec-
tious Diseases Division, 6431 Fannin, JFB 1.739, Houston, TX 77030.
E-mail: Theresa.J.Ochoa@uth.tmc.edu
tity in which patients have prolonged malabsorption or sen-
sitization to food antigens after an acute or subacute diarrheal
episode.
Persistent infectious diarrhea is responsible for 30 to 50
percent of the deaths caused by diarrhea in developing coun-
tries.5 Prior malnutrition, lack of breast-feeding, and associ-
ated systemic infections increase the risk of death occurring
during an episode of persistent diarrhea. Persistent diarrhea
seriously affects growth, nutritional status, and cognition.
Persistent diarrhea is a problem associated chiefly with chil-
dren, although it also occurs in adults, especially those with
acquired immunodeficiency syndrome (AIDS).
Pathophysiology
and Immunology
The pathogenesis of persistent diarrhea is complex. Evidence
suggests the role of multiple acute infections as well as single
prolonged intestinal infections. Irrespective of the initiating
factor, a vicious cycle ensues, exacerbated by the nutritional
consequences of poverty, poor hygiene, environmental con-
tamination, faulty feeding practices, and early weaning.
Whatever the relative contribution of infection and/or nutri-
tional and allergic phenomena to the pathogenesis of persis-
tent diarrhea and malnutrition, the final common pathway
probably involves injury to the small intestinal mucosa.6
Morphologic abnormalities of the small intestinal mucosa of
moderate to severe degree have been seen by scanning elec-

1045-1870/04/$-see frontmatter © 2004 Elsevier Inc. All rights reserved. 229

doi:10.1053/j.spid.2004.07.003
230
tron microscopy of infants with persistent diarrhea. De-
creases in number and height of microvilli, blunting of bor-
ders of enterocytes, loss of the glycocalyx, shortening of villi,
and presence of a mucus pseudomembrane coating the epi-
thelial surface are the abnormalities observed in most pa-
tients.7 These structural changes adversely affect intestinal
digestive, absorptive, and barriers functions. More than half
of the children with acute and persistent diarrhea develop
protein-losing enteropathy, as indicated by fecal alpha-1 an-
titrypsin determinations.8
The interplay between the immune system and the gut
probably is key to development of malnutrition. Data show-
ing that diarrhea exacerbates malnutrition, which in turn
predisposes to increases in both number and duration of
diarrhea episodes, are convincing. Determining whether im-
munological abnormalities are a causative factor or a conse-
quence of persistent diarrhea is difficult. Many studies have
looked at the immunological response to persistent diarrhea,
but the immunopathophysiology is not understood com-
pletely. Translocation of lipopolysaccharide across injured
gut results in chronic immunostimulation with raised IgG
and C-reactive protein.9 Various immunologic abnormalities
have been described, but no unifying concept has emerged.
For example, a study in Bangladesh of potentially antiviral
cytokines showed that during acute rotavirus infection, in-
terleukin (IL)-10, interferon-␥, and tumor necrosis factor
(TNF)-␣ were elevated in the plasma compared with control
children; however, the subsequent development of persistent
diarrhea was associated only with initially higher interfer-
on-␥ response.10 Children from Ghana with persistent diar-
rhea had a higher percentage of CD8⫹ cells and lower CD4/
CD8 ratio compared with children with acute diarrhea.11
Children from an urban Brazilian slum with Enteroaggrega-
tive E. coli (EAEC) and persistent diarrhea had significant
elevations in fecal lactoferrin, IL-8 and IL-1␤. These findings
suggest that EAEC triggers intestinal inflammation and may
contribute to childhood malnutrition.12 Malnourished Hai-
tian children with Cryptosporidium diarrhea had markers of
proinflammatory immune response, IL-8 and TNF-␣ recep-
tor, that were significantly elevated compared with a control
group without diarrhea.13 Similarly, Brazilian children with
Cryptosporidium infection had mild to moderately elevated
lactoferrin, and some had elevated IL-8.14
Recent studies have suggested that leptin, a hormone/cy-
tokine produced by adipose tissue, may play a central role in
the immunodeficiency of malnutrition.15 Starvation is asso-
ciated with low leptin levels; increased serum cortisol; thy-
mic atrophy caused by apoptosis of lymphocytes; depletion
of immature CD4⫹ and CD8⫹ cells; increased IL-6, C-reac-
tive protein, and the soluble receptors of TNF-␣ (sTNFR-p55
and sTNFR-p75); impaired cell-mediated immunity (as indi-
cated by delayed type hypersensitivity); and increased risk of
developing infection. In leptin-deficient animals, administra-
tion of leptin reverses the immunologic abnormalities.16-18
Thus, an inflammatory component may be present in per-
sistent diarrhea, regardless of the etiology, that may explain
why infection in malnourished children is associated with
more dehydration, fever, vomiting, prolonged intestinal ill-
T. J. Ochoa, E. Salazar-Lindo, and T. G. Cleary
ness, and longer hospitalization, as well as long-term growth
and developmental shortfalls.19,20
Risk Factors for
Developing Persistent Diarrhea
Some studies have found that malnutrition, immunosup-
pression, young age, and an increase in the number of previ-
ous episodes of diarrhea are risk factors for the development
of persistent diarrhea. In a longitudinal study of acute and
persistent diarrhea in 677 children in Peru, episodes of
longer duration were associated with age (⬍5 months) and
more severe illness in the first week. However, none of the
laboratory tests performed in the first week of illness (fecal
leukocytes, blood, reducing substances, pH, or fat) proved to
be of value in identifying episodes that would become per-
sistent.21 In a study in Bangladesh, malnourished children
had a 3.5-fold increased risk of developing persistent diar-
rhea and immunodeficient children had about twice the risk
of developing persistent diarrhea compared with immuno-
competent children.22 A cohort study among children in Bra-
zil showed that first episodes of persistent diarrhea were pre-
ceded by a doubling of acute diarrhea burdens and were
followed by a further three-fold increase in diarrhea burdens
during the next 18 months. Persistent diarrhea accounted for
only 8 percent of episodes of diarrhea, but it accounted for
more than one-third of the number of days with diarrhea.23
Multiple episodes of diarrhea due to almost any pathogen
render the child more susceptible to developing persistent
diarrhea. Both acute and persistent diarrheas commonly are
associated with infection by multiple pathogens in high-risk
settings. Children with persistent diarrhea are more suscep-
tible to developing further infections and need to be followed
closely for a prolonged period after they have their initial
diarrheal episode. Nonetheless, in the individual child, no
clinical or laboratory features of acute diarrhea reliably pre-
dict the development of persistent diarrhea. Thus, it is im-
portant that all diarrheal episodes have appropriate fluid and
dietary management and follow-up to detect the persistent
diarrheas that need special intervention.
Infectious
Agents Most Likely
to Cause Persistent Diarrhea
Specific enteropathogens are responsible for acute diarrhea,
dysentery, and persistent diarrhea. However, the spectrum of
illness overlaps and etiology varies depending on the clinical
setting (immunosuppression, human immunodeficiency vi-
rus [HIV], traveler’s diarrhea, or developing versus devel-
oped countries).24 One of the main difficulties in the man-
agement of persistent diarrhea is identifying the etiological
agent. For many of the pathogens (Table 1), optimal diagnos-
tic testing is unavailable, impractical, or prohibitively expen-
sive. Many of the diagnostic tests are done only in research
laboratories. Most studies of persistent diarrhea have failed to
find an infectious agent in all cases; on average, one-third of
Management of infection-associated persistent diarrhea 231

Table 1 Diagnosis of Specific Pathogens Associated With Persistent Diarrhea

Virus
Cytomegalovirus ● Colonic biopsy with hematoxylin and eosin stain or immunostain to
detect intranuclear cytomegalovirus inclusions.
● Viral culture
Rotavirus ● Enzyme immunoassay or latex agglutination on stools
Enteric adenovirus ● Enzyme immunoassay on stools
Astrovirus ● Enzyme immunoassay on stool
Enteric bacterial pathogens
Salmonella, Shigella, Yersinia, ● Standard stool culture (CIN-agar for Yersinia, Campy-BAP or
Campylobacter Skirrow media for Campylobacter)
EPEC ● Fluorescent actin staining of cells in tissue culture
● Detection of eae by PCR or hybridization with labeled DNA probes
● Small bowel biopsy for routine microscopy and electron
microscopy
EAEC ● Aggregative adherence to tissue culture cells
● Detection by PCR of virulence genes
ETEC ● Identification of LT or ST by ELISA or PCR
Clostridium difficile ● Toxin detection by enzyme immunoassay or tissue culture assay
Mycobacterium tuberculosis ● Acid-fast bacillus (AFB) stain and culture of stool
Mycobacterium avium complex ● Acid-fast bacillus (AFB) stain and culture of stool, blood culture, or
duodenal biopsy
Intestinal parasites
Giardia lamblia ● Antigen detection with immunofluorescent antibody or enzyme
immunoassays
● Direct microscopic detection of trophozoites or cysts in stool
sample
Cryptosporidium parvum ● Modified acid-fast stain of stool
● Enzyme immunoassay in stools
● Immunofluorescent antibody
Microsporidium ● Modified trichrome stain of stools
● Small bowel biopsy with hematoxylin and eosin, periodic acid-
Schiff, silver and Giemsa stains
Cyclospora cayetanensis ● Modified acid-fast stain of stools
Isospora belli ● Modified acid-fast or auramine-rhodamine stain of stools
● Detection of ova on routine parasite exam of stools
Entamoeba histolytica ● Periodic acid-Schiff and trichrome stain of stools
● ELISA and PCR in stools
● Serologic studies (for invasive amebiasis)
Strongyloides, Ascaris, Trichuris species ● Microscopic stool examination for eggs and parasites (stool
concentration for Strongyloides)
EAEC, enteroaggregative Escherichia coli; ELISA, enzyme-linked immunosorbent essay; EPEC, enteropathic E. coli; ETEC, enterotoxigenic E.
coli; PCR, polymerase chain reaction.

cases are negative for all known enteropathogens. We likely
do not know yet all relevant enteropathogens. Probably diar-
rhea sometimes persists long after the infectious trigger no
longer is detectable.
Most of the viruses that cause acute gastroenteritis also
have been associated with persistent diarrhea, especially in
immunodeficient children. Data from a study of Bangladeshi
children who developed persistent diarrhea after having ro-
tavirus infection suggested that persistent diarrhea is not
caused by persistence of the organism but to an alteration in
some host factor(s) that renders the children more suscepti-
ble to other infections or that leads to prolonged malabsorp-
tion.10 Similarly, in Bangladesh, astrovirus was detected more
frequently with diarrhea of increasing duration, suggesting
the need for further studies to determine whether astrovirus
plays a causative role in persistent diarrhea or is a secondary
agent.25
Many of the bacterial enteric pathogens responsible for
acute diarrhea and dysentery also can produce persistent di-
arrhea (eg, Salmonella, Shigella, Campylobacter, Yersinia, ente-
rotoxigenic E. coli, Clostridium difficile). Postshigellosis persis-
tent diarrhea is not an uncommon occurrence. A
community-based study of Bangladeshi children found that
despite the use of antibiotics in dysenteric episodes, persis-
tent diarrhea occurred in 23 percent of children with shigel-
losis. Persistence was related to antibiotic resistance, devel-
opment of infection during infancy, and Shigella species other
than that of Shigella dysenteriae1. Even nondysenteric shigel-
losis was associated with a high frequency of persistence.26
However, despite the fact that a series of acute infections
232
caused by different pathogens often is followed by persis-
tence, a few organisms are associated disproportionately with
persistent illness. The most important bacterial etiological
agents are enteropathogenic E. coli (EPEC) and EAEC.27
Many parasites cause persistent diarrhea (Microsporidium,
Isospora belli, Entamoeba histolytica, and Strongyloides); how-
ever, the intestinal protozoans Giardia, Cryptosporidium, and
Cylospora are the most important ones. Intestinal parasitic
infections have been linked with poorer nutritional out-
comes, including increased risk for nutritional anemia, pro-
tein-energy malnutrition, and growth deficits in children. We
will review these specific agents in more detail. Then the
agents unique to chronic diarrhea in children with AIDS will
be discussed.
EPEC
EPEC are defined as diarrheagenic E. coli that produce a char-
acteristic histopathology known as the attaching and effacing
lesion in intestinal epithelial cells; EPEC do not produce
Shiga toxins, invade cells, or produce enterotoxins. Typical
EPEC possess a virulence plasmid known as EAF (EPEC ad-
herence factor) that encodes localized adherence on cultured
epithelial cells. Atypical EPEC do not possess this plasmid.28
Typical EPEC, a leading cause of infantile diarrhea in devel-
oping countries, is a rare occurrence in industrialized coun-
tries, where atypical EPEC seem to be more important.29,30
The conventional method used to diagnose EPEC is based
on the identification of strains belonging to classic sero-
groups/serotypes. However, with new molecular techniques
(ie, DNA probes for the detection of genes coding EAF, the
virulence genes for bundle-forming-pilus, and enterocyte-
attaching-effacing factor), virulence genes may be found in
strains not belonging to classic serogroups/serotypes.31
Therefore, molecular identification is the most reliable
method for studying the epidemiology of EPEC diarrhea in
children.
Studies from Brazil showed that EPEC is the major entero-
pathogen in infants younger than 1 year of age, particularly in
those younger than 6 months of age. Infection with EPEC is
one of the main risk factors associated with death in children
with diarrhea. In comparing the clinical features of diarrhea
caused by EPEC versus other pathogens, children with EPEC
are more likely to fail oral rehydration therapy, have intoler-
ance to cow’s milk, require hospitalization, and develop per-
sistent diarrhea.7
EAEC
Diagnosis of EAEC, also referred to in the literature as
EAggEC, has long been problematic. EAEC are defined by
their ability to adhere to epithelial cells in a characteristic
“stacked-brick” pattern but otherwise are highly heteroge-
neous.32 New and sensitive molecular tests to detect EAEC
are available. However, the main problem with EAEC re-
mains the differentiation of pathogenic and nonpathogenic
clones. In studies of childhood diarrhea in Brazil, EAEC were
the leading cause of persistent diarrhea.12,33 Surprisingly,
T. J. Ochoa, E. Salazar-Lindo, and T. G. Cleary
children with EAEC in their stool had significant growth
impairment after their positive culture, even in the absence of
diarrhea.12
Giardia lamblia
The symptoms of giardiasis vary from asymptomatic passage
of cysts to chronic or recurrent diarrhea, sometimes with
malabsorption and weight loss. In a study on intestinal par-
asitic infections in rural Ecuadorian children, infection with
Giardia was associated with a risk of having stunted growth
that was twice that in children without giardiasis.34 The most
consistent predictor of Giardia and other protozoal infections
was a high intra- and peridomicilliary concentration of do-
mestic animals. In contrast to children with poor nutritional
status, well-nourished children tend to manifest fewer clini-
cal signs of malabsorption with episodes of giardiasis.35 The
most alarming aspect of giardiasis is its effect on stunting and
on intelligence. In a group of 210 Peruvian children followed
from birth to 2 years of age and then assessed for cognitive
function at 9 years of age, those with more than one episode
of giardiasis per year scored 4.1 points lower on the revised
Weschler intelligence scale than did children with one or
fewer episodes a year. The combined effect of stunting and
giardiasis appeared to account for an IQ deficiency of 15
points, highlighting the need for early intervention strate-
gies.36
Cryptosporidium parvum
C. parvum genotype 1 and genotype 2 strains predominate in
humans, with minor genotypes and “nonparvum” species
found in a few individuals.37 C. parvum infection varies from
asymptomatic colonization to persistent, profuse diarrhea in
both immunocompromised and immunocompetent hosts. A
study in West African children investigated episode-specific
determinants for the progression of an acute episode of diar-
rhea to one that persists; 12.5 percent of the diarrheal epi-
sodes were persistent. Current infection with C. parvum was
the most significant risk factor.38
Several studies have demonstrated that cryptosporidiosis
has an adverse effect on child growth, especially when infec-
tion is acquired during infancy. A cohort study of Peruvian
children infected with C. parvum showed that they experi-
enced growth faltering both in weight and in height for sev-
eral months after having infection, followed by a period of
catch-up growth. Younger children took longer to catch up in
weight than did older children. Catch-up growth, however,
did not occur in children infected in the first five months of
life.39 C. parvum-related intestinal damage and malabsorp-
tion are presumed to be the mechanisms associated with
growth retardation. In a cohort study of Brazilian children,
cryptosporidial infection at 0 to 2 years of age was associated
with reduced physical fitness at 6 to 9 years of age, even when
controlling for current nutritional status. Early diarrhea bur-
dens also correlated with impaired cognitive function.19
As with other agents associated with persistent diarrhea,
malnutrition has been demonstrated even after asymptom-
atic C. parvum infection in young Peruvian children.39,40
Management of infection-associated persistent diarrhea
Asymptomatic cryptosporidiosis is of special concern be-
cause it occurs very commonly and thus may have a major
adverse effect on child growth and intelligence.
Cryptosporidium also is an important pathogen in AIDS.
Clinical presentations include chronic diarrhea (36%), chol-
era-like disease (33%), transient diarrhea (15%), and relaps-
ing illness (15%).41 Patients infected with human immuno-
deficiency virus (HIV) who have CD4 counts greater than
200 cells/mm3 usually have self-limited infections, whereas
those with CD4 counts less than 150 cell/mm3 have chronic
diarrhea with wasting. Immune reconstitution with combi-
nations of antiretrovirals, commonly referred to as highly
active antiretroviral therapy (HAART), remains the most ef-
fective medical intervention for cryptosporidiosis in patients
with AIDSs.
Cyclospora cayetanensis
Recent data suggest that Cyclospora, like EPEC, EAEC, Giar-
dia, and Cryptosporidium, may be a major cause of persistent
diarrhea. However, the data are more limited. In developing
countries where C. cayetanensis is endemic (eg, Haiti, Guate-
mala, Peru, and Nepal), infected children of low socioeco-
nomic status often will have mild symptoms or be asymp-
tomatic. Studies in Guatemala demonstrated that children
aged 1.5 to 9 years were five times more likely than were
adults to have Cyclospora.42 In a Peruvian cohort, the inci-
dence of cyclosporiasis was fairly constant among 1- to
9-year-old children; the likelihood of having diarrhea de-
creased significantly with each episode of cyclosporiasis.43 In
most developed countries, the disease has been associated
primarily with food-borne outbreaks and cases of traveler’s
diarrhea. In immunocompetent individuals, infection ap-
pears to be self-limited. In immunocompromised persons,
severe diarrhea can last as long as 4 months or longer, even if
treated, and may require long-term suppressive therapy.44
Persistent Diarrhea in Patients With HIV
Patients with HIV are at risk for the acquisition of all the
pathogens mentioned above as well as for additional organ-
isms that rarely make immunocompetent individuals sick.
The lifetime incidence of diarrhea among those with HIV has
been estimate to be 30 to 70 percent. However, the use of
HAART has improved markedly the long-term outlook for
patients with adequately treated HIV infection. Immune re-
covery related to HAART has resulted in significant resolu-
tion of diarrhea caused by opportunistic pathogens previ-
ously thought to be untreatable, including microsporidia and
cryptosporidia.41,45
Not all cases of chronic diarrhea in patients with advanced
AIDS have an infectious etiology. Drug side effects (eg, diar-
rhea associated with protease inhibitors has ranged from 12
to 56%), gastrointestinal malignancies (Kaposi sarcoma and
lymphoma), and HIV enteropathy are important causes.45
Multiple studies have found that microsporidia, cytomegalo-
virus (CMV), cryptosporidia, and Mycobacterium avium intra-
cellulare complex are the most common opportunistic patho-
233
gens identified among HIV patients with chronic diarrhea,
and CD4 counts less than 200 cells/mm3.41
Microsporidiosis
Many species of microsporidia exist: two of them are major
gastrointestinal pathogens: Enterocytozoon bieneusi and En-
cephalitozoon intestinalis.46 E. bieneusi is responsible for 90
percent of cases of microsporidiosis in patients with AIDS.
Microsporidia are responsible for 14 to 60 percent of chronic
diarrhea in patients with HIV, especially those with CD4
counts of less than 100 cell/mm3. Infection of immunocom-
petent individuals usually is self-limited.
CMV
CMV colitis is found almost exclusively in patients with ad-
vanced AIDS. The CD4 count almost always is less than 50
cells/mm3. The most common presentation is chronic watery
diarrhea (in 80%) with abdominal pain (in 50%) and fever (in
40 to 80%).
Mycobacterium
avium intracellulare Complex
Chronic diarrhea caused by M. avium intracellulare complex
infection usually occurs as part of a systemic infection with
associated fever, severe anemia, night sweats, weight loss,
abdominal pain, and elevated alkaline phosphatase. Patients
almost always have advanced HIV infection with CD4 counts
of less than 50 cells/mm3.
Management
Management of persistent diarrhea is complex because the
etiology and pathogenesis are complex. It includes adequate
dietary management, micronutrient supplementation, ade-
quate rehydration, and antimicrobials.
Dietary Management
Dietary management is crucial in persistent diarrhea. A mul-
ticenter, hospital-based study showed that short-term treat-
ment of persistent diarrhea can be accomplished safely and
effectively using an algorithm relying primarily on locally
available foods and simple clinical guidelines.47 The initial
diet contained cereals, vegetable oil, and animal milk or yo-
gurt. The second diet offered if the patient did not improve
with the initial regimen was lactose-free, and energy from
cereals was replaced partially by simple sugars. The overall
success rate (cessation of the diarrheal episode and weight
gain) of the treatment algorithm was 80 percent. The children
at greatest risk for having treatment failure were those who
had associated acute illnesses (including cholera, septicemia,
and urinary tract infections), required intravenous antibiot-
ics, and had the highest initial diarrhea purging rates. Simi-
larly, a controlled trial of dietary management of children
with persistent diarrhea in Guinea–Bissau showed that
home-made dietary treatment (millet gruel) and micronutri-
ent supplements had an immediate and sustained beneficial
effect on growth in children with persistent diarrhea.48 A
234
recent review by Bhan describes the new treatment regimens
that have been introduce for the management of the severely
malnourished child in developing countries.49 Treatment in-
volves stabilization for the first week and rehabilitation dur-
ing the following weeks.
Some data support the use of probiotics in persistent diar-
rhea. For example, use of yogurt containing Lactobacillus bul-
garicus and Streptococcus thermophilus has been reported to
lead to resolution of persistent diarrhea within 5 days in 85
percent of children.50 In a recent study, Lactobacillus spp. and
Saccharomyces boulardii significantly reduced the number of
stools and duration of diarrhea in children with persistent
diarrhea.51
Exclusive breastfeeding and, to a lesser extent, partial
breastfeeding, protects against acute and persistent diarrhea
in the first six months of life.23,52 Thus, promotion of breast-
feeding is an essential element in preventing acute and per-
sistent diarrhea and the malnutrition associated with them.
Micronutrients
Children with persistent diarrhea and malnutrition may be
deficient in vitamin A, zinc, folic acid, copper, and seleni-
um.49 Deficiencies in zinc and vitamin A impair the function
of the immune system and have a direct effect on the struc-
ture and function of mucosa; thus, they are likely to be in-
volved in the recovery of the intestinal mucosa after injury.
The role of vitamin A, folate, and zinc as adjunct therapy in
children in developing countries has been reviewed by Ma-
halanabis and Bhan.53 Some studies suggest that in children
with acute diarrhea vitamin A supplementation reduces per-
sistent diarrhea episodes. Folate is not recommended rou-
tinely as adjunct therapy of diarrhea.
Recently, Black54 reviewed all randomized controlled trials
of zinc supplementation in infectious diseases. Zinc supple-
mentation has a marked effect on reducing prolonged epi-
sodes of diarrhea and reducing the rate of treatment failure
and death in persistent diarrhea. Zinc was found to have a
therapeutic benefit (typically resolution of small bowel dam-
age and shortening duration of diarrhea) in acute and persis-
tent diarrhea. In six of 9 trials that evaluated prevention of
diarrhea, a significantly lower incidence of diarrhea occurred
in the group that was given zinc than in the controls; a pooled
analysis demonstrated 18 percent (95% confidence interval,
7 to 28%) less diarrhea. Although unanimous agreement
does not exist, the weight of the evidence favors a role for zinc
supplementation. Moreover, a randomized controlled trial
showed that combined zinc and vitamin A supplementation
synergistically reduced the prevalence of persistent diar-
rhea.55
Oral Rehydration
The use of oral rehydration therapy for children with acute
infectious diarrhea is one of the greatest scientific advances
that has occurred during the past 50 years. The use of oral
rehydration salt (ORS) solution has contributed significantly
to decreased mortality rates from acute diarrhea in children;
its use also is crucial in persistent diarrhea. Although the
T. J. Ochoa, E. Salazar-Lindo, and T. G. Cleary
success of glucose-electrolyte based oral rehydration therapy
is unquestioned, controversy continues about the ideal com-
position of these solutions.56 Debate continues on the sodium
and glucose concentration, osmolality, and use of complex
substrates, such as cereals or defined glucose polymers, to
improve the efficacy of ORS. For example, a randomized
controlled trial was conducted to compare the clinical effi-
cacy of hypo-osmolar ORS solution (224 mmol/L) and stan-
dard ORS solution (311 mmol/L) in children with persistent
diarrhea. Total stool output and duration of diarrhea were
significantly less in the group receiving hypo-osmolar ORS.57
Hypo-osmolar ORS also has beneficial effects on the clinical
course of dehydrating acute watery diarrhea in children in
developing countries58 and in severely malnourished maras-
mic children.59 Both rice-based reduced osmolality ORS or
glucose-based reduced osmolality ORS appear to be more
effective than is standard ORS in children with persistent
diarrhea.60
Antimicrobials
Antimicrobial agents are indicated for the treatment of some
enteropathogens that cause persistent diarrhea, particularly
the parasites.24 The enteropathogenic bacteria, such as EPEC
and EAEC, likely would improve with treatment, if they
could be diagnosed rapidly.
Nitazoxanide, a nitrothiazolyl-salicylamide derivative, is a
broad-spectrum antimicrobial agent with activity against
protozoa, nematodes, cestodes, trematodes, and bacteria.61,62
Nitazoxanide is effective in the treatment of Cryptosporidium
in immunocompetent adults and children; in patients with
AIDS, its activity varies depending on the degree of immuno-
suppression and the duration of treatment.63,64 Intestinal
protozoans are important causes of chronic diarrhea, but
diagnosis is difficult to establish with currently available
tests. In this context, the use of nitazoxamide as empirical
therapy for persistent diarrhea is an option that needs to be
evaluated. Metronidazole and furazolidone also can be used
for Giardia, and trimethoprim-sulfamethoxazole can be used
for Cyclospora.
Extraintestinal infections (acute lower respiratory infec-
tions, urinary tract infections, sepsis, etc.) commonly associ-
ated with persistent diarrhea should be evaluated carefully
and treated promptly to improve the clinical outcome and
reduced persistent diarrhea treatment failures.47,65,66
Treatment of Persistent
Diarrhea in Patients With HIV
Diarrhea may resolve without specific antiparasitic treatment
during immune reconstitution induced by HAART. In devel-
oping countries, where the cost makes HAART less available,
algorithms exist for the management of chronic diarrhea in
HIV-infected adult patients. These algorithms include the
empiric use of trimethoprim-sulfamethoxazole (or norfloxa-
cin), metronidazole, and loperamide, with good response
rates.67,68
Treatment for microsporidiosis with albendazole often is
only partially effective, and relapse rates are very high, often
Management of infection-associated persistent diarrhea
requiring chronic maintenance therapy. Treating Cryptospo-
ridium has been difficult; current treatment options include
nitazoxanide or combination drug therapy, such as azithro-
mycin plus paromomycin, or nitazoxanide plus azithromycin
plus rifabutin. CMV colitis is treated with ganciclovir, valgan-
ciclovir, or foscarnet. M. avium complex can be treated effec-
tively with clarithromycin and ethambutol.
Conclusion
In summary, the pathogenesis and management of persistent
diarrhea is complex. Many pathogens can produce persistent
diarrhea and seriously affect growth, nutritional status, and
intellectual function. Some of these pathogens can have an
effect on children’s growth even in the absence of diarrhea.
The interplay between the immune system and the gut prob-
ably is key to development of malnutrition and growth fail-
ure.
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