++
Children with primary or acquired immunodeficiency are at increased
risk for infectious and inflammatory gastrointestinal disorders.1 The
risk and severity of infection depends on the type of immunodeficiency.
Individuals with deficiencies of antibody response are predisposed
to extracellular bacterial infections and intestinal pathogens.
Patients with deficiencies of T cells are predisposed to both intracellular
and extracellular infections. In addition, patients with primary
immunodeficiencies are more prone to develop autoimmune disorders
because of their decreased ability to distinguish self-organisms
from foreign organisms. Autoimmune diseases and celiac disease are
more common in the IgA-deficient patients.
+++
Clinical Features
and Differential Diagnosis
++
Gastrointestinal disorders in children with immunodeficiencies
can be associated with infectious (viruses, bacteria, mycobacteria,
fungi, or protozoa) and noninfectious disorders (autoimmune and
alloimmune). Dysmotility, malabsorption, and malnutrition can be associated
with any of these disorders. In addition, medical treatments prescribed
for children with immunodeficiencies may have important gastrointestinal
complications.
+++
Gastrointestinal
Infections
++
The pandemic of human immunodeficiency virus (HIV) infection and
acquired immunodeficiency syndrome (AIDS) has heightened our awareness
of opportunistic infections, most of which have been described either
in patients with primary immunodeficiencies or in immunosuppressed
patients with malignancies. These infections are listed in Table 391-1 according to the sites of gastrointestinal
involvement and are discussed in more detail in Section
17. In addition to those listed, immunodeficient patients also
are at increased risk for common bacterial and viral pathogens or
infections with multiple organisms.
++
++
Cytomegalovirus, rotavirus, adenovirus, and herpes simplex virus are
the most common viral agents. Cytomegalovirus is commonly identified
in children with immunodeficiency and can cause inflammation or
ulceration throughout the gastrointestinal (GI) tract, including
the pancreatobiliary system. Symptoms may include diarrhea, dysphagia,
vomiting, abdominal pain, and GI bleeding. Histologic identification
of cytomegalovirus within the intestinal tissue is required to establish
a pathogenic role because cytomegalovirus commonly is excreted in
the urine or stool of asymptomatic individuals. Rotavirus is a cause
of vomiting and diarrhea in immunocompromised children and may disseminate
into the liver parenchyma. In contrast, rotavirus rarely is a pathogen
in normal or immunocompromised adults, most of whom have previously
established immunity. Adenoviruses is reported to cause colitis
in adults with AIDS and fulminant hepatitis in immunocompromised children. Diagnosis
of adenovirus infection depends on histologic identification, which should
be confirmed by culture.2 Herpes simplex virus
usually causes oral and esophageal lesions and produces symptoms
of dysphagia and odynophagia. Other viruses, such as astrovirus, picornavirus,
and calicivirus, have been identified in the stool of HIV-infected
adults with diarrhea, and they also may have a role in pediatric
patients with diarrhea. In individuals without an identifiable pathogen,
HIV itself may cause both esophagitis and enteritis with either
dysphagia or diarrhea and malabsorption.
++
Salmonella, Shigella, Campylobacter, Yersinia, Escherichia
coli, and Clostridium difficile are the
most common bacterial infections in normal or immunocompromised
hosts. In the presence of bowel dysmotility, overgrowth or normal
bacterial flora in the small bowel can contribute to intestinal inflammation
and malabsorption. In the immunocompromised host, infections such
as Salmonella, Shigella, and Campylobacter can
be severe and prolonged, with a tendency to relapse and spread systemically.
In a reported series of bacteremia in HIV-infected children, Salmonella was
the second-most common bacterial isolate from blood. The common
use of antibiotics in immunocompromised patients increases their
risk of Clostridium difficile. Probiotic prophylaxis,
sometimes presumed to be beneficial to prevent opportunistic infections, should
probably not be used in the management of immunodeficient patients
without further controlled studies, since an increased incidence
of bacterial sepsis has been reported in this population.3 In
developing countries, strains of enteropathogenic E coli are
important causes of diarrhea in young HIV-infected children. In the
United States, gastroenteritis caused by enteropathogenic E
coli is rare, but it should be considered in patients with
a recent history of travel.
++
Mycobacterium avium-intracellulare, or M
avium complex (MAC), accounts for the great majority of
disseminated nontuberculous mycobacterial infections, involving
bone marrow, liver, kidneys, and the GI tract. Approximately 12% of
children with HIV infection have disseminated MAC. Although the
rate of GI involvement by MAC is uncertain, 90% of children
with disseminated MAC have GI symptoms such as abdominal pain, vomiting, anorexia,
and diarrhea. Hepatosplenomegaly is a common physical finding. Children
with disseminated MAC often have very low CD4 T-cell counts and also
have a poor prognosis, with a median survival period of 9 months. M
tuberculosis also can infect the GI tract, usually the
ileocecal region, and has been reported to cause peritonitis secondary
to intestinal perforation.
++
Candida and Histoplasma are
the most common fungal infections affecting immunodeficient children. Candida usually
causes oral thrush and esophagitis (see Chapter 394). Fungal balls in the stomach can cause obstructive symptoms. Histoplasma has
been reported to infect villi of the small intestine, resulting
in abdominal pain and diarrhea. Both fungi can disseminate systemically.
++
Giardia is common in normal and immunocompromised
children but often causes more severe diarrhea and abdominal pain
and has a more protracted course in children with immunodeficiency. Cryptosporidium typically
causes a chronic secretory diarrhea in immunocompromised patients,
but the severity of the diarrhea may vary. Cryptosporidium also
may colonize the biliary and pancreatic ducts and cause inflammation
and obstruction. Isospora has been reported as a cause of diarrhea
in immunodeficient adults, but it very rarely causes diarrhea in US
children. Microsporidia are intracellular protozoan organisms that
infect small intestinal epithelial cells. They are found in a significant
number of HIV-infected adults with diarrhea but have yet to be reported
in children.
+++
Immune-Mediated
Injury
++
Although infections are responsible for most cases of diarrhea,
immunologic reactions also can play a significant role in gastrointestinal (GI)
symptoms. Graft-versus-host disease and alloimmune reactions can
occur in patients with severe combined immunodeficiency from either
maternal-fetal transfusion or transfusion of nonirradiated blood
products; graft-versus-host disease more commonly results from bone
marrow transplantation in older children with hematologic malignancies. Clinical
signs and symptoms include skin rash, hepatitis, diarrhea, GI bleeding, and
eosinophilia. Rarely, exocrine pancreatic insufficiency results
from chronic graft-versus-host disease. Autoimmune mechanisms, as
suggested by the presence of antiepithelial cell antibodies, may
be responsible for intestinal injury in some patients with common variable
immunodeficiency. Autoimmune enteropathy more commonly begins in
infancy and presents with chronic diarrhea that frequently requires
therapy with total parenteral nutrition. Immunologic reactions to
food proteins, either cell-mediated or antibody (IgE)-mediated,
also can cause eosinophilic intestinal inflammation and malabsorption.
Eosinophilic inflammation may also be the result if immune dysregulation
in the absence of allergic reactions. High titers of antigliadin
and antimilk protein antibodies have been reported with HIV infection
and other intestinal disease such as Crohn disease. The clinical
relevance of these findings is unknown.
+++
Medication-Induced Gastrointestinal
Disorders
++
Medications used in the management of immunodeficiencies, whether
congenital or acquired, frequently lead to nausea, abdominal pain,
and vomiting. Mucosal injury, manifested by oral ulcers or diarrhea,
can result from bone marrow suppression caused by agents such as
methotrexate. Pancreatitis has been associated with such drugs as
the reverse-transcriptase inhibitors (didanosine and lamivudine),
antibiotics (trimethoprim-sulfamethoxazole and pentamidine), and
valproic acid. Elevated serum triglyceride and cholesterol levels,
possibly caused by mitochondrial damage in the hepatocytes, have been
reported in patients treated with the protease inhibitor ritonavir.
Most children with immunodeficiency are receiving multiple medications,
so the evaluation of potential causes of gastrointestinal symptoms
should always include a careful review of potential medication side
effects.
+++
Diagnostic Evaluation
++
Primary immunodeficiencies likely affect as many as 1 in 2000
to 1 in 10,000 live births.4 A child with immunodeficiency can
present with any one or a combination of gastrointestinal (GI) symptoms,
including diarrhea, growth failure, hepatosplenomegaly, GI bleeding,
abdominal pain, emesis, and dysphagia. Of these symptoms, diarrhea
probably is the most common. Suspicion of a possible immunodeficiency
disorder is further suggested when these disorders are associated
with abnormal skin/hair findings, cardiac disease (Williams
syndrome), ectodermal dysplasia, severe food allergies/eczema,
or recurrent oral thrush.
++
If a child with a known immunodeficiency presents with diarrhea, studies
on the stool should include occult blood (hemoccult), culture (for Salmonella,
Shigella, Campylobacter, Yersinia, and C difficile),
immunoassays for rotavirus Giardia antigen, and
acid-fast stain or immunofluorescent stain for Cryptosporidium and Isospora
belli. A complete blood count and blood culture should
be obtained if there is fever. An elevated eosinophil count suggests
a diagnosis of severe combined immunodeficiency, graft-versus-host
reaction, or an allergic gastroenteritis. Testing for IgE antibody
against a suspected food (eg, milk or soy protein) by a radioallergosorbent
test (RAST) may be warranted. Following extensive evaluation, an identifiable
cause of diarrhea can be found in 50% to 85% of
patients. However, the vigor of investigation must be individualized and
tempered because patients may have multiple infections, and many
known infectious causes have no specific therapy. After treatable
infections have been excluded, optimal management includes symptom
relief and aggressive nutritional management to improve the overall
quality of life.
++
In a child with known immunodeficiency presenting with abdominal
pain and vomiting, a partial bowel obstruction, cholangitis, or
pancreatitis should be considered in the differential diagnosis.
Serum aminotransferase levels as well as amylase and lipase concentrations
should be measured. Imaging studies such as an upright abdominal
radiograph to look for evidence of intestinal obstruction and abdominal
ultrasonography to detect biliary/pancreatic ductal dilatation
or edema of the pancreas may be helpful. Radiographic evidence of
intramural air in the small or large bowel (ie, pneumatosis) suggests
either bacterial overgrowth or severe tissue necrosis.
++
Assessment of absorptive function includes testing of stool for
reducing substance, pH, and fecal fat, as detailed in Chapter 408. A lactulose breath hydrogen test may help to diagnose
small bowel bacterial overgrowth (see Chapter 408),
but empiric therapy with metronidazole or other antibiotics is a reasonable
option. Testing the stool for α1-antitrypsin
may identify patients with protein-losing enteropathy. Serum protein,
albumin, prealbumin, and transferrin levels are helpful in assessing
the severity of protein malnutrition in a child with poor growth.
++
Fiberoptic endoscopy is indicated in evaluating patients with
dysphagia unresponsive to empiric therapy for Candida;
upper or lower gastrointestinal bleeding, or chronic diarrhea in whom
no pathogen or cause has been found by other tests. Diagnosis of
esophagitis caused by acid reflux, Candida, or
cytomegalovirus can be made by esophageal biopsy. Pathogens that
can be identified in biopsies of the small intestine and colon include Cryptosporidium,
cytomegalovirus, adenovirus, Histoplasma, Microsporidia, and Mycobacterium
avium-intracellulare.
++
Both specific and supportive treatments are needed in treating
a gastrointestinal disorder in a child with immunodeficiency. Specific therapy
is directed at the cause of the disorder. If an infectious agent is
found, appropriate therapy is initiated. Human immunoglobulin has
been used in conjunction with ganciclovir to treat cytomegalovirus
infection; oral human immunoglobulin has led to clearance of Cryptosporidium in
2 patients with immunodeficiency secondary to hematologic malignancies,
but this therapy is not well proven.5 A somatostatin
analog that reduces gastrointestinal secretion, octreotide, has
been used with some success as a supportive therapy in patients
with HIV infection and chronic diarrhea. Conditions that are caused
by rotavirus, adenovirus, and Microsporidia have
no known effective specific therapy. In these situations, optimizing
nutritional status and controlling symptoms are of prime importance.
The use of pharmacologic agents that decrease the gastric acidity
should be limited in duration in the immunocompromised child to
reduce the risk of bacterial or fungal overgrowth that is associated
with the loss of the gastric acid barrier.6 For
patients with bile duct obstruction associated with either pancreatitis
or cholangitis, a biliary stent placed endoscopically can lead to
significant symptomatic relief. Antibiotic prophylaxis should be
considered when endoscopy is performed in patients with neutropenia
or with an indwelling central venous catheter.
++
The approach to nutritional management depends on the degree
of intestinal injury and malabsorption. Because most diarrhea illnesses
in the immunocompromised host are prolonged, after correction of
fluids and electrolytes, an “elemental” diet consisting
of small peptides, glucose polymers, and medium-chain triglyceride
is most easily absorbed.7 If tolerated, the diet
can then be advanced to include more complex carbohydrates, long-chain
fats, and intact proteins. Patients who are nauseous and anorectic
may require placement of gastrostomy tube for feeding and administration
of medications, whereas patients who have intractable diarrhea,
vomiting, gastrointestinal bleeding, or pancreatitis may require
total parenteral nutrition. Prolonged placement of a nasogastric
feeding tube in the immunocompromised child should be avoided because
it increases the risk for sinusitis. In patients who require total
parental nutrition or have prolonged diarrhea or malnutrition, serum
levels of micronutrients such as selenium, zinc, vitamins, and carnitine
should be determined. Deficiencies of these micronutrients can potentiate
immunodeficiency.
++
Several studies have demonstrated that megestrol acetate can
stimulate appetite and improve weight for adults and children infected with
HIV. However, the weight gain appears to be mostly in the form of
body fat.8 Growth hormone, on the other hand, has
been shown to maintain lean body mass in adults with AIDS, and pediatric
trials show promise in decreasing protein catabolism in children
with HIV/AIDS.9 It is remarkable, but
not surprising, that since the advent of HAART (highly active antiretroviral
therapy) for patients with HIV infection, severe gastrointestinal
complications such as intractable diarrhea and wasting seem to have
diminished in frequency.10 Despite this progress,
adolescents with HIV have lower growth parameters when compared
to the general population, implying that gastrointestinal infections
are not the sole cause of growth failure in children and adolescents
with HIV.11 Combined antiretroviral therapies reduce
mortality and morbidity from diarrhea in HIV-infected children who
receive vitamin A supplements. Zinc supplements may also reduce
frequency, duration, and severity of diarrhea in immunodeficient
children.