Download GASTROINTESTINAL MANIFESTATIONS IN HIV

Chiang Mai Med Bull 2003;42(3):121-130.
Review article
GASTROINTESTINAL MANIFESTATIONS IN HIVINFECTED CHILDREN
Nuthapong Ukarapol, M.D.
Department of Pediatrics, Faculty of Medicine Chiang Mai University
Infection from human immunodeficiency virus (HIV) is still an important
problem in Southeast Asia. The incidence
of HIV-infected patients has been increasing over the last two decades. The
problem also affects infants born to HIVinfected mothers. Preventive programs
and health education seem to be the most
important measures, although the zidovudine (AZT) protocol has been able to
reduce the risk of vertical transmission
from 25% to 3-8%. However, there have
been many HIV-infected children
suffering from various illnesses. Diarrhea
and other gastrointestinal complications
are the most common ailments found in
the HIV-infected child. Thea DM, et al.
reported that thirty-seven percent of HIVinfected infants experienced diarrhea.(1)
Gastrointestinal manifestations in
HIV- infected children
The gastrointestinal tract is a common
site of opportunistic infections and neoplasms, particularly when the gastro-
intestinal immunity becomes weakened,
resulting in decreased gastric secretion,
diminished IgA response, and altered
gastrointestinal motility.(2)
The common gastrointestinal symptoms and signs in HIV-infected patients
are summarized in Table 1.(3-5)
I. Diarrhea
Diarrhea is a common cause of death
in HIV-infected infants. Thea DM, et al.
reported a mortality rate of 132 per 1,000
live births, compared to 12 per 1,000 live
births in normal infants.(1) Diarrhea can
be categorized into acute, recurrent,
persistent, and chronic, according to the
duration of the symptoms. Persistent and
chronic diarrhea is approximately 3 times
Table 1. Common gastrointestinal symptoms
and signs in HIV-infected patients
Diarrhea
Abdominal pain
Dysphagia and Odynophagia
Gastrointestinal bleeding
Weight loss and anorexia
Address requests for reprints: Nuthapong Ukarapol, M.D. Department of Pediatrics, Faculty of Medicine, Chiang
Mai University, Chiang Mai 50200, Thailand. E-mail:[email protected]
Received 23 June 2003, and in revised from 22 August 2003.
Ukarapol N.
122
more common in HIV-infected infants
than in uninfected ones. The bacterial
pathogens, however, are not much
different. The factors that predispose the
HIV-infected child to persistent diarrhea
include 1) more than 3 episodes of acute
diarrhea and 2) a symptomatic HIVinfected mother. The etiology of diarrhea
in HIV-infected patients seems to be
diverse. They are summarized in Table
2.(2,3,6-12)
The most common cause of diarrhea
in HIV-infected patients is opportunistic
infection, including bacteria, viruses,
funguses, and parasites. Kelly P, et al.
reported Microsporidia, Isospora belli,
and Cryptosporidium parvum infection
as the first 3 most common pathogens
detected in HIV-infected patients with
chronic diarrhea.(6) In nearly two-thirds
of the patients, the pathogens could be
identified by stool examination and
cultures,(13) whereas as many as 44-65%
of the patients required an endoscopy to
establish the correct diagnosis, particularly in those with cytomegalovirus
(CMV), Mycobacterium avium-intracellu-
lare, esophageal candidiasis, and Cryptoccoccus neoformans infection.(3,13) We
studied the utility of pediatric gastrointestinal (GI) endoscopy in HIV-infected
children with various GI symptoms and
found that gross endoscopic abnormalities were observed in 78.3%; whereas
histologic inflammation and opportunistic pathogens were identified in 87% and
43.5%, respectively. Cytomegalovirus
was the most common pathogen identified. Abnormal gross findings were
significantly associated with histologic
inflammation and identification of pathogens (p=0.006 and 0.046, respectively).
Specific changes in medical management
were made in 50% of cases as a result of
endoscopic investigation.(14) Miller TL,
et al. concluded that 1) AIDS stage, 2)
serious bacterial infection, treated with
antibiotics, which finally predisposed the
patients to fungal infections, and 3) many
gastrointestinal symptoms and signs,
were the predictive factors useful as a
guide to the possibility of endoscopic
abnormalities.(3) Nevertheless, normal
gross endoscopic findings could predict a
Table 2. Etiology of diarrhea in HIV-infected patients
Bacteria
Salmonella, Shigella, Campylobacter, Yersinia enterocolitica, E. coli, C.
difficile, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare,
Plesiomonas shigelloides, Aeromonas hydrophilia
Virus
Cytomegalovirus, adenovirus, rotavirus, Norwalk virus, calcivirus
Parasite
E. histolytica, Giardia, Cryptosporidium, Isospora, Microsporidia
Fungus
Candida albicans, Penicillium marneffei, Cryptoccocus neoformans,
Histoplasma spp, Coccidoides immitis
Neoplasm
Kapasi’s sarcoma, lymphoma
Miscellaneous
Diffuse infiltrative lymphocytosis syndrome, HIV enteropathy, malabsorption,
bacterial overgrowth, Zn deficiency
Gastrointestinal manifestations of HIV-infected children
normal histologic study in 83%, 79%
and 65% associated with esophagus,
stomach, and duodenum abnormalities,
respectively. The authors recommended
that tissue biopsies and cultures should
be carried out while doing endoscopy. In
contrast, Lim SG, et al. found that only
9.3% of their patients with a normal
endoscopic study were associated with
histologic abnormalities.(4) However, the
incidence of these abnormalities tended
to increase in the patients with CDC stage
IV. Therefore, they did not recommend a
routine surveillance biopsy in the patients
who still had a CD4 count of over 200
/cumm, except in those with diarrhea.
The benefits of doing endoscopy are
detailed in Table 3.
Pathogenesis of HIV enteropathy
Apart from skin and mucous membrane, the GI tract is the major route for
perinatal HIV infection.(15) Acquired HIV
infection postnatally from breastfeeding
is one of the major concerns. In these
patients, gastrointestinal diseases, in
particular diarrhea, are the most common
clinical presentations. Although enteric
pathogens are responsible in a majority
of cases, the etiology cannot be identi-
123
fied in up to one-third of cases. These
patients have been diagnosed as HIV
enteropathy, in which there is evidence
of 1) increased small bowel permeability,
2) malabsorption of lipids and sugar, 3)
certain histopathologic changes, and 4)
absence of pathogens identified. Pathogenesis of HIV enteropathy, however,
has yet to be clearly elucidated. Either
direct HIV-mediated effect or cytokinemediated mucosal change has been
postulated.(8,9,16-18) (Figure 1)
Concept of CD4+ T cell activation
and cytokine-mediated enteropathy
There has been evidence demonstrating that HIV is capable of infecting
directly into enterocytes.(19) After crossing
the GI epithelium, HIV will infect macrophages and lymphocytes in the lamina
propria, and some will be quiescent in
the mesenteric lymph nodes. GI infection by HIV causes dysregulation of the
gut immunity, for instance decreased
IgA secretion, and increased CD8+ T
cell and lymphoid population in the
lamina propria. These changes would
promote bacterial overgrowth and then
production of endotoxins. These processes would activate CD4+ T cells, and
Table 3. The benefits of doing endoscopy to access any feasible GI pathologies in HIV infected
patients.
1. Many etiologies require specific treatment and cannot be diagnosed by routine investigations.
2. Prescribing empirical treatment without performing upper endoscopy might put the patients at risk
of many side effects from unnecessary medicines, for instance H2 blocker for abdominal pain
may predispose the patient to fungal overgrowth, and antiviral drugs may cause hepatotoxicity
and hematotoxicity.
3. EGD can be helpful in identifying AIDS defined illnesses.
Ukarapol N.
124
Figure 1. Pathogenesis of diarrhea, malabsorption, and malnutrition in HIV-infected patients
as a result hasten viral replication, and
an eventually decrease in the CD4 population would invariably occur.(15) Activation of T cells results in the release of
various cytokines, particularly tumor
necrotic factor α and interferon γ. These
cytokines can cause microscopic changes
on the intestinal absorptive area, includeing villous atrophy and crypt hyperplasia, resulting in a decreased villus to
crypt ratio.(6,15) The ultrastructures were
also studied, which revealed irregular,
joined bases, shortened and broadened
microvilli, mitochondrial swelling, formation of lysosomal and vesicular bodies,
dilated endoplasmic reticulum in the
enterocyte as well as tubuloreticular
inclusions in the endothelial cells.(9,20)
As the CD4 population continues to
decrease, the histopathology will show
villous atrophy and crypt hypoplasia.(17)
As a result, the patients develop carbohydrate and fat malabsorption, demonstrated by the abnormal breath hydrogen
test, 14C-glycerol tripalmitin test, and
D-Xylose test(8,18,21), in which they
invariably develop diarrhea, malnutrition,
growth retardation, and immune dysfunction. However, there have also been
some studies that do not support inflammatory mediators and CD4+ T cell
activation as a role of HIV enteropathy.
(16,22,23)
Concept of direct HIV-mediated
enteropathy
The direct effect of HIV on the enterocyte function has also been studied. A
recent study demonstrated that Gp120 of
HIV envelop could stimulate a calcium
Gastrointestinal manifestations of HIV-infected children
signal of HT-29 intestinal cell lines
through a G-protein coupled receptor
GPR15/Bob at the basolateral membrane
of intestinal epithelium. This resulted in
microtubular changes and led to increased
intestinal permeability, malabsorption
and diarrhea, as seen in the patients with
HIV enteropathy.(24) This microtubule
change was confirmed by a study of the
small bowel and a rectal biopsy that were
stained immunocytochemically for acetylated tubulin in HIV-infected individuals.(25)
Diagnostic approach to the HIVinfected child with diarrhea
In addition to recording history carefully and physical examination, stool
examination for parasites and cultures
are the most important tools for diagnosing causative agents. As mentioned
above, endoscopy with a tissue biopsy
for histopathologic studies and cultures
might be essential in some patients.(14)
An ultrasound and CT abdomen would
be useful for diagnosing Penicillium
marneffei infection,(12) Mycobacterium
125
tuberculosis, and Mycobacterium aviumintracellulare infection.(26) Radin DR, et
al. retrospectively reviewed the CT
findings in HIV-infected patients with
Mycobacterium tuberculosis and Mycobacterium avium-intracellulare infection,
which are summarized in Table 4.(26)
II. Abdominal pain
Thuluvath PJ, et al. recommended
basic laboratories carried out routinely,
including complete blood count, urinalysis, electrolytes, stool examination and
culture, serum amylase, and plain abdomen for all HIV-infected patients
presenting with abdominal pain.(27) In
patients with upper abdominal pain, an
ultrasound abdomen, upper endoscopy,
and endoscopic retrograde cholangiography (ERCP) might be needed. Barium
enema and colonoscopy would be
required for patients with lower abdominal pain. If the etiology of abdominal
pain cannot be identified, the CT abdomen might be necessary to establish the
diagnosis of Mycobacterium aviumintracellulare and Penicillium marneffei
Table 4. Comparison of abdominal CT findings between Mycobacterium tuberculosis and
Mycobacterium avium-intracellulare infection in HIV-infected patients
Mycobacterium tuberculosis
Necrotic lymph nodes
Multiple focal visceral lesions
Hepatosplenomegaly
Bowel involvement
93%
44%
19% (liver)
26% (spleen)
Segmental ileocecal wall
thickening and extraluminal
gas due to duodenal fistula
Mycobacterium aviumintracellulare
14%
14%
45% (liver)
23% (spleen)
Jejunal wall thickening
Ukarapol N.
126
infection.(12) Thuluvath PJ also reported
that the most common causes of abdominal pain in HIV-infected patients are
sclerosing cholangitis, which is caused
by CMV and Cryptosporidium infection,
and CMV colitis. Apart from those
mentioned previously, shigella colitis,
lymphoma, Kaposi’s sarcoma, acute
pancreatitis, and Penicillium marneffei
mesenteric lymphadenitis are also responsible for abdominal pain in AIDS
patients.(12)
III. Dysphagia and odynophagia
Lesions leading to dysphagia and
odynophagia primarily locate in the esophagus, including esophagitis and esophageal ulcer. Candida albicans, cytomegalovirus, and Herpes simplex virus
are commonly responsible for these
symptoms. Table 5 details the distinction
between 3 causative agents.(2)
IV. Gastrointestinal bleeding
Aside from noninfectious causes and
acute infectious diarrhea, e.g. salmonella, shigella, Campylobacter, E. coli, and
E. histolytica, CMV ileitis and CMV
colitis are the most common causes of
gastrointestinal bleeding in HIV-infected
children.(5) If severe enough, they can
lead to bowel perforation and eventual
death.(28) Gangcyclovir and foscarnet are
administered for this infection with a fair
result. Recently, we found a patient with
chronic diarrhea and lower GI bleeding
that was caused by Penicillium marneffei
infection, and another case with upper
GI bleeding that resulted from diffuse
infiltrative lymphocytosis syndrome, in
which the stomach produced significant
gastritis. Mycobacterium tuberculosis
and Mycobacterium avium-intracellulare
are also able to produce colitis and cause
hematochezia.(2)
Hepatobiliary and pancreatic diseases
in HIV-infected children
There have been many reports regarding the diversity of etiologies contributing to hepatobiliary disorders in HIVinfected patients, including infections,
drugs, and malignancies.(29-33) The patients
might present with jaundice, right upper
quadrant pain, nausea, vomiting, and
abnormal liver function tests, in particu-
Table 5. Endoscopic findings in esophagitis and ulcer in HIV-infected patients
Endoscopic
findings
Location
Site of infection
Candida
White-yellowish plaque
Extending from the
mouth into the entire
esophagus
Attached to the
epithelium
CMV
Herpes simplex
Erythema, ulcers which Erythema, shallow
are deeper than those
ulcers
seen in HSV infection
Distal esophagus
Mid esophagus, the
near the level of the
left main bronchus
Endothelial cell
Epithelium cell
Gastrointestinal manifestations of HIV-infected children
lar, an elevation of transaminases and
alkaline phosphatase. Neither clinical
symptoms and signs nor the liver function tests could definitely predict the
etiology and liver pathology of HIVinfected patients.(30,33) Infections are still
the most common causes which contribute to these symptoms. Cappell MS, et
al. reviewed the causative agents, consisting of Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, salmonella, Cryptoccoccus neoformans, Candida albicans, Histoplama, Coccidioides
immitis, CMV, Herpes simplex, viral
hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and HIV.(29)
In Southeast Asia, disseminated Penicillium marneffei infection should be
included in the differential diagnosis.
Concerning CMV and Cryptosporidium,
there have been studies that report the
association between these pathogens and
sclerosing cholangitis.(31,32) Among these
infections, CMV and Mycobacterium
avium-intracellulare are the most common organisms, at 14% and 11%,
respectively.(30) Hepatitis B viral infection is more common in adults who
acquire HIV via intravenous drug abuse
and homosexual behavior. HBV infection in these patients tends to become
chronic and the risk of coinfection with a
delta virus is also increased. The incidence of hepatitis C virus infection has
risen as well. Apart from infections,
malignancy, for instance Kaposi’s sarcoma and non-Hodgkin lymphoma, is one
of the frequent complications in HIV-
127
infected patients. Since HIV-infected
patients have a tendency to be put on
various medications, drug-induced hepatotoxicity should be strongly considered.
Table 6 shows lists of drugs reputed to
cause hepatotoxicity.(30)
Jonas MM, et al. reported histologic
studies in HIV-infected children.(33)
They found that non-specific findings,
including portal inflammation, pericentral necrosis, steatosis, and lymphoma,
accounted for nearly half of the abnormalities noted in this study. Giant cell
transformation was the second most
common histologic finding, associated
with CMV infection, Kaposi’s sarcoma,
and non-Hodgkin lymphoma. Seventeen
percent of the liver tissues were attributed
to CMV infection. Kaposi’s sarcoma,
lymphoplasmocytic infiltration, and
granuloma were also noted in this study.
Approach to HIV-infected patients
suspected of having hepatobiliary
diseases(29-31, 33)
As shown in Figure 2, recording history carefully on medications and any
specific infections is an important initial
step for reaching the correct diagnosis.
Table 6. Lists of drugs commonly used in HIVinfected patients and reputed to cause
hepatotoxicity
Trimethoprim-sulfamethoxazole
Petamidine
Ketoconazole, Fluconazole
2’,3’-dideoxyinosine (ddI)
Ganciclovir
Antituberculosis drugs
Ukarapol N.
128
Jaundice, RUQ pain,
abnormal liver function tests
History - drugs and infection
Initial investigation
Serology for CMV, HAV, HBV, HDV, HCV
Blood culture for bacteria, Mycopbacterium, funguses, viruses
Bone marrow aspiration
Ultrasound and CT abdomen
Dilated bile duct
Focal lesion
Liver biopsy with special stains and cultures
ERCP
No diagnosis
Diagnosis
Liver biopsy with special stains and cultures
Figure 2. A guideline for approaching an HIV-infected patient suspected of having hepatobiliary
diseases.
Serology for CMV and viral hepatitis
should be carried out as well as blood
cultures for bacteria, Mycobacterium,
fungus, and viruses. Occasionally, bone
marrow culture might be helpful for
diagnosing disseminated fungal and
Mycobacterium
avium-intracellulare
infection. An ultrasound abdomen and
CT scan are also useful for the discovery
of any focal lesions. Then, a liver biopsy
can be performed under the guidance of
an ultrasound or a CT scan. On the
contrary, if these radiologic studies reveal
evidence of bile duct dilatation, the
ERCP should be the next step in investigations. This method is the greatest tool
for diagnosing sclerosing cholangitis.
Besides diagnosis, it also provides
various treatment for some patients, e.g.
sphincteromy in the presence of stones
in the common bile duct. If the ERCP
cannot give any helpful information, a
liver biopsy with special stains and
cultures is crucial.
Pancreatitis in HIV-infected children
The incidence of pancreatitis in HIVinfected children reported by Miller TL,
et al.(34) was 17%. It was associated with
CMV, Cryptosporidium, Mycobacterium
avium-intracellulare, and P. carinii infection. The important risk factors attributed
to pancreatitis were 1) exposure to pentamidine isethionate and 2) low CD4 count.
Other medications that could be responsible for this condition were trimethoprimsulfamethoxazole and 2’, 3’–dideoxyinosine. Serum amylase is much less sensi-
Gastrointestinal manifestations of HIV-infected children
tive than serum lipase. Unfortunately,
HIV-infected patients with pancreatitis
have a poor prognosis.
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