Transcript Gastrointestinal Manifestations of HIV

Gastrointestinal Manifestations of
HIV-infected Children
Nuthapong Ukarapol, M.D.
Division of Gastroenterology
Department of Pediatrics
Chiang Mai University
Introduction
• GI involvement : one of most common
complications in the HIV-infected patients
• Thea DM et al. reported that 37% of HIVinfected infants experienced diarrhea. (N Engl
J Med 1993; 329:1696-702)
GI immunity and pathogenesis of diarrhea
Altered GI immunity
decreased IgA secretion
decreased gastric secretion
altered GI motility
Predispose GI tract to
Opportunistic infections
Neoplasms
Common gastrointestinal symptoms & signs
Diarrhea
Abdominal pain
Dysphagia and Odynophagia
Gastrointestinal bleeding
Weight loss and anorexia
Diarrhea
death rate (no /1000 live
births)
Diarrhea-related death and HIV
infection in 429 Zairian infants
250
Diarrhea
200
acute
diarrhea
persistent
diarrhea
other
150
100
50
0
HIV
Non-HIV
Thea DM, et al. N Engl J Med 1993; 329:1696-702.
HIV infection
CD4-infected cells cross
endothelium into the GI
lamina propria
Dormant in the
mesenteric lymph
nodes
HIV is uptaken by macrophage
Decreased IgA
Increased CD8 and lymphoid population in the lamina propria
Bacterial overgrowth
Increased enodtoxin
Decreased CD4
population
Accelerate viral
replication
Villous atrophy
Crypt hypoplasia
T cell activation
(CD4)
TNF, IFN
Decreased lactase and disaccharidase activity
Fat malabsorption
Mucosal injury
anorexia
Villous atrophy
Crypt hyperplasia
malnutrition
Malabsorption
Malnutrition
Any opportunistic or nonopportunisticGI infection
Diarrhea
Pathogenesis of diarrhea in HIV-infected patients
Etiology of diarrhea in HIV-infected patients
Table 2. Etiology of diarrhea in the 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
Etiology of diarrhea in HIV-infected patients
• Microsporidia, Isospora belli, and
Cryptosporidium parvum infection : the first
3 most common pathogens detected in the
HIV-infected patients with chronic diarrhea.
(Kelly P Q J Med 1996; 89:813-7.)
Cryptosporidium
Microspora
Isospora belli
Diagnostic technique in the HIVinfected patients with diarrhea
stool examination&cultures
Endoscopy
CMV
MAI
Cryptococcus
neoformans
Penicillium
TB
Miller TL, et al. J Pediatr 1997; 130:766-73.
Rene E, et al. Dig Dis Sci 1989; 34:773-80.
Diagnosis: Diarrhea & HIV infection
The benefits of doing endoscopy to access any feasible GI pathologies in the HIV
infected patients.
1. Many etiologies require specific treatment and cannot be diagnosed by routine
investigations.
2. Prescribing empirical treatment without performing EGD might put the patients at risk
on many side effects from the 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.
Diagnosis: Diarrhea & HIV infection
• Predictive factors for positive findings in
EGD in the HIV-infected patients with
diarrhea
1. AIDS stage
2. Serious bacterial infection
3. Many GI symptoms
Miller TL, et al. J Pediatr 1997; 130:766-73.
Diagnosis: Diarrhea & HIV infection
• No gross abnormalities :
NPV for normal histologic
study:83% esophagus,79%
stomach,65% duodenum
Miller TL, et al. J Pediatr 1997;
130:766-73.
recommended that tissue
biopsies and cultures
should be carried out while
doing endoscopy
• Only 9.3 % of normal
endoscopic findings were
associated with histologic
abnormalities
Lim SG, et al. Gut 1993; 34:1429-32.
did not recommend routine
surveillance biopsy in the patients
who still have CD4 count over 200
/cumm, except in the patients with
diarrhea
CMV colitis with chronic diarrhea
Diagnosis: HIV-infected children
with diarrhea
• Stool examination and cultures
• Endoscopy
• Ultrasound
• CT abdomen
Penicillium marneffei infection, Mycobacterium
tuberculosis, and Mycobacterium aviumintracellulare
Diagnosis: Diarrhea & HIV infection
Comparison of the abdominal CT findings between Mycobacterium tuberculosis
and Mycobacterium avium-intracellulare infection in the HIV-infected patients
Mycobacterium
Mycobacterium
tuberculosis
avium-intracellulare
Necrotic ymph nodes
93%
14%
Multiple focal visceral
44%
14%
lesions
Hepatosplenomegaly
19% (liver)
45% (liver)
26% (spleen)
23% (spleen)
Bowel involvement
Segmental ileocecal wall
Jejunal wall thickening
thickening and extraluminal
gas due to duodenal fistula
Randin DR. AJR 1991; 156:487-91.
Ultrastructure of Intestinal Biopsy in HIVinfected patients without identifiable pathogen
•
•
•
•
Irregular microvilli
joined bases microvilli
shortened and broadened microvilli
tubuloreticular inclusions in the endothelium cells
– immune function disturbances and viral infections
Fontana M, et al. J Pediatr Gastroenterol Nutr 1993; 17:255-9.
A 6 m/o HIV infected infant presented with chronic diarrhea.
After extensive investigations, no specific causes could be identified.
Irregular microvilli
joined bases microvilli
shortened and broadened microvilli
Rx: antiretroviral agents
AZT & Lamivudine
Outcomes:
1. Diarrhea stopped
2. Weaning off special formula
3. Gaining weight
Restart medication
stop medication
start medication
AIDS enteropathy
Abdominal pain
Etiology of abdominal pain in HIVinfected patients
No diagnosis
Other
PMC
Consipation
IBS
Liver tumor
scleosing cholangitis
CMV
Gastric neoplasm
acute pancreatitis
0
5
Thuluvath PJ, et al. Q J Med 1991; 78:275-85.
10
number
15
20
Abdominal pain & HIV infection
• Other possibility : Penicillim marneffei
mesenteric lymphadenitis Ukarapol N, et al. J Med Assoc
Thai 1998; 81:637-40.
Penicillim marneffei mesenteric lymphadenitis
Ukarapol N, et al. J Med Assoc Thai 1998; 81:637-40.
• Report 3 cases of HIV-infected children with
fever and abdominal pain: mimic acute abdomen
• Physical signs of peritonitis were noted.
• The first 2 patients were diagnosed as acute
ruptured appendicitis and had an operation done.
• The last patient was diagnosed as sepsis.
case 1
case 2
case 3
Investigations
Hb/Hct
( gm% /%)
WBC(/x10-6 l)
Plt(/ x10-6 l)
9.7/29.8
7.1/23
9.4/30
3150
140000
7400
73000
4400
219000
case 1
Initial Tx exploratomy
laparotomy
case 2
exploratomy
laparotomy
case 3
Ceftriazone I.V.
Operative normal appendix normal appendix not done
findings multiple and
enlargement of
matted mesenteric mesenteric nodes
and paraaortic
LN enlargement
U/S abdomen not done
multiple small* Matted enlarge
round hypoechoic multiple LN around
lesions at porta celiac artery and
hepatis(LN)
mesenteric vessels
Abdominal ultrasound
History of acute
abdomen with signs of
peritonism
Penicillium marneffei
mesenteric
lymphadenitis
case 1
case 2
P. marneffei
case 3
mesenteric
LN biopsy
P. marneffei
not done
BM smear
P. marneffei
P. marneffei
P. marneffei
Skin smear
not done
P. marneffei
not done
BM culture
P. marneffei
P. marneffei
P. marneffei
Hemoculture P. marneffei
P. marneffei
P. marneffei
Conclusion
I. This report presented clinical manifestrations of
P. marneffei infection which are different from
previous reports including
- abdominal pain
- clinical signs which mimic peritonitis
II. We suggest things that might help to correct
diagnosis.
1. history of HIV infection
2. skin lesions of P. marneffei infection
3. anemia, leukopenia and thrombocytopenia
4. abdoninal ultrasound
5. skin and bone marrow smear
6. blood and bone marrow culture
7. Endemic area of P. marneffei
Abominal pain
yes
yes
Prolonged fever
Pancytopenia
Skin lesion
no
CBC, UA, stool exam&c/s
serum amylase, lipase, LFTs
plain abdomen
Blood culture
Explor
Smear skin lesion
Bone marrow exam&culture
Ultrasound abdomen
P marneffei
no
Peritonitis
Upper
abdominal pain
EGD
ERCP
Diagnosis
Lower
abdominal pain
BE
Colonoscopy
No diagnosis
Diagnosis
CT abdomen, liver biopsy
Dysphagia/ Odynophagia
Dysphagia & Odynophagia in HIVinfected patients
• Esophagitis, Esophageal ulcer
–Candida albicans
–Cytomegalovirus
–Herpes simplex virus
Upper endoscopy:
at the EG junction
Erythema,
Friability,
Ulcer
CMV Esophagitis
Ulcer
Upper endoscopy:
White plaques on the
esophageal mucosa
Candida Esophagitis
Dysphagia & Odynophagia in HIVinfected patients
Endoscopic findings in esophagitis and ulcer in HIV-infected patients
Candida
CMV
Herpes simplex
Endoscopic
White-yellowish
Erythema, ulcers
Erythema, shallow
findings
plaque
which are deeper
ulcers
than those seen in
HSV infection
Location
Extending from the
Distal esophagus
mid esophagus,
mouth into the entire
near the level of left
esophagus
main bronchus
Site of infection Attach to the
Endothelial cell
Epithelium cell
epithelium
Stoane JM, et al. Radiol Clin North Am 1996; 34:779-90.
GI bleeding
GI bleeding & HIV infection
• Non-infectious causes
• Infectious causes e.g. salmanella, shigella,
Campylobacter, E. coli, E. histolytica, CMV ileitis
and CMV colitis
• Penicillium marneffei
• Mycobacterium tuberculosis, Mycobacterium
avium-intracellulare
• Diffuse infiltrative lymphocytosis syndrome in
the stomach
Penicillium marneffei
Colitis
Penicillium
marneffei :
duodenal biopsy
Diffuse infiltrative lymphocytosis:
in the stomach
Gastrointestinal cytomegalovirus
disease in AIDS children
Nuthapong Ukarapol1, Wattana Chartapisak1, Nirush
Lertprasertsuk2, Lumduan Wongsawasdi1, Vinaisak
Kattipattanapong3, Jesda Singhavejsakul3, Virat
Sirisantana1
1
Department of Pediatrics, 2 Department of Pathology, 3
Department of Pediatric Surgery
Faculty of Medicine, Chiang Mai University, Thailand
Patients & Methods
• 1995-2001
• 8 patients with histologically confirmed
gastrointestinal CMV infection were
retrospectively reviewed.
Results:
• 6 of 8 < 1 year old
• median age 4.5 months (2 months-8 year 7
months)
Clinical manifestations
Symptoms & signs
# of the patients
Fever
7
Chronic diarrhea
5
Abdominal distention
5
GI bleeding
4
Bowel perforation
3
Vomiting
2
Odynophagia
1
Retrosternal pain
1
Laboratories
Lab
Hb(gm/dl)
WBC (x103/L)
Platelet (x109/L)
Albumin (gm/dl)
AST (U/L)
ALT (U/L)
CMV IgM
CMV IgG
mean (range)
8.2 (5.2-10.2)
10595 (2000-17300)
1.53 (0.05-5.47)
3.01 (2-3.8)
119.7 (13-563)
48.7 (8-241)
negative 5/5
negative 2/5
Laboratories
• 2 patients had a CD4 count done: with severe
immunosuppression in 1 patient.
– CD4 count (cells/µl) : 1080 (33%), 490 (16%)
• 2 patients were diagnosed as CMV retinitis
• 1 patient also had CMV pneumonitis
• 1 patient was suspected having CMV hepatitis
Endoscopic findings:
• 4 colonoscopy
• 3 EGD
• 1 flexible sigmoidoscopy
Indications
1. Lower GI hemorrhage
2. Chronic diarrhea
3. Odynophagia
Endoscopic findings
Included
•
•
•
•
•
mucosal edema
loss of normal vascular pattern
patchy erythema
friability
multiple ulcers
GI location
site
#
Colon
small bowel
esophagus & stomach
4
4
1
Immunochemistry stain with polyclonal antibody to CMV Ag
Outcome
• 6 patients died (4-bowel perforation, 1-massive
lower GI bleeding, 1-chronic diarrhea)
• Two patients with fever, chronic diarrhea, and
lower GI bleeding developed first remisssion after
being treated with a 14-day course of ganciclovir
(10 MKD I.V.). After the completion of
ganciclovir therapy, zidovudine and didanosine
were started.
Outcome
• Relapse occurred 6 weeks and 2 weeks after first
remission in these two patients.
• A second course of ganciclovir was reintroduced with a
short-period of remission in one case (2 weeks).
• Hepatotoxicity from combination of 3 antiviral drugs was
suspected in 1 patient. The medicines were then
discontinued.
Discussion
• the virus can infect all parts of the GI tract,
however, the colon and esophagus are the most
common sites. (In contrast to our study=
colon&small bowel: small kids?)
• In this report, chronic diarrhea and fever are the
most common clinical presentations.
Discussion
Pathogenesis : results from either
• Vasculitis, caused by CMV infection in the endothelial cells, has been
postulated as playing a major role in the development of GI mucosal ulceration
following thrombosis and local ischemia.
• or Primary CMV infection in the epithelial cells of
the gastrointestinal tract can also result in mucosal erosion and ultimately
ulceration.
Discussion
• Diagnosis should rely exclusively on the finding of typical
intranuclear and intracytoplasmic inclusion bodies in the
gastrointestinal biopsy.
• Endoscopy is crucial.
Discussion
• Maintenance therapy for gastrointestinal CMV disease has
not been established.
• At present, the restoration of the immune system by antiretroviral
agents seems to be the best in preventing the relapse.
• gastrointestinal CMV disease in AIDS patients is known to
relapse within 3-4 months. (2-6 weeks in this study)
• If relapse occurs, the second course of ganciclovir or other
alternative drugs such as foscarnet was suggested in adult AIDS
patients.
Conclusion
• Regarding patients with an unidentified cause of chronic
diarrhea, fever, and lower GI bleeding, an early diagnosis
using GI endoscopy might be useful to establish
diagnosis accuracy and provide appropriate medical
treatment.
• Ganciclovir treatment might be of benefit, but relapses
are frequently noted.
Hepatobiliary disease
Hepatobiliary tract diseases &
HIV infection
• Jaundice, RUQ pain, nausea, vomiting,
abnormal LFTs (transminases, alkaline
phosphatase)
• Neither clinical symptoms & signs nor
LFTs could definitely predict the etiology
and liver pathology of the HIV-infected
patients
Etiology of hepatobiliary tract diseases
• Infection
• Drugs
• Malignancy
Etiology of hepatobiliary tract diseases
• Infection: most common cause
– Mycobacterium avium-intracellulare, Mycobacterium tuberculosis,
salmonella, Cryptoccoccus neoformans, Candida albicans,
Histoplama, Coccidioides immitis, CMV, Herpes simplex, viral
hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and
HIVMycobacterium avium-intracellulare, Mycobacterium tuberculosis,
salmonella, Cryptoccoccus neoformans, Candida albicans,
Histoplama, Coccidioides immitis, CMV, Herpes simplex, viral
hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and
HIV
Cappell MS. Am J Gastroenterol 1991; 86:1-15.
Viral hepatitis v.s. HIV
• Increased risk of HBV infection associated
with IVDU & homosexual
• Increased risk of chronic hepatitis B
infection
• Increased risk of HDV coinfection
• Increased incidence of HCV infection
Sclerosing cholangitis
• CMV & Cryptosporidium associated with
sclerosing cholangitis, papillitis, acalculous
cholecystitis, stones
• ERCP with biopsy is helpful for diagnosis.
• Treatment can be provided by ERCP.
Yabut B,et al. J Pediatr Gastroenterol Nutr 1996; 23:624-7.
5 y/o girl with HIV infection
gradual onset of jaundice
epigastric pain
pale-colored stools
hepatomegaly (span 9cm)
LFTs albumin 3.2 gm%, globulin 5.5 gm%, alkaline phosphatase 1022
Cholesterol 392 mg%, AST/ALT 450/350 IU/L, TB/DB 7.95/4.88 mg%
GGT 180
Investigation: Continue
HBs Ag negative, HCV antibody negative
CMV IgM negative, CMV IgG >3200
Ultrasound: mild dilatation of intrahepatic bile
duct with diffuse thickening of bile duct wall
CT: Bile duct dilatation
Liver pathology: Moderate mixed inflammatory
cells infiltration at the portal tracts, AFB
negative.
ERCP
Irregularity of bile ducts
Stenosis & dilatation
Bead-like appearance
Dx: Sclerosing cholangitis
Etiology of hepatobiliary tract diseases
Lists of the drugs commonly used in HIV-infected
patients and are reputed to cause hepatotoxicity
Trimethoprim-sulfamethoxazole
Petamidine
Ketoconazole, Fluconazole
2’,3’-dideoxyinosine (ddI)
Ganciclovir
Antituberculosis drugs
Bonacini M. Am J Med 1992; 92:404-11.
Etiology of hepatobiliary tract diseases
• Malignancy
Kaposi’s sarcoma
Non-Hodgkin lymphoma
50
Liver pathology in HIV-infected children
40
30
%
20
Normal
Kaposi
CMV
Giant cell
transformation
0
nonspecific
findings
10
Jonas MM,et al. J Pediatr Gastroenterol Nutr 1989; 9:73-81.
Liver pathology in HIV-infected
children
• Giant cell transformation: associated with CMV,
Kaposi’s sarcoma, NHL
• Nonspecific findings
–
–
–
–
portal inflammation
steatosis
pericentral necrosis
lymphoma
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
No diagnosis
ERCP
Diagnosis
Liver biopsy with special stains and cultures
Diagnostic approach to an HIV-infected patients suspected
having hepatobiliary diseases
Pancreatitis & HIV infection
• 17% in HIV-infected children (Miller TL, et al. J Pediatr
1992; 120:223-7.)
• Associated with CMV, Cryptosporidium,
Mycobacterium avium-intracellulare, and P carinii
infection
• Risk factor
– Exposure to Pentamidine
– Low CD4 count
Pancreatitis & HIV infection
• Other drugs:
– Trimethoprim-sulfamethoxazole, ddI
• Serum amylase is much less sensitive
than serum lipase
• Poor prognosis
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