Gastrointestinal Manifestations of HIV-infected Children

1
Gastrointestinal Manifestations of HIV-infected
Children

• Nuthapong Ukarapol, M.D.
• Division of Gastroenterology
• Department of Pediatrics
• Chiang Mai University

2
Introduction

• GI involvement one of most common complications
  in the HIV-infected patients
• Thea DM et al. reported that 37 of HIV-infected
  infants experienced diarrhea. (N Engl J Med 1993
  3291696-702)

3
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
4
Common gastrointestinal symptoms signs
Diarrhea Abdominal pain Dysphagia and
Odynophagia Gastrointestinal bleeding Weight
loss and anorexia
5
Diarrhea
6
Thea DM, et al. N Engl J Med 1993 3291696-702.
7
HIV infection
CD4-infected cells cross endothelium into the GI
lamina propria
HIV is uptaken by macrophage
Decreased IgA Increased CD8 and lymphoid
population in the lamina propria
Dormant in the mesenteric lymph nodes
Bacterial overgrowth
Any opportunistic or non-opportunisticGI infection
Increased enodtoxin
Decreased CD4 population
Accelerate viral replication
T cell activation (CD4)
Villous atrophy Crypt hypoplasia
TNF, IFN
anorexia
Decreased lactase and disaccharidase activity Fat
malabsorption Mucosal injury
Villous atrophy Crypt hyperplasia
malnutrition
Malabsorption
Malnutrition
Diarrhea
Pathogenesis of diarrhea in HIV-infected patients
8
Etiology of diarrhea in HIV-infected patients
9
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 89813-7.)

10
Cryptosporidium
Isospora belli
Microspora
11
CMV MAI Cryptococcus neoformans Penicillium TB
Miller TL, et al. J Pediatr 1997 130766-73.
Rene E, et al. Dig Dis Sci 1989 34773-80.
12
Diagnosis Diarrhea HIV infection
13
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 130766-73.
14
Diagnosis Diarrhea HIV infection

• No gross abnormalities
• NPV for normal histologic study83 esophagus,79
  stomach,65 duodenum
• Miller TL, et al. J Pediatr 1997 130766-73.

• Only 9.3 of normal endoscopic findings were
  associated with histologic abnormalities
• Lim SG, et al. Gut 1993 341429-32.

did not recommend routine surveillance biopsy in
the patients who still have CD4 count over 200
/cumm, except in the patients with diarrhea
recommended that tissue biopsies and cultures
should be carried out while doing endoscopy
15
CMV colitis with chronic diarrhea
16
Diagnosis HIV-infected children with diarrhea

• Stool examination and cultures
• Endoscopy

• Ultrasound
• CT abdomen

Penicillium marneffei infection, Mycobacterium
tuberculosis, and Mycobacterium
avium-intracellulare
17
Diagnosis Diarrhea HIV infection
Randin DR. AJR 1991 156487-91.
18
Ultrastructure of Intestinal Biopsy in
HIV-infected 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 17255-9.

19
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
20
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
21
Abdominal pain
22
Thuluvath PJ, et al. Q J Med 1991 78275-85.
23
Abdominal pain HIV infection

• Other possibility Penicillim marneffei
  mesenteric lymphadenitis Ukarapol N, et al. J Med
  Assoc Thai 1998 81637-40.

24
Penicillim marneffei mesenteric lymphadenitis
Ukarapol N, et al. J Med Assoc Thai 1998
81637-40.

• 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.

25
case 1 case 2 case 3
Investigations Hb/Hct 9.7/29.8
7.1/23 9.4/30 ( gm /) WBC(/x10-6 l) 3150
7400 4400 Plt(/ x10-6 l) 140000
73000 219000
26
case 1 case 2 case 3
Initial Tx exploratomy exploratomy
Ceftriazone I.V. laparotomy
laparotomy 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
27
Abdominal ultrasound
History of acute abdomen with signs of peritonism
Penicillium marneffei mesenteric lymphadenitis
28
case 1 case 2 case 3
mesenteric P. marneffei P. marneffei not
done LN biopsy BM smear P. marneffei
P. marneffei P. marneffei Skin smear not
done P. marneffei not done BM culture P.
marneffei P. marneffei P. marneffei Hemocultu
re P. marneffei P. marneffei P. marneffei
29
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
30
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
31
Abominal pain
Peritonitis
yes
no
Prolonged fever Pancytopenia Skin lesion
CBC, UA, stool examc/s serum amylase, lipase,
LFTs plain abdomen
yes
no
Blood culture Smear skin lesion Bone marrow
examculture Ultrasound abdomen
Explor
Lower abdominal pain
Upper abdominal pain
EGD ERCP
BE Colonoscopy
P marneffei
Diagnosis
Diagnosis
No diagnosis
CT abdomen, liver biopsy
32
Dysphagia/ Odynophagia
33
Dysphagia Odynophagia in HIV-infected patients

• Esophagitis, Esophageal ulcer
• Candida albicans
• Cytomegalovirus
• Herpes simplex virus

34
Upper endoscopy at the EG junction
Erythema, Friability, Ulcer
CMV Esophagitis
Ulcer
35
Upper endoscopy
White plaques on the esophageal mucosa
Candida Esophagitis
36
Dysphagia Odynophagia in HIV-infected patients
Stoane JM, et al. Radiol Clin North Am 1996
34779-90.
37
GI bleeding
38
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

39
Penicillium marneffei Colitis
Penicillium marneffei duodenal biopsy
40
Diffuse infiltrative lymphocytosis in the
stomach
41
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
42
Patients Methods

• 1995-2001
• 8 patients with histologically confirmed
  gastrointestinal CMV infection were
  retrospectively reviewed.

43
Results

• 6 of 8 lt 1 year old
• median age 4.5 months (2 months-8 year 7 months)

44
Clinical manifestations
45
Laboratories
46
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

47
Endoscopic findings
Indications 1. Lower GI hemorrhage 2. Chronic
diarrhea 3. Odynophagia

• 4 colonoscopy
• 3 EGD
• 1 flexible sigmoidoscopy

48
Endoscopic findings
Included

• mucosal edema
• loss of normal vascular pattern
• patchy erythema
• friability
• multiple ulcers

49
GI location
50
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Immunochemistry stain with polyclonal antibody to
CMV Ag
53
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.

54
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.

55
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
  colonsmall bowel small kids?)
• In this report, chronic diarrhea and fever are
  the most common clinical presentations.

56
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.

57
Discussion

• Diagnosis should rely exclusively on the finding
  of typical intranuclear and intracytoplasmic
  inclusion bodies in the gastrointestinal biopsy.
• Endoscopy is crucial.

58
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.

59
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.

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Hepatobiliary disease
61
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

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Etiology of hepatobiliary tract diseases

• Infection
• Drugs
• Malignancy

63
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 861-15.
64
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

65
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
23624-7.
66
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
67
Investigation Continue
HBs Ag negative, HCV antibody negative CMV IgM
negative, CMV IgG gt3200
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.
68
ERCP
Irregularity of bile ducts Stenosis
dilatation Bead-like appearance
Dx Sclerosing cholangitis
69
Etiology of hepatobiliary tract diseases
Bonacini M. Am J Med 1992 92404-11.
70
Etiology of hepatobiliary tract diseases

• Malignancy

Kaposis sarcoma Non-Hodgkin lymphoma
71
Jonas MM,et al. J Pediatr Gastroenterol Nutr
1989 973-81.
72
Liver pathology in HIV-infected children

• Giant cell transformation associated with CMV,
  Kaposis sarcoma, NHL
• Nonspecific findings
• portal inflammation
• steatosis
• pericentral necrosis
• lymphoma

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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
Diagnosis
No diagnosis
Liver biopsy with special stains and cultures
Diagnostic approach to an HIV-infected patients
suspected having hepatobiliary diseases
74
Pancreatitis HIV infection

• 17 in HIV-infected children (Miller TL, et al. J
  Pediatr 1992 120223-7.)
• Associated with CMV, Cryptosporidium,
  Mycobacterium avium-intracellulare, and P carinii
  infection
• Risk factor
• Exposure to Pentamidine
• Low CD4 count

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Pancreatitis HIV infection

• Other drugs
• Trimethoprim-sulfamethoxazole, ddI
• Serum amylase is much less sensitive than serum
  lipase
• Poor prognosis

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