THE GI TRACT IN HIV: A SOUTH
AFRICAN EXPERIENCE
TOMAS SLAVIK
AMPATH PATHOLOGY LABORATORIES
PRETORIA
SOUTH AFRICA
Dr Marcia Gottfried
(1953 – 2008)
1.
2.
3.
4.
Introduction
Infections
Neoplasms
Other pathology
• Drugs
• IRIS
• HIV enteropathy
INTRODUCTION
GLOBAL HIV DATA
• 1983
– Montagnier: isolation of a LAV from patient with AIDS 1
– Gallo: isolation of HTLV in patients with AIDS 2
• WHO / UNAIDS statistics 3
Worldwide
– up to 2008: 60 million infected, 25 million deaths
– in 2008:
• 33,4 million infected
• 2,7 new infections
• 2,0 million deaths
Sub-Saharan Africa
– in 2008:
• 22,4 million infected (67 % of global burden)
• 1,4 million deaths (72 % of global burden)
1.
2.
3.
Barré-Sinoussi F, Chermann JC, Rey F et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science.
1983;220:868-71.
Gallo RC, Sarin PS, Gelmann EP et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science. 1983;220:865-7.
WHO/UNAIDS Epidemic Update, 2009.
HIV IN SOUTHERN AFRICA REGION
• Nine countries in southern Africa have
disproportionate share of global AIDS burden
(adult HIV prevalence > 10%)
• In 2007 1
– Swaziland: highest infection rate in world (26 %)
– South Africa = 5,7 million infected (12,7 %)
• Rate of HIV infection stabilizing, prevalence
increasing slightly
– availibility of ARV to adults
• 2003: 2 %
• 2008: 44 %
1.
WHO/UNAIDS Epidemic Update, 2009.
South African National Antenatal
Clinic Survey 1
1.
South African Department of Health, National Antenatal Survey, 2009.
THE GI TRACT AND HIV
• GI tract is the largest lymphoid organ in the body 1
– Major site of HIV replication, with massive CD4 depletion in
acute infection and only partial restoration 2
• Wide spectrum of GI pathology seen in HIV, often as
part of multisystem disease
• Incidence and nature of GI pathology has changed
dramatically with advent of effective anti-retroviral
therapy (ART) 3
– CD4 count most useful parameter when evaluating biopsies
in HIV patient (< 200/mm3)
1. Antony SJ. HIV enteropathy – a challenge in diagnosis and management. J Natl Med Assoc. 1994;86:347-351.
2. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1(1):23-30.
3. Wilcox CM, Saag MS. Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut. 2008;57:861-870.
INFECTIONS
GENERAL
• Extremely wide infectious pathology
spectrum, ranging from viral to parasitic
• GI infections were commonest cause of
diarrhea, malabsorption and wasting in preHAART era
• Dramatic decrease in prevalence post-HAART
era 1
– drop from 85 % to 12 % in MSM over 10 yrs
• High prevalence of GI dysfunction and
chronic diarrhea in HIV remains a problem
post-HAART
1.
Knox TA, Spiegelman D, Skinner SC et al. Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection.
Am J Gastroenterol 2000; 95:3482-3489.
INFECTIONS
•
VIRAL
•
FUNGAL
•
BACTERIAL
•
PARASITIC
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–
Cytomegalovirus
Herpes simplex
Varicella-zoster
Adenovirus
Epstein-Barr virus
Mycobacterium tuberculosis
M. avium complex
Bartonella henselae / quitana
Clostridium difficile
Salmonella spp.
Shigella flexneri
Campylobacter jejuni
Aeromonas hydrophila
Plesiomonas shigelloides
Yersinia enterocolitica
Escherichia coli (enterotoxigenic and adherent)
Listeria monocytogenes
Neisseria gonorrhoeae
Treponema pallidum
Intestinal spirochaetosis
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Candida albicans
Pneumocystis jirovecii (carinii)
Cryptococcus neoformans
Histoplasma capsulatum
Cryptosporidium parvum
Microsporidia (Enterocytozoon
bieneusi, Septata intestinalis
Isospora belli
Cyclospora cayetanensis
Entamoeba histolytica
Giardia intestinalis
Toxoplasma gondii
Leishmania donovani
Strongyloides stercoralis
VIRAL
Cytomegalovirus (CMV)
• Commonest viral pathogen in HIV - increased
risk if CD4 count < 50/ml 1
• CMV retinitis - commonest form of disease, but
other organs include
* CNS (poliradiculopathy, mononeuritis
multiplex, peripheral neuropathy)
* GI tract (esophagitis, gastritis, proctocolitis)
* pancreatitis
* biliary tract involvement
1.
U.S. Public Health Service, Infectious Diseases Society of America. Guidelines for the treatment of opportunistic infections in adults and adolescents
infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 2004; 53(RR-15):1.
CMV and the GI tract
• Esophageal and colorectal involvement most common
• Esophagus:
–
–
–
–
dysphagia, odynophagia and retrosternal pain
up to 45 % of esophageal ulceration in HIV caused by CMV 1
usually large shallow, hemorrhagic ulcers
up to 30 % also have Candida or herpes simplex esophagitis 2
• Colorectum:
– diarrhea (either bloody or watery), abdominal pain, fever and
weight loss 2
– ulcers (single or multiple / superficial or deep), mucosal
hemorrhage, pseudomembranes and obstructive inflammatory
masses
• Nuclear and cytoplasmic viral inclusions, preferentially
involving stromal and endothelial cells
–
remember levels and immunohistochemistry
1. Wilcox CM, Schwartz DA, Clark WS. Esophageal ulceration in human immunodeficiency virus infection. Causes,
response to therapy and long term outcome. Ann Intern Med. 1995;123:143-149.
2. Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus
infection. Arch Intern Med 1991; 151:1567-1572.
3. Chetty R, Roskell DE. Cytomegalovirus infection in the gastrointestinal tract. J Clin Pathol 1994; 47:968-972.
CMV
Alcian-blue/PAS
BACTERIAL
Mycobacteria
• Mycobacterium avium (-intracellulare)
complex (MAC) commonest GI isolate in
developed countries vs M. tuberculosis in
developing world
• Difference possibly as a result of cross
resistance to less pathogenic MAC in
developing world (due to endemic TB)
• Both preferentially involve small bowel, but
also colon, stomach, esophagus and regional
lymph nodes
• Rarely: M. kansasii, M. bovis
M. tuberculosis
• Ileocecum most often involved, but can occur anywhere from
mouth to the anus 1
• Active pulmonary disease sometimes present (20%) 2
• Usually cause transverse/circumferential ulcerative ileal lesions,
also stricturing ulcers, nodular mucosal thickening and
inflammatory masses
• Histology varies depending on immune status in HIV
– Well-formed epithelioid granulomas with scant organisms
– Poor or absent granulomas, abundant neutrophils and necrosis
• Differentiate from Crohn’s disease and Yersinia
pseudotuberculosis on histology 3
TB has
–
–
–
–
1.
2.
3.
abundant large (>400um), confluent necrotizing granulomas
histiocyte palisading at ulcer base
absence of mucosal chronicity away from active disease
acid-fast bacilli
Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88:989-999.
Horvath KD, Whelan RL. Intestinal tuberculosis: Return of an old disease. Am J Gastroenterol 1998;93:692-696.
Pulimood AB, Peter S, Ramakrishna BS, et al. Segmental colonoscopic biopsies in the differentiation of ileocolonic tuberculosis from Crohn's
disease. J Gastroenterol Hepatol 2005;20:688-696.
MAC
MTB
ESOPHAGUS
(ulcerative esophagitis)
DUODENUM
(D3 “malignant” ulcer)
COLON
(caecal polyp)
Mycobacterium tuberculosis
Mycobacterium avium complex
MAC = PAS+
Intestinal spirochaetosis
• Initially described and usually seen in MSM 1
• Can also occur in other conditions
(diverticulosis, UC and adenomas) 2
• Thought to be caused by Brachyspira aalborgi
or B. pilosicoli
• In HIV, often symptomatic (diarrhea,
abdominal complaints and anal
pain/discharge)
• Symptoms alleviated by antimicrobial therapy
• Endoscopic abnormalities absent or mild
• Differentiate from E. coli (enteroadherent)
– silver- and gram-negative, straight bacilli
1.
2.
Surawicz CM. Intestinal spirochetosis in homosexual men. Am J Med 1988; 82:587-592.
Koteish A, Kannangai R, Abraham S et al. Colonic spirochetosis in children and adults. Am J Clin Pathol 2003; 120:828-832.
PAS
Warthin-Starry
Gram
Clostridium difficile
(“pseudomembranous”) colitis
• C. difficile-associated colitis
– increased risk in HIV (hospitalized, recent antibiotics) 1
– commonest cause of HIV-associated bacterial diarrhea in US 2
• Usually seen after oral antibiotics, up to weeks after therapy 3
• Endoscopy
– white to yellow plaques / pseudomembranes with contact bleeding
– patchy, most often left-sided
• Histology
– crypt distention (“ballooning”) by mucus, scattered neutrophils
– intercrypt necrosis with fibrin deposition
– adherent laminated plumes of fibrin, mucin, neutrophils (“volcano
lesion”)
– severe: mucosal necrosis, toxic megacolon
• Definite diagnosis: stool C. difficile toxin +
1. Saddi VR, Glatt AE. Clostridium difficile-associated diarrhea in patients with HIV: a 4 year survey. J Acquir Immune Defic Syndr. 2002;31:542-43.
2. Sanchez TH, Brooks JT, Sullivan PS et al. Bacterial diarrhea in persons with HIV infection, United States, 1992-2002 Clin Infect Dis. 2005;41(11):1621-7.
3. Surawicz CM, McFarland LV. Pseudomembranous colitis: Causes and cures. Digestion 1999; 60:91-100.
PARASITIC
Cryptosporidiosis
• Cryptosporidium parvum infestation more common
and severe in HIV
• In HIV: most often involves proximal small bowel, but
may affect any part of GI tract
• Advanced HIV (< 200 CD4/mm3) 1,2
– persistent infection (60%)
– biliary tract disease (29%)
– fulminant disease (8%)
• Associated with
– mixed inflammation, crypt abscesses, villous atrophy and crypt
hyperplasia
– organisms: 2 - 5 um basophilic spheres protruding from apex of
crypt / surface enterocytes; GMS and Giemsa positive 3
• Remember to think of Cyclospora cayetanensis
1.
2.
3.
Navin TR, Weber R, Vugia DJ et al. Declining CD4+ T-lymphocyte counts are associated with increased risk of enteric parasitosis and chronic diarrhea: results of a 3-year
longitudinal study. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Feb 1;20(2):154-9.
Manabe YC, Clark DP, Moore RD, et al. Cryptosporidiosis in patients with AIDS:correlates of disease and survival. Clin Infect Dis. 1998;27:536-42.
Clayton F, Heller T, Kotler DP. Variation in the enteric distribution of Cryptosporidia in acquired immunodeficiency syndrome. Am J Clin Pathol 1994;102:420-5.
Grocott silver
ISOSPORIDIOSIS
• Isospora belli
– infestation much less common than
cryptosporidiosis
– involves
• small bowel (most often)
• colon
• rarely: disseminated sites 1
• Histology
– mixed inflammation (often eosinophils), villous
atrophy, crypt hyerplasia; may be chronic with
lamina
propria fibrosis
– organisms: large (about 20 um); ovoid to “bananashaped”, peri-/subnuclear intra-epithelial location
GMS, PAS and Giemsa +
1. Lindsay DS, Dubey JP, Blagburn BL. Biology of Isospora spp. from humans, nonhuman primates, and domestic animals. Clin Microbiol Rev.
1997;10(1):19-34.
Entamoeba histolytica
PAS
Gastric toxoplasmosis
NEOPLASMS
GENERAL
• GI tract is one of the commonest sites for
primary neoplasms in HIV patients 1
• Introduction of ART: decrease in GI infections
and relative increase in tumours
• Wide spectrum of neoplasia – stromal /
mesenchymal, lymphoid and epithelial
• Two commonest tumours
– Kaposi sarcoma
– non-Hodgkin lymphoma (NHL)
1.
Koshy M, Kauh J, Gunthel C et al. State of the art: gastrointestinal malignancies in the human immunodeficiency virus (HIV) population.
Int J Gastrointest Cancer. 2005;36(1):1-14.
NEOPLASMS
• Stromal
– Kaposi sarcoma
– EBV-associated smooth muscle tumours
• Lymphoid
– Non-Hodgkin
•
•
•
•
•
Burkitt lymphoma
Diffuse large B-cell lymphoma NOS
Plasmablastic lymphoma
Primary effusion lymphoma
MALT
– Hodgkin lymphoma
– Posttransplant lymphoproliferative disorder
• Epithelial
– Squamous carcinoma
NEOPLASMS
• Stromal
– Kaposi sarcoma
– EBV-associated smooth muscle tumours
• Lymphoid
– Non-Hodgkin
•
•
•
•
•
Burkitt lymphoma
Diffuse large B-cell lymphoma NOS
Plasmablastic lymphoma
Primary effusion lymphoma
MALT
– Hodgkin lymphoma
– Posttransplant lymphoproliferative disorder
• Epithelial
– Squamous carcinoma
KAPOSI SARCOMA AND THE GI TRACT
• Remains the commonest HIV-associated GI
and visceral malignancy in HAART era 1
– 40 % of patients at initial presentation
– up to 80 % at autopsy
• GI tract second most common site affected
(after skin) 2
• Complicates skin involvement in up to 50 % of
cases 3
• Stomach most common GI site, followed by
esophagus, colon and small bowel
1.
2.
3.
Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: Emerging challenges in the era of highly active antiretroviral therapy. Oncologist 2005; 10:412-426.
Ho-Yen C, Chang F, van der Walt J et al. Gastrointestinal malignancies in HIV-infected or immunosuppressed patients: pathologic features and review of the
literature. Adv Anat Pathol. 2007;14(6):431-443.
Friedman SL, Wright TL, Altman DF. Gastrointestinal Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Endoscopic and autopsy findings.
Gastroenterology. 1985;89:102-108.
KAPOSI SARCOMA AND THE GI TRACT
• May be asymptomatic, but often have
nausea and abdominal pain (GI hemorrhage
very rare) 1
• Endoscopy
– velvet-blue submucosal mass (without ulceration /
bleeding)
– linitis plastica-like
• Biopsy may fail to establish diagnosis in up to
2/3 cases 2
• One of HHV-8 associated tumours 3
• Kaposi sarcoma
• Primary effusion lymphoma
• HIV-associated Castleman disease
1.
2.
3.
Shah SB, Kumar KS. Kaposi’s sarcoma involving the gastrointestinal tract. Clin Gastroenteroll Hepatol. 2008;6:A20.
Friedman SL, Wright TL, Altman DF. Gastrointestinal Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Endoscopic and autopsy findings.
Gastroenterology. 1985;89:102-108.
Sunil M, Reid E, Lechowicz MJ. Update on HHV-8-Associated Malignancies. Curr Infect Dis Rep. 2010 Mar;12(2):147-154.
HHV-8
CD34
Bacillary angiomatosis
Peptic ulcer base
LYMPHOMA
• Pre-HAART: Burkitt and primary CNS lymphoma 1000 x
more common in HIV 1
• HAART era: incidence of lymphoma (all types) still 60
– 200 increased in HIV 2
• Most common
–
–
–
–
Burkitt lymphoma
diffuse large B-cell lymphoma (often CNS)
plasmablastic lymphoma
primary effusion lymphoma
• Hodgkin lymphoma: increased in HIV patients since
advent of HAART 3
• Secondary involvement of GI tract in 25 % of
systemic lymphomas, with poor prognosis and shorter
survival 4
1.
2.
3.
4.
Beral V, Peterman T, Berkelman R et al. AIDS-associated non-Hodgkin lymphoma. Lancet 1991;337:805-9.
Engels EA, Pfeiffer RM, Goedert JJ et al. Trends incancer risk among people with AIDS in the United States 1980-2002. AIDS 2006;20:1645-54.
Clifford GM, Polesel J, Rickenbach M et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking and highly active antiretroviral therapy. J Natl Cancer Inst
2005;97:425-32.
Ho-Yen C, Chang F, van der Walt J et al. Gastrointestinal malignancies in HIV-infected or immunosuppressed patients: pathologic features and review of the literature. Adv Anat Pathol.
2007;14(6):431-443.
PLASMABLASTIC LYMPHOMA
• Rare aggressive NHL first documented in oral
cavity of HIV patients 1
• Also occurs in other mucosal and extranodal
sites, including GI tract (anorectum) 2
• Diffuse proliferation of large neoplastic
lymphoid cells resembling B immunoblasts, but
having phenotype of plasma cells (EBER +)
• Morphology
– HIV-associated (2/3): monomorphic plasmablastic, oralmucosal distribution
– Non-HIV(1/3): more often plasmacytic differentiation and
nodal involvement
1. Flaitz CM, Nichols CM, Walling DM et al. Plasmablastic lymphoma: an HIV-associated entity with primary oral manifestations. Oral Oncol. 2002;38(1):96-102.
2. Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: Emerging challenges in the era of highly active antiretroviral therapy. Oncologist 2005;10:412-426.
CD 20
CD 30
EMA
CD 138
VS38c
OTHER
OTHER PATHOLOGY
1. Drugs
2. Immune reconstitution
inflammatory syndrome (IRIS)
3. HIV enteropathy
DRUGS
• HIV patients have chronic multidrug exposure
–
–
–
–
ART
• NRTI
• NNRTI
• PI
• Fusion/entry inhibitors
• Integrase inhibitors
antimicrobials
anti-neoplastics
other
• Various sites involved (from mouth to anorectum)
– esophagus: “pill” esophagitis, eosinophilic esophagitis
– stomach: reactive gastropathy, acute erosive gastritis
– small bowel and colorectum: eosinophilic enterocolitis, C.
difficile colitis, chemotherapy-induced enterocolitis
• NB: Clinical history - type of drug and duration of
use
IRIS
• Immune reconstitution inflammatory syndrome (IRIS)
refers to an immune hyperactivation and exhuberant,
dysregulated inflammatory response seen in HIV
patients who commence combination ART
• Affects about 15 % of patients (mortality 4,5 %) 1
• Occurs in patients with
– Underlying infection: CMV, cryptococcosis, TB, PMLE
– Kaposi sarcoma
• Thought to be a change in nature of immune response
with rapidly altered CD4 levels and HIV load 2
• Risk of IRIS associated with CD4 count prior to therapy
(highest if <50/mm3)
• NB for pathologist as
– it “unmasks” a previously unsuspected infection
– alters the histology of an existing infection
1. Müller M, Wandel S, Colebunders R et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic
review and meta-analysis. Lancet Infect Dis. 2010;10(4):251-61.
2. Mori S, Levin P. A brief review of potential mechanisms of immune reconstitution inflammatory syndrome in HIV following antiretroviral therapy. Int J STD AIDS.
2009;20(7):447-52.
HIV ENTEROPATHY
• Enigmatic syndrome characterized by chronic diarrhea in absence of
identifiable pathogen/cause
• Already alluded to by Kotler et al (1984) 1
• Despite intensive microbiologic and histologic GI investigation, almost 20
% of HIV patients with chronic diarrhea have no identifiable cause 2
• Potential causes include 3
•
•
•
•
undetected opportunistic organisms
drugs
direct “virotoxicity of HIV”
local activation of GI immune system
• Morphologic changes described include 4,5
– villous atrophy
– epithelial apoptosis
– inflammation / crypt hyperplasia
• Currently thought to have functional pathogenesis, due to increased
intestinal permeability and local immune dysregulation 3
1.
2.
3.
4.
5.
Kotler DP, Gaetz HP, Lange M et al. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:421-8.
Blanshard C, Francis N, Gazzard BG. Investigation of chronic diarrhoea in acquired immunodeficiency syndrome. A prospective study of 155 patients..Gut 1996;39(6):824-32.
Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1(1):23-30.
Greenson JK, Belitsos PC, Yardley JH et al. AIDS enteropathy: occult enteric infections and duodenal mucosal aspirations in chronic diarhhea. Ann Intern Med 1991;114:366-72
Batman PA, et al. Jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology. J Clin Pathol 1989;42:275-281.
HIV ENTEROPATHY IN AFRICAN PATIENTS
Cassol E, Rossouw T, Malfeld S, Slavik T, Vieira W, Pretorius E et al. Microbial translocation is associated with macrophage
activation in the colon of Africans with advanced HIV1/AIDS (Submitted to Gastrointestinal Endoscopy).
• 34 advanced HIV, treatment-naïve patients with
chronic diarrhea underwent double-lumen endoscopy
• 15 healthy and HIV non-enteropathy controls also
included
• Biopsies of duodenum, jejenum, ileum, right and left
colon taken
• 9 study patients excluded (opportunistic/other
infections)
• 6 cryptosporidiosis, 1 each with giardiasis, candidiasis and
schistosomiasis
• Only 1 / 25 had normal histology at all 5 sites
HIV ENTEROPATHY: ENTERIC MUCOSAL
MORPHOLOGY
100
90
80
70
60
50
40
30
20
10
0
HIV
Control
villous
atrophy
apoptosis
acute
enteritis
chronic
enteritis
HIV ENTEROPATHY: ENTERIC MUCOSAL
MORPHOLOGY
100
90
80
70
60
50
40
30
20
10
0
HIV
Control
acute
colitis
chronic
chronic apoptosis
ND colitis destrutive
colitis
HIV ENTEROPATHY IN AFRICAN PATIENTS
• Additionally
•
•
•
•
CD 68+ mucosal macrophage distribution
electron microscopy
biopsy flow cytometry for cytokines, HIV viral load
serum LPS levels
• Results point to massive bacterial translocation
with
– locally activated (but dysregulated) immune
response
– minimal villous atrophy and intact epithelial
ultrastructure, but redistribution of mucosal
macrophages with common non-specific
inflammation
control
control
CD68 - duodenum
CD68 - colon
HIV
HIV
CONCLUSION
APPROACH TO GI BIOPSY IN HIV
• Know the clinical history
– CD4 count
– other systemic manifestations
– drugs
• Remember the extremely wide
spectrum of pathology
• Look for double (triple) pathology
APPROACH TO GI BIOPSY IN HIV
• With infectious pathology, use the
helpline (911-MICRO)
• HAART era: remember pathology
which may seen in healthy / non-HIV
patients
• Know what to expect, then expect the
unexpected…
SOUTH
AFRICA
A world in one country…