THE GI TRACT IN HIV: A SOUTH AFRICAN

EXPERIENCETOMAS SLAVIK

AMPATH PATHOLOGY LABORATORIESPRETORIA

SOUTH AFRICA

Dr Marcia Gottfried (1953 – 2008)

1. Introduction2. Infections3. Neoplasms4. Other pathology

• Drugs• IRIS

• HIV enteropathy

INTRODUCTION

GLOBAL HIV DATAGLOBAL 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. 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.

2. Gallo RC, Sarin PS, Gelmann EP et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science. 1983;220:865-7.3. WHO/UNAIDS Epidemic Update, 2009.

HIV IN SOUTHERN AFRICA REGIONHIV 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

South African National Antenatal Clinic Survey 1

1. South African Department of Health, National Antenatal Survey, 2009.

THE GI TRACT AND HIVTHE 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.

INFECTIONSINFECTIONS

GENERALGENERAL

• Extremely wide infectious pathology spectrum, ranging from viral to parasitic

• GI infections were commonest cause of diarrhea, malabsorption and wasting in pre-HAART 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.

INFECTIONSINFECTIONS

• VIRAL– Cytomegalovirus– Herpes simplex– Varicella-zoster– Adenovirus– Epstein-Barr virus

• BACTERIAL– 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

• FUNGAL– Candida albicans– Pneumocystis jirovecii (carinii)– Cryptococcus neoformans– Histoplasma capsulatum

• PARASITIC– Cryptosporidium parvum– Microsporidia (Enterocytozoon

bieneusi, Septata intestinalis– Isospora belli– Cyclospora cayetanensis– Entamoeba histolytica– Giardia intestinalis– Toxoplasma gondii– Leishmania donovani– Strongyloides stercoralis

VIRALVIRAL

Cytomegalovirus (CMV)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 tractCMV 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

BACTERIALBACTERIAL

MycobacteriaMycobacteria

• 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. tuberculosisM. 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– abundant large (>400um), confluent necrotizing granulomas – histiocyte palisading at ulcer base– absence of mucosal chronicity away from active disease – acid-fast bacilli

1. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol 1993;88:989-999. 2. Horvath KD, Whelan RL. Intestinal tuberculosis: Return of an old disease. Am J Gastroenterol 1998;93:692-696. 3. 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

ESOPHAGUS(ulcerative esophagitis)

MTB

DUODENUM(D3 “malignant” ulcer)

COLON(caecal polyp)

Mycobacterium tuberculosis Mycobacterium avium complex

MAC = PAS+

Intestinal spirochaetosisIntestinal 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 bacilli1. Surawicz CM. Intestinal spirochetosis in homosexual men. Am J Med  1988; 82:587-592. 2. Koteish A, Kannangai R, Abraham S et al. Colonic spirochetosis in children and adults. Am J Clin Pathol  2003; 120:828-832.

PAS Gram

Warthin-Starry

Clostridium difficile (“pseudomembranous”) colitisClostridium 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.

PARASITICPARASITIC

CryptosporidiosisCryptosporidiosis

• 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. 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. 2. Manabe YC, Clark DP, Moore RD, et al. Cryptosporidiosis in patients with AIDS:correlates of disease and survival. Clin Infect Dis. 1998;27:536-42.3. 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

ISOSPORIDIOSISISOSPORIDIOSIS• 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

“banana-shaped”, peri-/subnuclear intra-epithelial locationGMS, 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.

PAS

Entamoeba histolytica

Gastric toxoplasmosis

NEOPLASMSNEOPLASMS

GENERALGENERAL

• 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.

NEOPLASMSNEOPLASMS

• 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

NEOPLASMSNEOPLASMS

• 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 TRACTKAPOSI 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. Cheung MC, Pantanowitz L, Dezube BJ. AIDS-related malignancies: Emerging challenges in the era of highly active antiretroviral therapy. Oncologist  2005; 10:412-426.

2. 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.

3. 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 TRACTKAPOSI 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. Shah SB, Kumar KS. Kaposi’s sarcoma involving the gastrointestinal tract. Clin Gastroenteroll Hepatol. 2008;6:A20.2. Friedman SL, Wright TL, Altman DF. Gastrointestinal Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Endoscopic and autopsy findings.

Gastroenterology. 1985;89:102-108.3. 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

LYMPHOMALYMPHOMA

• 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. Beral V, Peterman T, Berkelman R et al. AIDS-associated non-Hodgkin lymphoma. Lancet 1991;337:805-9.2. Engels EA, Pfeiffer RM, Goedert JJ et al. Trends incancer risk among people with AIDS in the United States 1980-2002. AIDS 2006;20:1645-54.3. 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;97:425-32.4. 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 LYMPHOMAPLASMABLASTIC 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, oral-

mucosal 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 EMA

CD 30 VS38cCD 138

OTHEROTHER

OTHER PATHOLOGYOTHER PATHOLOGY

1. Drugs2. Immune reconstitution

inflammatory syndrome (IRIS)

3. HIV enteropathy

DRUGSDRUGS

• 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

IRISIRIS• 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 ENTEROPATHYHIV 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. Kotler DP, Gaetz HP, Lange M et al. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984;101:421-8.2. Blanshard C, Francis N, Gazzard BG. Investigation of chronic diarrhoea in acquired immunodeficiency syndrome. A prospective study of 155 patients..Gut 1996;39(6):824-32.3. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008;1(1):23-30.4. Greenson JK, Belitsos PC, Yardley JH et al. AIDS enteropathy: occult enteric infections and duodenal mucosal aspirations in chronic diarhhea. Ann Intern Med 1991;114:366-725. 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 PATIENTSHIV 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 MORPHOLOGYHIV ENTEROPATHY: ENTERIC MUCOSAL MORPHOLOGY

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apoptosis acuteenteritis

chronicenteritis

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Control

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HIV ENTEROPATHY: ENTERIC MUCOSAL MORPHOLOGYHIV ENTEROPATHY: ENTERIC MUCOSAL MORPHOLOGY

HIV ENTEROPATHY IN AFRICAN PATIENTSHIV 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

CD68 - duodenum

CD68 - colon

control HIV

HIVcontrol

CONCLUSIONCONCLUSION

APPROACH TO GI BIOPSY IN HIVAPPROACH 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

• 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…

APPROACH TO GI BIOPSY IN HIVAPPROACH TO GI BIOPSY IN HIV

SOUTH AFRICA

A world in one country…