The impact of Helicobacter pylori and intestinal helminth infections on gastric adenocarcinoma and inflammatory bowel disease in Sub-Saharan Africa.

Gastric adenocarcinoma (GCA) is the 5th leading cancer globally with an estimated 1.1 million cases reported in 2020. Ninety percent of non-cardia GCAs are attributable to Helicobacter pylori (H. pylori), the most prevalent bacterial infection globally. Rates of H. pylori infection are highest in Sub-Saharan Africa (SSA), yet surprisingly low numbers of GCAs are reported in the region. A similar phenomenon is seen with the inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis. These disorders have risen dramatically over the past century in high income countries across the globe, with sharp increases noted more recently in newly industrialized regions. In contrast IBD is rare in most regions in SSA. For both diseases this may reflect under-reporting or limited access to diagnostic modalities, but an alternative explanation is the high burden of infection with gastrointestinal parasites endemic to SSA which may attenuate the risk of developing GCA and IBD. In this mini review we discuss the complex interplay between these microorganisms, GCA, and IBD, as well as a possible protective role of H. pylori and the development of IBD.

Inflammatory bowel disease in sub-Saharan Africa: epidemiology, risk factors, and challenges in diagnosis.

Over the past century, the incidence of inflammatory bowel disease (IBD) in high-income countries has shown a sharp rise that then plateaued, and a similar trend has been observed in newly industrialised countries. IBD has long been considered uncommon in sub-Saharan Africa, possibly reflecting low exposure to environmental risk factors described in high-income populations. Alternatively, individuals living in sub-Saharan Africa might have a different genetic disposition. However, some cases of IBD might remain undetected in sub-Saharan Africa because of a lack of awareness, deficiencies in diagnostic and clinical capacity, and a substantial rate of misdiagnosis due to the high burden of infectious diseases. There are few published data describing the natural history of IBD in sub-Saharan Africa, and the true burden of the disease remains largely unknown, although there is some evidence that the incidence of IBD is rising in this region. This Series paper summarises the present understanding of IBD and challenges facing clinicians when diagnosing this disease in sub-Saharan Africa.

Challenges in the management of inflammatory bowel disease in sub-Saharan Africa.

Inflammatory bowel disease (IBD) is generally considered a disease of high-income countries and is regarded as rare in sub-Saharan Africa. However, this assumption is almost certainly an underestimate, and the high burden of communicable diseases makes IBD in sub-Saharan Africa difficult to detect. Furthermore, some gastrointestinal infections can closely mimic IBD, contributing to delays in diagnosis and complicating therapeutic decision making. Constraints in endoscopic capacity alongside a scarcity of qualified diagnostic pathologists add to the difficulties. Implementing evidence-based guidelines recommended by international societies is challenging, mostly due to high costs and unavailability of medication. However, cost-effective approaches can still be implemented to manage IBD in sub-Saharan Africa as the predominant disease phenotype is mild-to-moderate ulcerative colitis, which often responds to treatment with basic medication. In this Series paper, we summarise the current management of IBD in sub-Saharan Africa and propose how it can be tailored to suit the epidemiological and socioeconomic specificities of the region. We also discuss measures required to address existing challenges, such as educating health-care workers about the diagnosis and management of IBD or improving endoscopic capacity.

CD73 expression in tissue granulomas in distinguishing intestinal tuberculosis from Crohn's disease in a South African cohort.

INTRODUCTION: Overlap of clinical, endoscopic and radiographic features, coupled with a poor microbiological yield makes differentiating Crohn's disease (CD) from intestinal tuberculosis (ITB) challenging. A potential histological differentiating mechanism is the use of immunohistochemical staining for the mesenchymal stem cell marker CD73, as a pilot study showed ITB but not CD granulomas stained positive for this marker. The aim of this study was to assess the value of CD73 in differentiating ITB from CD granulomas in a South African cohort. METHODS: Patients with confirmed CD or ITB were identified from a pathology database. Tissue sections were reviewed by a pathologist to confirm the presence of granulomas. These were then stained with a mouse monoclonal anti-CD73 antibody. The slides were examined together by a pathologist and gastroenterologist in a blinded manner for anti-CD73 staining around granulomas. RESULTS: Ninety six cases were available for analysis; 50 cases of ITB and 46 cases of CD. Thirty percent of CD granulomas (14/46) stained positive for CD73, whereas CD73 positivity was seen in 52% (26/50) of cases of ITB. This was statistically significant (OR 2.48, 95% CI 1.1-5.72, p = .03). The area under the curve (AUC) was 0.61. Sensitivity of CD73 in predicting ITB was 52% and specificity was 70%. Overall CD73 staining of granulomas correctly classified only 60% of cases. CONCLUSIONS: In our study we have shown that significantly more patients with ITB express CD73 in their granulomas than those with CD. However the relatively poor sensitivity, specificity and AUC make this test unlikely to be of value in our clinical practice.

Correction: The Influence of Second-Hand Cigarette Smoke Exposure during Childhood and Active Cigarette Smoking on Crohn's Disease Phenotype Defined by the Montreal Classification Scheme in a Western Cape Population, South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0139597.].

Correction: The association between environmental exposures during childhood and the subsequent development of Crohn's disease: A score analysis approach.

[This corrects the article DOI: 10.1371/journal.pone.0171742.].

A comparison of Clostridium difficile diagnostic methods for identification of local strains in a South African centre.

Accurate diagnosis of Clostridium difficile infection is essential for disease management. A clinical and molecular analysis of C. difficile isolated from symptomatic patients at Groote Schuur Hospital, South Africa, was conducted to establish the most suitable clinical test for the diagnosis and characterization of locally prevalent strains. C. difficile was detected in stool samples using enzyme-based immunoassays (EIA) and nucleic acid amplification methods, and their performance was compared with that of C. difficile isolation using direct selective culture combined with specific PCR to detect the C. difficile tpi gene, toxin A and B genes and binary toxin genes. Toxigenic isolates were characterized further by ribotyping. Selective culture isolated 32 C. difficile strains from 145 patients (22 %). Of these, the most prevalent (50 %) were of ribotype 017 (toxin A- B+) while 15.6 % were ribotype 001 (toxin A+B+). No ribotype 027 strains or binary toxin genes (cdtA and cdtB) were detected. The test sensitivities and specificities, respectively, of four commercial clinical diagnostic methods were as follows: ImmunoCard Toxins A & B (40 % and 99.1 %), VIDAS C. difficile Toxin A & B (50 % and 99.1 %), GenoType CDiff (86.7 % and 88.3 %) and Xpert C. difficile (90 % and 97.3 %). Ribotype 001 and 017 strains had a 100 % detection rate by Xpert C. difficile, 100 % and 93.3 % by GenoType CDiff, 75 % and 53.3 % by ImmunoCard and 75 % and 60 % by VIDAS, respectively. The overall poor performance of EIA suggests that a change to PCR-based testing would assist diagnosis and ensure reliable detection of locally prevalent C. difficile 017 strains.

Vitamin D Deficiency Increases the Risk for Moderate to Severe Disease Activity in Crohn's Disease Patients in South Africa, Measured by the Harvey Bradshaw Index.

OBJECTIVE: Vitamin D has immunoregulatory properties and appears to influence disease outcomes in patients with Crohn's disease (CD). The primary aim of this study was to evaluate the association between vitamin D status and CD activity in South Africa. METHODS: In a cross-sectional study performed between September 2011 and January 2013, serum 25-hydroxyvitamin D (25(OH)D) was measured in 186 consecutive patients with CD seen at 2 inflammatory bowel disease (IBD) centers and 199 healthy controls in the Western Cape, South Africa. Lifestyle and clinical variables were identified using an investigator-administered questionnaire, as well as clinical examination and patient case notes. Vitamin D status was evaluated in 2 ways: ≤ 20 ng/mL vs ≥ 21 ng/mL and ≤ 29 ng/mL vs ≥ 30 ng/mL. Disease activity was measured by the Harvey Bradshaw Index (HBI). Various 25(OH)D threshold concentrations for predicting a higher HBI score were also investigated. RESULTS: On multiple log-binomial regression analysis, higher HBI scores and not having taken vitamin D supplementation in the 6 months prior to enrollment were identified as risk factors for vitamin D deficiency in patients with CD, defined either as ≤ 20 ng/mL or as ≤ 29 ng/mL (p < 0.03). Compared to patients with HBI < 5, those with HBI ≥ 8 were 2.5 times more likely to have 25(OH)D concentrations ≤ 21 ng/mL (prevalence risk [PR] = 2.5; 95% confidence interval [CI], 1.21-6.30). The risk was similar, though not as high, when defined as ≤ 29 ng/mL (PR = 2.0; 95% CI, 1.13-3.51). When vitamin D deficiency was defined as <20, <30, <40, and <50 ng/mL, the sensitivity and specificity obtained were 44.9% and 78.8%; 75.5% and 62.4%; 86.7% and 44.7%; and 92.9% and 23.5%, respectively (area under the curve = 0.71; p < 0.0001). CONCLUSION: Low serum 25(OH)D was associated with increased CD activity in a South African cohort.

The Influence of Second-Hand Cigarette Smoke Exposure during Childhood and Active Cigarette Smoking on Crohn's Disease Phenotype Defined by the Montreal Classification Scheme in a Western Cape Population, South Africa.

BACKGROUND: Smoking may worsen the disease outcomes in patients with Crohn's disease (CD), however the effect of exposure to second-hand cigarette smoke during childhood is unclear. In South Africa, no such literature exists. The aim of this study was to investigate whether disease phenotype, at time of diagnosis of CD, was associated with exposure to second-hand cigarette during childhood and active cigarette smoking habits. METHODS: A cross sectional examination of all consecutive CD patients seen during the period September 2011-January 2013 at 2 large inflammatory bowel disease centers in the Western Cape, South Africa was performed. Data were collected via review of patient case notes, interviewer-administered questionnaire and clinical examination by the attending gastroenterologist. Disease phenotype (behavior and location) was evaluated at time of diagnosis, according to the Montreal Classification scheme. In addition, disease behavior was stratified as 'complicated' or 'uncomplicated', using predefined definitions. Passive cigarette smoke exposure was evaluated during 3 age intervals: 0-5, 6-10, and 11-18 years. RESULTS: One hundred and ninety four CD patients were identified. Cigarette smoking during the 6 months prior to, or at time of diagnosis was significantly associated with ileo-colonic (L3) disease (RRR = 3.63; 95% CI, 1.32-9.98, p = 0.012) and ileal (L1) disease (RRR = 3.54; 95% CI, 1.06-11.83, p = 0.040) compared with colonic disease. In smokers, childhood passive cigarette smoke exposure during the 0-5 years age interval was significantly associated with ileo-colonic CD location (RRR = 21.3; 95% CI, 1.16-391.55, p = 0.040). No significant association between smoking habits and disease behavior at diagnosis, whether defined by the Montreal scheme, or stratified as 'complicated' vs 'uncomplicated', was observed. CONCLUSION: Smoking habits were associated with ileo-colonic (L3) and ileal (L1) disease at time of diagnosis in a South African cohort.

The association between childhood environmental exposures and the subsequent development of Crohn's disease in the Western Cape, South Africa.

BACKGROUND: Environmental factors during childhood are thought to play a role in the aetiolgy of Crohn's Disease (CD). However the association between age at time of exposure and the subsequent development of CD in South Africa is unknown. METHODS: A case control study of all consecutive CD patients seen at 2 large inflammatory bowel disease (IBD) referral centers in the Western Cape, South Africa between September 2011 and January 2013 was performed. Numerous environmental exposures during 3 age intervals; 0-5, 6-10 and 11-18 years were extracted using an investigator administered questionnaire. An agreement analysis was performed to determine the reliability of questionnaire data for all the relevant variables. RESULTS: This study included 194 CD patients and 213 controls. On multiple logistic regression analysis, a number of childhood environmental exposures during the 3 age interval were significantly associated with the risk of developing CD. During the age interval 6-10 years, never having had consumed unpasteurized milk (OR = 5.84; 95% CI, 2.73-13.53) and never having a donkey, horse, sheep or cow on the property (OR = 2.48; 95% CI, 1.09-5.98) significantly increased the risk of developing future CD. During the age interval 11-18 years, an independent risk-association was identified for; never having consumed unpasteurized milk (OR = 2.60; 95% CI, 1.17-6.10) and second-hand cigarette smoke exposure (OR = 1.93; 95% CI, 1.13-3.35). CONCLUSION: This study demonstrates that both limited microbial exposures and exposure to second-hand cigarette smoke during childhood is associated with future development of CD.

The association between race and Crohn's disease phenotype in the Western Cape population of South Africa, defined by the Montreal Classification System.

BACKGROUND: Inter-racial differences in disease characteristics and in the management of Crohn's disease (CD) have been described in African American and Asian subjects, however for the racial groups in South Africa, no such recent literature exists. METHODS: A cross sectional study of all consecutive CD patients seen at 2 large inflammatory bowel disease (IBD) referral centers in the Western Cape, South Africa between September 2011 and January 2013 was performed. Numerous demographic and clinical variables at diagnosis and date of study enrolment were identified using an investigator administered questionnaire as well as clinical examination and patient case notes. Using predefined definitions, disease behavior was stratified as 'complicated' or 'uncomplicated'. RESULTS: One hundred and ninety four CD subjects were identified; 35 (18%) were white, 152 (78%) were Cape Coloured and 7(4%) were black. On multiple logistic regression analysis Cape Coloureds were significantly more likely to develop 'complicated' CD (60% vs. 9%, p = 0.023) during the disease course when compared to white subjects. In addition, significantly more white subjects had successfully discontinued cigarette smoking at study enrolment (31% vs. 7% reduction, p = 0.02). No additional inter-racial differences were found. A low proportion of IBD family history was observed among the non-white subjects. CONCLUSIONS: Cape Coloured patients were significantly more likely to develop 'complicated' CD over time when compared to whites.

Childhood helminth exposure is protective against inflammatory bowel disease: a case control study in South Africa.

BACKGROUND: Inflammatory bowel disease (IBD) is more common in countries with improved hygiene, suggesting that environmental exposures may be associated with its development. The primary objective of this study was to examine the association between self-reported childhood helminth infection and the development of IBD in South Africa. METHODS: Unmatched case-control study. Logistic regression was used to model associations with IBD. RESULTS: There were 88 patients with Crohn's disease (CD), 63 with ulcerative colitis (UC), and 219 control subjects. Of the 151, 93 (61.6%) IBD subjects (35 of 63 [55.6%] had UC and 58 of 88 [65.9%] had CD) reported childhood helminth exposure compared with 200 of 219 (91.3%) non-IBD subjects (P < 0.001). Helminth infection (adjusted odds ratio [AOR] = 0.2; 95% confidence interval [CI], 0.1-0.4), shared housing (AOR = 0.1; 95% CI, 0.04-0.4), and raw beef consumption (AOR = 0.2; 95% CI, 0.1-0.6) were protective, whereas urban dwelling (AOR = 4.2; 95% CI, 2.0-8.8) and parental tertiary education (AOR = 18.2; 95% CI, 3.2-103.7) were associated with CD. Helminth infection (AOR = 0.2; 95% CI, 0.1-0.6), mixed race (AOR = 0.1; 95% CI, 0.03-0.5), smoking (AOR = 0.2; 95% CI, 0.07-0.5), shared housing (AOR = 0.1; 95% CI, 0.01-0.4), and raw beef consumption (AOR = 0.1; 95% CI 0.04-0.5) were protective against UC, whereas parental tertiary education (AOR = 12.7; 95% CI, 1.0-157.4) was associated with UC. CONCLUSION: This study demonstrates a protective association of childhood helminth infection against the development of IBD and supports the "hygiene hypothesis" that improved living conditions may increase the incidence of IBD. Our epidemiologic conclusions provide support that helminths may have immunomodulatory effects which provides protection against the development of IBD later in life.

The efficacy of endoscopic therapy in bleeding peptic ulcer patients.

BACKGROUND: Endotherapy is the primary modality for the control of bleeding from peptic ulceration. OBJECTIVE: To assess the efficacy of endoscopic intervention for high-risk bleeding peptic ulcer disease and to benchmark our surgical and mortality rates. METHODS: Two hundred and twenty-seven patients with peptic ulcers stratified by Rockall and Forrest scores as at high risk for re-bleeding underwent therapeutic intervention (adrenalin injection) between January 2004 and December 2009. The median age of the patients was 57 years (range 19 - 87 years); 60% were males. Results. Primary endoscopic haemostasis failed in 51/227 patients (22.5%); 18 patients (7.9%) required surgery for bleeding not controlled at initial or second endoscopy; and 29 patients (12.8%) died, 12 by day 3 and 17 by day 30. Fifteen patients, all with significant medical co-morbidity, died after successful primary endotherapy, and 4 died after surgery. Surgical patients required more blood (odds ratio (OR) 1.45, p=0.0001) than those not undergoing surgery, but had similar mortality. Rebleeding was the only predictor of death in patients who died by day 3 (OR 18.77). A high Rockall score was the only predictor of death by day 30 (OR 1.98). CONCLUSION: The overall surgical and mortality rates were 7.9% and 12.8%, respectively. Over half the deaths resulted from medical co-morbidity, despite successful primary endotherapy. This finding is supported by the use of the Rockall score as a predictor of mortality at day 30. Improving the technical success of primary endoscopic haemostasis, currently 77.5%, has the potential to reduce rebleeding after primary endotherapy, a predictor of death at day 3 in this study.

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study.

BACKGROUND AND AIM: The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. METHODS: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. RESULTS: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4). CONCLUSIONS: Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010.

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohn's disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.