A Thesis Submitted to the School of Public Health,
Faculty of Health Sciences,
University of the Witwatersrand,
in fulfilment of the requirements for the degree of Doctor of Philosophy
Johannesburg, South Africa 2016. / Introduction
Human immunodeficiency virus (HIV) has been associated with invasive enteric infections in
HIV-infected patients, since it was first described in the 1980s. In South Africa, HIV remains
an important health challenge, despite the introduction of antiretroviral therapy (ART) in
2003. In association with this, is an ongoing problem of invasive enteric infections, including
those due to Shigella and Salmonella, including Salmonella enterica serovar Typhi
(Salmonella Typhi). There are few South African data available as to the incidence of
invasive disease due to these pathogens and how these data may contrast with the
presentation and outcome in HIV-uninfected patients. The associated risk factors for
mortality due to invasive enteric pathogens and whether there has been a response with ART
as an intervention also needs further elucidation.
Aims
This work was undertaken to better describe the burden of invasive enteric infections
(Shigella, nontyphoidal Salmonella and Salmonella Typhi) in association with HIV, define
risk factors for mortality and establish whether the introduction of ART has impacted on
disease burdens due to these pathogens.
Methods
Laboratory-based surveillance for enteric pathogens was initiated in 2003. Basic
demographic details (age and gender) were collected on all patients where possible. In 25
hospital sites in all nine provinces, additional clinical information was collected by trained
surveillance officers, including HIV status, data reflecting severity of illness, other immune
suppressive conditions, antimicrobial and antiretroviral usage and outcome (survival versus
death). Laboratories were requested to transport all isolates to the Centre for Enteric Diseases
(CED) at the National Institute for Communicable Diseases of the National Health
Laboratory Service (NHLS) in Johannesburg for further characterisation, including
serotyping, antimicrobial susceptibility testing and molecular typing where relevant (whether
isolates could respectively be classified as Salmonella Typhimurium ST313 and Salmonella
Typhi H58). Additional cases were sought through audits of the Central Data Warehouse
(CDW) of the NHLS.
Annual incidence rates were calculated according to published estimates of population by age
group by the Actuarial Society of South Africa for the Department of Statistics of the South
African government. Analyses were specifically directed at invasive shigellosis, Salmonella
meningitis, typhoid fever in South Africa and nontyphoidal salmonellosis in Gauteng
Province, South Africa. Data were recorded in an Access database and analysed using chisquared
test to establish differences between HIV-infected and uninfected individuals and
univariate and multivariate analysis to compare risk factors for mortality. Data in the number
of patients accessing ART were derived through audits of the CDW, by using the numbers of
patients on whom viral loads were done annually as a proxy.
Results
Between 2003 and 2013, a total of 10111 invasive enteric isolates were received by CED. For
patients for whom sex was recorded, 3283/6244 (52.6%) of patients presenting with invasive
enteric infections were male; invasive disease was predominantly observed in children less
than five years of age (1605/6131; 26.2%) and those who were aged between 25 and 54 years
(3186/6131; 52.0%), with the exception of typhoid fever where the major burden was in
patients aged 5 to 14 years (302/855; 35.3%).
KH Keddy 81-11384 PhD
iv
More HIV-infected adult women were observed with invasive shigellosis (P=0.002) and with
typhoid fever compared with adult men (P=0.009). Adults aged ≥ 15 years were more likely
to die than children aged < 15 years (invasive shigellosis, odds ratio [OR]=3.2, 95%
confidence interval [CI]=1.6 – 6.6, P=0.001; Salmonella meningitis, OR=3.7, 95% CI=1.7 –
8.1, P=0.001; typhoid fever, OR=3.7, 95% CI=1.1 – 14.9, P=0.03; invasive nontyphoidal
salmonellosis, OR=2.0, 95% CI=1.6 – 2.5, P<0.001).
HIV-infected patients had a significantly higher risk of mortality compared with HIVuninfected
patients (invasive shigellosis, OR=4.1, 95% CI=1.5 – 11.8, P=0.008; Salmonella
meningitis OR=5.3, 95% CI=1.4-20.0, P=0.013; typhoid fever, OR=11.3, 95% CI=3.0 – 42.4,
P<0.001; invasive nontyphoidal salmonellosis OR=2.5, 95% CI=1.7 – 3.5, P<0.001). In all
patients, severity of illness was the most significant factor contributing to mortality (invasive
shigellosis, OR=22.9, 95% CI=2.7 – 194.2, P=0.004; Salmonella meningitis OR=21.6, 95%
CI=3.5 – 133.3, P=0.01; typhoid fever, OR=10.8, 95% CI=2.9 – 39.5, P<0.001; invasive
nontyphoidal salmonellosis OR=5.4, 95% CI=3.6 – 8.1, P<0.001). Between 2003 and 2013,
ART was significantly associated with decreasing incidence rates of invasive nontyphoidal
salmonellosis in adults aged 25 - 49 years (R=-0.92; P<0.001), but not in children (R=-0.50;
P=0.14).
Conclusion
Decreasing incidence rates of invasive nontyphoidal salmonellosis and shigellosis suggest
that ART is having an impact on opportunistic enteric disease in HIV. Further work is
necessary however, to fully understand the associations between age, sex and invasive enteric
pathogens. Specifically, this work would include typhoid fever, Shigella transmission from
child to adult carer, development of invasive enteric infections in HIV-exposed children and
whether the decreasing incidence rates can be sustained. Moving forward, an understanding
of invasive enteric infections in the HIV-uninfected patient may assist in targeting severity of
illness as a risk factor for mortality. / MT2017
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/23087 |
| Date | January 2017 |
| Creators | Keddy, Karen Helena |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (xx, 189 leaves), application/pdf |
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