The impact of the SARS-CoV-2 epidemic on mortality in South Africa in 2020.

BACKGROUND: The impacts on mortality of both the SARS-CoV-2 epidemic and the interventions to manage it differ between countries. The Rapid Mortality Surveillance System set up by the South African Medical Research Council based on data from the National Population Register (NPR) provides a means of tracking this impact on mortality in South Africa. OBJECTIVES: To report on the change in key metrics of mortality (numbers of deaths, life expectancy at birth, life expectancy at age 60, and infant, under-5, older child and adolescent, young adult, and adult mortality) over the period 2015 - 2020. The key features of the impact are contrasted with those measured in other countries. METHODS: The numbers of registered deaths by age and sex recorded on the NPR were increased to account for both registered deaths that are not captured by the NPR and an estimate of deaths not reported. The estimated numbers of deaths together with estimates of the numbers in the population in the middle of each of the years were used to produce life tables and calculate various indicators. RESULTS: Between 2019 and 2020, the number of deaths increased by nearly 53 000 (65% female), and life expectancy at birth fell by 1 year for females and by only 2.5 months for males. Life expectancy at age 60 decreased by 1.6 years for females and 1.2 years for males. Infant mortality, under-5 mortality and mortality of children aged 5 - 14 decreased by 22%, 20% and 10%, respectively, while that for older children and adolescents decreased by 11% for males and 5% for females. Premature adult mortality, the probability of a 15-year-old dying before age 60, increased by 2% for males and 9% for females. CONCLUSIONS: COVID-19 and the interventions to manage it had differential impacts on mortality by age and sex. The impact of the epidemic on life expectancy in 2020 differs from that in most other, mainly developed, countries, both in the limited decline and also in the greater impact on females. These empirical estimates of life expectancy and mortality rates are not reflected by estimates from agencies, either because agency estimates have yet to be updated for the impact of the epidemic or because they have not allowed for the impact correctly. Trends in weekly excess deaths suggest that the drop in life expectancy in 2021 will be greater than that in 2020.

Unnatural deaths, alcohol bans and curfews: Evidence from a quasi-natural experiment during COVID-19.

BACKGROUND: Coronavirus disease-19 (COVID-19) restrictions, particularly relating to the sale of alcohol and hours of curfew, have had a marked effect on the temporal pattern of unnatural deaths in South Africa. Methods. Death data were collected over 68 weeks from January 2020 to April 2021, together with information on the nature of restrictions (if any) on the sale of alcohol, and hours of curfew. Data were analysed using a simple ordinary least square (OLS) regression model to estimate the relative contribution of restrictions on the sale of alcohol and hours of curfew to the pattern of excess unnatural deaths. Results. The complete restriction on the sale of alcohol resulted in a statistically significant reduction in unnatural deaths regardless of the length of curfew. To the contrary, periods where no or limited restrictions on alcohol were in force had no significant effect, or resulted in significantly increased unnatural deaths. Conclusions. The present study highlights an association between alcohol availability and the number of unnatural deaths and demonstrates the extent to which those deaths might be averted by disrupting the alcohol supply. While this is not a long-term solution to addressing alcohol-related harm, it further raises the importance of implementing evidence-based alcohol control measures.

Viruses, variants and vaccines.

The current SARS-CoV-2 pandemic has brought a number of major global clinical, sociological and economic issues into sharp focus. We address some of these issues, focusing on short-term factors such as virus mutations and vaccine efficacy, and also considering the longer-term implications of the current pandemic. We discuss societal responses to the presence of a pathogen that will probably remain in circulation for decades or longer, and to future new emergent viruses.

Tracking mortality in near to real time provides essential information about the impact of the COVID-19 pandemic in South Africa in 2020.

BACKGROUND: Producing timely and accurate estimates of the impact of COVID-19 on mortality is challenging for most countries, but impossible for South Africa (SA) from cause-of-death statistics. Objectives. To quantify the excess deaths and likely magnitude of COVID-19 in SA in 2020 and draw conclusions on monitoring the epidemic in 2021. Methods. Basic details of deaths registered on the National Population Register by the Department of Home Affairs (DoHA) are provided to the South African Medical Research Council weekly. Adjustments are made to the numbers of weekly deaths to account for non-registration on the population register, as well as late registration of death with the DoHA. The weekly number of deaths is compared with the number predicted based on the Holt-Winters time-series analysis of past deaths for provinces and metropolitan areas. Excess deaths were calculated for all-causes deaths and natural deaths, using the predicted deaths as a baseline. In addition, an adjustment was made to the baseline for natural deaths to account for the drop in natural deaths due to lockdown. Results. We estimated that just over 550 000 deaths occurred among persons aged ≥1 year during 2020, 13% higher than the 485 000 predicted before the pandemic. A pronounced increase in weekly deaths from natural causes peaked in the middle of July across all ages except <20 years, and across all provinces with slightly different timing. During December, it became clear that SA was experiencing a second wave of COVID-19 that would exceed the death toll of the first wave. In 2020, there were 70 000 - 76 000 excess deaths from natural causes, depending on the base. Using the adjusted base, the excess death rate from natural causes was 122 per 100 000 population, with a male-to-female ratio of 0.78. Deaths from unnatural causes halved for both males and females during the stringent lockdown level 5. The numbers reverted towards the predicted number with some fluctuations as lockdown restrictions varied. Just under 5 000 unnatural deaths were averted. Conclusions. Tracking the weekly numbers of deaths in near to real time has provided important information about the spatiotemporal impact of the pandemic and highlights that the ~28 000 reported COVID-19 deaths during 2020 substantially understate the death toll from COVID-19. There is an urgent need to re-engineer the system of collecting and processing cause-of-death information so that it can be accessed in a timely way to inform public health actions.

Child mortality trends and causes of death in South Africa, 1997 - 2012, and the importance of a national burden of disease study.

BACKGROUND: The Rapid Mortality Surveillance System has reported reductions in child mortality rates in recent years in South Africa (SA). In this article, we present information about levels of mortality and causes of death from the second SA National Burden of Disease Study (SA NBD) to inform the response required to reduce child mortality further. OBJECTIVES: To estimate trends in and causes of childhood mortality at national and provincial levels for the period 1997 - 2012, to highlight the importance of the SA NBD. METHODS: Numbers of registered child deaths were adjusted for under-reporting. Adjustments were made for the misclassification of AIDS deaths and the proportion of ill-defined natural causes. Non-natural causes were estimated using results from the National Injury Mortality Surveillance System for 2000 and the National Injury Mortality Survey for 2009. Six neonatal conditions and 11 other causes were consolidated from the SA NBD and the Child Health Epidemiological Reference Group lists of causes of death for the analysis. The NBD cause-fractions were compared with those from Statistics South Africa, the United Nations Children's Fund (UNICEF) and the Institute for Health Metrics and Evaluation (IHME). RESULTS: Under-5 mortality per 1 000 live births increased from 65 in 1997 to 79 in 2004 as a result of HIV/AIDS, before dropping to 40 by 2012. The neonatal mortality rate declined from 1997 to 2001, followed by small variations. The death rate from diarrhoeal diseases began to decrease in 2008 and the death rate from pneumonia from 2010. By 2012, neonatal deaths accounted for 27% of child deaths, with conditions associated with prematurity, birth asphyxia and severe infections being the main contributors. In 1997, KwaZulu-Natal, Free State, Mpumalanga and Eastern Cape provinces had the highest under-5 mortality, close to 80 per 1 000 live births. Mortality rates in North West were in the mid-range and then increased, placing this province in the highest group in the later years. The Western Cape had the lowest mortality rate, declining throughout the period apart from a slight increase in the early 2000s. CONCLUSIONS: The SA NBD identified the causes driving the trends, making it clear that prevention of mother-to-child transmission of HIV, the Expanded Programme on Immunisation and programmes aimed at preventing neonatal deaths need to be equitably implemented throughout the country to address persistent provincial inequalities in child deaths. The rapid reduction of childhood mortality since 2005 suggests that the 2030 Sustainable Development Goal target of 25 per 1 000 for under-5 mortality is achievable for SA. Comparison with alternative estimates highlights the need for cause-of-death data from civil registration to be adjusted using a burden-of-disease approach.

HIV/AIDS mortality trends pre and post ART for 1997 - 2012 in South Africa - have we turned the tide?

BACKGROUND: South Africa (SA) has one of the largest HIV/AIDS epidemics in the world and the most extensive antiretroviral therapy (ART) programme globally, which was rolled out from 2004. This paper reports the trends in HIV/AIDS mortality pre and post ART rollout in SA. Methods. Vital registration cause-of-death data from Statistics South Africa were adjusted for under-reporting of deaths using demographic methods. Misattributed HIV/AIDS deaths were identified by regressing excess mortality on a lagged indicator HIV antenatal clinic prevalence for causes found to be associated with HIV/AIDS. Background trends in the source-cause mortality rates were estimated from the trend in cause-specific mortality experienced among 75 - 84-year-olds. Mortality rates were calculated using mid-year population estimates and the World Health Organization world standard age-weights. Results. We estimated over 3 189 000 HIV/AIDS deaths for 1997 - 2012. In 1997, 60 336 (14.5%) of deaths were attributed to HIV/AIDS; this number peaked in 2006 at 283 564 (41.9%) and decreased to 153 661 (29.1%) by 2012; female mortality rates peaked in 2005 and those of males in 2006. Men aged 35 years and older had higher mortality rates than did women. While the rates at ages below 65 years in 2012 were lower than those in 2006, rates of those age 65 years and older remained unchanged. Conclusion. The number of HIV/AIDS deaths has almost halved since the ART rollout. Of concern is the high mortality in men 45 years and older and the high mortality of men compared with women in the older ages by 2012; this gap has increased with age. Treatment and prevention programmes should strategise how to target men.

Burden of disease in South Africa: Protracted transitions driven by social pathologies.

For several decades, researchers from the South African Medical Research Council have made invaluable contributions towards improving the health of the population through the analysis and interpretation of cause of death data. This article reflects the mortality trends in pre-and post-apartheid South Africa (SA), and describes efforts to improve vital statistics, innovations to fill data gaps, and studies to estimate the burden of disease after adjusting for data deficiencies. The profound impact of HIV/AIDS, particularly among black African children and young adults, is striking, within a protracted epidemiological transition and the current reversals of multiple epidemics. Over the next 20 years, it will be important to sustain and enhance the country's capacity to collect, analyse and utilise cause of death data. SA needs to support development in the region, harnessing new data platforms and approaches such as including verbal autopsy tools in the official system and improving data linkage.

Emerging Trends in Non-Communicable Disease Mortality in South Africa; 1997 - 2010

OBJECTIVES:National trends in age-standardised death rates (ASDRs) for non-communicable diseases (NCDs) in South Africa (SA) were identified between 1997 and 2010.METHODS:As part of the second National Burden of Disease Study; vital registration data were used after validity checks; proportional redistribution of missing age; sex and population group; demographic adjustments for registration incompleteness; and identification of misclassified AIDS deaths. Garbage codes were redistributed proportionally to specified codes by age; sex and population group. ASDRs were calculated using mid-year population estimates and the World Health Organization world standard.RESULTS:Of 594 071 deaths in 2010; 38.9% were due to NCDs (42.6% females). ASDRs were 287/100 000 for cardiovascular diseases (CVDs); 114/100 000 for cancers (malignant neoplasms); 58/100 000 for chronic respiratory conditions and 52/100 000 for diabetes mellitus. An overall annual decrease of 0.4% was observed resulting from declines in stroke; ischaemic heart disease; oesophageal and lung cancer; asthma and chronic respiratory disease; while increases were observed for diabetes; renal disease; endocrine and nutritional disorders; and breast and prostate cancers. Stroke was the leading NCD cause of death; accounting for 17.5% of total NCD deaths. Compared with those for whites; NCD mortality rates for other population groups were higher at 1.3 for black Africans; 1.4 for Indians and 1.4 for coloureds; but varied by condition.CONCLUSIONS:NCDs contribute to premature mortality in SA; threatening socioeconomic development. While NCD mortality rates have decreased slightly; it is necessary to strengthen prevention and healthcare provision and monitor emerging trends in cause-specific mortality to inform these strategies if the target of 2% annual decline is to be achieved

The role of immunity in the epidemiology of gonorrhoea, chlamydial infection and trichomoniasis: insights from a mathematical model.

Most mathematical models of sexually transmitted infections (STIs) assume that infected individuals become susceptible to re-infection immediately after recovery. This paper assesses whether extending the standard model to allow for temporary immunity after recovery improves the correspondence between observed and modelled levels of STI prevalence in South Africa, for gonorrhoea, chlamydial infection and trichomoniasis. Five different models of immunity and symptom resolution were defined, and each model fitted to South African STI prevalence data. The models were compared in terms of Bayes factors, which show that in the case of gonorrhoea and chlamydial infection, models that allow for immunity provide a significantly better fit to STI prevalence data than models that do not allow for immunity. For all three STIs, estimates of the impact of changes in STI treatment and sexual behaviour are significantly lower in models that allow for immunity. Mathematical models that do not allow for immunity could therefore overestimate the effectiveness of STI interventions.

Declines in HIV prevalence can be associated with changing sexual behaviour in Uganda, urban Kenya, Zimbabwe, and urban Haiti.

OBJECTIVE: To determine whether observed changes in HIV prevalence in countries with generalised HIV epidemics are associated with changes in sexual risk behaviour. METHODS: A mathematical model was developed to explore the relation between prevalence recorded at antenatal clinics (ANCs) and the pattern of incidence of infection throughout the population. To create a null model a range of assumptions about sexual behaviour, natural history of infection, and sampling biases in ANC populations were explored to determine which factors maximised declines in prevalence in the absence of behaviour change. Modelled prevalence, where possible based on locally collected behavioural data, was compared with the observed prevalence data in urban Haiti, urban Kenya, urban Cote d'Ivoire, Malawi, Zimbabwe, Rwanda, Uganda, and urban Ethiopia. RESULTS: Recent downturns in prevalence observed in urban Kenya, Zimbabwe, and urban Haiti, like Uganda before them, could only be replicated in the model through reductions in risk associated with changes in behaviour. In contrast, prevalence trends in urban Cote d'Ivoire, Malawi, urban Ethiopia, and Rwanda show no signs of changed sexual behaviour. CONCLUSIONS: Changes in patterns of HIV prevalence in urban Kenya, Zimbabwe, and urban Haiti are quite recent and caution is required because of doubts over the accuracy and representativeness of these estimates. Nonetheless, the observed changes are consistent with behaviour change and not the natural course of the HIV epidemic.

Sentinel surveillance of sexually transmitted infections in South Africa: a review.

OBJECTIVES: To review studies of sexually transmitted infection (STI) prevalence in South Africa between 1985 and 2003 in selected sentinel populations. To examine how STI prevalence varies between populations and to identify the limitations of the existing data. METHODS: Studies of the prevalence of syphilis, chancroid, granuloma inguinale, lymphogranuloma venereum, gonorrhoea, chlamydia, trichomoniasis, bacterial vaginosis, candidiasis, and herpes simplex virus type 2 (HSV-2) were considered. Results were included if they related to women attending antenatal clinics or family planning clinics, commercial sex workers, individuals in the general population (household surveys), patients with STIs, patients with genital ulcer disease (GUD), or men with urethritis. RESULTS: High STI prevalence rates have been measured, particularly in the case of HSV-2, trichomoniasis, bacterial vaginosis and candidiasis. The aetiological profile of GUD appears to be changing, with more GUD caused by HSV-2 and less caused by chancroid. The prevalence of gonorrhoea and syphilis is highest in "high risk" groups such as sex workers and attenders of STI clinics, but chlamydia and trichomoniasis prevalence levels are not significantly higher in these groups than in women attending antenatal clinics. CONCLUSIONS: The prevalence of STIs in South Africa is high, although there is extensive variability between regions. There is a need for STI prevalence data that are more nationally representative and that can be used to monitor prevalence trends more reliably.

Mutational analysis of the hydantoin hydrolysis pathway in Pseudomonas putida RU-KM3S.

The biocatalytic conversion of 5-mono-substituted hydantoins to the corresponding D-amino acids or L-amino acids involves first the hydrolysis of hydantoin to a N-carbamoylamino acid by an hydantoinase or dihydropyrimidinase, followed by the conversion of the N-carbamoylamino acid to the amino acid by N-carbamylamino acid amidohydrolase ( N-carbamoylase). Pseudomonas putida strain RU-KM3S, with high levels of hydantoin-hydrolysing activity, has been shown to exhibit non-stereoselective hydantoinase and L-selective N-carbamoylase activity. This study focused on identifying the hydantoinase and N-carbamoylase-encoding genes in this strain, using transposon mutagenesis and selection for altered growth phenotypes on minimal medium with hydantoin as a nitrogen source. Insertional inactivation of two genes, dhp and bup, encoding a dihydropyrimidinase and beta-ureidopropionase, respectively, resulted in loss of hydantoinase and N-carbamoylase activity, indicating that these gene products were responsible for hydantoin hydrolysis in this strain. dhp and bup are linked to an open reading frame encoding a putative transport protein, which probably shares a promoter with bup. Two mutant strains were isolated with increased levels of dihydropyrimidinase but not beta-ureidopropionase activity. Transposon mutants in which key elements of the nitrogen regulatory pathway were inactivated were unable to utilize hydantoin or uracil as a nitrogen source. However, these mutations had no effect on either the dihydropyrimidinase or beta-ureidopropionase activity. Disruption of the gene encoding dihydrolipoamide succinyltransferase resulted in a significant reduction in the activity of both enzymes, suggesting a role for carbon catabolite repression in the regulation of hydantoin hydrolysis in P. putida RU-KM3S cells.

Over-production of hydantoinase and N-carbamoylamino acid amidohydrolase enzymes by regulatory mutants of Agrobacterium tumefaciens.

While the hydantoin-hydrolysing enzymes from Agrobacterium strains are used as biocatalysts in the commercial production of D-p-hydroxyphenylglycine, they are now mostly produced in heterologous hosts such as Escherichia coli. This is due to the fact that the activity of these enzymes in the native strains is tightly regulated by growth conditions. Hydantoinase and N-carbamoylamino acid amidohydrolase (NCAAH) activities are induced when cells are grown in the presence of hydantoin or an hydantoin analogue, and in complete medium, enzyme activity can be detected only in early stationary growth phase. In this study, the ability of Agrobacterium tumefaciens RU-OR cells to produce active enzymes was found to be dependent upon the choice of nitrogen source and the presence of inducer, 2-thiouracil, in the growth medium. Growth with (NH4)2SO4 as the nitrogen source repressed the production of both enzymes (nitrogen repression) and also resulted in a rapid, but reversible loss of hydantoinase activity in induced cells (ammonia shock). Mutant strains with inducer-independent production of the enzymes and/or altered response to nitrogen control were isolated. Of greatest importance for industrial application was strain RU-ORPN1F9, in which hydantoinase and NCAAH enzyme activity was inducer-independent and no longer sensitive to nitrogen repression or ammonia shock. Such mutants offer the potential for native enzyme production levels equivalent to those achieved by current heterologous expression systems.