Stem Cell Transplant in Immune-deficiency-associated Vaccine-derived Poliovirus.

Patients with severe primary immunodeficiency are at risk for complications from live-attenuated vaccines. Here, we report a case of a vaccine-associated paralytic polio and Bacille Calmette-Guérin disease in a 6-month-old girl with severe combined immunodeficiency resulting from homozygous recombinant activating gene 1 deficiency. The patient was successfully treated with intravenous immunoglobulins and oral pocapavir for poliovirus, and antimycobacterial therapy for regional Bacille Calmette-Guérin disease, allowing stem cell transplant. Following transplantation, poliovirus type 3 with 13 mutations was detected from cerebrospinal fluid but not from stool, indicating ongoing viral evolution in the central nervous system despite pocapavir treatment. Clinical improvement and immune reconstitution allowed the patient to be successfully discharged with no further detection of poliovirus.

SARS-CoV-2 genomic surveillance in wastewater as a model for monitoring evolution of endemic viruses.

As global SARS-CoV-2 burden and testing frequency have decreased, wastewater surveillance has emerged as a key tool to support clinical surveillance efforts. The aims of this study were to identify and characterize SARS-CoV-2 variants in wastewater samples collected from urban centers across South Africa. Here we show that wastewater sequencing analyses are temporally concordant with clinical genomic surveillance and reveal the presence of multiple lineages not detected by clinical surveillance. We show that wastewater genomics can support SARS-CoV-2 epidemiological investigations by reliably recovering the prevalence of local circulating variants, even when clinical samples are not available. Further, we find that analysis of mutations observed in wastewater can provide a signal of upcoming lineage transitions. Our study demonstrates the utility of wastewater genomics to monitor evolution and spread of endemic viruses.

The role of wastewater-based epidemiology for SARS-CoV-2 in developing countries: Cumulative evidence from South Africa supports sentinel site surveillance to guide public health decision-making.

The uptake of wastewater-based epidemiology (WBE) for SARS-CoV-2 as a complementary tool for monitoring population-level epidemiological features of the COVID-19 pandemic in low-and-middle-income countries (LMICs) is low. We report on the findings from the South African SARS-CoV-2 WBE surveillance network and make recommendations regarding the implementation of WBE in LMICs. Eight laboratories quantified influent wastewater collected from 87 wastewater treatment plants in all nine South African provinces from 01 June 2021 to 31 May 2022 inclusive, during the 3rd and 4th waves of COVID-19. Correlation and regression analyses between wastewater levels of SARS-CoV-2 and district laboratory-confirmed caseloads were conducted. The sensitivity and specificity of novel 'rules' based on WBE data to predict an epidemic wave were determined. Amongst 2158 wastewater samples, 543/648 (85 %) samples taken during a wave tested positive for SARS-CoV-2 compared with 842 positive tests from 1512 (55 %) samples taken during the interwave period. Overall, the regression-co-efficient was 0,66 (95 % confidence interval = 0,6-0,72, R2 = 0.59), ranging from 0.14 to 0.87 by testing laboratory. Early warning of the 4th wave of SARS-CoV-2 in Gauteng Province in November-December 2021 was demonstrated. A 50 % increase in log copies of SARS-CoV-2 compared with a rolling mean over the previous five weeks was the most sensitive predictive rule (58 %) to predict a new wave. Our findings support investment in WBE for SARS-CoV-2 surveillance in LMICs as an early warning tool. Standardising test methodology is necessary due to varying correlation strengths across laboratories and redundancy across testing plants. A sentinel site model can be used for surveillance networks without affecting WBE finding for decision-making. Further research is needed to identify optimal test frequency and the need for normalisation to population size to identify predictive and interpretive rules to support early warning and public health action.

Measles incidence in South Africa: a six-year review, 2015-2020.

In 2012 the World Health Organization (WHO) aimed to eliminate measles in five regions by 2020. This retrospective descriptive study reviewed measles surveillance data in South Africa for the period 2015-2020 to document the epidemiology of measles and the progress made towards meeting the 2020 measles elimination goal.A total of 22,578 specimens were tested over the period 2015-2020 yielding 401 (1.8%) confirmed measles cases, 321 (1.4%) compatible and 21,856 (96.8%) discarded cases. The most affected age group was 0-4 year olds. At the provincial level, South Africa achieved adequate surveillance, defined as more than two cases of febrile rash notified annually per 100 000 popoulation, except for KwaZulu-Natal and Limpopo in 2020, probably due to COVID-19 lockdown restrictions. Of confirmed cases, only 26% were vaccinated, 3% were too young to receive vaccines, 5% were not vaccinated, and 65% had unknown vaccination status. Measles vaccine effectiveness amongst 1-4 year olds was 80%. Using the standard case definition, South Africa achieved the measles elimination target of less than one case per one million nationally in years 2015, 2016 and 2020. The years 2017 to 2019 had incidence rates exceeding one per million nationally. Using a narrow case definition, that excluded positive rubella cases, improved the indicators with only the year 2017 having an incidence rate of more than one per million.South Africa displays intermittent measles outbreaks approximately six-yearly interspersed by inter-epidemic periods in which the country meets measles elimination targets. Intense effort is needed to increase the vaccine coverage to avoid periodic outbreaks. Enhanced molecular testing of each case will be required as measles incidence declines regionally.

A citywide, clonal outbreak of Pseudomonas aeruginosa.

BACKGROUND: Outbreaks of community-acquired Pseudomonas aeruginosa are typically small and localized. We investigated an increase in community-acquired infections with P. aeruginosa in Cape Town, South Africa. METHODS: Cases were defined as P. aeruginosa isolated from any clinical sample, and "wild-type" as those susceptible to all antibiotics tested. The residential addresses of community-acquired wild-type cases were mapped. Whole-genome sequencing and multilocus sequence typing were used to determine clonality and identify virulence genes. A clinical study in a subset of patients with bloodstream infection compared demographic and clinical characteristics between sequence types (STs). RESULTS: The outbreak lasted 10 months from December 2016 to September 2017 with 3,321 documented cases. At the peak, cases reached 2.3-fold baseline rates. Cases were distributed widely across the city. Multilocus ST 303 was predominant during the outbreak. A total of 51 virulence genes were differentially present in ST303 compared with other STs, including genes involved in biofilm formation, iron uptake, and gut penetration. CONCLUSION: The investigation confirmed a citywide outbreak of P. aeruginosa. We identified a predominant outbreak-associated clone, ST303, which harbored genes that could contribute to virulence and survival in adverse environmental conditions such as those associated with drought.

Establishment of Outbreak Thresholds for Hepatitis A in South Africa Using Laboratory Surveillance, 2017-2020.

As South Africa transitions from endemic to intermediate endemicity, hepatitis A surveillance needs strengthening to monitor trends in disease incidence and to identify outbreaks. We used passive laboratory-based surveillance data from the National Health Laboratory Services to calculate national hepatitis A incidence and to establish thresholds for outbreaks. Incidence was calculated by age and geographic location. The static threshold used two or three standard deviations (SDs) above the mean hepatitis A incidence in 2017-2019, and a cumulative summation (CuSum2) threshold used three SDs above the mean of the preceding seven months. These thresholds were applied to hepatitis A data for 2020. From 2017 to 2020, the mean incidence of hepatitis A IgM was 4.06/100,000 and ranged from 4.23 to 4.85/100,000 per year. Hepatitis A incidence was highest in the Western Cape province (WCP) (7.00-10.92/100,000 per year). The highest incidence was in the 1-9-year-olds. The incidence of hepatitis A in 2020 exceeded the static threshold in two districts of the WCP: Cape Winelands in January and Overberg district in August. The provincial incidence did not exceed the static and CuSum2 thresholds. District-level analysis using either threshold was sensitive enough to monitor trends and to alert district health authorities, allowing early outbreak responses.

Congenital Syphilis Case Surveillance in South Africa 2017-19: Experience, Challenges and Opportunities.

BACKGROUND: Untreated or inadequately treated maternal syphilis infection may be transmitted from mother to child resulting in congenital syphilis (CS) infection. In South Africa (SA), CS is a notifiable medical condition (NMC). The NMC surveillance system (NMCSS) was improved by introducing an electronic notification application, a new case notification form and training resources in July 2017. We describe CS surveillance in SA and report on experiences from implementing an improved NMCSS from August 2017 to December 2019. METHODS: We present the CS case definition, data collected by the CS case investigation and notification forms and data flow through the NMCSS. Descriptive statistics were used to analyse CS notifications received from August 2017 to December 2019. Qualitative inductive analysis of the stakeholder communications diary was conducted to identify CS surveillance challenges. RESULTS: There were 418 CS notifications submitted from 80 facilities in 35 out of 52 districts. Of the notified cases, 194 (46.8%) were male and the median age at notification was 7 days (interquartile range: 3-16 days). The majority were diagnosed in hospital (98.6%). KwaZulu-Natal Province notified the most cases (52.9%) followed by Gauteng (28.0%). Challenges in CS surveillance included the lack of awareness of the CS case definition, completed paper-based notifications not reaching the NMCSS and the limited ability of the system to distinguish improved notifications from increase in disease burden. CONCLUSION: Improved CS surveillance through NMCSS was implemented in SA. Training, support and mentoring on CS and the notification system will be needed to inform elimination efforts.

The importation and establishment of community transmission of SARS-CoV-2 during the first eight weeks of the South African COVID-19 epidemic.

BACKGROUND: We describe the epidemiology of COVID-19 in South Africa following importation and during implementation of stringent lockdown measures. METHODS: Using national surveillance data including demographics, laboratory test data, clinical presentation, risk exposures (travel history, contacts and occupation) and outcomes of persons undergoing COVID-19 testing or hospitalised with COVID-19 at sentinel surveillance sites, we generated and interpreted descriptive statistics, epidemic curves, and initial reproductive numbers (Rt). FINDINGS: From 4 March to 30 April 2020, 271,670 SARS-CoV-2 PCR tests were performed (462 tests/100,000 persons). Of these, 7,892 (2.9%) persons tested positive (median age 37 years (interquartile range 28-49 years), 4,568 (58%) male, cumulative incidence of 13.4 cases/100,000 persons). Hospitalization records were found for 1,271 patients (692 females (54%)) of whom 186 (14.6%) died. Amongst 2,819 cases with data, 489/2819 (17.3%) travelled internationally within 14 days prior to diagnosis, mostly during March 2020 (466 (95%)). Cases diagnosed in April compared with March were younger (median age, 37 vs. 40 years), less likely female (38% vs. 53%) and resident in a more populous province (98% vs. 91%). The national initial Rt was 2.08 (95% confidence interval (CI): 1.71-2.51). INTERPRETATION: The first eight weeks following COVID-19 importation were characterised by early predominance of imported cases and relatively low mortality and transmission rates. Despite stringent lockdown measures, the second month following importation was characterised by community transmission and increasing disease burden in more populous provinces.

Molecular characterisation and epidemiology of enterovirus-associated aseptic meningitis in the Western and Eastern Cape Provinces, South Africa 2018-2019.

BACKGROUND: Enteroviruses are amongst the most common causes of aseptic meningitis. Between November 2018 and May 2019, an outbreak of enterovirus-associated aseptic meningitis cases was noted in the Western and Eastern Cape Provinces, South Africa. OBJECTIVES: To describe the epidemiology and phylogeography of enterovirus infections during an aseptic meningitis outbreak in the Western and Eastern Cape Provinces of South Africa. METHODS: Cerebrospinal fluid samples from suspected cases were screened using a polymerase chain reaction targeting the 5'UTR. Confirmed enterovirus-associated meningitis samples underwent molecular typing through species-specific VP1/VP2 primers and pan-species VP1 primers. RESULTS: Between November 2018 and May 2019, 3497 suspected cases of aseptic meningitis were documented in the Western and Eastern Cape Provinces. Median age was 8 years (range 0-61), interquartile range (IQR=4-13 years), 405/735 (55%) male. 742/3497 (21%) cases were laboratory - confirmed enterovirus positive by routine diagnostic PCR targeting the 5'UTR. 128/742 (17%) underwent molecular typing by VP1 gene sequencing. Echovirus 4 (E4) was detected in 102/128 (80%) cases. Echovirus 9 was found in 7%, Coxsackievirus A13 in 3%. 10 genotypes contributed to the remaining 10% of cases. Synonymous mutations were found in most cases, with sporadic amino acid changes in 13 (12.7%) cases. CONCLUSION: The aseptic meningitis outbreak was associated with echovirus 4. Stool samples are valuable for molecular typing in CSF confirmed EV-associated aseptic meningitis.

Strengthening health systems to improve the value of tuberculosis diagnostics in South Africa: A cost and cost-effectiveness analysis.

BACKGROUND: In South Africa, replacing smear microscopy with Xpert-MTB/RIF (Xpert) for tuberculosis diagnosis did not reduce mortality and was cost-neutral. The unchanged mortality has been attributed to suboptimal Xpert implementation. We developed a mathematical model to explore how complementary investments may improve cost-effectiveness of the tuberculosis diagnostic algorithm. METHODS: Complementary investments in the tuberculosis diagnostic pathway were compared to the status quo. Investment scenarios following an initial Xpert test included actions to reduce pre-treatment loss-to-follow-up; supporting same-day clinical diagnosis of tuberculosis after a negative result; and improving access to further tuberculosis diagnostic tests following a negative result. We estimated costs, deaths and disability-adjusted-life-years (DALYs) averted from provider and societal perspectives. Sensitivity analyses explored the mediating influence of behavioural, disease- and organisational characteristics on investment effectiveness. FINDINGS: Among a cohort of symptomatic patients tested for tuberculosis, with an estimated active tuberculosis prevalence of 13%, reducing pre-treatment loss-to-follow-up from ~20% to ~0% led to a 4% (uncertainty interval [UI] 3; 4%) reduction in mortality compared to the Xpert scenario. Improving access to further tuberculosis diagnostic tests from ~4% to 90% among those with an initial negative Xpert result reduced overall mortality by 28% (UI 27; 28) at $39.70/ DALY averted. Effectiveness of investment scenarios to improve access to further diagnostic tests was dependent on a high return rate for follow-up visits. INTERPRETATION: Investing in direct and indirect costs to support the TB diagnostic pathway is potentially highly cost-effective.

Fatal Rodentborne Leptospirosis in Prison Inmates, South Africa, 2015.

Leptospirosis is a neglected zoonotic disease. In 2015, leptospirosis was diagnosed in 2 prison inmates in South Africa. Using real-time PCR and DNA sequencing, we identified Leptospira interrogans serogroup Icterohaemorrhagiae in rodents and water samples within the prison. Leptospirosis might be frequently underdiagnosed in South Africa.

Outbreak of Listeriosis in South Africa Associated with Processed Meat.

BACKGROUND: An outbreak of listeriosis was identified in South Africa in 2017. The source was unknown. METHODS: We conducted epidemiologic, trace-back, and environmental investigations and used whole-genome sequencing to type Listeria monocytogenes isolates. A case was defined as laboratory-confirmed L. monocytogenes infection during the period from June 11, 2017, to April 7, 2018. RESULTS: A total of 937 cases were identified, of which 465 (50%) were associated with pregnancy; 406 of the pregnancy-associated cases (87%) occurred in neonates. Of the 937 cases, 229 (24%) occurred in patients 15 to 49 years of age (excluding those who were pregnant). Among the patients in whom human immunodeficiency virus (HIV) status was known, 38% of those with pregnancy-associated cases (77 of 204) and 46% of the remaining patients (97 of 211) were infected with HIV. Among 728 patients with a known outcome, 193 (27%) died. Clinical isolates from 609 patients were sequenced, and 567 (93%) were identified as sequence type 6 (ST6). In a case-control analysis, patients with ST6 infections were more likely to have eaten polony (a ready-to-eat processed meat) than those with non-ST6 infections (odds ratio, 8.55; 95% confidence interval, 1.66 to 43.35). Polony and environmental samples also yielded ST6 isolates, which, together with the isolates from the patients, belonged to the same core-genome multilocus sequence typing cluster with no more than 4 allelic differences; these findings showed that polony produced at a single facility was the outbreak source. A recall of ready-to-eat processed meat products from this facility was associated with a rapid decline in the incidence of L. monocytogenes ST6 infections. CONCLUSIONS: This investigation showed that in a middle-income country with a high prevalence of HIV infection, L. monocytogenes caused disproportionate illness among pregnant girls and women and HIV-infected persons. Whole-genome sequencing facilitated the detection of the outbreak and guided the trace-back investigations that led to the identification of the source.

Human surveillance and phylogeny of highly pathogenic avian influenza A(H5N8) during an outbreak in poultry in South Africa, 2017.

BACKGROUND: In June 2017, an outbreak of the highly pathogenic avian influenza A(H5N8) was detected in commercial poultry farms in South Africa, which rapidly spread to all nine South African provinces. OBJECTIVES: We conducted active surveillance for the transmission of influenza A(H5N8) to humans working with infected birds during the South African outbreak. METHODS: Influenza A(H5N8)-positive veterinary specimens were used to evaluate the ability of real-time PCR-based assays to detect contemporary avian influenza A(H5N8) strains. Whole genome sequences were generated from these specimens by next-generation sequencing for phylogenetic characterization and screening for mammalian-adaptive mutations. RESULTS: Human respiratory samples from 74 individuals meeting our case definition, all tested negative for avian influenza A(H5) by real-time PCR, but 2 (3%) were positive for human influenza A(H3N2). 54% (40/74) reported wearing personal protective equipment including overalls, boots, gloves, masks, and goggles. 94% (59/63) of veterinary specimens positive for H5N8 were detected on an influenza A(H5) assay for human diagnostics. A commercial H5N8 assay detected H5 in only 6% (3/48) and N8 in 92% (44/48). Thirteen (13/25; 52%) A(H5N8) genomes generated from veterinary specimens clustered in a single monophyletic clade. These sequences contained the NS (P42S) and PB2 (L89V) mutations noted as markers of mammalian adaptation. CONCLUSIONS: Diagnostic assays were able to detect and characterize influenza A(H5N8) viruses, but poor performance is reported for a commercial assay. Absence of influenza A(H5N8) in humans with occupational exposure and no clear impression of molecular adaptation for mammalian infection suggest that this avian pathogen continues to be low-risk human pathogen.

Epidemiological investigation of a typhoid fever outbreak in Sekhukhune District, Limpopo province, South Africa - 2017.

BACKGROUND: Typhoid fever remains a public health concern in South Africa, where the risk of transmission is high because of poor access to safe water and sanitation. This study describes the investigation of typhoid fever outbreak in Limpopo province. METHODOLOGY: Following notification of laboratory-confirmed cases, a descriptive study was conducted at Sekhukhune District, Limpopo province. A suspected case was defined as any person residing in Makhuduthamaga Municipality from November 2017 to January 2018, presenting with fever and gastrointestinal symptoms. Data were collected using case investigation forms. Whole-genome sequencing (WGS) was carried out on Salmonella Typhi isolates and polymerase chain reaction (PCR) test was done for Salmonella species from water samples. Location of cases and water sources were mapped using ArcGIS mapping tool. RESULTS: Amongst 122 cases, 54% (n = 66) were female and 6% (n = 7) laboratory-confirmed. The median age of the cases was 11 years (range 2-83 years), with 79% (n = 102) being children under the age of 14 years. Salmonella species were detected in 37% (10/27) of water samples and geographic information system (GIS) mapping showed clustering of cases in Tswaing-Kgwaripe and Vlakplaas villages. Six isolates were available for WGS analysis, with resulting data showing that five of the six isolates were genetically related. Phylogenetic analysis showed that the five isolates clustered together were genetically related showing < 22 single nucleotide polymorphisms when compared to each other. CONCLUSION: Molecular epidemiology of isolates suggests a common source outbreak, supported by the detection of Salmonella species from water sources. Consumption of water from contaminated open water sources, because of ongoing interruption of municipal water supply, was the likely cause of the outbreak. The investigation highlights the importance of consistent safe water supply and the ability of district surveillance systems to identify and contain outbreaks.

Accelerated Immunodeficiency-associated Vaccine-derived Poliovirus Serotype 3 Sequence Evolution Rate in an 11-week-old Boy With X-linked Agammaglobulinemia and Perinatal Human Immunodeficiency Virus Exposure.

Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus.

Atypical presentation of herpes simplex virus type 1 infection in paediatric burns patients in a large tertiary hospital, South Africa.

INTRODUCTION: Herpes simplex virus has been reported in the literature to commonly complicate burn wounds. However, there is paucity of such data in the South African setting. CASE PRESENTATION: Eight paediatric burns patients with ages ranging between 10 months and 5 years presented with a febrile maculopapular rash illness in a paediatric ward of a large South African tertiary hospital. The rash became vesicular in three cases, involving the limbs and face. Varicella was suspected. MANAGEMENT AND OUTCOME: Medical records of suspected cases were reviewed. Blood, vesicular fluid and scab samples were collected. Electron microscopy of vesicular fluid revealed herpes virus particles. Laboratory testing confirmed herpes simplex virus type 1. CONCLUSION: Herpes simplex virus type 1 infection can present atypically in burns patients.

Outbreak of influenza A in a boarding school in South Africa, 2016.

INTRODUCTION: We investigated an outbreak of influenza-like illness (ILI) at a boarding school in Eastern Cape Province, South Africa. We aimed to confirm the etiological agent, estimate attack rates and identify risk factors for illness. METHODS: We conducted a retrospective cohort study including senior school boarders (n=308). Students with ILI (cough and fever) were identified through school medical records. We also conducted a questionnaire-based cross-sectional study among senior students including boarders (n=107) and day students (n=45). We collected respiratory specimens for respiratory pathogen testing by real-time polymerase chain reaction from a subset of symptomatic students. We calculated attack rates of medically attended ILI (medILI) and identified factors associated with medILI using logistic regression. We calculated seasonal influenza vaccine effectiveness (VE) against medILI. RESULTS: Influenza A (H3N2) virus was detected in 61% (23/38) of specimens. Attack rate for medILI was 13% among boarders (39/308) in the cohort study and 20% in both day students (9/45) and boarders (21/107) in the cross-sectional study. Playing squash was associated with medILI (aOR 5.35, 95% confidence interval [95% CI]: 1.68-17.07). Of the boarders, 19% (57/308) were vaccinated before the outbreak. The adjusted VE against medILI was 18% (aOR 0.82, 95% CI 0.38-1.78). The outbreak led to cancellation of several events and the need for academic remedial sessions. CONCLUSION: We confirmed an influenza A (H3N2) virus outbreak with a high attack rate. The outbreak affected academic and sports activities. Participation in sports and social gatherings while experiencing ILI should be discouraged to reduce viral transmission and impact on school activities.

Hepatitis A virus seroprevalence in South Africa - Estimates using routine laboratory data, 2005-2015.

INTRODUCTION: South Africa is considered highly endemic for hepatitis A virus (HAV) although few seroprevalence studies have been conducted over the past two decades. The World Health Organization recommends integrating HAV vaccination into national childhood immunization schedules where there is transition from high to intermediate endemicity. As a means of gauging age-specific rates of infection, we report HAV seroprevalence rates among specimens tested for HAV serology within South Africa's public health sector from 2005-2015. MATERIALS AND METHODS: Hepatitis A serology results (Anti-HAV IgM, IgG and total antibody) from 2005-2015 were extracted from South Africa's National Health Laboratory Service's Corporate Data Warehouse (NHLS CDW), the central data repository of all laboratory test-sets within the public health sector. Results were extracted according to test-set, result, date of testing, health facility, name, surname, age, and sex. Anti-HAV IgG results were merged with total antibody results to reflect anti-HAV seroprevalence. Testing volume, positivity rates and age-specific anti-HAV seroprevalence rates by year and geographic distribution are described. RESULTS AND DISCUSSION: A total of 501 083 HAV IgM results were retrieved, of which 16 423 (3.3%) were positive, 484 259 (96.6%) negative and 401 (0.1%) equivocal; and 34 710 HAV total antibody/IgG tests of which 30 675 (88.4%) were positive, 4 020 (11.6%) negative and 15 equivocal. Whereas IgM positivity was highest among the 1-4 year age group (33.5%) and lowest among patients >45 years (<0.5%), total antibody positivity ranged from its lowest level of 52.7% in the 1-4 year age group increasing to levels of >90% only after 25 years of age. CONCLUSION: Anti-HAV total antibody testing within the South African public health sector demonstrates seroprevalence rates reach levels >90% only in adulthood, suggesting South Africa could be in transition from high to intermediate endemicity. Prospective studies with geographically representative sampling are required to confirm these findings and evaluate provincial and urban/rural heterogeneity.

Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.

BACKGROUND: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. METHODS: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. FINDINGS: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2<20% for the primary outcome). INTERPRETATION: Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. FUNDING: US National Institutes of Health.