Ebrahim Variava

The use of decentralized GeneXpert by trained non-laboratory technicians in rural clinics in South Africa

The GeneXpert automated molecular assay, that can diagnose TB in 2 h, was endorsed by the World Health Organization both for identifying TB and rifampicin resistance [5]. South Africa was one of the first few countries to implement GeneXpert [5] however GeneXpert units were located mostly within the National Health Laboratory Services (NHLS) and not at point of care [4]. Placing it at the point of care is possible, as it requires uncomplicated processing that can be done by persons with basic computer skills [5]. There is limited data on the use of this test in rural settings, as well as its use by non-laboratory technicians. This correspondence reports on the outcomes of the use of GeneXpert by lay counselors in Dr Kenneth Kaunda sub-district in the Matlosana Municipality, NorthWest Province, South Africa. The study received local ethics approvals from the University of Witwatersrand, regional hospitals and Provincial research committees. The Dr Kenneth Kaunda sub-district has one hospital and 16 clinics andan estimated TB incidence of 750/100,000 in 2011 [2]. Rooms at four primary care clinics were renovated to accommodate the four-cartridge GeneXpert machines. Prior to this project all TB samples were sent to the central laboratory for testing. Six lay counselors with basic computer skills received two weeks training on basic infection control measures, sample preparation and processing on an open bench. A trained technician from NHLS conducted a monthly external quality assurance at each clinic. Samples for testing were received from: contacts of TB patients and TB suspects presenting at the clinic. Procurement and renovation challenges resulted in two clinics starting four months later. GeneXpert testing was operational for tenmonths, and a total of 2196 specimens were tested, from 2181 participants (15 tests had to be repeated). The average number of specimens tested per day increased from 2 to 3 in the first month to a maximum of about 7 specimens by month three (Figure 1). Of 2181 sputum specimens that completed the testing, 538 were of contacts from 203 households, and 1643 from TB suspects. 9% (197/2181) of cases had MTB on GeneXpert testing, 1.5% (8/538) among household contacts and 11.5% (189/1643) in TB suspects. In the newly diagnosed TB cases, 7% (13/197) had rifampicin resistance. The overall error rate was 2.6% (57/2196). The error rate in the first month was 10.2% and this improved to 7.9% by month 2, and 3.9% by month 3. The lowest error rate achieved was 1.3%. Error rates reports were available on 44 specimens as follows: 21 signal loss in amplification; 10 syringe pressure reading high; 9 probe check failure, 3 cartridge integrity test failure and 1 temperature not within acceptable limit. Interventions to reduce error rates included additional training and quality assurance by the NHLS and operators with minimal error rates were paired to work with those with high error rates. All the GeneXpert Machines were fully functional throughout the study and did not need any repairs. This data review shows that GeneXpert can be operated outside of laboratories by non-technicians with minimal error rates. However, the costs of testing could increase if each clinic was to be equipped with GeneXpert and technicians [4]. Yet placing the assays in central laboratories increases the turnaround time for releasing the results to the patients especially if the laboratory is far. The use of non-laboratory technicians minimizes costs of

Healthcare utilization for common infectious disease syndromes in Soweto and Klerksdorp, South Africa

Introduction Understanding healthcare utilization helps characterize access to healthcare, identify barriers and improve surveillance data interpretation. We describe healthcare-seeking behaviors for common infectious syndromes and identify reasons for seeking care. Methods We conducted a cross-sectional survey among residents in Soweto and Klerksdorp, South Africa. Households were interviewed about demographic characteristics; recent self-reported episodes of pneumonia, influenza-like illness (ILI), chronic febrile respiratory illness and meningitis in individuals of all ages; recent diarrhea in children aged < 5 years; and consultation with healthcare facilities and providers. Results From July-October 2012, we interviewed 1,442 households in Klerksdorp and 973 households in Soweto. Public clinics were consulted most frequently for pneumonia, ILI and diarrhea in a child <5 years old at both sites; public hospitals were most frequently consulted for chronic respiratory and meningitis syndromes. Of all illness episodes reported, there were 110 (35%) in Klerksdorp and 127 (32%) in Soweto for which the person did not seek care with a licensed medical provider. Pharmacies were often consulted by individuals with pneumonia (Klerksdorp: 17, 16%; Soweto: 38, 22%) or ILI (Klerksdorp: 35, 24%; 44, 28%). Patients who did not seek care with a licensed provider reported insufficient time (Klerksdorp: 7%; Soweto, 20%) and lack of medications at the facility (Klerksdorp: 4%; Soweto: 8%) as barriers. Conclusion Public government healthcare facilities are commonly consulted for infectious syndromes and pharmacies are frequently consulted particularly for respiratory diseases. Improving medication availability at healthcare facilities and streamlining healthcare delivery may improve access of licensed providers for serious illnesses.

Intra-host and intra-household diversity of influenza A viruses during household transmissions in the 2013 season in 2 peri-urban communities of South Africa

Limited information is available on influenza virus sequence drift between transmission events. In countries with high HIV burdens, like South Africa, the direct and indirect effect of HIV on influenza sequence drift between transmission events may be of public health concern. To this end, we measured hemagglutinin sequence diversity between influenza transmission events using data and specimens from a study investigating household transmission dynamics of seasonal influenza viruses in 2 peri-urban communities in South Africa during the 2013 influenza season. Thirty index cases and 107 of 110 eligible household contacts were enrolled into the study, 47% (14/30) demonstrating intra-household laboratory-confirmed influenza transmission. In this study 35 partial hemagglutinin gene sequences were obtained by Sanger sequencing from 11 index cases (sampled at enrolment only) and 16 secondary cases (8 cases sampled at 1 and 8 cases sampled at 2 time-points). Viral sequence identities confirmed matched influenza transmission pairs within the 11 households with corresponding sequenced index and secondary cases. Phylogenetic analysis revealed 10 different influenza viral lineages in the 14 households. Influenza A(H1N1)pdm09 strains were shown to be genetically distinct between the 2 communities (from distinct geographic regions), which was not observed for the influenza A(H3N2) strains. Intra-host/intra-household influenza A(H3N2) sequence drift was identified in 2 households. The first was a synonymous mutation between the index case and a household contact, and the second a non-synonymous mutation between 2 serial samples taken at days 0 and 4 post enrolment from an HIV-infected secondary case. Limited inter-household sequence diversity was observed as highlighted by sharing of the same influenza strain between different households within each community. The limited intra-household sequence drift is in line with previous studies also using Sanger sequencing, corroborating the presence of strict selective bottlenecks that limit sequence variance. We were not able to directly ascertain the effect of HIV on influenza sequence drift between transmission events.

Drug-resistant tuberculosis: the rise of the monos

The diagnostic and therapeutic landscape of tuberculosis has never been more dynamic: efficacious 1-month-preventive treatment regimens; rapid and improving tuberculosis assays; WHO guidelines that include shorter-course regimens for multidrug-resistant (MDR) and isoniazid monoresistant strains; policy on use of novel-class drugs such as diarylquinalone (bedaquiline) and the nitroimidazoles (delaminid and pretominid); and repurposing existing drugs such as linezolid, clofazamine, and imipenem. The timely report by Nazir Ahmed Ismail and colleagues in the Lancet Infectious Diseases contributes to this landscape by describing the prevalence of combinations of drug resistance in Mycobacterium tuberculosis detected in adults attending South African health facilities with at least one symptom suggestive of tuberculosis, in a survey done between 2012–14. The report provides the most comprehensive and recent estimates of drug resistance in South Africa and compares with those from a previous survey from 2001–02 that used similar methods, and will assist policy, clinical, and pharmacological practice for management of tuberculosis. South Africa’s extreme burden of the HIV–tuberculosis syndemic has increased the prevalence of drug-resistant tuberculosis. Indeed, at our MDR clinic and hospital in Matlosana (North West Province, South Africa), more than 60% of patients with any rifampin resistance are co-infected with HIV. However, the report by Ahmed Ismail and colleagues did not include either basic or comprehensive HIV data; stratification by HIV status was reported only for adults with any rifampicin resistance and for those with MDR tuberculosis. Most cases of rifampicin monoresistant (RMR) tuberculosis were detected in HIV-infected individuals who had primary RMR tuberculosis, making it unlikely that this strain was selected because of interactions between rifampicin and efavirenz. Other studies have shown similar interactions between RMR-tuberculosis and HIV infection, and among individuals with HIV infection, lower CD4 cell counts seemed to be a risk factor for RMR tuberculosis. An important finding of Ahmed Ismail and colleagues’ study debunks the dogma that rifampicin monoresistance equates to multidrug resistance. Indeed, rifampicin monoresistance accounted for almost half the total rifampicin resistance detected in some provinces of South Africa, and worryingly, rifampicin resistance had almost doubled compared with findings from the previous survey. Because current treatment guidelines do not discriminate between MDR-tuberculosis and RMR-tuberculosis, we might be overtreating RMR-tuberculosis. Regimens of shorter duration that contain fewer drugs, are antiretroviral friendly, and avoid injectable agents would be appropriate, especially if RMR-tuberculosis is less virulent, or has a better prognosis than MDRtuberculosis. Ahmed Ismail and colleagues reported that the prevalence of isoniazid-monoresistant tuberculosis more than doubled from 2·7% (95% CI 2·2–3·2) in a survey in 2001–02 to 4·9% (4·1–5·8) in 2012–14. Isoniazid preventative treatment might be a potential risk factor for isoniazid-monoresistant tuberculosis, despite findings from clinical trials of preventive treatment not supporting this concept. However in Ahmed Ismail and colleagues’ study, isoniazidmonoresistant tuberculosis was not typed and the frequencies of katG and inhA genes, either alone or in combination, were not reported. Knowing data for these genes would assist with treatment decisions regarding giving either high-dose isoniazid or adding ethionamide to the MDR treatment regimen. Similarly quinolone resistance was not reported for patients with isoniazid monoresistance in this study—the prevalence of quinolone resistance in individuals with isoniazid-monoresistant tuberculosis would assist when considering the new WHO treatment guideline for isoniazid-monoresistant tuberculosis in which levofloxacin is recommended for 6 months. Sputum cultures were phenotypically tested, which despite being cumbersome had strengths, because resistance that is not genotypically detected might be diagnosed with Löwenstein-Jensen media rather than automated culture with sensitivity. The Xpert MTB/RIF (Cepheid, Sunnyvale California) and line probe MTBDR plus (Hain Lifescience, Nehren, Germany) do not detect the rifampin-resistance mutation Ile 491 Phe rpo B. This is of concern because a survey of MDR-tuberculosis in Swaziland, which borders three provinces of ist oc k/ sh au n

Performance of Surveillance Case Definitions in Detecting Respiratory Syncytial Virus Infection Among Young Children Hospitalized With Severe Respiratory Illness—South Africa, 2009–2014

BackgroundnRespiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection (ALRTI) in young children, but data on surveillance case definition performance in estimating burdens have been limited.nnnMethodsnWe enrolled children aged <5 years hospitalized for ALRTI (or neonatal sepsis in young infants) through active prospective surveillance at 5 sentinel hospitals in South Africa and collected nasopharyngeal aspirates from them for RSV molecular diagnostic testing between 2009 and 2014. Clinical data were used to characterize RSV disease and retrospectively evaluate the performance of respiratory illness case definitions (including the World Health Organization definition for severe acute respiratory infection [SARI]) in identifying hospitalized children with laboratory-confirmed RSV according to age group (<3, 3-5, 6-11, 12-23, and 24-59 months).nnnResultsnOf 9969 hospitalized children, 2723 (27%) tested positive for RSV. Signs and symptoms in RSV-positive children varied according to age; fever was less likely to occur in children aged <3 months (57%; odds ratio [OR], 0.8 [95% CI, 0.7-0.9]) but more likely in those aged ≥12 months (82%; OR, 1.7-1.9) than RSV-negative children. The sensitivity (range, 55%-81%) and specificity (range, 27%-54%) of the SARI case definition to identify hospitalized RSV-positive children varied according to age; the lowest sensitivity was for infants aged <6 months. Using SARI as the case definition would have missed 36% of RSV-positive children aged <5 years and 49% of those aged <3 months; removing the fever requirement from the definition recovered most missed cases.nnnConclusionnIncluding fever in the SARI case definition lowers the sensitivity for RSV case detection among young children hospitalized with an ALRTI and likely underestimates its burden.

Human bocavirus, coronavirus, and polyomavirus detected among patients hospitalised with severe acute respiratory illness in South Africa, 2012 to 2013

To investigate the prevalence of human bocavirus (hBoV), human coronaviruses (hCoV), and human polyomaviruses (hPyV) among patients with severe acute respiratory illness (SARI), in South Africa.

High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen

South African patients with rifampicin-resistant tuberculosis (TB) and resistance to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and preXDR-TB) were granted access to bedaquiline through a clinical access programme with strict inclusion and exclusion criteria. PreXDR-TB and XDR-TB patients were treated with 24u2005weeks of bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female and the median age was 34u2005years (interquartile range (IQR) 27–42). 134 (67.0%) were living with HIV; the median CD4+ count was 281 cells·μL−1 (IQR 130–467) and all were on antiretroviral therapy. 16 out of 200 patients (8.0%) did not complete 6u2005months of bedaquiline: eight were lost to follow-up, six died, one stopped owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of 200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven (3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from treatment and nine (4.5%) had treatment failure. 22 adverse events were attributed to bedaquiline, including a QT interval corrected using the Fridericia formula (QTcF) >500u2005ms (n=5), QTcF increase >50u2005ms from baseline (n=11) and paroxysmal atrial flutter (n=1). Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this preXDR-TB and XDR-TB cohort. The use of bedaquiline with at least three other active drugs is associated with a high treatment success rate among preXDR-TB and XDR-TB patients in South Africa, a region of high HIV prevalence http://ow.ly/Zo7h30mii2S

Epidemiology and Molecular Identification and Characterization of Mycoplasma pneumoniae, South Africa, 2012–2015

During 2012–2015, we tested respiratory specimens from patients with severe respiratory illness (SRI), patients with influenza-like illness (ILI), and controls in South Africa by real-time PCR for Mycoplasma pneumoniae, followed by culture and molecular characterization of positive samples. M. pneumoniae prevalence was 1.6% among SRI patients, 0.7% among ILI patients, and 0.2% among controls (p<0.001). Age <5 years (adjusted odd ratio 7.1; 95% CI 1.7–28.7) and HIV infection (adjusted odds ratio 23.8; 95% CI 4.1–138.2) among M. pneumonia–positive persons were associated with severe disease. The detection rate attributable to illness was 93.9% (95% CI 74.4%–98.5%) in SRI patients and 80.7% (95% CI 16.7%–95.6%) in ILI patients. The hospitalization rate was 28 cases/100,000 population. We observed the macrolide-susceptible M. pneumoniae genotype in all cases and found P1 types 1, 2, and a type 2 variant with multilocus variable number tandem repeat types 3/6/6/2, 3/5/6/2, and 4/5/7/2.

Relevance and acceptability of using the Quantiferon gold test (QGIT) to screen CD4 blood draws for latent TB infection among PLHIV in South Africa: formative qualitative research findings from the TEKO trial

BackgroundTuberculosis (TB) is the leading cause of mortality among people living with HIV (PLHIV), despite the availability of effective preventive therapy. The TEKO trial is assessing the impact of using a blood test, Quantiferon-TB Gold In-Tube Test (QGIT), to screen for latent TB compared to the Tuberculin Screening Test (TST) among PLHIV in South Africa.MethodsFifty-six qualitative interviews were conducted with PLHIV and clinical providers participating in the TEKO trial. We explored TB screening, diagnosis, and treatment guidelines and processes and the use of the QGIT to screen for latent TB infection at the time of CD4 blood draw. Thematic content analysis was conducted.ResultsConsiderable variability in TB screening procedures was documented due to lack of personnel and clarity regarding current national TB guidelines for PLHIV. Few clinics had started using the TST per national guidelines and many patients had never heard of isoniazid preventive therapy (IPT). Nearly all participants supported the idea of latent TB screening using routine blood drawn for CD4 counts.ConclusionsFindings indicate that screening for latent TB infection using QGIT from blood drawn for CD4 counts among PLHIV is an acceptable approach to increase latent TB detection given the challenges associated with ensuring systematic latent TB screening in overburdened public clinics.Trial registrationThe results presented here were from formative research related to the TEKO trial (Identifier NCT02119130, registered 10 April 2014).

The Burden and Clinical Presentation of Pulmonary Tuberculosis in Adults With Severe Respiratory Illness in a High Human Immunodeficiency Virus Prevalence Setting, 2012–2014

Abstract Background Understanding the burden and clinical presentation of tuberculosis in patients with severe respiratory illness (SRI) has important implications for anticipating treatment requirements. Methods Hospitalized patients aged ≥15 years with SRI at 2 public teaching hospitals in periurban areas in 2 provinces (Edendale Hospital in Pietermaritzburg, KwaZulu-Natal Province and Tshepong Hospital in Klerksdorp, North West Province) were enrolled prospectively from 2012 to 2014. Tuberculosis testing included smear microscopy, culture, or Xpert MTB/Rif. Results We enrolled 2486 individuals with SRI. Of these, 2097 (84%) were tested for tuberculosis, 593 (28%) were positive. Tuberculosis detection rate was 18% (133 of 729) in individuals with acute (≤14 days) presentation and 34% (460 of 1368) in those with chronic (>14 days) presentation. Among laboratory-confirmed tuberculosis cases, those with acute presentation were less likely to present with cough (88% [117 of 133] vs 97% [447 of 460]; ajusted odds ratio [aOR] = 0.2, 95% confidence interval [CI] = 0.1–0.5), night sweats (57% [75 of 132] vs 73% [337 of 459]; aOR = 0.4, 95% CI = 0.3–0.7), or be started on tuberculosis treatment on admission (63% [78 of 124] vs 81% [344 of 423]; aOR = 0.4, 95% CI = 0.3–0.7), but they were more likely to be coinfected with pneumococcus (13% [16 of 124] vs 6% [26 of 411]; aOR 2.3, 95% CI 1.3–5.3) than patients with chronic presentation. Annual incidence of acute and chronic tuberculosis-associated SRI per 100000 population was 28 (95% CI = 22–39) and 116 (95% CI = 104–128), respectively. Conclusions In this setting, tuberculosis, including acute presentation, is common in patients hospitalized with SRI.