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Syphilis

Sexually transmitted infections are amongst the fastest spreading high-incidence notifiable diseases in China

31 May, 17 | by Leslie Goode, Blogmaster

Sexually transmitted infections emerge from a recent epidemiological study as a particularly pressing concern for Chinese public health at the present time.  Yang & Li (Y&L) assess trends in incidence and mortality in 45 notifiable infectious diseases across China over the decade since the SARS tragedy in 2003 brought important changes in Chinese public health strategies (2003-2013). The main interest of the authors is to investigate the effectiveness of the new strategies.  But, for readers of this journal, what will be especially interesting about this study is the unique profile of three sexually transmitted – or potentially sexually transmitted – diseases: syphilis, HCV and HIV.

In terms of current incidence these three occupy 6th, 8th, and 15th place among the 45, with yearly incidence per 100,000 of, respectively, 20.75, 9.33, and 3.11.  In respect to mortality, HIV far outstrips all the others (even TB), with 48,199 deaths over the ten year period.  However, syphilis, HCV and HIV differ from other high-incidence diseases – hepatitis B, TB, mumps and bacterial dysentery (respectively, 2nd to 5th in the incidence table) – in that their year-on-year incidence is increasing, and at an impressive rate (estimated at a yearly 16.3%, 19.2% and 16.3% averaged over the decade).  These increases are unparalled except in the case of hand, foot and mouth.  The trend in STI incidence emerges particularly strongly against the background of overall trends in the other notifiable diseases. These have, on the whole, been towards stabilization in the latter half of the decade (2009-2013), following an earlier rise likely due in part to technological progress in laboratory detection and case identification (2003-2009).

This raises the questions whether, in the case of STIs, there are particular social factors at work.

For the authors of the study, syphilis, HCV and HIV fall into the category of those diseases whose recent spread can be attributed to the enormous demographic upheavals that have brought over 10% of the population from poor rural areas to the big urban centres in search of economic opportunities, and to ‘augmented human connectivity’.  As regards population mobility, the opinion of Y&L is corroborated by Chen & Tucker (STIs), and – in the case of MSM populations – by Yu & Shang (STIs).  Interestingly, Y&S identify a class of ‘recent migrants’ to the big cities, whose risk profile appears to differ very considerably from that of longer-term residents. Young FSM – many of them also recent migrants to urban centres – appear to represent another high-risk group (Zhang & Luchters (STIs)).  As for the related factor of ‘augmented human connectivity’, this has also been strongly corroborated (Tang & Tucker (STIs)).  Other studies, however, have traced regional outbreaks in these infections – syphilis, HCV and HIV – to causes that are less obviously linked to recent demographic change.  Zhang & Tang (STIs), for example, emphasize the part played in Guangxi by female sex workers who are patronized by older rural workers.  Epidemiological factors, especially over such a vast area, will obviously be complex and multifactorial.

 

Global patterns in ante-natal syphilis prevalence: Why is sub-Saharan Africa different?

18 Jul, 16 | by Leslie Goode, Blogmaster

‘Can a meaningful pattern be discerned in the large variations in syphilis rates over the last century?’ This is the question addressed by a recent systematic review – Kenyon & Tsoumanis (K&T) – based on published data on ante-natal syphilis prevalence (ASP) from those countries for which that data is available since at least 1951.   This cutoff reduces the number of countries that qualify for inclusion, but allows more recent trends in the late twentieth, and early twenty-first, centuries, to be set against the background of the impact of the introduction of penicillin in the 1950s. A pattern emerges from the data, which K&T then to seek to explain by investigating its association with various potential variables through multivariate analysis: per capita GDP; circumcision practice; health expenditure; efficacy of diagnosis/treatment; geographical region.

The pattern itself is: in most parts of the world, a more or less steep decline following the introduction of penicillin – ultimately, by the 1990s, to below 1%, and by the 2000s, to below (massively below, in many cases) 0.5%; in sub-Saharan Africa alone, a decline plateauing out at around 6% up until the end of the twentieth century, when there is a further decline to just above 1.5%.  A limitation of the study is its concentration on eleven countries for which ASP data is available from before the days of penicillin, with only two of those countries being in sub-Saharan Africa (South Africa and Zimbabwe).  So far as concerns more recent evidence for ASP prevalence, the kind of rates that the authors give for SA and Zimbabwe seem, broadly, to be replicated in other countries of sub-Saharan Africa (Otieno-Nyunya & Kaiser/STIs (Kenya); Makasa & Sandoy/STIs (Zambia); Kirakoya-Samadoulougou & Nagot/STIs (Burkina-Faso);  Ardu-Sarkodie & Peeling/STIs (Ghana), and their rates for the other regions to be replicated in other non-sub-Saharan African settings (Cheng & Cai/STIs (China); Galdava & Domeika/STIs (Georgia) Thirumoorthy & Lim/STIs (Singapore)).

As for the explanation of this pattern, the authors find no association on multivariate analysis with any of their potential variables, save with residence in sub-Saharan Africa.  This is itself an interesting negative finding, and prompts the authors to consider other population-level correlations also included in the evidence reviewed – notably, with prevalence of HIV and HSV-2; ‘the populations that in the 1990s had high prevalences of syphilis and HSV-2 went on to have high HIV prevalences’.  The correlation with prevalence of HSV-2 is of particular interest because it is unlikely that the prevalence of the one infection could have influenced that of the other (see also: Hochberg & Dandona/STIs).  To K&T, it suggests the likely importance of ‘more connected sexual networks’ and ‘greater partner concurrency’ in explaining traditionally – and currently – high relative ASP levels in sub-Saharan Africa.  However, they refer to studies that contest this hypothesis, and emphasize the need for further research to elucidate the factors underpinning difference in syphilis rates – especially given the possibility that the successful use of ART in those countries may be accompanied by the re-establishment of former sexual networks.

What can cost-effectiveness modelling tell us about the feasibility of eliminating congenital syphilis in sub-Saharan Africa?

20 Nov, 13 | by Leslie Goode, Blogmaster

The WHO global initiative for the elimination of congenital syphilis (2007) set the goal of expanding antenatal testing to >90% by 2015.  In sub-Saharan Africa (SSA) recent estimates place the number of mothers infected with active syphilis at 535,000 p.a..  Adverse outcomes – stillbirths, neo-natal morbidity and congenital disease – affect 53%-82% of these pregnancies, as compared with 10%-21% of women without syphilis.  Yet, perhaps surprisingly,  74% of pregnant women in SSA are reported to attend an antenatal clinic at least once.  Administration at the routine visit of a simple point-of-care test (POCT), plus, in the case of detection, an intra-muscular injection of benthazine penicillin, is all that, in most cases, would be required to deal with the problem.

A recent modelling study (Kuznik & Manabe ) seeks to make the economic case for universal POCT syphilis screening in 43 countries in SSA.  It estimates the cost of increasing syphilis testing at antenatal clinics from whatever it is at present to 100% through universal adoption of the immunochromatographic strip test (ICT), and the benefits that would result in terms of saved lives and reduced morbidity.  It then calculates the cost-benefit in US dollars per Disability Adjusted Life Year (DALY).

The findings are given for each of the 43 countries considered. Here are the aggregate findings for SSA as a whole.  In order to ensure screening coverage for the 23.5 million (74%) pregnant mothers attending ante-natal clinics, the cost is estimated at a comparatively modest US$20.8 million per year, and would, it is claimed, reduce incidence of still-birth, neo-natal death and congenital syphilis by 64,000, 25,000 and 32,000, respectively.  Of the 43 countries in the model the cost of such an intervention per DALY averted would be less than US$20 in 37 cases, and less than US$10 in 23 cases.

The study claims to be the first to have evaluated the cost-effectiveness of ICT across SSA.  What is the value of this exercise?  It seems to consist primarily in the extra rhetorical “punch” it can lend to the argument in favour of doing something – and something very cheap – in order to alleviate the deplorable ravages of perinatal mortality and morbidity due to syphilis.  One can only applaud the intentions of its authors.  At the same time, one is struck by the inadequacy of the measure employed (cost per DALY ) to capture any real sense of the economic (let alone human) cost of MCST.  The impressive figures they arrive at for cost-effectiveness of the proposed interventions owes not a little to the fact that the lost life-years averted happen to be those of the stillborn or neonatal deceased.  This does not belittle the cost, but feels a rather odd way of looking at perinatal outcomes.  Consequently the whole exercise, while it may be well-intentioned and ticks all the official boxes, strikes this reader at least as rather specious.  One wonders if it can offer any real ground for the prioritization of MCST as against other equally laudable interventions: if it does, one feels somehow that it ought not to!

Relevant to the real economic cost confronting any country deciding to switch to the ICT would presumably be the relative cost of the ICT compared to an established alternative (e.g. Rapid Plasma Reagin (RPR)).  After all, using ICT to make up the shortfall in current testing levels presupposes the country has made the switch from RPR to ICT – which may already have cost implications (Vickerman and Watts).  Ultimately, however, the main the challenge of making this switch, may not be economic cost at all, but a problem of institutional organization and training (STI blog/Peeling & Mabey).   Peeling & Mabey observe in relation to one area in which POCT for syphilis was being introduced as part of a trial “a 65% drop over the first six months in the percentage of antenatal clinics passing the quality assurance controls due to high staff turn-over: but, subsequently, with the HWC training mechanism kicking in, there was a return to 100% levels of proficiency”.  Here and elsewhere (Peeling & Mabey) make the case for the importance of “programme science” to “address the gap” between test performance and successful deployment.

Are point-of-care tests the answer to meeting WHO target for congenital syphilis?

3 Apr, 13 | by Leslie Goode, Blogmaster

Congenital syphilis (syphilis transmitted from mother to child (MTCT)) remains a scourge in many low- and middle- income countries (LMIC) causing stillbirth and neonatal death.  This is despite the existence of inexpensive, cost-effective and feasible testing and treatment – and despite the fact that a majority of pregnant women, even in LMIC, attend antenatal clinics (ANC), where such testing and treatment could, in principal, be offered.  A recent multi-country study, for example, found levels of testing of 1.7% and 17.8% respectively in rural ANCs in Uganda, and 51 health facilities in Tanzania (http://blogs.bmj.com/sti/2012/06/25/sustained-health-systems-strengthening-holds-the-key-to-prevention-of-mother-to-child-transmission-of-syphilis/).  The year 2007 saw the launch of a WHO initiative for the Global Elimination of Congenital Syphilis, with the goal that by 2015 ≥90% of pregnant of women should be tested.

One complicating factor of any public health policy where syphilis is concerned is the difficulty of establishing definitive diagnosis.  This complicates the task of quantifying MTCT and assessing progress in eliminating it. It also makes it difficult to evaluate screening tools, such as the relatively recent point-of-care tests (POCT) that promise to extend effective diagnosis to countries without a robust laboratory infrastructure.   In both cases – the assessment of the scale of MTCT, and evaluating screening tools – researchers have had to find a way round the absence of a good reference standard.  Two recently-published papers have addressed themselves to these problems.  One is an analysis of global surveillance data (Newman & Broutet) using modelling to estimate total global adverse outcomes from syphilis, and the impact on these outcomes, of testing in ANCs for the year following launch of the WHO initiative (2008) (http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001396).  The other (Jafari and Pai) addresses itself to evaluating the diagnostic accuracy of POCT, employing the technique of Bayesian analysis to get round the problem of an inadequate reference standard for syphilis (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054695).

Newman & Broutet estimate global adverse events for 2008 at 521,000, including 212,000 stillbirths and 92.000 neonatal deaths.  This provides a baseline for evaluating subsequent progress.  Of the adverse events, 66% are estimated to involve women who attended ANCs – which indicates the potential improvements that might be achievable through ANCs.  As things were in 2008, testing and treatment by ANCs was reckoned to have averted a quarter of the adverse events that might otherwise have been expected;  the model predicts that achievement in 2008 of the 2015 WHO target for testing in ANCs would have eliminated over half of these events.

So much then for the potential for improvement.  Such future developments will be dependent on the success of POCTs, which promise both an inexpensive form of screening without the need for laboratory infrastructure, and the possibility of same day treatment for ANC attendees.  There remains the question of their effectiveness compared with traditional methods of diagnosis.  Here again the difficulty of establishing definitive diagnosis has been a problem.  The absence of a reference standard has, according to Jafari & Pai, impeded the comparative evaluation of POCTs.  A recent meta-analysis of electronic databases using a Bayesian hierarchical latent class model has attempted to put a figure on sensitivity and specificity of four globally used POCTs with both serum and whole blood samples. These estimates are comparable of those for lab-based testing: with serum (sensitivity/specificity) Determine 90.04/94.15; SD Bioline 87.06/95.85; VisiTect 85.13/96.45; Syphicheck 74.48/99.14; with whole blood Determine 86.32/95.85; SD Bioline 84.5/97.95; VisiTect 74.26/99.43; Syphicheck 74.47/99.58. As it turns out, these estimates are close to those of Mabey, Zheng et al., using treponemum pallidum haemagglutination assay or fluorescent treponemal antibody absorbed as a reference standard (http://sti.bmj.com/content/82/suppl_5/v13.full.pdf+html).

POCTs have also been shown to be cost effective (http://sti.bmj.com/content/82/suppl_5/v38.abstract?sid=82a53292-0a5a-46d1-a01d-9cf6bbade9ae).  So a substantial reduction of syphilis related adverse events seems achievable even in LMICs – if they can meet the training and organizational challenges to deployment of POCTs in ANCs.   According a recent paper of Mabey & Peeling, it is this latter area of health service organization that we find the greatest obstacle to delivering the promise of POCTs  (http://blogs.bmj.com/sti/2012/06/25/sustained-health-systems-strengthening-holds-the-key-to-prevention-of-mother-to-child-transmission-of-syphilis/).

 

Was the “sexual revolution” triggered by the decline of syphilis?

26 Mar, 13 | by Leslie Goode, Blogmaster

The year 1939 saw total US syphilis deaths at 15 per 100,000 and syphilis deaths of black males at 72.5 per 100,000: this is a death rate comparable to that for HIV/AIDS at the height of the epidemic in 1995 when total deaths and deaths of black males stood, respectively, at 16.2 and 80.2 per 100,000.  Subsequently, in the late 40s and early 50s, incidence and mortality from syphilis were to fall precipitously – thanks to penicillin.  A recent paper in the Archives for Sexual Behavior by an economist, Andrew Francis, argues for the importance of this collapse in the “cost” of syphilis in spurring the sexual revolution (http://link.springer.com/article/10.1007%2Fs10508-012-0018-4). His exploration of this hypothesis prompts general reflection on the link between the “cost” of disease (which he equates with absence of an effective treatment) and sexual behaviour.

The paper correlates data across US states on syphilis incidence and mortality with measures of “risky non-traditional sex” – which, in the context of the poverty of relevant data for the period, is evaluated on the basis of gonorrhoea rate, illegitimate birth ratio and teen birth share.  Coefficients are given from regressions of measures of sexual behaviour on indicators for the number of years since syphilis collapse (which varies by state).  As regards illegitimate birth ratio and teen birth share, a positive correlation emerges which goes back as early as three years or less from syphilis collapse; gonorrhoea, however, continues to decline from its WW2 peak, as we might expect.

Ultimately, however, Francis’s argument rests also on the claim that his own explanation of sexual revolution fits the facts better than the alternative explanations, of which the most familiar is that “anti-conception technology”, especially the pill, played a decisive role.  Francis admits that, from the late sixties, conception technologies and measures of risky behaviour increase simultaneously.  Yet measures of risky sexual behaviour, he claims, had already been rising sharply for a decade before anti-conception technology began to make its impact.  His own data show that the two changes do not coincide.   Nor do measures of permissive values or religious observance show any discontinuous change that would coincide with the increase in risky behaviour.  So if Francis’ hypothesis is wrong, then the precise timing of the sexually revolution remains mysterious.  Francis gestures vaguely towards the possibility of the change in sexual behaviour being triggered by still less definable “economic, social and cultural changes”.

The obvious recent parallel to the syphilis collapse in our own times would be impact of the introduction of HAART on HIV/AIDS mortality.  The concern that an effective therapy might lead to disinhibition has been widely discussed in STI journal and elsewhere.  An increase in risk-taking behaviour among MSM during the late 1990s has been established:  http://sti.bmj.com/content/77/3/184.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Stolte & Coutinho: Amsterdam);  http://sti.bmj.com/content/80/6/451.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Elford & Hart: London); http://sti.bmj.com/content/80/6/518.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed(Cox & Allard: Montreal); http://sti.bmj.com/content/79/1/7.abstract?sid=5d909365-4627-4232-8ef4-a93445f5baed (Stephensen & Williams: London).  But opinions on the contribution of HAART to changing sexual behaviour seem divided, with Stolte & Coutinho supporting the hypothesis, and the others inclined to attribute it to other factors.  The probable future emergence of multi-resistant gonorrhoea (http://sti.bmj.com/content/87/Suppl_2/ii39) represents the inverse case (loss of a therapy leading to potential inhibition).  If the diminished “cost” of an STI (syphilis) can spur an increase in risky sexual behaviour, should we not expect an increased cost to have the opposite result?  Time will tell.

Sustained health systems strengthening holds the key to prevention of mother-to-child transmission of syphilis

25 Jun, 12 | by Leslie Goode, Blogmaster

Half a million still-births annually are due to syphilis in pregnancy – deaths that could be averted by means of a single dose of penicillin.  An important project, reported in PLoS Medicine by Mabey, Peeling et al., to introduce point-of-care syphilis tests (POCTs) at ante-natal clinics (ANCs) in six countries, has resulted in all six countries adopting a policy to recommend POCTs; it has also influenced two of those countries, Brazil and China, to make syphilis testing for pregnant women a major public health priority (http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001233).

The past failure to address the problem of mother-to-child transmission is nothing to do with the efficacy of the intervention or its cost-effectiveness.  A recent systematic review, covered by this blog, indicates an odds ratio of 0.46 for reduced perinatal death and of 0.42 for reduced still birth (http://blogs.bmj.com/sti/2011/06/29/screening-for-syphilis-in-pregnancy-evidence-for-the-effectiveness-of-doing-something/?preview=true&preview_id=407&preview_nonce=8747e0989c).  The cost effectiveness of ante-natal screening is strongly endorsed by Terris-Prestholt, Ndeki et al. (2003) (http://sti.bmj.com/content/82/suppl_5/v38.abstract?sid=82a53292-0a5a-46d1-a01d-9cf6bbade9ae).  In the past an important obstacle to testing in low and middle income countries (LMICs) may have been the absence of a medical laboratory infrastructure.  But cheap and effective POCTs now offer a means to conduct screening in ANCs, which are attended by most pregnant women even in limited resource settings.  The relative merits of four POCT devices are compared by Mabey, Galban, et al. (2006) (http://sti.bmj.com/content/82/suppl_5/v26.abstract?sid=87c460fb-7f2f-49e6-b978-8720b427de3f).  You will find technical description of a POCT in this blog (http://blogs.bmj.com/sti/2011/10/02/what-fluidics-engineering-can-do-to-prevent-vertical-hivsyphilis-transmission-in-low-resource-settings/?preview=true&preview_id=495&preview_nonce=99cf925437).

So what are the obstacles to POCT deployment?

Mabey, Peeling et al. focus on the training and organizational challenges to deployment of POCTs in LMICs.  From the research angle, their project is a piece of “implementation research”.  What they set out to evaluate in their paper is the way in which the project meets the challenges of: 1. training the health care workers to implement the tests; 2. maintaining the quality of tests through a quality assurance program; 3. ensuring the continuity of supply chains for material and staff.  At the outset, design and location of the project were agreed with local authorities and stakeholders; next, training was offered not only to health-workers (HCWs) but to supervisors – and in the latter case the training included the assessment and training of HCWs, stock management etc.;  the project was then allowed to run.

What emerged in one area (Tanzania),was, interestingly, a 65% drop over the first six months in the percentage of ANCs passing the quality assurance controls due to high staff turn-over: but, subsequently, with the HWC training mechanism kicking in, there was a return to 100% levels of proficiency.  Also interesting was the initial resistance of laboratory staff in another area (Peru) to the idea of HWCs doing the work of laboratory technicians, though this was finally overcome.

In due course detailed papers will be published on the data from each of the countries involved: Brazil, China, Peru, Zambia, Uganda and Tanzania.  The published paper stresses the power and value of implementation research, and its potential application to other areas (e.g. HIV).  An implication of this approach is the significance of obstacles to improved health care delivery represented by the structural and organizational considerations.  The secret of obtaining better outcomes for prevention of mother-to-child transmission and other interventions may, therefore, lie in sustained health systems strengthening .

Did syphilis really originate in the New World? An old theory reconsidered.

31 Jan, 12 | by Leslie Goode, Blogmaster

Outside Naples, 1495, an unknown epidemic struck the mercenary army of the French King Charles VIII, subsequently considered to be the first recorded outbreak of syphilis in the Old World.  As early as the sixteenth century, the sudden emergence of the disease was popularly attributed to Columbus’ recent voyage to the New World.  Yet doubts have frequently been raised.  Did syphilis really originate in the Americas?  Or had it always existed in the Old World, and just by coincidence emerged with exceptional virulence shortly after Columbus’ return?

Twenty years ago, a comprehensive review of evidence for treponemal disease in the New and Old Worlds (Baker & Armalagos 1988) lent support to the popular theory of Columbian origin.  Since then, however, a growing number of cases of treponemal disease have been reported in the pre-Columbian Old World.  A paper published last month (Harper & Armelagos) returns to the old question in the light of the new evidence, and provides a comprehensive assessment of the evidence to date.

The evidence is hard to assess – for two reasons.  The first is the difficulty of the identification of dry bone lesions that are specific to treponemal disease – let alone syphilis.  The second relates to the dating of the evidence; this is rendered more complex by the so-called “marine reservoir effect”, as a result of which ante-mortem consumption of marine foods can generate dates that are too early by a factor of hundreds of years.

On the first issue Harper et al. argue that it is impossible with certainty to distinguish syphilis from other treponemal disease in the fossil record, but concur with Hackett (1976) that there are two macroscopic features that may be considered diagnostic of treponemal disease.  These features do occur in the fossil record.  Ultimately, it is the second issue, that of dating, which poses the greater obstacle to any conclusive argument on the origin of syphilis.  Of the 54 papers reviewed 12 include information on radiocarbon dating, and of these only 4 discuss the effect of marine reservoir.  None of the cases considered can with certainty be assigned to the pre-Columbian period.  Ultimately, therefore, the evaluation of Harper et al. concludes that there is not a single published case from the Old World that can be confidently diagnosed as treponemal, and that has a radiocarbon date that places it firmly in the pre-Columbian period.  Yet there is overwhelming evidence for its prevalence in the New World before this date, and for its occurrence in the Old World thereafter.

Thus, 20 years after Baker & Armelagos’ comprehensive review, the evidence still suggests that syphilis or its progenitor arose in the New World.

Kristin N. Harper, George J. Armelagos et al., “The Origin and Antiquity of Syphilis Revisited: An Appraisal of Old World Pre-Columbian Evidence for Treponemal Infection”, Yearbook of Physical Anthropology 54: 99-133, 2011.

http://onlinelibrary.wiley.com.libproxy.ucl.ac.uk/doi/10.1002/ajpa.21613/full

Baker B. & Armelagos G., “The origin and antiquity of syphilis: paleopathological diagnosis and interpretation”, Current  Anthropol ogy, 29:703–738, 1988.

Hackett C.,  Diagnostic criteria of syphilis, yaws and treponarid (treponematoses) and of some other diseases in dry bones (for use in osteo-archaeology), Berlin: Springer-Verlag, 1976.

What fluidics engineering can do to prevent vertical HIV/syphilis transmission in low resource settings

2 Oct, 11 | by Leslie Goode, Blogmaster

The economic case for investment in the prevention of vertical (mother to child) transmission of HIV and syphilis is easily made – even in low resource settings.  Yet the virtual elimination of maternal HIV transmission remains a goal still to be achieved in many regions, while syphilis in pregnant mothers is often unaddressed with tragic consequences in terms of peri-natal mortality.

The final resolution of these problems will no doubt require a multi-dimensional and holistic approach of the kind recommended by the UNAIDS report.  Yet a recently trialled technology, designed by biomedical engineers from Columbia University, may ease the way to that solution:  it promises to deliver a point-of-care HIV/syphilis test that replicates all the steps of ELISA (enzyme-linked immunosorbent assay), with a sensitivity and specificity to match traditional benchtop assays – but at low cost, with minimal equipment, and requiring no user interpretation (all important considerations in low resource settings).

A recent paper in Nature Medicine describes the technology – the “mChip” assay (mobile microfluidic chip for immunoassay on protein markers), and reports the encouraging results of three trials undertaken in Rwanda.

The device consists in a microfluidic cassette (5.4 cm x 8.5 cm) costing $0.10.  A metal spacer, displacing 6 ml of air in a syringe, is used to draw into the cassette a fluid plug consisting in 14 reagents separated by air spacers.  The procedure produces a signal that can be detected using low cost optics such as light emitting diodes and photodetectors (costing $0.50 and $6.00 respectively).  The test requires less than 1μl of unprocessed whole blood and is complete in 15 minutes.

When tested in Muhima Hospital Kigali on 70 specimens of known HIV status the device demonstrated an overall sensitivity of 100% and a specificity of 96%.  It was also evaluated on 101 archived specimens from couples receiving HIV voluntary counselling, and showed similar levels of sensitivity (100%) and specificity (94%).  Thirdly, the ability of the device to perform a combined HIV-syphilis test was investigated at Project Ubuzima, using 67 serum and plasma samples collected for a separate research study on female sex workers in Kigali.  The duplex test showed sensitivities of 100% and 94% and specificities of 95% and 76% for HIV and syphilis respectively.

A paper covered in a previous blog (Screening for syphilis in pregnancy: evidence for the effectiveness of doing something) reviews the disastrous failure in many low resource contexts to test and treat syphilis in pregnancy.  For all the priority rightly given to the prevention of HIV, the inclusion of syphilis in the duplex test seems a commendable element.

Curtis D Chin et al., “Microfluidics-based diagnostics of infectious diseases in the developing world”, Nature Medicine 17, 1015-1019, 31st July 2011

http://www.nature.com/nm/journal/v17/n8/full/nm.2408.html

Screening for syphilis in pregnancy: evidence for the effectiveness of doing something

29 Jun, 11 | by Leslie Goode, Blogmaster

2 million pregnant women, mostly in low and middle-income countries, have syphilis in pregnancy resulting in adverse outcomes in 69% of cases. Given known low costs of screening and treatment, the figures are appalling. Is it really lack of evidence for the effectiveness of interventions that is holding things back?  Yet one can only support the aims of a recent systematic review in the Lancet in seizing any opportunity to attract wider public attention to this issue.
The problem for the reviewers, however, is that randomised controlled trials providing the kind of evidence the authors require would no longer be ethical. Given the low-grade nature of the available evidence, there has been a tendency to conclude that there existed no intervention studies showing the effect of interventions on preterm birth. Not content with this, the authors of this review return again to the evidence in order to glean whatever may be gleaned.
The resulting 10 studies are very heterogeneous. As for the interventions themselves, it is evidently hard to generalize beyond the important common features of decentralized testing and same-day treatment. The outcomes are similarly varied and include, in various combinations: i. proportion of women receiving ante-natal screening (5 studies); ii. proportion of women receiving at least one dose of penicillin (6); iii. infants born with congential syphilis (4); iv. peri-natal deaths (3); v. stillbirths (3). Evidence of increased uptake of testing and treatment (i. and ii.) is disappointingly inconclusive; but evidence of adverse pregnancy outcomes (especially iv. and v. ) is stronger, allowing the inclusion in the headline findings of a figure for reduced peri-natal death (RR) of 0.46, and for still birth of 0.42.
Given the small number of studies and their heterogeneity, would we have learnt more about the components of these studies from a narrative presentation? Is the preference for the systematic review format driven by the need to obtain useful headline figures that would furnish statistical ammunition for the worthy cause of syphilis prevention?
It is interesting that in one study reviewed (Potter et al.) syphilis testing was increased only in an intervention that included improved HIV-PMTCT services.

S. Hawkes, “Effectiveness of interventions to improve screening for syphilis in pregnancy: a systematic review and meta-analysis”, The Lancet, published online 16th June 2011

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70104-9/abstract

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