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By Carol A. Kemper, MD, FACP, Section Editor: Updates, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.
Snooping out counterfeit anti-malarials
FDA develops device capable of recognizing fake anti-malaria drugs. Medical News Today, April 25, 2013.
The practical uses for mass spectrometers have exploded in recent years — from newborn screening and detection of genetic mutations, therapeutic blood monitoring, and detection of anabolic steroid abuse — to identification of false, unapproved or inappropriately labeled products such as cosmetics, product tampering, and pharmaceutical screening. Spectrometer/flurometer technology is also being used at the U.S. borders and by the U.S. post to screen mail. It is likely the recent letter laced with ricin mailed to President Obama was detected using this technology. Such technology detects the peak wavelength of a product within a second, revealing its chemical composition. However, these devices are often large, bulky and expensive — typically costing tens of thousands of dollars.
The FDA’s Office of Regulatory Affairs, Forensic Chemistry Center, has developed a hand held counterfeit detection device (CDx) that may be used in screening counterfeit pharmaceuticals. In a unique public-private partnership, a smaller hand-held CD3 device has been developed to detect the quality and composition of anti-malarial drugs, and will be field tested in Ghana this year. It is estimated that nearly half of the circulating antimalarial drugs are fake or contain inferior concentrations of drug. Not only do these counterfeit or substandard drugs cost lives, but they may be promoting drug-resistant Plasmodium strains by exposing organisms to sub-therapeutic concentrations of drug. These smaller devices are more portable and cost around $1000 per unit, although the FDA is contracting with Corning Incorporated to develop a cheaper version of the device for larger-scale manufacturing and use in developing countries.
Teflon to some
ProMED-mail post. Fungal pneumonia – UK: (Scotland) bagpipe alert. Sunday March 10, 2013; www.promedmail.org; and McNeil, Donald Jr., A warning to clean bagpipes. The New York Times, March 18, 2013.
I read with astonishment the tale of the 77-year-old Scottish bagpiper who nearly died from invasive pulmonary fungal pneumonia, acquired from his synthetic bagpipes. The gentleman is considered a prominent piper in the bagpiping community, and his illness has served as an alert to pipers worldwide. He was ill for a month before being admitted to hospital with progressive pneumonia, failing to respond to antibacterials. Learning of his avocation, a consultant cottoned to the diagnosis and started antifungal therapy. Once his son brought in the bagpipes for inspection, both Rhodoturula and Fusarium were cultured from the bag.
Fungal pneumonia has rarely been reported in bagpipers, including one case of pulmonary cryptococcosis reported over 20 years ago. However, bagpipes made of newer synthetic materials may arguably pose a greater risk. In past days, bagpipes were constructed of cowhide or sheepskin, and required regular “seasoning” with a secret sauce to seal the pores in the skin and protect the bag. It is believed this secret sauce contained such natural antibacterials as fennel, lemongrass, and honey. As an apiarist, I can assure you, nothing, including mold, grows in honey. But the newer bags, made of synthetic materials with a zippered closure, are supposed be easier to clean and maintain, and the recommendations are they should be opened and cleaned with a disinfectant on a regular basis. The man who nearly died admitted it had been 18 months since he had cleaned his bag, apparently reluctant to alter them since they had been playing so well.
Another interesting tidbit from this article - bagpipes are just one of many uses for Gore-Tex, a synthetic material made from finely spun polytetrafluorethylene resin — also originally known as Teflon. Some of the newer materials made from this perfluoronated carbon resin are space-age, and can withstand extreme temperatures, have great insulating properties, are chemically inert, and can be used for anything from protective clothing, to circuit boards and cables, and to replacing human tissues. As a junior chemical engineering student, I had great fun one summer working on the quality engineering of one of the original Gore-Tex products at 3M Corporation. Apparently Teflon to some, but not to Fusarium.
Rethinking TB screening in a low risk population
Thanassi W, et al. Delineating a retesting zone using receiver operating characteristic analysis on serial QuantiFERON tuberculosis test results in US healthcare workers. Pulmonary Medicine 2012; 291294; Epub ahead of publication 2012 Dec 30, 2012.
Daley CL, et al. A summary of meeting proceedings on addressing variability around the cut-point in serial interferon-gamma release assay testing. Infect Control Hosp Epidemiol. 2013 June:34(6). Epub 2013 April 19.
The TB interferon gamma release assays (IGRAs) were specifically designed to capture as many people at risk for reactivation TB as possible. To this end, in 2010 the QuantiFERON Gold In-Tube assay was further modified to include a third Tb antigen in the well, which increased the sensitivity of the assay, possibly at the expense of specificity. It is important to keep in mind, these assays were not necessarily intended to be used as a screening test in a low risk population (such as health care workers [HCWs] and college bound students in the United States). With the increased sensitivity of the assay, our clinic has seen an increase in the percentage of positive tests being processed by the laboratory — which is good if trying to capture more patients at risk for reactivation TB — but not so good if we are incorrectly capturing people at low risk who have not been infected, who may be needlessly exposed to INH chemoprophylaxis.
Using the QuantiFERON Gold assay to annually screen our clinic physicians over the past 2 years, an increasing number of physicians had a positive TB screening test for the first time following several years of negative TST testing — which generated the usual concerns and, in some corners, alarm. These positive test results prompted clinical assessment, examination of potential exposures, chest radiographics, frequent retesting, and several physicians were begun on INH. Suddenly what was supposed to be a lower-cost screening tool was generating costs in other ways.
Most of these positive tests were in the lower range - and over the next year, as the number of “positive” physicians began to pile up, it was increasingly suspected these test results represented false-positives. Increasing data now confirm our suspicions that, for screening purposes in a low risk population (e.g., physicians and HCWs), there may indeed be a range of IGRA assay results requiring re-interpretation and where retesting makes sense.
Currently, a positive QuantiFERON Gold In-Tube interferon gamma release assay is defined by a positive control (mitogen) and a positive TB antigen > .35 IU/ mL. Data generated by the TB Epidemiologic Studies Consortium, reviewing serial IGRA test results in HCWs (HCWs) at 6, 12, and 18 months, found a great deal of discordance among the three tests (81% of the HCWs had negative results for all 3 tests, 1.4% had positive results for all 3 tests, leaving 17.6% with discordant results). The number of HCWs with “conversion” was lowest for the skin TST (0.9%), and higher for either the QuantiFERON Gold (6.1%) and T-Spot TB test (8.3%). Many of those with a positive test were negative on retesting. In other preliminary studies, the rate of “conversion” diminished with repeated testing over an 18-month period.
Thanassi and colleagues at the Veterans Affairs Palo Alto Health Care System examined 4,019 unique HCW QuantiFERON Gold results, identifying a possible range of tests results requiring retesting. All VAPAHCS HCWs are U.S. citizens, although also included in this group were researchers, students, volunteers and Peace Corps personnel who may be screened only once when visiting the campus. Most of these persons are at low risk for TB conversion, residing and working in the Palo Alto, California area.
Of 4,019 HCWs tested between January 1, 2009 and June 30, 2011, 2,706 (67%) were negative once, and 293 (7%) were positive once, without retesting; 781 (19%) tested negative more than once and never tested positive. Therefore, the overall negative test frequency at the VAPAHCS was 86%, while 14% tested positive at least once. Of those with a positive result on initial testing, 42% had negative results on retesting.
This provided a robust data set to tease apart. The problem comes down to a lack of a gold standard confirming latent TB infection — how do you know which test result is true? But the data give clues — firstly, reversions occur far more commonly than conversions, and the conversion rate itself is a combination of true disease and falsely positives that may subsequently revert to negative. Secondly, the IGRAs have a recognized specificity, based on measurements in person with actual TB. And thirdly, the phenomenon of regression to the mean is, in part, likely responsible for some of the reversions.
The authors conducted an elegant receiver operating characteristic analysis, retrospectively examining and identifying characteristics between those with two consecutive positive test results and those with a positive followed by a negative test result. Only those with at least two tests were included in the analysis. These predictors were then confirmed in a second logistic regression analysis on an independent sample.
Of 575 initially positive HCWs, 300 (52.2%) had a repeat negative test (reversion) and 275 (47.8%) had two sequential positive tests. Analysis suggested two separation points for the QuantiFERON TB test results for the reversion group. The most statistically significant separation point that predicted reversion was 1.11 IU/ml. The second less robust separation point was 0.72 IU/ml. Using these revised cut-points, 75% of low risk individuals with a screening test result between 0.35-1.11 IU/mL had a subsequent negative test. Eighty percent of those with a screening test result between 0.35-0.72 IU/mL had a subsequent negative test.
The authors have proposed that HCWs at low risk with no identifiable exposure being routinely screened for TB exposure and test positive, should be retested if their initial TB Quant test result is between 0.35-1.11 IU/mL. A subsequent negative test should be considered a negative test. A summary of the Third Global IGRA Symposium suggests that HCW with no identifiable risk factors with a test result below 1.5 IU/mL should be retested, although the period for retesting is not known. Those individuals that test positive again should be clinical evaluated for symptoms, and considered for INH chemoprophylaxis. Although not stated, it would be reasonable to proceed with a symptom assessment and screening chest radiograph for all positives, even in the lower range, at least until the repeat negative test is available.