END OF TB

END OF TB

The World Health Organization (WHO) has presented new guidelines as part of its Post-2015 Global Tuberculosis Strategy (End TB). This document outlines a 20-year blueprint and now addresses the management of latent tuberculosis. The new guidelines promote for the first time the screening of specific vulnerable populations for latent TB infection and treating the infection to prevent progression to active TB disease, which currently kills 1.5 million people a year. The guidelines recommend programmatic intervention for more than 100 countries with an incidence below 100 cases per 100,000. An estimated nine million people worldwide had active TB disease in 2013 and 1.5 million died of the disease, according to the WHO. While treatment efforts in the past two decades have reduced the death toll from the ongoing TB epidemic, the disease is still taking lives in all regions of the world. The WHO is putting forward a broad strategy to end the global epidemic by 2035, reduce TB deaths by 95%, cut active cases by 90%, and eliminate the catastrophic economic burdens in TB-affected regions. The strategy outlines actions to strengthen TB treatment and prevention; mobilize resources; accelerate development of new drugs, vaccines, and diagnostics; and reform social support.

For the first time, the WHO calls on health authorities to confront the problem of latent TB infection (LTBI)—a global pool of two billion people infected with Mycobacterium tuberculosis, who stand up to a 10% chance of developing active, contagious TB disease. The WHO recommends screening the most at-risk populations, such as HIV-positive patients, young children, people in contact with active TB patients, and immunocompromised patients, and providing preventive treatment to those considered at risk of active TB development. The strategy also calls for more study of preventive treatment in a range of high-risk groups

VISION	A world free of tuberculosis – zero deaths, disease and suffering due to tuberculosis
GOAL	End the global tuberculosis epidemic
MILESTONES FOR 2025	– 75% reduction in tuberculosis deaths (compared with 2015); – 50% reduction in tuberculosis incidence rate (compared with 2015) (less than 55 tuberculosis cases per 100 000 population) – No affected families facing catastrophic costs due to tuberculosis
TARGETS FOR 2035	– 95% reduction in tuberculosis deaths (compared with 2015) – 90% reduction in tuberculosis incidence rate (compared with 2015) (less than 10 tuberculosis cases per 100 000 population) – No affected families facing catastrophic costs due to tuberculosis
PRINCIPLES
1. Government stewardship and accountability, with monitoring and evaluation 2. Strong coalition with civil society organizations and communities 3. Protection and promotion of human rights, ethics and equity 4. Adaptation of the strategy and targets at country level, with global collaboration
PILLARS AND COMPONENTS
1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION A. Early diagnosis of tuberculosis including universal drug-susceptibility testing, and systematic screening of contacts and high-risk groups B. Treatment of all people with tuberculosis including drug-resistant tuberculosis, and patient support C. Collaborative tuberculosis/HIV activities, and management of co-morbidities D. Preventive treatment of persons at high risk, and vaccination against tuberculosis
2. BOLD POLICIES AND SUPPORTIVE SYSTEMS A. Political commitment with adequate resources for tuberculosis care and prevention B. Engagement of communities, civil society organizations, and public and private care providers C. Universal health coverage policy, and regulatory frameworks for case notification, vital registration, quality and rational use of medicines, and infection control D. Social protection, poverty alleviation and actions on other determinants of tuberculosis
3. INTENSIFIED RESEARCH AND INNOVATION A. Discovery, development and rapid uptake of new tools, interventions and strategies B. Research to optimize implementation and impact, and promote innovations

CENTRAL LABORATORY ROLE: TO COPE WITH DEMAND FOR POC

CENTRAL LABORATORY ROLE: TO COPE WITH DEMAND FOR POC

The healthcare landscape is undergoing dramatic changes: hospitals are consolidating into regional networks with highly specialized medical care performed in core facilities, generalized medical care provided in satellite hospitals, and ambulatory services offered at point-of-care (POC) locations.

Diagnostic laboratory testing is undergoing a similar transformation. Complex, non-urgent tests are performed in core facility laboratories or in reference sites; routine, acute diagnostic tests are performed in core laboratories or in satellite hospital facilities; and point-of-care testing is performed in outpatient clinics, physician office laboratories, retail clinics, and in-home testing. With an increased effort to provide cost-effective, timely medical care for ambulatory patients, patients are seeking treatment at local physician offices and retail clinics at a rate higher than ever before, and POC laboratory testing has become one of the fastest areas of growth in the medical field, with the number of tests increasing at an estimated 10% to 12% annually.

The transformation of POC testing is not without challenges. Testing has to be accurate, technically uncomplicated, inexpensive, and actionable. It is also critical to note that, particularly in the POC arena, lab tests play a role much larger than identifying or isolating disease-causing organisms. These tests are the start of an end-to-end chain of care that provides timely information to providers and determines patient outcomes. Accurate results are critical to ensuring antibiotic stewardship, initiating prompt and appropriate treatments, and preventing unnecessary auxiliary tests. These results inform the provider’s treatment decisions and allow for immediate action. Thus, as techniques are enlisted to ensure appropriate procedural characteristics to meet POC demands (e.g., turnover time, implementation cost, etc.), the effectiveness of each test must continue to hold equal importance.

An additional challenge for POC testing is somewhat unique—the accommodation of seasonal variation in test volume. Hospital-based laboratories provide a broad menu of diagnostic tests and have a proportionately large technical staff available to meet the testing demands. During peak test volumes for diagnostic services, the laboratory has the flexibility to adjust staffing to meet these needs. In contrast to this situation, POC testing sites generally have minimal staffing to perform tests, and the service providers (e.g., technician, medical assistant, secretary, nurse) will frequently have other responsibilities. Thus, the heavy influx of POC testing that occurs at certain times of the year yields an exceptionally high demand for on-location diagnostic tests.

As a result of the increasing mandate for POC testing, there is a need for laboratories to implement strategies that accommodate quick turnover in large volumes; labs must not only ensure that there are enough tests available at all times, but also ensure that newly developed tests are suitable for procedural operations at POC locations and meet the end goal of prompt and quality patient care. Diagnostic tests for influenza virus are a noteworthy example of the tremendous burden on labs and healthcare providers every year. In the traditional flu season, which lasts from October to March, there are millions of flu tests administered. Not only does this yield a higher-than-average demand for almost half of the year, but this demand is being realized almost entirely at POC locations. The majority of symptomatic patients go directly to their local physician office at first sign of illness. As a result, it becomes even more critical for front-line providers and their lab partners to weigh the benefits of various POC diagnostics in order to handle such a high volume of tests in a compact timeframe.

Influenza diagnostics has undergone dramatic changes in the past decade. Historically, in vitro viral culture was the most sensitive available test, but this could only be performed in hospital-based laboratories, requiring specialized technical expertise and testing facilities, and results were not available for a number of days. Thus, this testing was confirmatory and not particularly helpful for the management of acute infections. A transformation occurred when real time nucleic acid amplification tests (e.g., real time polymerase chain reaction, RT-PCR) became available. These tests are now the gold standard for detecting influenza virus in clinical labs, as they have shown high sensitivity and specificity. However, on the procedural level, these tests do not lend themselves to operational compatibility at POC locations. Commercially available RT-PCR tests have a turnaround time of one to six hours and are run frequently in batches, which can further delay results. Additionally, although testing has been greatly simplified with the introduction of commercial platforms and diagnostic assays, testing is still generally restricted to hospital-based laboratories and has not been extended to POC facilities.

The solution for POC testing lies in the development of immunoassays for the detection of influenza antigens. In principle, immunoassays offer solutions to the procedural limitations of PCR tests; commercial immunoassays for influenza virus have a turnaround time of 15 to 30 minutes, require much less costly equipment, and are generally easy for point-of-care providers to operate. However, the accuracy of the first-generation tests has been appropriately questioned. The most common tests show only 10 percent to 70 percent accuracy based on the commercial assay and circulating strains of influenza virus.⁸ The majority of these tests use a manual visual read system for results in which the user determines assay results by reading an output of colored lines to indicate a negative or positive sample. The inherent subjectivity of such readings has been shown to result in user variability and error rates as high as 56 percent. Thus, while operationally these tests are a good fit for POC locations handling either small or large volumes of tests, they fall short in facilitating the end-goal of POC testing, which is to help providers make accurate diagnoses. Instead, providers find themselves torn between incurring additional costs by requesting repeat samples, and making actionable decisions based on an uncertain result.

Many believe that the best strategy to fulfill the need in point-of-care testing is to commit to meeting both procedural and quality standards in lab diagnostics. A newer generation of tests—digital immunoassay rapids (DIAs)—is designed to meet such requirements. Built to handle large volumes of tests in a short period of time and integrate into larger output systems, DIAs are a promising solution. By offering an instrument-based, digital read-out test that can be measured objectively and using immunoassay crafted particles and antibodies, these tests ensure precise detection and have been shown to be nearly as accurate as PCR. Digital immunoassays take just over 10 minutes, and some are CLIA-waived. Current systems, and similar systems in development, have the potential to help lab operations align with the shift to POC occurring in clinical settings. The rapid turnover between test times and ability to be easily used by many locations and providers allow the physician network to handle high patient volume. Providers can then consider the option of initiating treatment early in the infection, when it has the best chance of being effective and leading to successful patient outcome.

Ultimately, the shift toward point-of-care diagnostics is positive: the more access people have to quality local care, the more likely they are to be seen when needed, and the less likely they are to receive unnecessary and costly tests—all of which will inevitably result in a positive impact on patient health. The laboratory is in many ways the start of this chain of care. Thus, it is critical that diagnostics continue to be developed to adequately equip POC sites with the tools they need to meet a high and timely demand. By strategically incorporating procedural and functional elements, diagnostic providers can ensure that tests are capable of performing at the level and frequency necessary to function in point-of-care and provide patients with the most convenient, quality care possible.

FLUORESCENCE-BASED POC FOR URINE PREGNANCY

FLUORESCENCE-BASED POC FOR URINE PREGNANCY

The introduction of urine dipstick technology, with its speed and simplicity, led to an explosion of point-of-care testing (POCT). Urine pregnancy is one of the most commonly performed POCTs, with millions of patients tested annually in emergency rooms, outpatient clinics, and other non-laboratory settings. Testing is performed to aid in the early detection of pregnancy, depending on the clinical situation.

Despite this enormous utility and testing volume, there has been relatively little advancement in testing technology. Most tests require manual timing and visual interpretation. Visually read tests are subject to individual observer capabilities and make record keeping, billing, and QA/QC monitoring a challenge, particularly when run in busy patient care settings. We are now seeing the emergence of new instrumented, connected technologies that will aid both patients and health professionals.

Defining next generation POC urine pregnancy testing

The following criteria can be used by laboratories to define next-generation technology and screen the many testing possibilities:

Ø  Excellent sensitivity and specificity

Ø  Time. The total time from sample collection to reporting the test result must be as short as possible and within the time frame of a typical patient visit.

Ø  Objective results that eliminate operator interpretation

Ø  Ease of use

Ø  Size. Instrumentation must be small enough for all settings

Ø  Onboard data storage, LIMS, EMR, WIFI, and/or cellular wireless capabilities must be available to properly document and store testing for medical, legal, test utilization monitoring, accounting, and/or billing purposes.

To meet the above criteria, some diagnostic companies are moving to fluorescence-based chemistries combined with small, easy-to-use, and yet sophisticated analyzers. The use of innovative fluorophores coupled with monoclonal antibodies yields substantial improvements in sensitivity. Fluorophores with sufficiently large Stokes shifts prevent interference from naturally fluorescent compounds found in biological samples. The placement of a large number of fluorescent molecules inside individual microbeads yields a highly amplified signal in the assay. Further, some manufacturers have made strides by working with fluorophores that are resistant to bleaching under ambient light, obviating the need to protect from ambient light.

From the point of view of instrumentation, highly experienced device manufacturers are developing analyzers with sophisticated assay analysis software that further improves assay performance by controlling for a multitude of sample and user-related issues. These newer analyzers also ensure both ease of use for the end user and accurate results for the patient and the clinician.

Benefits of next-generation assays and systems

When new and emerging POC analyzers are coupled with the latest science in assay chemistry, the following benefits can be expected:

Ø  Improved patient care and physician satisfaction

Ø  Reduced operator-to-operator variability

Ø  Reduction of procedural variation and operator errors through automation, barcoding, and other instrument control features

Ø  The ability to automatically capture, store, and transmit patient results.

Choosing the right POCT device

Given the challenges that laboratories are facing today, including financial constraints, increasing demands, and personnel shortages, many labs can greatly benefit from adopting next-generation POC immunoassay analyzers. The greatly improved performance, objectivity, connectivity options, and ease of use means the laboratory can complement its existing instruments and platforms with a faster, easy-to-use, and cost-effective solution. The incumbent technologies still have a place, but they can be better allocated when coupled with a next-generation POC analyzer.

Next-generation POC assay systems are now available that give medical professionals, including laboratory managers, options that did not exist even two or three years ago. These options include objective and automated results, customizable settings, and the ability to directly transmit the results to office, hospital and/or laboratory information systems.

THE DIRECT-MEASURED LIPID PANEL

THE DIRECT-MEASURED LIPID PANEL

Various guidelines recommend a comprehensive approach to identify patients at risk for cardio-metabolic risk stratification.^5,20,21 Unlike the traditional cholesterol panel, the vertical auto profile (VAP) test is a direct-measured lipid panel. VAP tests are used for comprehensive lipid analysis and simultaneous determination of cholesterol concentration for all five lipoprotein classes and subclasses. The VAP test directly measures LDL. It is also accurate in non-fasting individuals, unlike calculated LDL, which could be low in patients who do not fast as directed prior to testing. Furthermore, the VAP test provides measurements of various lipid components including HDL, TC (VLDL), non-HDL, apolipoprotein B100 (apoB100), Lp(a), IDL, LDL-R, LDL-R subclasses, and remnant lipoproteins such as VLDL3, HDL2 and HDL3.

The VAP test uses single vertical spin, inverted rate zonal, and density gradient ultracentrifugation simultaneously to measure concentrations of cholesterol for all five lipoproteins LDL, VLDL, IDL, HDL, Lp(a), and subclasses. The VAP procedure takes less than one hour to perform and involves the following steps: ultracentrifugation, enzymatic treatment, and software analysis. Ultracentrifugation involves a two-layer density gradient with the bottom layer having a 1:40 serum dilution, followed by centrifugation at 65,000 rpm, which is followed by cholesterol analysis using a continuous flow VAP cholesterol analyzer.

In 1985, the National Cholesterol Education Program (NCEP) was launched by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. NCEP has put together guidelines for the benefits of lowering cholesterol levels for the prevention of CAD. The NCEP ATP (III) guidelines include the following: 1) measurement of direct LDL; 2) non-HDL and metabolic syndrome (secondary targets of therapy); and 3) emerging risk factors such as Lp(a), small LDL pattern, HDL subclasses, lipoprotein remnants, and apoB. The VAP test complies with NCEP, ATP(III) guidelines.

One advantage of the VAP test is that it measures additional classes of lipoproteins such as Lp(a), IDL, and also subclasses of LDL, HDL (HDL2 and HDL3) and VLDL subclasses (VLDL1,VLDL2,VLDL3). The routine and standard lipid panel testing consists of ordering total cholesterol, LDL, HDL, and triglycerides. By measuring additional lipid parameters, the VAP test can identify patients who are at high risk for CAD and who otherwise would not be identified through routine and standard lipid panel testing.

Various risk assessment tools or models have been developed for cardiovascular disease prevention. Examples of these models include U.S. Framingham risk score (FRS) and the European Systematic Coronary Risk Evaluation (SCORE). Age, gender, total cholesterol, LDL, HDL, smoking, systolic blood pressure, and diabetes are among the factors in the ATP(III) FRS. ATP(III) FRS, however, underestimates the total atherosclerotic vascular disease.

VAP Test:

VAP stands for vertical auto profile, and it tests cholesterol measurements more specifically than previous cholesterol tests. Jere Segrest, a scientist at the University of Alabama in Birmingham, developed the VAP test. In 1999, a company called Atherotech, also located in Birmingham, was formed. Atherotech patented the test and is currently the only company with rights to produce it.

Previous blood cholesterol tests examined the levels of high density lipoproteins (HDL), also called “good cholesterol.” These tests also examined and counted the presence of low density lipoproteins (LDL), or bad cholesterol. These earlier tests were roughly 40% accurate in predicting risk for heart attack.

What scientists discovered while developing the VAP test is that HDL and LDL could be broken down further into subtypes by reclassifying density. These subtypes could further define cholesterol levels and risk of heart attack. High levels of LDL are considered to increase risk for heart attack and necessitate treatment. The VAP test expands on this knowledge. It examines a subtype of LDL called Lp(a), which, when it is the predominant form of LDL, can increase the risk of heart attack up to 25 times.

High levels of HDL were once considered to mean a reduced risk of heart attack. However, HDL is further classed into subtypes, HDL1 and HDL2. While either type of HDL reduces risk, the VAP test measurement separates the two types of HDL. HDL2 is far superior to HDL1, providing more protection for the heart.

The scientists at Atherotech believe that understanding these subtypes can more than double the ability to predict heart attack. Their material has been supported by data from clinical trials at both the University of Alabama and Richmond Medical College. In fact, one aspect of the study at Richmond Medical College, using the VAP test for diagnostics, showed that people with low levels of HDL2 were at a greatly increased risk for abnormally young heart attack.

Most insurance companies recognize studies supporting the VAP test. Virtually all health insurance companies and Medicare pay for it. However, since the test is relatively new, a patient may have to request the VAP instead of the standard cholesterol test.

When a person is uninsured, or has insurance that does not cover the VAP test, it can be ordered online. With shipping and handling, it costs about 100 US dollars (USD). A lab or doctor’s office must administer the test, but it is a simple blood test, much like the previous test for cholesterol. Most labs already have the VAP test on hand, or Atherotech’s website can guide you to a site or doctor that administers the test.

COMPARISON: Standard Lipid profile vs VAP Cholesterol panel

Standard Lipid Profile

*Measures total cholesterol

*Measures HDL

*Calculates LDL using the Friedewald formula (LDL = TC – HDL – TRIG/5)

*Measures triglycerides

*Requires fasting

The VAP Cholesterol Test

*Directly measures total cholesterol

*Directly measures HDL and separates into HDL2 and HDL3 (HDL2 is the “best” cholesterol and when low, is a risk factor for CAD, HDL3 is the least protective HDL)

*Directly measures LDL and separates into 3 components: LDL-R; Lp(a); and IDL (Total LDL may be normal, but one of the 3 components of LDL may be elevated and indicate a risk for CAD. Lp(a) is a genetic risk factor that, when elevated, could indicate a higher risk for heart disease. IDL is also a genetic risk factor.)

*Measures LDL pattern density. (Pattern A indicates large, buoyant LDL particles. Pattern B indicates small, dense LDL particles and is most atherogenic).

*Directly measures triglycerides.

*Directly measures triglyceride-rich lipids: VLDL (1,2,3 and total) (VLDL 3 is small, dense and most dangerous).

*Fasting not required. ATPIII requires expanded lipid test when triglycerides > 400mg/dL and suggests direct measured LDL in non-fasting state.

The following definitions will help you read your VAP Cholesterol Test and understand your lipids and their measurements.

LDL-Cholesterol-Direct a direct measure of your Low Density Lipoprotein cholesterol. LDL is considered to be

your “bad” or “heart disease” cholesterol.

Total HDL-Cholesterol-Direct a direct measure of your High Density Lipoprotein cholesterol. HDL is considered to be the “good” or “protective” type of cholesterol.

Total VLDL-Cholesterol-Direct a direct measure of your Very Low Density Lipoprotein cholesterol, a major carrier of energy rich molecules called “triglycerides;” excess VLDL increases risk for heart disease and diabetes.

SUM Total Cholesterol the sum of your HDL + LDL + VLDL. As a sum total of three diff erent cholesterol measurements, SUM Total Cholesterol alone should not be used to predict the risk of heart disease or stroke.

Triglycerides-Direct a direct measure of energy rich Triglyceride molecules used by the body. Elevated triglycerides are a risk factor which can lead to the formation of “heart disease” lipoproteins.

Total Non-HDL Cholesterol the sum of your LDL + VLDL; the higher the number, the greater the risk of heart disease.

Total apoB100 a measurement of apolipoprotein B100, which helps form, carry and deliver “bad” cholesterol particles to cells. Knowing your apoB100 value greatly increases the VAP’s risk predictive value.

Lp(a) Cholesterol a measurement of “lipoprotein a” cholesterol in your body. A highly inherited risk factor for heart disease, Lp(a) does not respond to traditional LDL-lowering drugs.

IDL Cholesterol a measurement of your Intermediate Density Lipoprotein cholesterol. A strongly inherited risk factor for heart disease, it is elevated in patients with a family history of diabetes.

LDL-R (Real)-C the “Real” cholesterol circulating in your body; it is a component of Total LDL Cholesterol.

Sum Total LDL-C a the sum of Lp(a) + IDL + Real LDL.

Real-LDL Size Pattern refers to LDL cholesterol’s density. A description of type rather than amount of cholesterol, Real-LDL Size Pattern can be A, A/B or B. Pattern A is the safest density, as the human body can rid itself more easily of excess Pattern A LDL. Pattern B LDL carries the highest threat; it is much more susceptible to oxidation (a primary cause of atherosclerosis) and remains in the bloodstream longer than Pattern A LDL. The longer you are exposed to bad cholesterol groups, the greater your risk for disease. Treatments for Pattern B LDL and elevated LDL cholesterol are diff erent, so both measurements must be known for effective treatment. Pattern A/B patients have a mix of both patterns and should work toward a Pattern A LDL value.

Metabolic Syndrome Consider Insulin Resistance/Metabolic Syndrome: If this value is marked as being a risk factor, it is because your profi le indicates the combined presence of Pattern B LDL, low HDL/HDL2 and elevated triglycerides, creating an elevated risk for diabetes due to insulin resistance.

HDL-2 the protective portion of HDL. Low HDL2 is a risk factor for Coronary Artery Disease (CAD), even in patients with normal cholesterol.

HDL-3 important but does not play as great a protective role in protecting against CAD as does HDL-2.

VLDL-3 a triglyceride-rich lipid which can represent an independent risk factor for heart disease.

Lipid testing into the future

Lipid testing has come a long way and continues to evolve further. Analytical methods that are able to test various lipoprotein fractions and subfractions are essential for the detection of various lipid disorders. Measurement with a comprehensive lipid profile that includes specific and sensitive tests helps detect dyslipidemia and associated disorders earlier and more accurately, leading to better management of various cardiovascular disorders. Proper testing is a major factor for stopping the progression of CAD and lowering the burden of disease. Clinical laboratories should consider adding the lipoprotein subfractions discussed here to their future lipid test menu. Physicians should begin ordering such tests and evaluating these parameters.