QuantiFERON

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Interferon-gamma release assays (IGRAs) are diagnostic tools for latent tuberculosis infection (LTBI). They are surrogate markers of Mycobacterium tuberculosis infection and indicate a cellular immune response to M. tuberculosis if the latter is present.

Contents

Active vs latent tuberculosis

IGRAs cannot distinguish between latent infection and active tuberculosis (TB) disease, and should not be used as a sole method for diagnosis of active TB, which is a microbiological diagnosis. A positive IGRA result may not necessarily indicate TB infection, but can also be caused by infection with non-tuberculous mycobacteria. A negative IGRA does not rule out active TB disease; a number of studies have shown that up to a quarter of patients with active TB have negative IGRA results.

BCG Status

Because IGRAs are not affected by Bacille Calmette–Guérin (BCG) vaccination status, IGRAs are useful for evaluation of LTBI in BCG-vaccinated individuals, particularly in settings where BCG vaccination is administered after infancy or multiple (booster) BCG vaccinations are given. In contrast, the specificity of tuberculin skin test (TST) varies depending on timing of BCG and whether repeated (booster) vaccinations are given.

Commercial IGRA test

QuantiFERON, also known as QFT, is the registered trademark of an interferon gamma release assay (IGRA) for tuberculosis diagnosis manufactured by QIAGEN. The QFT-GIT assay is an ELISA-based, whole-blood test that uses peptides from three TB antigens (ESAT-6, CFP-10, and TB7.7) in an in-tube format. The result is reported as quantification of IFN-gamma in international units (IU) per mL. An individual is considered positive for M. tuberculosis infection if the IFN-gamma response to TB antigens is above the test cut-off (after subtracting the background IFN-gamma response in the negative control).

Mantoux vs IGRA test

Since IGRAs are more costly and technically complex to do than the Mantoux test, in their 2011 policy statement, the WHO did not recommend replacing the Mantoux test by IGRAs as a public health intervention in low- and middle-income countries. [1]

QuantiFERON-TB (QFT)

QuantiFERON-TB Gold In-Tube (QFT-GIT), the third generation test, has replaced QuantiFERON-TB (QFT) and QuantiFERON-Gold, which are no longer marketed.

According to the U.S. Centers for Disease Control, [2] in 2001, the QuantiFERON-TB test (QFT) was approved by the Food and Drug Administration (FDA) as an aid for detecting latent Mycobacterium tuberculosis infection. This test is an in vitro diagnostic aid that measures a component of cell-mediated immune reactivity to M. tuberculosis. The test is based on the quantification of interferon-gamma (IFN-γ) released from sensitized lymphocytes in whole blood incubated overnight with purified protein derivative (PPD) from M. tuberculosis and control antigens.

Tuberculin skin testing (TST) has been used for years as an aid in diagnosing latent tuberculosis infection (LTBI) and includes measurement of the delayed type hypersensitivity response 48–72 hours after intradermal injection of PPD. TST and QFT do not measure the same components of the immunologic response and are not interchangeable. Assessment of the accuracy of these tests is limited by lack of a standard for confirming LTBI.[ citation needed ]

As a diagnostic test, QFT:

  1. requires phlebotomy
  2. can be accomplished after a single patient visit
  3. assesses responses to multiple antigens simultaneously
  4. does not boost anamnestic immune responses (see Latent tuberculosis#Boosting).

Compared with TST, QFT results are less subject to reader bias and error. In a CDC-sponsored multicenter trial, QFT and TST results were moderately concordant (overall kappa value = 0.60). The level of concordance was adversely affected by prior bacille Calmette-Guérin (BCG) vaccination, immune reactivity to nontuberculous mycobacteria (NTM), and a prior positive TST. [3] In addition to the multicenter study, two other published studies have demonstrated moderate concordance between TST and QFT. [4] [5] However, one of the five sites involved in the CDC study reported less agreement. [6] Although there have been studies confirming the increased future risk of active TB in individuals with positive TST, the same was not true for those with a positive IGRA result. A recently published study [7] demonstrated that a positive IGRA result is predictive of future active TB risk. Moreover, IGRA was at least as sensitive and was more specific compared to traditional TST. In this study of immunocompetent recently exposed close contacts of active TB cases, the progression rate to active disease among untreated QFT positive individuals was significantly greater than for untreated TST positives (14.6% versus 2.3%). Although the numbers were small, all of the close contacts who went on to develop active TB were QFT positive, but only 83% were TST positive.[ citation needed ]

As noted above, prior BCG vaccination can produce false positive TST results. In a study of military personnel returning from missions, about one-half of the positive TSTs were falsely positive. [8] In a more recent study of military returning from missions, Franken et al. [9] reported evidence suggesting false positive TST results are common and that QFT testing could guide more targeted treatment and alleviate unnecessary anti-tuberculous treatment.

The FDA's cutpoint for a positive result was established at >0.34 International Units/millilitre (IU/ml), though this has proven functionally problematic in low prevalence areas, such as among US and Canadian healthcare workers. In areas of low risk and low prevalence, the positive predictive value of any test is diminished. In the case of serially screened North American healthcare workers, QFT results just above this cutpoint produce false-positive test results that upon repeat testing revert to negative, [10] where tuberculosis screening is often mandated on an annual basis. [11] Research at Stanford University and the Veterans Administration has reported the use of a retesting (or borderline) zone below 1.1 IU/ml mitigates 76% of the false-positives, or reversions. [12] [13]

Limitations of QFT include the need to draw blood and process it within 16 hours after collection and limited laboratory and clinical experience with the assay. There is need for further study of the utility of QFT in predicting the progression to active tuberculosis, particularly in children and immunocompromised hosts. [12]

To its disadvantage, QFT can yield false positive results with Mycobacterium szulgai , Mycobacterium kansasii , and Mycobacterium marinum . [14]

QuantiFERON-TB Gold

The QuantiFERON-TB Gold test (QFT-G) is a whole-blood test for use as an aid in diagnosing Mycobacterium tuberculosis infection, including latent tuberculosis infection (LTBI) and tuberculosis (TB) disease. [15] This test was approved by the U.S. Food and Drug Administration (FDA) in 2005.

Blood samples are mixed with antigens (substances that can produce an immune response) and controls. For QFT-G, the antigens include mixtures of synthetic peptides representing two M. tuberculosis proteins, ESAT-6 and CFP-10. After incubation of the blood with antigens for 16 to 24 hours, the amount of interferon-gamma (IFN-gamma) is measured.

If the patient is infected with M. tuberculosis, their white blood cells will release IFN-gamma in response to contact with the TB antigens. The QFT-G results are based on the amount of IFN-gamma that is released in response to the antigens.

Clinical evaluation and additional tests (such as a chest radiograph, sputum smear, and culture) are needed to differentiate between a diagnosis of latent TB or active TB.

Advantages of the test are:

Disadvantages and limitations of the test are:

QuantiFERON-TB Gold In-Tube

On 10/10/2007 the US FDA [19] gave approval for the Quantiferon TB Gold In Tube to be marketed in the US

The FDA states:

Approval for a modification of the quantiferon-tb gold to an in-tube collection system that consists of three blood collection tubes, nil, tb antigen, and mitogen. The device, as modified, will be marketed under the trade name quantiferon-tb gold in-tube and is indicated for use as an in vitro diagnostic test using a peptide cocktail simulating esat-6, cfp-10 and tb 7.7(p4) proteins to stimulate cells in heparinized whole blood drawn directly into specialized blood collection tubes. Detection of interferon-y by enzyme-linked immunosorbent assay (elisa) is used to identify in vitro responses to these peptide antigens that are associated with mycobacterium tuberculosis infection.

According to the FDA approved package insert [20] Quantiferon TB Gold In Tube has a consistent specificity of >99% in low risk individuals and a sensitivity as high as 92% in individuals with active disease, depending on setting and extent of disease. The specificity in two studies of a few hundred people is 96-98% in a health immunised population.

The package insert also advises that the kit provides three collection tubes which have had antigens dried onto their walls and that these tubes must be transferred to an incubator within 16 hours of blood collection.

On 25 June 2010, the US Centers for Disease Control and Prevention (CDC) updated the tuberculosis (TB) testing guidelines providing guidance to US public health officials, clinicians, and laboratory workers regarding screening for and diagnosis of TB infection. The updated guidelines provide new direction for TB control in the US. [11]

Previously, QuantiFERON®-TB Gold was able to be used in any situation in which the Tuberculin Skin Test (TST) was used, without preference. The 2010 guidelines establish a new benchmark because they recommend IGRAs as the preferred TB testing method in many patients, including those who are BCG vaccinated or are unlikely to return for TST reading.[ citation needed ]

Availability

In the United States, the test is widely available from state public health laboratories, hospitals, and commercial laboratories.

In January 2008 the CDC advised - via their TB Notes Newsletter [21] - TB controllers and others of a link [22] to a list of laboratories in the US and Canada offering to perform the Quantiferon Gold test.

The California Tuberculosis Controllers Association have also provided a list of public health laboratories [23] in California that are testing with Quantiferon.

Related Research Articles

<span class="mw-page-title-main">BCG vaccine</span> Vaccine primarily used against tuberculosis

Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible. In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated. Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well. BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacterial infections. Additionally, it is sometimes used as part of the treatment of bladder cancer.

<span class="mw-page-title-main">Tuberculosis</span> Infectious disease

Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease which, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss. Infection of other organs can cause a wide range of symptoms.

<span class="mw-page-title-main">Mantoux test</span> Immunological method to test for tuberculosis

The Mantoux test or Mendel–Mantoux test is a tool for screening for tuberculosis (TB) and for tuberculosis diagnosis. It is one of the major tuberculin skin tests used around the world, largely replacing multiple-puncture tests such as the tine test. The Heaf test, a form of tine test, was used until 2005 in the UK, when it was replaced by the Mantoux test. The Mantoux test is endorsed by the American Thoracic Society and Centers for Disease Control and Prevention. It was also used in the USSR and is now prevalent in most of the post-Soviet states, although Soviet mantoux produced many false positives due to children's allergic reaction.

<span class="mw-page-title-main">Tuberculosis diagnosis</span>

Tuberculosis is diagnosed by finding Mycobacterium tuberculosis bacteria in a clinical specimen taken from the patient. While other investigations may strongly suggest tuberculosis as the diagnosis, they cannot confirm it.

This is a list of AIDS-related topics, many of which were originally taken from the public domain U.S. Department of Health Glossary of HIV/AIDS-Related Terms, 4th Edition.

Peripheral tuberculous lymphadenitis is a form of tuberculosis infection occurring outside of the lungs. In general, it describes tuberculosis infection of the lymph nodes, leading to lymphadenopathy. When cervical lymph nodes are affected, it is commonly referred to as "Scrofula." A majority of tuberculosis infections affect the lungs, and extra-pulmonary tuberculosis infections account for the remainder; these most commonly involve the lymphatic system. Although the cervical region is most commonly affected, tuberculous lymphadenitis can occur all around the body, including the axillary and inguinal regions.

<span class="mw-page-title-main">Miliary tuberculosis</span> Medical condition

Miliary tuberculosis is a form of tuberculosis that is characterized by a wide dissemination into the human body and by the tiny size of the lesions (1–5 mm). Its name comes from a distinctive pattern seen on a chest radiograph of many tiny spots distributed throughout the lung fields with the appearance similar to millet seeds—thus the term "miliary" tuberculosis. Miliary TB may infect any number of organs, including the lungs, liver, and spleen. Miliary tuberculosis is present in about 2% of all reported cases of tuberculosis and accounts for up to 20% of all extra-pulmonary tuberculosis cases.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with Mycobacterium tuberculosis, but does not have active tuberculosis (TB). Active tuberculosis can be contagious while latent tuberculosis is not, and it is therefore not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these people will go on to develop active tuberculosis. This is particularly true, and there is added risk, in particular situations such as medication that suppresses the immune system or advancing age.

Tuberculosis (TB) vaccines are vaccinations intended for the prevention of tuberculosis. Immunotherapy as a defence against TB was first proposed in 1890 by Robert Koch. Today, the only effective tuberculosis vaccine in common use is the Bacillus Calmette-Guérin (BCG) vaccine, first used on humans in 1921. It consists of attenuated (weakened) strains of the cattle tuberculosis bacillus. It is recommended for babies in countries where tuberculosis is common.

rBCG30 is a prospective vaccine against tuberculosis created by a team headed by Marcus A. Horwitz at UCLA. It is a live vaccine, consisting of BCG genetically modified to produce abundant amounts of a 30kDa antigen that has been shown to produce a strong immune response in animals and humans. The vaccine completed a Phase I double-blind randomized controlled clinical trial that demonstrated that rBCG30 was safe and immunogenic; during nine months of follow-up, rBCG30, but not BCG, induced significantly increased Antigen 85B-specific immune responses in eight immunological assays.

Lipoarabinomannan, also called LAM, is a glycolipid, and a virulence factor associated with Mycobacterium tuberculosis, the bacteria responsible for tuberculosis. Its primary function is to inactivate macrophages and scavenge oxidative radicals.

Interferon-γ release assays (IGRA) are medical tests used in the diagnosis of some infectious diseases, especially tuberculosis. Interferon-γ (IFN-γ) release assays rely on the fact that T-lymphocytes will release IFN-γ when exposed to specific antigens. These tests are mostly developed for the field of tuberculosis diagnosis, but in theory, may be used in the diagnosis of other diseases which rely on cell-mediated immunity, e.g. cytomegalovirus and leishmaniasis and COVID-19. For example, in patients with cutaneous adverse drug reactions, challenge of peripheral blood lymphocytes with the drug causing the reaction produced a positive test result for half of the drugs tested.

<span class="mw-page-title-main">Interferon-gamma receptor</span> Mammalian protein found in Homo sapiens

The interferon-gamma receptor (IFNGR) protein complex is the heterodimer of two chains: IFNGR1 and IFNGR2. It binds interferon-γ, the sole member of interferon type II.

T-SPOT.TB is a type of ELISpot assay used for tuberculosis diagnosis, which belongs to the group of interferon gamma release assays. The test is manufactured by Oxford Immunotec in the UK. It is available in most European countries, the United States as well as various other countries. It was developed by researchers at the University of Oxford in England.

ESAT-6 or Early Secreted Antigenic Target 6 kDa, is produced by Mycobacterium tuberculosis, it is a secretory protein and potent T cell antigen. It is used in tuberculosis diagnosis by the whole blood interferon γ test QuantiFERON-TB Gold, in conjunction with CFP-10.

The antibodies from lymphocyte secretions (ALS) assay is an immunological assay to detect active diseases like tuberculosis, cholera, typhoid etc. Recently, ALS assay nods the scientific community as it is rapidly used for diagnosis of Tuberculosis. The principle is based on the secretion of antibody from in vivo activated plasma B cells found in blood circulation for a short period of time in response to TB-antigens during active TB infection rather than latent TB infection.

The co-epidemic of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major global health challenges in the present time. The World Health Organization (WHO) reports 9.2 million new cases of TB in 2006 of whom 7.7% were HIV-infected. Tuberculosis is the most common contagious infection in HIV-Immunocompromised patients leading to death. These diseases act in combination as HIV drives a decline in immunity while tuberculosis progresses due to defective immune status. This condition becomes more severe in case of multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Tuberculosis can occur at any stage of HIV infection. The risk and severity of tuberculosis increases soon after infection with HIV. A study on gold miners of South Africa revealed that the risk of TB was doubled during the first year after HIV seroconversion. Although tuberculosis can be a relatively early manifestation of HIV infection, it is important to note that the risk of tuberculosis progresses as the CD4 cell count decreases along with the progression of HIV infection. The risk of TB generally remains high in HIV-infected patients, remaining above the background risk of the general population even with effective immune reconstitution and high CD4 cell counts with antiretroviral therapy.

<span class="mw-page-title-main">Lalita Ramakrishnan</span> Indian-American microbiologist

Lalita Ramakrishnan is an Indian-born American microbiologist who is known for her contributions to the understanding of the biological mechanism of tuberculosis. As of 2019 she serves as a professor of Immunology and Infectious Diseases at the University of Cambridge, where she is also a Wellcome Trust Principal Research Fellow and a practicing physician. Her research is conducted at the MRC Laboratory of Molecular Biology, where she serves as the Head of the Molecular Immunity Unit of the Department of Medicine embedded at the MRC LMB. Working with Stanley Falkow at Stanford, she developed the strategy of using Mycobacterium marinum infection as a model for tuberculosis. Her work has appeared in a number of journals, including Science, Nature, and Cell. In 2018 and 2019 Ramakrishnan coauthored two influential papers in the British Medical Journal (BMJ) arguing that the widely accepted estimates of the prevalence of latent tuberculosis—estimates used as a basis for allocation of research funds—are far too high. She is married to Mark Troll, a physical chemist.

Novel Njweipi Chegou is a Cameroonian molecular biologist who is a professor at the Stellenbosch University Immunology Research Group. His research considers pulmonary and extrapulmonary tuberculosis. He leads the Diagnostics Research Laboratory. He was awarded the Royal Society Africa Prize in 2022.

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