BCG vaccine explained

Type:vaccine
Target:Mycobacterium tuberculosis
Vaccine Type:attenuated
Tradename:BCG Vaccine, BCG Vaccine AJV
Dailymedid:BCG_Vaccine
Routes Of Administration:Percutaneous, intravesical, intradermal
Atc Prefix:J07
Atc Suffix:AN01
Legal Au:S4
Legal Au Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:/ Schedule D[2] [3]
Legal Uk:POM
Legal Uk Comment:[4]
Legal Us:Rx-only
Legal Us Comment:[5]
Legal Status:Rx-only[6]
Drugbank:DB12768
Chemspiderid:none
Unii:8VJE55B0VG
Unii2:5H5854UBMZ
Kegg:D03063
Kegg2:D06466

The Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB).[7] It is named after its inventors Albert Calmette and Camille Guérin.[8] [9] In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible.[7] 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.[7] Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well.[7] 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.[10] [11]

Rates of protection against tuberculosis infection vary widely and protection lasts up to 20 years. Among children, it prevents about 20% from getting infected and among those who do get infected, it protects half from developing disease. The vaccine is given by injection into the skin. No evidence shows that additional doses are beneficial.

Serious side effects are rare. Often, redness, swelling, and mild pain occur at the site of injection. A small ulcer may also form with some scarring after healing. Side effects are more common and potentially more severe in those with immunosuppression. Although no harmful effects on the fetus have been observed, there is insufficient evidence about the safety of BCG vaccination during pregnancy and therefore the vaccine is not recommended for use during pregnancy. The vaccine was originally developed from Mycobacterium bovis, which is commonly found in cattle. While it has been weakened, it is still live.

The BCG vaccine was first used medically in 1921. It is on the World Health Organization's List of Essential Medicines.[12], the vaccine is given to about 100 million children per year globally.[13] However, it is not commonly administered in the United States.[14] [15]

Medical uses

Tuberculosis

See also: Tuberculosis vaccines.

The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally.[16] BCG vaccination can cause a false positive Mantoux test.[17]

The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.

A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%.[18] Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.[19]

A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%.[20] The studies included in this review were limited to those that used interferon gamma release assay.

The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.[21]

BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.[22]

The 100th anniversary of BCG was in 2021. It remains the only vaccine licensed against tuberculosis, which is an ongoing pandemic. Tuberculosis elimination is a goal of the World Health Organization (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.[23]

Efficacy

A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.[24]

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.[25]
  2. Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in Birmingham, United Kingdom, examined children born to families who originated from the Indian subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.[26]
  3. Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially Mycobacterium avium, Mycobacterium marinum and Mycobacterium intracellulare) results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will, therefore, appear not to be efficacious because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi.[27] In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known.[28] An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.[29]
  4. Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites such as helminthiasis changes the immune response to BCG, making it less effective.[30] As Th1 response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.[31]

Mycobacteria

BCG has protective effects against some nontuberculosis mycobacteria.

Cancer

See also: Cancer immunotherapy, Cancer vaccine and Coley's toxins.

BCG has been one of the most successful immunotherapies.[33] BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977.[34] By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer.

Method of administration

A pre-injection tuberculin skin test is usually carried out before administering BCG. A reactive tuberculin skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have IL-12 receptor pathway defects.[37]

BCG is given as a single intradermal injection at the insertion of the deltoid. If BCG is accidentally given subcutaneously, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with antibiotics immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.[38]

The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of smallpox vaccination, which it may resemble.[37]

When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter.[39]

Adverse effects

BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids—large, raised scars. The insertion to the deltoid muscle is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.[37]

BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional lymph nodes, causing either suppurative (production of pus) and nonsuppurative lymphadenitis. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration. For nonresolving suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce.[40]

Uncommonly, breast and gluteal abscesses can occur due to haematogenous (carried by the blood) and lymphangiomatous spread. Regional bone infection (BCG osteomyelitis or osteitis) and disseminated BCG infection are rare complications of BCG vaccination, but potentially life-threatening. Systemic antituberculous therapy may be helpful in severe complications.[41]

When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection,[42] however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon.[43] When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation).[44]

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with severe combined immune deficiency), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given.[45] In 2007, the WHO stopped recommending BCG for infants with HIV, even if the risk of exposure to tuberculosis is high,[46] because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).[47] [48]

Usage

The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO currently recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden. This is a partial list of historic and current BCG practice around the globe. A complete atlas of past and present practice has been generated.

Americas

Europe

BCG vaccine in Europe!Country!Mandatory now!Mandatory in the past!Years vaccine was mandatory
[54] 1952–1990
[55] N/A
1950–present
[56] 1951–present
1948–present
[57] 1953–2010
[58] 1946–1986
?–present
[59] 1941–2006
[60] [61] [62] 1950–2007
[63] 1961–1998 (East Germany began 1951)
[64] [65] ?–2016
[66] [67] 1953–present
[68] 1950s–2015
N/A
1940s–present
?–present
?–present
?-1979
1950–present
[69] 1947–1995, voluntary 1995–2009
1955–present
[70] ?–2016
[71] 1928–present
1962–present
1928–present
1953–2012
1947–2005
[72] 1965–1981
[73] 1940–1975
1960s–1987
[74] 1952–present
[75] ?–present
[76] [77] [78] [79] N/A

Asia

Middle East

Africa

South Pacific

Manufacture

BCG is prepared from a strain of the attenuated (virulence-reduced) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually Middlebrook 7H9.[94] Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.[95]

A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by Schering-Plough, and in turn acquired by Merck & Co.). A similar application is the product of Onko BCG[96] of the Polish company Biomed-Lublin, which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain,[97] was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals). Statens Serum Institut in Denmark has marketed BCG vaccine prepared using Danish strain 1331. The production of BCG Danish strain 1331 and its distribution was later undertaken by AJVaccines company since the ownership transfer of SSI's vaccine production business to AJ Vaccines Holding A/S which took place on 16 January 2017.[98] [99] Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.

According to a UNICEF report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2 million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018."

Supply shortage

In 2011, the Sanofi Pasteur plant flooded, causing problems with mold. The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug.[100] By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines.[101] On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG. A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers.[102]

Dried

Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting.[103]

History

The history of BCG is tied to that of smallpox. By 1865 Jean Antoine Villemin had demonstrated that rabbits could be infected with tuberculosis from humans;[104] by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits.[105] Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or "virus", as he called it).[106] [107] In 1882 Robert Koch regarded human and bovine tuberculosis as identical.[108] But in 1895, Theobald Smith presented differences between human and bovine tuberculosis, which he reported to Koch.[109] [110] By 1901 Koch distinguished Mycobacterium bovis from Mycobacterium tuberculosis.[111] Following the success of vaccination in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and cowpox: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using M. bovis were conducted in Italy with disastrous results, because M. bovis was found to be just as virulent as M. tuberculosis.[112]

Albert Calmette, a French physician and bacteriologist, and his assistant and later colleague, Camille Guérin, a veterinarian, were working at the Institut Pasteur de Lille (Lille, France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.[113]

Public acceptance was slow, and the Lübeck disaster, in particular, did much to harm it. Between 1929 and 1933 in Lübeck, 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.[114]

Dr. R. G. Ferguson, working at the Fort Qu'Appelle Sanatorium in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from residential schools were used as involuntary participants in BCG vaccine trials between 1933 and 1945.[115] In 1928, BCG was adopted by the Health Committee of the League of Nations (predecessor to the World Health Organization (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war.[116]

BCG is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed BCG from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).[117] [118]

Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".[119]

Research

Tentative evidence exists for a beneficial non-specific effect of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including sepsis and respiratory infections when given early,[120] with greater benefit the earlier it is used.[121]

In rhesus macaques, BCG shows improved rates of protection when given intravenously.[122] [123] Some risks must be evaluated before it can be translated to humans.[124]

The University of Oxford Jenner Institute is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.[125]

Type 1 diabetes

, BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D).[126] [127]

COVID-19

Use of the BCG vaccine may provide protection against COVID-19.[128] [129] However, epidemiologic observations in this respect are ambiguous.[130] The WHO does not recommend its use for prevention .[131]

, twenty BCG trials are in various clinical stages.[132], the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes.[133] On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were double-blind randomized controlled trials.[134]

External links

Notes and References

  1. Web site: Summary for ARTG Entry:53569 BCG VACCINE Mycobacterium bovis (Mycobacterium bovis (Bacillus Calmette and Guerin (BCG) strain) (BCG) strain) 1.5mg powder for injection multidose vial with diluent vial . Therapeutic Goods Administration (TGA) .
  2. Web site: Regulatory Decision Summary - Verity-BCG . Health Canada . 23 October 2014 . 5 June 2022 . 5 June 2022 . https://web.archive.org/web/20220605182527/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00744 . live .
  3. Web site: Verity-BCG Product information . Health Canada . 25 April 2012 . 5 June 2022.
  4. Web site: BCG Vaccine AJV - Summary of Product Characteristics (SmPC) . (emc) . 21 September 2020 . 10 August 2020 . https://web.archive.org/web/20200810163558/https://www.medicines.org.uk/emc/product/9890 . live .
  5. Web site: BCG Vaccine- bacillus Calmette–Guerin substrain TICE live antigen injection, powder, lyophilized, for solution . DailyMed . 3 September 2020 . 21 September 2020.
  6. Yamamoto S, Yamamoto T . Historical review of BCG vaccine in Japan . Japanese Journal of Infectious Diseases . 60 . 6 . 331–336 . November 2007 . 18032829 . 10.7883/yoken.JJID.2007.331.
  7. ((World Health Organization)) . BCG vaccines: WHO position paper – February 2018 . Weekly Epidemiological Record . 93 . 8 . 73–96 . February 2018 . 29474026 . 10665/260307 . free .
  8. Hawgood BJ . Albert Calmette (1863-1933) and Camille Guérin (1872-1961): the C and G of BCG vaccine . Journal of Medical Biography . 15 . 3 . 139–146 . August 2007 . 17641786 . 10.1258/j.jmb.2007.06-15 . 41880560 .
  9. Luca S, Mihaescu T . History of BCG Vaccine . Maedica . 8 . 1 . 53–58 . March 2013 . 24023600 . 3749764 .
  10. Fuge O, Vasdev N, Allchorne P, Green JS . Immunotherapy for bladder cancer . Research and Reports in Urology . 7 . 65–79 . May 2015 . 26000263 . 4427258 . 10.2147/RRU.S63447 . free .
  11. Houghton BB, Chalasani V, Hayne D, Grimison P, Brown CS, Patel MI, Davis ID, Stockler MR . Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: a systematic review with meta-analysis . BJU International . 111 . 6 . 977–983 . May 2013 . 23253618 . 10.1111/j.1464-410X.2012.11390.x . 24961108 .
  12. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  13. 23 January 2004. BCG Vaccine: WHO position paper. Weekly Epidemiological Record. 4. 79. 25–40. live. https://web.archive.org/web/20150921165240/http://www.who.int/wer/2004/en/wer7904.pdf. 21 September 2015.
  14. Web site: The Role of BCG Vaccine in the Prevention and Control of Tuberculosis in the United States A Joint Statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices . www.cdc.gov . In the United States, the use of BCG vaccination is rarely indicated. BCG vaccination is not recommended for inclusion in immunization or TB control programs, and it is not recommended for most HCWs. Physicians considering the use of BCG vaccine for their patients are encouraged to consult the TB control programs in their area. . 23 July 2024 . 23 July 2024 . https://web.archive.org/web/20240723024657/https://www.cdc.gov/MMWR/PREVIEW/MMWRHTML/00041047.htm . live .
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  16. Web site: FREEZE - DRIED GLUTAMATE BCG VACCINE (JAPAN) FOR INTRADERMAL USE . https://web.archive.org/web/20211019034749/https://www.who.int/immunization_standards/vaccine_quality/68_bcg.pdf . 19 October 2021 . live . World Health Organization . 18 November 2021 . English.
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  23. Web site: Tuberculosis kills as many people each year as COVID-19. It's time we found a better vaccine. Kupz A. The Conversation. 14 January 2021. 18 June 2021. 24 June 2021. https://web.archive.org/web/20210624201633/https://theconversation.com/tuberculosis-kills-as-many-people-each-year-as-covid-19-its-time-we-found-a-better-vaccine-151590. live.
  24. Fine PE, Carneiro IA, Milstein JB, Clements CJ . Chapter 8: Reasons for variable efficacy . Issues relating to the use of BCG in immunization programmes: a discussion document . http://whqlibdoc.who.int/hq/1999/WHO_V%26B_99.23.pdf . 1999 . World Health Organization . Geneva, Switzerland . 10665/66120 . free . WHO/V&B/99.23 . 17 February 2014 . 20 February 2011 . https://web.archive.org/web/20110220232037/http://whqlibdoc.who.int/hq/1999/WHO_V%26B_99.23.pdf . live .
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  30. Natukunda A, Zirimenya L, Nassuuna J, Nkurunungi G, Cose S, Elliott AM, Webb EL . The effect of helminth infection on vaccine responses in humans and animal models: A systematic review and meta-analysis . Parasite Immunology . 44 . 9 . e12939 . September 2022 . 35712983 . 9542036 . 10.1111/pim.12939 .
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  33. Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, Lagranderie M, Marchal G, Orgeur M, Bouchier C, Bachmann A, Ingersoll MA, Brosch R, Albert ML, Thalmann GN . Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy . European Urology . 66 . 4 . 677–688 . October 2014 . 24674149 . 10.1016/j.eururo.2014.02.061 .
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