Taking TB to the Frontline

N E W S L E T T E R O F F E M S F E D E R AT I O N O F E U RO P E A N M I C RO B I O L O G I C A L S O C I E T I E S

The epidemic of tuberculosis (TB) re-mains one of the greatest global chal-lenges to medicine and public health. It affects 8.8 million people every year with up to 1.5 million deaths. While not only the underprivileged gets TB, most victims do belong to this group that the illness is considered as the affliction of the poor. And rightly so, the World Health Organization’s Global TB Report 2011 pointed to 22 countries from the developing world with the highest rate of TB. The control and ultimate elimination of this disease still rests on prompt diagnosis and therapeutic interven-tion to reduce ongoing transmission. The need to improve efficiency in TB Diagnostics directly in clinical mate-rial on location, in outpatient clinics and at bedside, by reducing time and expense has increased the need for rapid point-of-care testing. This issue of the FEMS Focus will review the magnitude of the TB epidemic, new technologies and trends for TB diag-nostics and highlight the suitability for applications in practice.

Tone Tonjum & Chared Verschuur-Ballo,

Editors

December 2011 No.12

To enlighten us on the issue of tuberculosis (TB), FEMS interviewed Dr Mario Raviglione, Director of the Stop TB Department of the World Health Organization (WHO). The Stop TB Department helps countries implement the WHO Stop TB Strategy, which intends to “dramatically reduce the burden of TB and halve TB deaths and prevalence by 2015”. Dr Raviglione is positive that this can be achieved.

From the Editorial Team

What are the highlights of the 2011 Global TB Report?

Dr Mario Raviglione: There are several highlights in this report. First of all, the report shows that the incidence of tu-berculosis continues to decline although very slowly, 1% per year. Importantly also, the TB incidence rate per capita as well as the absolute numbers of cases are coming down. That is a very posi-tive message. Moreover, revised esti-mates of mortality show less than what we thought until a year ago with a total of 1.4 million deaths estimated in 2010. This number has decreased from the 1.7 million of the year before because

we have better data from a number of countries worldwide showing that in-deed the deaths are less than previously estimated. At the same time, it is im-portant to note that the trend on mor-tality rates suggests that the target that was set a decade ago - of reducing the

number of deaths in the world by half - will be achieved globally, and in all regions of the world with the exception of Africa. This is good news.Bad news is that the incidence is coming down far too slowly to foresee any elimination in the near future.

Photomicrograph of a sputum sample con-taining Mycobacterium tuberculosis. M. tuberculosis bacteria can attack any part of the body, but usually the lungs causing Tuberculosis. It is spread when infected individuals cough or sneeze, releasing microdroplets into the air that contain the bacteria, which others then inhale.Source: CDC

Upon checking the report, we’ve noticed that the top 22 countries with the highest TB burden belong to the developing world, what does this mean?TB is a global disease. It is a real pandemic. There is not one single country in the world that has ever eliminated tuberculosis, not one, so TB is everywhere in the world. This includes western European countries, North America, Japan and every other rich country in the world. However, once you look at the number of cases, you will find that 95% of all cases are in the developing world, including the 22 highest-burden countries highlighted in our new report. Why? Simply because most of the poorest people live in developing countries. When you look at the rich coun-tries, you still find a lot of tuberculosis among their poorest populations; however, the poor-est in those rich countries are a much smaller number than they are in, Africa, India or China for example. That is why TB, being intrinsically linked to poverty, hits the devel-oping world the hardest.

Are there any special programmes being de-veloped to ensure that countries give enough attention to tuberculosis?The world knows that tuberculosis is a disease of the developing world. Our data being pub-lished now in our 16th annual report keeps re-peating the same message every year: develop-ing countries must give focus on the problem of tuberculosis. Most countries in the world now have national tuberculosis programmes.

Many of them benefit today from major fi-nancing mechanisms such as the Global Fund, which has put hundreds of millions of dollars into TB control. However, what we are find-ing out now is that not only is there a financial crisis which puts financing at risk but also that in some parts of the world, namely Africa, the contribution of domestic resources remains very limited. If funding streams from both in-ternational and domestic sources run dry, it is going to be very difficult, actually impossible, to control tuberculosis.

What is the magnitude of the TB epidemic globally? There are 8.8 million new cases every year and there are about 1.4 million deaths. So that is a huge problem. Once you compare it with any other curable disease, you will find out that TB kills more than any other. It also kills nearly like AIDS. A large part of these TB deaths occur in the one-third of es-timated cases, about 3 million people, who have TB and are not diagnosed or picked up by TB programmes. We do not know what is

happening to them and we estimate that the mortality of these might be very high. The total financing for 2012 is in the area of 4.4 billion dollars in terms of TB control.

What is the magnitude of the TB epidemic in Europe? We estimate that of the 8.8 million cases that exist in the world, about 400,000 are in Eu-rope, though we should distinguish between Western and Eastern Europe. In Western Eu-rope, it is an epidemic that is concentrated among the poorest groups, i.e. the migrants,

the homeless and also vulnerable groups like the elderly. There are a lot of elderly people whose immune system inevitably become weaker as they get older. When they were younger, they may have been infected with tuberculosis and had it for many decades but were able to fight off the infection from developing into TB disease. But, as they get older, their immune system can no longer fight back in the same way and they become

increasingly vulnerable to falling ill with ac-tive TB. The same situation can happen with the poorest groups who have poor health. So that is the western European epidemic, lim-ited to the poorest and weakest fragments of the population. You will also find that in big Western European cities, like Lon-don and particularly areas like its East End, there are alarming rates of TB because of poor migrants who have come from high TB prevalent countries. When you go to East-ern Europe, and especially the former USSR countries, the picture is different. Yes you have migration but it is not of the same type and extent of that in Western Europe. It is a disease that is particularly scary because in that part of the world, the epidemic is largely caused by multidrug-resistant tuberculosis, often referred to as MDR-TB.

How many of these cases are due to a MDRTBor XDR-TB strains?XDR-TB, or extensively drug-resistant TB, is a subset of multidrug-resistant TB. You have MDR-TB when you have resistance to the first line, or standard, anti-TB drugs, namely riampicin and isoniazid. If you have further resistance, to the first line and also the sec-ond line anti-TB drugs used to treat MDR-TB, you enter into what is called XDR-TB. Cases of XDR-TB are resistant to basically all first and second line drugs making it virtually untreatable. 10 to 15% of MDR-TB cases is XDR-TB. In a country like Russia, in some oblasts, up to 25% of all cases are MDR and up to 5% of those cases could be XDR-TB.

Why is TB able to spread globally?Because it is a disease that is airborne. Nor-mally you do not acquire TB infection from

Mario C. Raviglione has been Director of the Stop TB Department at the World Health Organization (WHO) since 2003. He joined WHO in 1991 to work on TB/HIV research and TB epidemiology in Europe. He contrib-uted to the development of the DOTS strategy in 1994, and set up the global drug-resistance surveillance project (1994) and the global TB surveillance & monitoring system (1995). In his first decade at WHO, he also worked on experimental regimens for treatment of latent infection in the mouse model (early 1990s), described the feasibility of preventive therapy in Africa (1995), first reported the TB control

crisis in Eastern Europe (1993), and co-devel-oped estimates and projections of the global TB epidemic. Between 1999 and 2003, he was Co-ordinator for Strategy and Operations globally, taking charge particularly of surveillance and programme monitoring; operational research; TB/HIV and multi drug-resistant TB responses; and DOTS expansion worldwide. Currently, as Director of the Stop TB Department of WHO, he is responsible for setting norms, policies and standards on global TB control, coordinating technical support, monitoring the global situa-tion, and developing innovative interventions through translation of new evidence into poli-cies & practice and through addressing system challenges such as community and private sector engagement. As part of this work, he developed the Stop TB Strategy in 2006. He has been a member of the Stop TB Partnership Coordinat-ing Board since its establishment in 2001 and has worked in many countries worldwide. He has published over 250 articles and chapters on the topics of infectious diseases, HIV/AIDS and TB in the most influential health journals and books, including in the last five editions of the prestigious Harrison’s Principles of Internal Medicine and is among the top 10 most cited authors in the TB field. He is editor of the 3rd and 4th (2006, 2009) edition of “Tuberculosis

Source: World Health Organization

• 8.8millionpeoplefellillofTBin2010.• 1.1millionofthesecasesareamongpeoplewithHIV.• 1.4millionpeoplediedfromTBin2010.• 95%ofTBdeathsareinthedevelopingworld.• The22highestTBburdencountriesalsobelongtothe

developingworld.• 9.7 million children were orphaned as a result ofTB

deathsin2009.• 320,000womendiedfromTBin2010.• TBisamongthe3maincausesofdeathamongwomen

aged15-44.• TB death rate has fallen by 40% since 1990. The

numberofdeathsisalsodeclining.• 5.7millionTBcaseswerenotifiedthroughTBDOTSpro-

grammesin2010.• Globally,thepercentageofpeoplesuccessfullytreated

reacheditshighestlevelat87%in2009.• Since 1995, 46 million people have been successfully

treatedandupto6.8millionlivessavedthroughDOTSandtheStopTBStrategy.

• In2010,therewasanestimatedprevalenceof650,000casesofmultidrug-resistantTB(MDR-TB).

• TB can rapidly be diagnosed directly in clinical speci-mens by PCR-mediated detection of M. tuberculosisDNA.

• Worldwide,theshareofdomesticfundingforTBpro-videdbyaffectedcountriesroseto86%.

• 82%ofinternationalTBfundingfor2012isprovidedbytheGlobalFund.

• 10TBdrugs,10vaccinecandidatesand“point-of-care”testsforTBpreventionarecurrentlyinthepipeline.

Source:WHO

TB in numbers

- A comprehensive International Approach”, a landmark multi-author book, and associ-ate editor of other books. As a leading expert in TB, he has served as a visiting professor at Johns Hopkins and Geneva Universities. He is professor at the medical schools of the Univer-sity of Brescia and the University of Modena & Reggio Emilia in Italy. He has lectured at top international health conferences in about 50 countries world-wide and sits in a variety of scientific committees. He has worked as WHO focal point on G8 global health issues in 2009 and on World Health Day 2011 devoted to combating antimicrobial resistance. He graduated from the University of Turin in Italy in 1980, and trained in internal medicine and infectious diseases in New York (where he was Chief Medical Resident at Cabrini’s Medical Centre) and Boston, where he was appointed an AIDS Clinical Research Fellow at Beth Israel Hospital, Harvard Medical School. In 2005, he received the Princess Chichibu TB Global Award for his achievements in TB control. In 2009 he was nominated Fellow of the Royal Academy of Physicians (F.R.C.P., London, UK). In 2010 he received the Wolfheze 20 Year Jubilee Award for his contributions to modern TB control practices in Europe.

short casual contact but if you are in close contact for a relatively prolonged period of time with a person who has infectious TB, you can acquire the infection. More so, TB re-spects no border, so a person who is infectious and travels can transfer TB to another person. TB can spread quickly, especially in poor and crowded areas, among people living with HIV or where many people live crammed together under one roof in a single room. So you just need a father or a mother that has TB and there is a risk that their children may also ac-quire the infection, and later on in their lives fall ill with TB disease themselves.

Is POC diagnostics in TB a priority? Why?It is a top priority for research because that will be the way to diagnose tuberculosis as quickly and effectively as possible. If you have a point-of-care diagnostic, it would be much easier to test a person who has a cough or other important symptoms suggesting TB. Unfortunately, we do not have that yet. We

“Once you compare it with any other curable disease,

you will find out that TB kills more than any other. “

TB can rapidly be diagnosed directly in clini-cal specimens by PCR-mediated detection of M. tuberculosis DNA

Colorized scanning electron micrograph (SEM) depicting some of the ultrastructural details seen in the cell wall configuration of a number of Gram-positive Mycobacterium tuberculosis bacteria. Source: CDC/Janice Haney Carr

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WHO TB page: Stop TB Strategy:

Global TB Control Report 2011:General information on TB:

ECDC Tuberculosis program:

still have today, in the majority of develop-ing countries, the old system of microscopy where you test using a sputum smear and then analyze the smear under a micro-scope and try to identify TB germs. With this method, there is inevitably a good chance cases of TB could be missed. It is also time-consuming because you need to “culture” the sputum and this could take weeks or even months What we obviously need is a diagnostic which allows you to take the blood or sputum from someone who has been coughing and then give them an immediate TB result in a few minutes. That would be a good way to combat tu-berculosis much more effectively because you would be able to detect the case imme-diately and treat the person straight away. This would cure them quickly and avoid them exposing others to infectious TB.

When will it be made available?At the moment, there is no point-of-care technology that gives you a TB result in a few minutes. Researchers are working on it as a priority. However, the expectation is such that we won’t have a point-of-care test before 2015. Today, nevertheless, we have GenXpert, a new technology that allows the diagnosis of TB and of rifampicin drug re-sistance within 100 minutes. It still requires a performing laboratory with electricity and the use of a computer: that is why we cannot consider it yet a real POC machine.

What recent technical advances can facili-tate TB POC diagnostics into reality?It is research that has to look into the po-tential to detect pieces of the mycobacte-rium, whether they are the antigens, or the antibodies that the human body produces when infected with tuberculosis. These have to be studied and have to be analyzed in such a way that we identify some good identifier of disease that can be detected quickly. At the moment, it is essentially ba-sic research that is lacking and that could allow us to understand better how we could ‘spot’ this type of probe so that we can make a TB diagnosis quickly.

What is more important and/or relevant to detect: The bug or the human responses to TB?Both - and this is big a struggle - how to actually find the pieces of the bug or the antigens that would indicate the presence of active tuberculosis in humans. At the

moment we cannot really identify what needs to be detected and where it has to be detected in the human body – whether it is the sputum, or the blood. The other strug-gle is to understand what is the human response to tuberculosis, because human beings develop some sort of immunity to tuberculosis that is however often not suf-ficient to protect them from evolving from infection to disease.

What can we do to prevent TB disease?There are many things that we can do to prevent TB. First, BCG vaccine still works against the most serious forms of tubercu-losis in infants. So BCG has to be given to children as soon as possible, after birth. Second, to prevent TB, there is an effec-tive chemoprophylaxis. There are simple drugs (one or two in combination) that can be given for 6 to 9 months to people infected with tuberculosis. It protects up to 70 percent of people. The procedure is that, if you have TB and you do not know, you can take 6 months of isoniazid (INH). This will get rid of the bacilli that you might be hosting somewhere in your lung and which could produce the disease later on in your life. This will ‘sterilize’ the lungs from the bugs. The problem is that it is administered to people who are feeling perfectly well so it is very difficult to get them to complete a full course of this type of treatment without an intensive support

and follow-up. Chemoprophylaxis is rec-ommended especially among people living with HIV because they are at a very high risk of developing tuberculosis. The third one, as we always say, is good control TB practices. Good TB control is diagnosing TB rapidly and putting the person with TB on treatment as quickly as possible. By doing this, you make the person non-infectious and non-contagious within a matter of two or three weeks. Since you prevent the spread of the infection to oth-ers in the family or in the community, it is considered the most cost-effective way of preventing TB. #

Global TB Control Report 2011

The World Health Organization recently published the sixteenth global report on tuberculosis (TB). The series started in 1997. It provides a comprehensive and up-to-date assessment of the TB epidemic and progress in implementing and financing TB prevention, care and control at global, regional and country levels using data reported by 198 countries that account for over 99% of the world’s TB cases. Printed copies of the report have been made available from 31 October. You may access the full report on:http://bit.ly/WHO_IB.

WHO publishes Global TB Control 2011 report

The World Health Organization recently published the sixteenth global report on tuberculosis (TB). The series started in 1997. It provides a comprehensive and up-to-date assessment of the TB epidemic and

nancing TB prevention, care and control at global, regional and country levels using data reported by 198 countries that account for over 99% of the world’s TB cases.Printed copies of the report have been made available from 31 October. You