Emil von Behring: The Founder of Serum Therapy.

Upbringing and Education

Emil Behring (1854-1917) was born on March 15, 1854 in Hansdorf, West Prussia, as the first child of the couple August and Auguste Behring. His father was a village school teacher, who during his first marriage had had four children and after the birth of Emil had another eight children.

A talented pupil, Emil Behring was above all assisted by the village minister, who made it possible for him to attend the Gymnasium (High School) in the village Hohenstein. His orientation as a theology student appeared to have changed after a friend who was a military doctor arranged for him to start his medical studies at the University of Berlin. He obtained a scholarship and from 1874 through 1878 he studied at the Academy for Military Doctors at the Royal Medical-Surgical Friedrich-Wilhelm-Institute, where he also earned his medical degree. In the following years he had to perform as a military doctor and also worked as a troop doctor in various garrisons. After having been assigned as captain of the medical corps to the Pharmacological Institute at the University of Bonn, he was given a position at the Hygiene Institute of Berlin in 1888 as an assistant to Robert Koch (1843-1910), one of the pioneers of bacteriology. During this time, Behring’s first authoritative publication on diphtheria and tetanus serum therapy appeared.

Emil von Behring in a military uniform.
Photo: Courtesy of Aventis Behring

The Behring Family

During his early years as a military doctor, Behring’s income was not sufficient for him to think about starting a family. Only in 1896, when he had a regular salary, did he marry the 20 year old Else Spinola. They went on a three-month honeymoon to the island of Capri. Else, born August 30, 1876 in Berlin, was the daughter of Werner Spinola, Administrative Director of Charité, the university medical clinic in Berlin.

In 1898, after having become professor at the University in Marburg (then part of Prussia), Behring moved with his family into a house in Wilhelm-Roser-Strasse in Marburg, where his six sons were born. Behring was a family man, though rather patriarchal, which at that time was quite normal. In the circle of his family he felt content, although his scientific work presumably did not leave him much time for his wife and children.

wedding photo
Wedding picture of Emil and Else von Behring.
Photo: Courtesy of Aventis Behring

On March 31, 1917, Behring died and was entombed in a mausoleum at the Marburg Elsenhöhe. After Behring’s death, Else von Behring served as chairwoman of the Women’s National Organisation in Marburg, Germany. She died in 1936 of a heart attack at the age of only 59.

Family and Friends

On the list of his sons’ godfathers, it appears obvious who stood closest to Emil von Behring besides his family. His first son, Fritz, had the bacteriologist Friedrich Loeffler (1852-1915) and Behring’s friend and co-worker, Erich Wernicke as godfathers. The godfather of his third son, Hans, was the Prussian Under-Secretary of Education and Cultural Affairs, Friedrich Althoff. His fifth son, Emil, had as a godfather the Russian researcher Elias Metschnikoff (1845-1916), founder of the theory of phagocytosis, with whom Behring had continuous scientific exchange of ideas. Emil’s second godfather was the pupil of Louis Pasteur, Émile Roux (1853-1933), who like Behring Sr. dealt with the fight against diphtheria. In 1913, the godfather of his sixth son, Otto, was the physician Ludolph Brauer (1865-1951), who had taught together with Behring at the Marburg Medical Faculty as a professor of internal medicine.

The Development of the Diphtheria-Therapeutic-Serum

Behring, who in the early 1890s became an assistant at the Institute for Infectious Diseases, headed by Robert Koch, started his studies with experiments on the development of a therapeutic serum. In 1890, together with his university friend Erich Wernicke, he had managed to develop the first effective therapeutic serum against diphtheria. At the same time, together with Shibasaburo Kitasato he developed an effective therapeutic serum against tetanus.

Behring and colleagues
Behring together with his colleagues Wernicke (left) and Frosch (center) in Robert Koch’s laboratory in Berlin.
Photo: Courtesy of Aventis Behring

The researchers immunized rats, guinea pigs and rabbits with attenuated forms of the infectious agents causing diphtheria and alternatively, tetanus. The sera produced by these animals were injected into non-immunized animals that were previously infected with the fully virulent bacteria. The ill animals could be cured through the administration of the serum. With the blood serum therapy, Behring and Kitasato firstly used the passive immunization method in the fight against infectious diseases. The particularly poisonous substances from bacteria – or toxins – could be rendered harmless by the serum of animals immunized with attenuated forms of the infectious agent through antidotes or antitoxins.

Shibasaburo Kitasato.
Photo: Courtesy of Aventis Behring

The Introduction of Serum Therapy

The first successful therapeutic serum treatment of a child suffering from diphtheria occurred in 1891. Until then more than 50,000 children in Germany died yearly of diphtheria. During the first few years, there was no successful breakthrough for this form of therapy, as the antitoxins were not sufficiently concentrated. Not until the development of enrichment by the bacteriologist Paul Ehrlich (1854-1915) along with a precise quantification and standardization protocol, was an exact determination of quality of the antitoxins presented and successfully developed. Behring subsequently decided to draw up a contract with Ehrlich as the foundation of their future collaboration. They organized a laboratory under a railroad circle (Stadtbahnbogen) in Berlin, where they could then obtain the serum in large amounts by using large animals – first sheep and later horses.

In 1892, Behring and the Hoechst chemical and pharmaceutical company at Frankfurt/Main, started working together, as they recognized the therapeutic potential of the diphtheria antitoxin. From 1894, the production and marketing of the therapeutic serum began at Hoechst. Besides many positive reactions, there was also noticeable criticism. Resistance, however, was soon put aside, due to the success of the therapy.

The Marburg Years

Behring was given the opportunity to start a university career through one of the leading officers (Ministerialrat) of the Prussian Ministry of Education and Cultural Affairs, Friedrich Althoff (1839-1908), who wanted to improve the control of epidemics in Prussia by supporting bacteriological research. After a short period as professor at the University of Halle-Wittenberg, Behring was recruited by Althoff to take over the vacant chair in hygiene at Philipps Marburg University on April 1, 1895. His appointment as full professor followed shortly thereafter against the will of the faculty, who besides all of Behring’s outstanding discoveries, wanted a university lecturer who would broadly represent the field. However, Althoff rejected all counterproposals and Behring took over as Director of the Institute of Hygiene at Marburg. His position included giving lectures for hygiene and concurrently held a teaching contract in the history of medicine. In 1896, the Marburg Institute of Hygiene moved to a building on a road nearby Pilgrimstein Road, previously the Surgery Clinic. Behring divided the Institute into two departments, a Research Department for Experimental Therapy and a Teaching Department for Hygiene and Bacteriology. He remained Director of the Institute until his retirement as professor in May 1916.

Scientific Contacts

Behring belonged to a scientific discussion group called “The Marburg Circle” (das Marburger Kränzchen), whose other members were the zoologist Eugen Korschelt (1858-1946), the surgeon Paul Friedrich (1864-1916), the botanist Arthur Meyer (1850-1922), the physiologist Friedrich Schenk (1862-1916), the pathologist Carl August Beneke (1861-1945) and the pharmacologist August Gürber (1864-1937). They often met at Behring’s home where they had rounds of vivid and prolific scientific discussions.

Active Protective Vaccination against Diphtheria

Old vials (1897 and 1906) with hand-written labels.
Photo: Courtesy of Aventis Behring

The therapeutic serum developed by Behring prevented diphtheria for only a short period of time. In 1901, Behring, therefore, for the first time, used a diphtheria innoculation of bacteria with reduced virulence. With this active immunization he hoped to help the body also produce antitoxins. As a supporter of the humoral theory of immune response, Behring believed in the long-term protective action of these antitoxins found in serum. It is well-established knowledge today that active vaccination stimulates the antitoxin (antibody) producing cells to full function.

The development of an active vaccine took a few years. In 1913, Behring went public with his diphtheria protective agent, T.A. (Toxin-Antitoxin). It contained a mixture of diphtheria toxin and therapeutic serum antitoxin. The toxin was meant to cause a light general response of the body, but not to harm the person who is vaccinated. In addition, it was designed to provide long-term protection. The new drug was tested at various clinics and was proven to be non-harmful and effective.

Tetanus Therapeutic Serum during World War I

In 1891, tetanus serum was introduced considerably more quickly in clinical practices than the diphtheria serum. The Agricultural Ministry supported research efforts to develop a therapeutic agent against tetanus to protect agriculturally valuable animals. The large amounts of serum required were obtained through the immunization of horses. However, there was no substantial clinical testing on humans; this led the Military Administration to accept it only on a small scale at the beginning of World War I.

During the first months of the war, this restraint led to massive losses of human lives. Also, after the distribution of the tetanus antitoxins in the military hospitals, many futile attempts at therapy were noted. At the end of 1914, as a result of Behring’s constructive assistance, the injection of serum was established as preventing disease. Starting in April 1915, the mistakes in dosage and the shortage of supplies were overcome and the numbers of sick fell dramatically. Behring was declared “Saviour of the German Soldiers” and was awarded the the Prussian Iron Cross medal.

Historical engraving showing how the medicinal serum was obtained from immunized horses.
Photo: Courtesy of Aventis Behring

An Attempt to Develop a Therapeutic Method against Tuberculosis

After Robert Koch had failed with his tuberculosis therapy in 1893, Behring began to search for an effective therapeutic agent against this disease. However, very soon, he had to admit that combating tuberculosis using a healing serum was not feasible. Therefore, he concentrated on working on a preventive vaccination, which, however, required precise knowledge of the mechanism of infection. In Behring’s view, the tubercle bacillus was transmitted to children through the milk of a mother or a cow infected with tuberculosis. He then started treating milk with formaldehyde, so as to eliminate this source of infection. This procedure was not accepted due to the bad smell of the milk. Moreover, the transmission of tubercle bacilli through the respiratory tract was proven to be more likely than through the digestive system, as had been claimed by Behring.

From 1903, Behring worked on active immunization through attenuated tuberculosis infectious agents, which he then tried on cows, however, with only moderate success. His aim was to obtain a protective and therapeutic agent for humans. A number of agents (tuberculase, tulase, tulaseactin, tulon) failed to make a breakthrough. At the beginning of World War I, Behring halted his efforts to combat tuberculosis and dedicated himself entirely to the further development of tetanus serum.

Behring’s Relationship to Paul Ehrlich

Paul Ehrlich was Behring’s colleague at Robert Koch’s institute. Here, he was able to work out a reliable and reproducible standardization method for diphtheria serum. However, in later years, tension developed between the two researchers. Differences with Ehrlich’s pupil, Hans Aronson, resulted in bad feelings, which increased when Ehrlich’s Royal Institute of Experimental Therapy was founded at Frankfurt/Main. The previous friendship between the two researchers never fully succumbed, through the mediation of Friedrich Althoff. However, it was subsequently demonstrated that the only photograph showing Behring and Ehrlich together, which appeared on the cover of a Berlin newspaper on the occasion of their 60th birthday in 1914, was a photomontage made up of two separate photographs.

Report of the Berliner Illustrirte Zeitung (Berlin Illustrated Newspaper) about Emil von Behring and Paul Erlich and their work on the occasion of their 60th birthday.
Photo: Courtesy of Aventis Behring

Behring’s Health

Behring lived entirely for his idea of revolutionizing medicine through serum therapy. This idea hung above him and motivated him, in his own words, “like a demon.” His enormous concentration on his work often drove him to physical illnesses, as well as to deep depressions, which forced him to take time off work for a sanatorium stay from 1907 through 1910.

Acknowledgements and Honors

In 1903, Emil von Behring was given the title of “Wirklicher Geheimer Rat mit dem Prädikat Excellenz” by the German emperor Wilhelm II. The diploma says: “This is in order that Behring should remain in unbroken loyalty to Myself and the Royal Family and to fulfill his official responsibility with continuous eagerness, whereby he who has the right connected to his present character, will receive the highest protection by Myself”. A splendid uniform was provided along with the title.

In 1901, when the Nobel Prizes were awarded for the first time, Behring received the Prize in Physiology or Medicine.

A detail (right) and the diploma for the first Nobel Prize in Physiology or Medicine, awarded to Behring in 1901.
Photo: Courtesy of Aventis Behring

Behring Jubilee in 1940

On December 4, 1940, the Philipps University Marburg celebrated the 50th anniversary of the original publication of Emil von Behring’s decisive discovery of serum therapy. Top leaders of the National Socialist Party, the rectors of numerous German universities, representatives of the Behringwerke and many scientists and friends of Emil von Behring from abroad were also present. The celebration, which continued over a few days, began with lectures and addresses by officials, both of the state and party. Finally, a foundation certificate for a new Institute for Experimental Therapy was handed over. The professors then moved from the university auditorium (Aula), to unveal a new Behring Memorial close to the St. Elisabeth Church. The celebration was followed by a two-day scientific meeting, presenting the state of the art of immunology and the fight against infectious diseases.

The Background of the Celebration

In the view of the National Socialists, Else von Behring was regarded as a “half-Jew”, as her mother came from a Jewish family. With the help of a number of friends she was able to get her sons accepted by Hitler as “Aryans” and not stigmatized as “half-breeds”. After the death of Else von Behring in 1936, no obstacles were left for the Nazi party to use Emil von Behring as a glorified representative of national socialist “Germanic” science. During the ceremony there were, however, some signs of tension. Although one of Behring’s sons participated in the ceremony, he was not greeted by any of the official speakers. Only the Danish researcher, Thorvald Madsen from Copenhagen, who had previously been chairman of the Health Organisation of the League of Nations, dared to mention Behring’s friendly connection with researchers from enemy countries, such as those at the Institut Pasteur in Paris. Courageously, he also recalled the great bacteriologist Paul Ehrlich, despised by the Nazis due to his Jewish origin, who had played a significant role in Behring’s successes.

Factbox: A look at the Nobel Medicine Prize.

Here is a look at the 2012 Nobel Prize for Physiology or Medicine, which was awarded jointly on Monday to John B. Gurdon and Shinya Yamanaka.

* The 2012 prize was awarded “for the discovery that mature cells can be reprogrammed to become pluripotent”. The two scientists discovered that mature, specialized cells can be reprogrammed to become immature cells capable of developing into all tissues of the body. Their findings revolutionized understanding of how cells and organisms develop.

* Nobel Prizes in Physiology or Medicine have been awarded 102 times since 1901. In all but 38 cases they were given to more than one recipient.

* Of the 199 individuals awarded the Nobel Prize in Physiology or Medicine, only ten are women. Of these eight, Barabara McClintock is the only one who has received an unshared Nobel Prize.

* Famous Winners: Robert Koch, the German physician and bacteriologist, won in 1905 for his work on tuberculosis. Frederick Banting, the Canadian physiologist who with his assistant Charles Best discovered insulin, the principal remedy for diabetes, won the prize in 1923.

* The oldest living recipient is Rita Levi-Montalcini, the first Nobel laureate to reach her hundredth birthday, who won the prize in 1986 with Stanley Cohen for their discoveries of growth factors. She celebrated her 103rd birthday last April.

Sources: Reuters, http://nobelprize.org.


CDC Grand Rounds: the TB/HIV Syndemic.

CDC Grand Rounds: the TB/HIV Syndemic.

This is another in a series of occasional MMWR reports titled CDC Grand Rounds. These reports are based on grand rounds presentations at CDC on high-profile issues in public health science, practice, and policy. Information about CDC Grand Rounds is available at http://www.cdc.gov/about/grand-rounds.

Since Robert Koch‘s 1882 discovery of Mycobacterium tuberculosis, substantial progress has been made in tuberculosis (TB) control. Nevertheless, in the latter part of the 20th century, a long period of neglect of both quality program implementation and research led to persistently high TB incidence rates and failure to develop new tools to adequately address the problem. Today, most of the world continues to rely on the same diagnostic test invented by Koch approximately125 years ago and on drugs developed 40 years ago. The world now faces a situation in which approximately 160 persons die of TB each hour (1.45 million died in 2009), in which a quarter of all deaths in persons with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (PWHA) are caused by TB, and in which the evolution of the bacteria has outpaced the evolution of its treatment to such an extent that some forms of TB are now untreatable (1). More recently, renewed attention has been given to reducing the global burden of TB (2), but much remains to be done.

Misconceptions Regarding TB

Misconceptions about TB infection and disease impede patient care, program implementation, and policy innovation. The first misconception is that TB infection and TB disease are the same. For TB disease prevention and control purposes, the global population can be divided into three discrete groups: those without TB infection, those with TB infection, and those whose TB infection has developed into TB disease. The lifetime risk that a person with TB infection will develop TB disease is 5%–10%; that risk is much higher among PWHA (3,4). A successful control strategy must, therefore, address each group.

A second misconception about TB is that it is no longer a major public health problem. In fact, of the 7 billion persons in the world, 2.3 billion are already infected with TB, and about 9 million develop TB disease each year. Furthermore, TB causes about 1.4–2 million deaths annually (Figure 1) (1).

A third misconception is that TB can be diagnosed easily by a physician or laboratory. To diagnose TB infection, only two tests are validated currently: the tuberculin skin test (TST) and the interferon gamma blood test. Unfortunately, TST is neither sensitive nor specific for TB infection, and both tests can be difficult to implement in resource-limited settings. To diagnose TB disease, most laboratories examine sputum with a microscope to look for TB bacilli, the same approach that Koch invented. In PWHA, the sensitivity of microscopic examination is low, approximately 40% (5–7). Given the high risk for death in PWHA who have untreated TB, this low sensitivity is a critical challenge that must be addressed. Culture of sputum for M. tuberculosis is considered the gold standard test, but it is difficult to use and, in resource-limited settings, challenging to implement. Culturing M. tuberculosis, a slow-growing airborne pathogen, requires laboratories that employ high levels of biosafety and specialized technicians. In 2010, the Xpert MTB/Rif assay, a sensitive, easy-to-use, polymerase chain reaction (PCR)–based test was validated. With no need for sophisticated biosafety or specialized technicians and a turn-around time of 2 hours for both TB diagnosis and detection of drug resistance, this assay has the potential to improve TB control in the developing world (8). Limiting its current use is the relatively high cost of the necessary equipment and supplies, a lack of evidence that the assay’s use is feasible in routine practice, and the fact that it has not yet been demonstrated to improve patient outcomes in resource-limited settings.

TB/HIV Syndemic*

TB and HIV act synergistically within a population to cause excess morbidity and mortality. PWHA are more likely to develop TB disease because of their immunodeficiency; HIV infection is the most powerful risk factor for progressing from TB infection to disease (4). Diagnosing TB disease among PWHA is particularly challenging because PWHA who have pulmonary TB frequently have negative sputum smears and up to one third might have completely normal chest radiographs (5). Furthermore, TB in PWHA often occurs outside the lungs, evading traditional diagnostic tests. Because TB is both common and difficult to diagnose, many PWHA feel ill but are unaware that they have TB. A recent review found that when systematic efforts were undertaken to diagnose TB, approximately 8% of patients who went to HIV care and treatment facilities were found to have TB disease (9), although the exact proportion varies substantially depending on the epidemiology of TB in the area. Finally, TB is a frequent cause of death for PWHA, particularly if HIV disease is advanced and antiretroviral therapy (ART) has not yet been initiated. Persons with both diseases must adhere to complex drug regimens that might interact with each other and might have overlapping toxicities.

Combating the Dual Burden of Disease

TB disease and death can be prevented in PWHA by early TB diagnosis and effective treatment of both diseases. Early diagnosis and treatment ensure that TB treatment is provided before the illness reaches an advanced stage, thereby decreasing mortality, and ensures that the duration of infectiousness is limited, thereby reducing transmission of TB to others. TB disease also can be prevented by treating persons with TB infection. Treatment of TB infection requires reliably excluding the presence of TB disease to avoid the development of drug resistance; drug resistance could emerge if a patient receives a single drug to treat TB infection when the patient, in fact, requires a multidrug regimen to treat TB disease.

Until recently, no internationally accepted, evidence-based, sensitive approach existed to screen PWHA for TB disease, although some preliminary data had begun to suggest that commonly used approaches were inadequate. CDC investigators partnered with the U.S. Agency for International Development (USAID), ministries of health, and nongovernmental organizations in three Southeast Asian countries to derive a TB screening algorithm that would solve this problem. This study concluded that asking patients about three symptoms (i.e., cough, fever of any duration, or night sweats lasting longer than 3 weeks) accurately categorized PWHA for targeted interventions. Patients with none of these three symptoms can be considered free of TB disease and offered treatment to prevent TB disease, if indicated; patients with at least one of these symptoms should have further diagnostic tests performed for TB disease (5,6) These criteria mark a significant improvement over the 2007 World Health Organization (WHO) guidelines in which screening was based primarily on the presence of chronic cough (10). Screening for cough lasting more than 2 weeks was only 33% sensitive for TB disease in this study; screening for the combination of symptoms increased sensitivity to 93% (Figure 2) (5). The increased sensitivity under the new criteria will lead to fewer missed diagnoses of TB disease, at the cost of requiring TB diagnostic evaluation for more people.

Although this approach simplifies TB screening, a comparable approach for simplifying diagnosis of TB disease remains elusive. In the same study, investigators learned that adding liquid culture of two sputum specimens more than doubled the yield of TB case detection among PWHA, compared with microscopic examination alone of the same two sputum specimens, as recommended by WHO at the time (76% versus 31% sensitivity) (6). Unfortunately, liquid culture is not widely available in resource-poor settings and requires high levels of training, biosafety, and supervision. It is hoped that introduction of the Xpert MTB/Rif assay, which is more sensitive than smear but less sensitive than liquid culture, along with other emerging diagnostic techniques, will improve diagnostic accuracy in PWHA who have symptoms of TB (8).

In persons who screen negative for TB disease, treatment of TB infection should be considered. The tuberculin skin test (TST) identifies persons with TB infection who can benefit from isoniazid preventive therapy (IPT), a regimen that involves ingesting isoniazid daily for at least 6 months. In the pre-ART era, clinical trials confirmed that IPT was effective in reducing the development of TB disease in TST-positive PWHA by 64% (11). Subsequently, in 1998, WHO recommended that all PWHA living in TB-endemic countries receive 6 months of IPT, and that TST screening generally was not needed in countries with a high burden of TB. Follow-up studies found that the benefit of IPT waned as early as 6 months after completion of IPT. In 2009, only 0.3% of PWHA globally received IPT (1). ART also can reduce the risk for TB disease in PWHA by 54%–92% and might have a synergistic effect when used with IPT (12). In collaboration with the Botswana Ministry of Health, and with funding from CDC and USAID, CDC conducted a clinical trial in Botswana to evaluate how much better TB could be prevented with a 36-month regimen of IPT in PWHA who had access to government-provided ART. This study found that among those with positive TSTs, 36 months of IPT reduced TB incidence by 74%, compared with persons receiving only 6 months IPT. When the analysis was limited to TST-positive trial participants randomized to the 36-month IPT arm who successfully completed the initial 6 months of IPT, the reduction in TB was 92%. As with previous studies, no significant benefit from IPT was observed for TST-negative participants (Figure 3). ART provided an added benefit to IPT’s protective effect, reducing TB risk a further 50% in all groups (13).

These findings have enormous implications for controlling the TB epidemic in countries with a high burden of HIV. If 36 months of IPT were provided to all TST-positive PWHA in Botswana, countrywide TB incidence would decline 45%†(Figure 4). A cost-effectiveness model of 10,000 PWHA in Botswana demonstrated that providing 36 months of IPT for PWHA with a positive TST result, in addition to ART for those with CD4 <250 cells/µL, could avert more incident TB cases with fewer resources than increasing the threshold for ART initiation alone (CD4 <350 or 500), suggesting any cost-effective TB prevention strategy should include the provision of IPT for TST-positive PWHA.

From Evidence to Guidance to Global TB Control

The strong evidence provided by the studies described above has been combined with results from other studies to update the global guidelines for TB screening and prevention (14). A recent WHO publication outlines four updated recommendations for resource-constrained settings: 1) PWHA should be screened with the new symptom-based algorithm, and those who do not report current cough, fever, weight loss, or night sweats are unlikely to have active TB and should be offered IPT (a minor modification to the algorithm developed in the CDC Southeast Asia study); 2) PWHA who report any of the aforementioned symptoms are considered suspects for TB disease and should be evaluated further for TB and other diseases as clinically indicated; 3) PWHA who are TST positive or have unknown TST status and are unlikely to have TB disease based on symptom screening should receive IPT for at least 6 months; and 4) in settings where feasible, PWHA should receive IPT for at least 36 months, or even lifelong. Where feasible, TST should be used to help identify those who would benefit most from IPT (15).

TB control relies on an international strategy known as “DOTS” (directly observed treatment, short course) that includes finding as many highly infectious patients with TB as possible, initiating effective treatment, directly observing drug ingestion to ensure adherence, and standardized monitoring, evaluation, and reporting. DOTS has saved approximately 7 million lives globally since 1990 (1). In the United States, the experience in New York City provides an example of the progress that can be made through full implementation of the DOTS strategy (16). However, although TB prevalence and deaths around the world did fall in the period after widespread global DOTS implementation, treatment programs generally have not resulted in a rapid reduction in global TB incidence (17). Multiple factors explain this phenomenon: insufficient resources and commitment to implement DOTS, in part because TB occurs predominantly in the poorest populations; a focus entirely on treatment of TB disease but not TB infection; the HIV epidemic; the emergence of multidrug resistant TB strains; and limited attention to the social determinants of sustained TB transmission and reactivation. Modeling studies suggest that detecting more infectious TB cases and successfully treating them will, on its own, be insufficient to drive down TB incidence and prevalence quickly and that the global TB strategy must address the large burden of latent TB infection that exists globally (18). The simplified symptom-based screening approach derived in the Southeast Asian study and the effective approach to chemoprophylaxis documented in the Botswana clinical trial help address this need.

The Way Forward

In a 2010 “call to action,” global leaders in TB control outlined crucial areas that must be addressed to accelerate the decline in global TB incidence to more than 1% per year and to meet the target for the 2015 Millennium Development Goal (Figure 5) (19). Achieving this will require fully implementing the DOTS strategy globally, and it will also require going far beyond that to address the limited impact that would be expected with DOTS alone, as outlined in WHO’s latest STOP TB strategy (20). WHO calls for improvements in TB screening and diagnosis, including the use of newer TB diagnostic assays. In addition to these steps, treatment of latent TB infection also is needed (18). In settings with a high prevalence of HIV infection, implementing IPT can reduce TB incidence greatly. Finally, scientific advances are needed in three key areas to develop 1) an effective TB vaccine; 2) a shorter, simpler anti-TB drug regimen with efficacy against both drug-susceptible and drug-resistant TB; and 3) new diagnostic tests that can simply and accurately diagnose both TB infection and disease (21).

The fundamentals of TB control are early and accurate TB diagnosis, effective treatment, and prevention. The gap between what we know and what we need to know is large, but the gap between what we know and what we are implementing in practice is both larger and more harmful. By closing both our knowledge gap and our implementation gap, we can eliminate this deadly syndemic.

Reported by

Haileyesus Getahun, MD, PhD, Mario Raviglione, MD, World Health Organization, Geneva, Switzerland. Jay K. Varma, MD, Global Disease Detection Br, Center for Global Health; Kevin Cain, Div of Tuberculosis Elimination, Taraz Samandari, Div of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; Tanja Popovic, MD, PhD, Thomas Frieden, MD, Office of the Director, CDC. Corresponding contributor: Kevin Cain, kcain@cdc.gov, 404-639-2247.


  1. World Health Organization. Global tuberculosis control: WHO global report 2010. Geneva, Switzerland: World Health Organization; 2011. Available at http://www.who.int/tb/publications/global_report/archive/en/index.html. Accessed June 27, 2012.
  2. CDC. Ten great public health achievements—worldwide, 2001–2010. MMWR 2011;60:814–8.
  3. American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161(4 Pt 2):S221–47.
  4. Getahun H, Gunneberg C, Granich R, Nunn P. HIV infection-associated tuberculosis: the epidemiology and the response. Clin Infect Dis 2010;50(Suppl 3):S201–7.
  5. Cain KP, McCarthy KD, Heilig CM, et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. N Engl J Med 2010;362:707–16.
  6. Monkongdee P, McCarthy KD, Cain KP, et al. Yield of acid-fast smear and mycobacterial culture for tuberculosis diagnosis in people with human immunodeficiency virus. Am J Respir Crit Care Med 2009;180:903–8.
  7. Frieden TR, ed. Toman’s tuberculosis: case detection, treatment and monitoring: questions and answers. 2nd ed. Geneva, Switzerland: World Health Organization; 2004. Available at http://www.who.int/tb/publications/toman/en/index.html. Accessed June 29, 2012.
  8. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med 2010;363:1005–15.
  9. Kranzer K, Houben RM, Glynn JR, Bekker LG, Wood R, Lawn SD. Yield of HIV-associated tuberculosis during intensified case finding in resource-limited settings: a systematic review and meta-analysis. Lancet Infect Dis 2010;10:93–102.
  10. World Health Organization. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: recommendations for HIV-prevalent and resource-constrained settings. Geneva, Switzerland: World Health Organization; 2007. Available at http://www.who.int/hiv/pub/tb/pulmonary/en/index.html. Accessed June 26, 2012.
  11. Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2010;(1):CD000171.
  12. Lawn SD, Wood R, De Cock KM, Kranzer K, Lewis JJ, Churchyard GJ. Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis 2010;10:489–98.
  13. Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011;377:1588–98.
  14. Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med 2011;8:e1000391.
  15. World Health Organization. Guidelines for intensified tuberculosis case finding and isoniazid preventive therapy for people living with HIV in resource constrained settings. Geneva, Switzerland: World Health Organization; 2011. Available at http://www.who.int/hiv/pub/tb/9789241500708/en/index.html. Accessed June 29, 2012.
  16. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City—turning the tide. N Engl J Med 1995;333:229–33.
  17. Dye C, Lonnroth K, Jaramillo E, Williams BG, Raviglione M. Trends in tuberculosis incidence and their determinants in 134 countries. Bull World Health Organ 2009;87:683–91.
  18. Dye C, Williams BG. Eliminating human tuberculosis in the twenty-first century. J R Soc Interface 2008;5:653–62.
  19. Marais BJ, Raviglione MC, Donald PR, et al. Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action. Lancet 2010;375:2179–91.
  20. Raviglione MC, Uplekar MW. WHO’s new Stop TB strategy. Lancet 2006;367:952–5.
  21. Abu-Raddad LJ, Sabatelli L, Achterberg JT, et al. Epidemiological benefits of more-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl Acad Sci USA 2009;106:13980–5.

* Additional information available at http://www.cdc.gov/nchhstp/programintegration/definitions.htm.

† Assuming provision of antiretroviral therapy to all PWHA if CD4 <200 cells/µL.

Three recent studies highlight the importance of maintaining a healthy gut to avoid disease and optimize your health. The first, published in the journal Celli, shows that “host-specific microbiota appears to be critical for a healthy immune system.”

Source: CDC.