When Simón Bolívar died on this day 185 years ago, tuberculosis was thought to have been the disease that killed him. An autopsy showing tubercles of different sizes in his lungs seemed to confirm the diagnosis, though neither microscopic examination nor bacterial cultures of his tissues were performed.
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By Timothy D. McHugh
Tuberculosis (TB) is a disease of poverty and social exclusion with a global impact. It is these underlying truths that are captured in the theme of World TB Day 2014 ‘Reach the three million: a TB test, treatment and cure for all’. Of the nine million cases of tuberculosis each year, one-third does not have access to the necessary TB services to treat them and prevent dissemination of the disease in their communities. The StopTB Partnership is calling for ‘a global effort to find, treat and cure the three million’ and thus eliminate TB as a public health problem. So is the scientific community making sufficient progress to realise this target?
Early diagnosis is a cornerstone of management of the individual and we know that as the disease progresses and the bacterial load and severity of disease increase, the likelihood of a poor outcome is exacerbated. It is important to distinguish between diagnosis of tuberculosis and detection, which is confirmation of the presence of mycobacteria. Diagnosis for the three million (and many more) is largely dependent on the clinical expertise of the healthcare worker, with minimal input from technology. Whereas detection requires input from microbiological services and the principal tool in this area is sputum smear microscopy. A sputum sample with no evidence of acid fast bacilli is the accepted predictor of low risk of transmission, and so early application is critical in the management pathway. With improvements such as the auramine stain and LED fluorescent microscopy, the smear remains a cost effective component of TB screening programmes. The emergence of multi-drug resistant tuberculosis has accentuated the need for prompt confirmation of drug susceptibility and this is where molecular tools have potential impact. The WHO supported roll out of GeneXpert in resource poor settings is going ahead and we are seeing change in practice, but it is too soon to determine the public health impact of this innovation. The challenge for microbiology is not to get drawn into a ‘one size fits all’ solution. In many settings, the low technology, low cost and rapid screening of smears serves to break the chain of transmission of drug sensitive tuberculosis. Whereas, in areas of high endemicity of drug resistant TB, such as South Africa, an equally fast indication of drug resistance is essential.
Photo by WHO/Jean Cheung
Diagnosis leads to treatment. TB is curable but treatment regimens are long, toxic and complex to deliver. Following the stakeholders meeting in Cape Town in 2000 there has been a major effort to open up the drug development pipeline. There are two aspects to this, firstly new agents and secondly clinical trials. There is a new enthusiasm for exploring new compounds with action against TB and the publication of the whole genome of Mycobacterium tuberculosis allowed the interrogation of its biochemistry, opening the door for medicinal chemists to contribute their expertise. The development of MDRTB has led us to reconsider compounds previously excluded as too toxic or too difficult to administer; these drugs, such as PAS and thioridazene, are now being re-visited or forming the basis of fresh iterations of chemical screening programmes. After 30 years of no new drugs for TB treatment, two phase 3 trials (RIFAQUIN and OFLATUB) were reported in 2013 and a third (REMoxTB) is expected to report shortly. These studies have shaken things up. They each have potential to make improvements in TB treatment. However, it could be argued that their real benefit lies in the development of a network of facilities capable of undertaking TB clinical trials, as exemplified by the Global Alliance for TB Drug Development and the EDCTP funded PanACEA consortium, and their contribution to the active debate about how to efficiently deliver clinical trials that have a real impact on individuals and populations. We are now looking outside the world of TB and to, for example, cancer trial methodology for innovations such as the multi-arm multi-stage (MAMS) approach. A significant challenge here is to convert the results of studies undertaken, with the aim of full regulatory approval, into the rather more complex environment of programmatic delivery.
The host-pathogen interaction for M. tuberculosis is manifest in the pathology of tuberculosis and has proven to be a fruitful area of immunological research. This, together with the (variable) success of BCG vaccination, has led us to the reasonable expectation of a vaccine for control of tuberculosis. There has been much innovation in this area and new studies are in the pipeline. The quest for immunological markers of disease continues. Useful diagnostic tools for latency have been developed in the shape of IGRA tests (Tuberculosis: Diagnosis and Treatment), but, more importantly, recent advances lead us to the idea that we may be able to define a host response signature to tuberculosis. If successful, this approach may allow us to select those patients for whom a shorter course of therapy is adequate. From the UK MRC studies it was clear that as many as 80% of patients would be cured with a four-month regimen; the difficulty was that they could not be identified in advance or during treatment. A host response biomarker may well enable us to address this issue.
M. tuberculosis is a fascinating organism with many features of its biology that are distinct from other bacteria. For this reason the TB research community has become rather insular, not necessarily drawing on the experience from the wider bacteriology community. This was further exacerbated by the apparent fall in incidence of TB through the 1960s and 70s. Complacency is the term that comes to mind. Despite the commitment of groups such as those led by Mitchison and Grossett, there has been very little innovation in detection and diagnosis, and no new drug introduced to first line treatment after the 1960s. The declaration by WHO of TB as a global health emergency alerted us to the need for new ideas and new tools to meet this challenge. Twenty years down the line, we have rolled out new diagnostics and a new drugs pipeline that flows with the first phase 3 trials reporting shortly. Similarly, innovation in vaccine design and application moves forward and importantly our understanding of operational and behavioural aspects of controlling TB increases. However, we must not become complacent again. M. tuberculosis is not just an academic challenge and as long as the three million exist, we need to focus all our knowledge to achieve a TB test, treatment and cure for all.
Timothy D. McHugh is Professor of Medical Microbiology at the Centre for Clinical Microbiology, University College London. This is an adapted version of Professor McHugh’s commentary for the Transactions of the Royal Society of Tropical Medicine and Hygiene.
The Transactions of the Royal Society of Tropical Medicine and Hygiene publishes authoritative and impactful original, peer-reviewed articles and reviews on all aspects of tropical medicine.
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Image credit: From the TB in Brazil series by WHO/Jean Cheung. Via the Stop TB Partnership.
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THE BALLAD OF JESSIE PEARL -
Shannon Hitchcock
setting: 1920's, North Carolina
age range: 12 and up
release date: February 1, 2013
study guide based on Common Core State Standards
Please tell us about your book.
It’s 1922 and Jessie has big plans for her future, but that’s before tuberculosis strikes. Though she has no talent for cooking, cleaning, or nursing, she puts her dreams on hold to help her family. She falls in love for the first time ever, and suddenly what she wants is not so simple any more.
What inspired you to write this story?
A snippet of a family story and my son’s 8th grade history project. His teacher had each student collect ten family stories. Each story had to take place during a different decade. I decided to write a novel loosely based on one of the stories Alex collected.
Could you share with readers how you conducted your research?
I read novels set in the 1920’s, North Carolina history books, memoirs written from sanatoriums, and doctors’ accounts of the disease. I also contacted a local historian in my hometown who helped me locate resources about life on a tobacco farm in the early 1900’s.
What are some special challenges associated with writing historical fiction?
Not to tell everything you know, but just enough to add flavor to the story.
What topics does your book touch upon that would make your book a perfect fit for the classroom?
THE BALLAD OF JESSIE PEARL could be used in a cross curricular unit by ELA and Social Studies teachers. Keely Hutton, who’s an eighth grade ELA teacher, reviewed my curriculum guide and gave this feedback:
With JESSIE you have the perfect opportunity to tie in [the following]:
non-fiction pieces about the time period
TB
women’s rights and roles in family/society
health care during epidemics
historically what was happening during those years in the US and the world
Murphy, Jim and Alison Blank. 2012.
The Invincible Microbe: Tuberculosis and the Never-Ending Search for a Cure. New York: Clarion.
The minute I saw this book, I knew that I would read it, not because I am a fan of nonfiction and Jim Murphy, but for personal reasons. While my mother would often tell me stories of what it was like to be a child during WWII, my stepfather was older. He lived what I considered to be a fascinating, history-book life. He was an orphan. He remembered the Great Depression. He was a runaway. He was a "runner" on Wall Street. He had tuberculosis. He recalled being forced to march outside in the cold New York winter wearing nothing but a t-shirt and underpants, a common aspect of a patient's "curing" regimen. I can only imagine that a poor orphan boy's regimen was harsher than most. To this day, I cannot look at a sepia-tinged photo of poor scantily clad children in the snow without thinking of my stepfather. The girls on the cover of
The Invincible Microbe, "curing" outside on a porch, may be smiling in the photo, but I don't believe for a minute that it was by choice. To the end of his days, my stepfather loved rich foods and warm temperatures - small wonder.
So, to me growing up, TB was a thing of the past - a disease like polio, generally eradicated and of no concern to me. Then came the late 1980's and 1990's. My sister lived in Manhattan, and lo and behold, tuberculosis was suddenly a topic of discussion again. There was an outbreak in the City. She was worried. So to me, tuberculosis was then an urban thing, of no concern to me, except where my sister was concerned. My sister moved away from the City, and I thought little of it again ... until my children were born. Then to me, TB was "the bubble test," and I thought little of it, except that it seemed to be an easier test than the "tine test" I remembered from childhood, and I was thankful that my kids were protected...
or so I thought, until I read
The Invincible Microbe.
The Invincible Microbe: Tuberculosis and the Never-Ending Search for a Cure, tells the story of TB from its known beginning, in prehistoric times, through the days of magical, prayerful, and deadly "cures," until today, when TB is still a scourge in five areas of the world
(Democratic Republic of Congo, Ghana, The Philippines, Swaziland, Vietnam) and is only as far away from you as a plane ride.
Thoroughly researched, sourced and indexed, with numerous photographs,
The Invincible Microbe is a chronological look at the Tuberculosis germ, containing first-hand accounts (including a poem written by Robert Louis Stevenson en route to a sanatorium in Saranac Lake), period advertising, and quotes from scientific journals and other sources. It incorporates both the scientific and social aspects of infectious disease, answering such questions as:
How were breakthroughs in identification and treatment of the disease achieved? How did the medical community vet new procedures and ideas? How was public health policy created? How did the germ mutate to survive? How did Tuberculosis attack the human body? How was it spread? Who decided which patients received treatment and which do not?
Sadly, these questions are still being answered, and to date, Tuberculosis has no cure.
Comprehensive and engrossing, this is a book that will appeal to ages 10 to adult.
Want to know more about TB?
Check the Tuberculosis section of the World Health Organization (WHO) website.
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This sounds like a book I want to read. Thank you!
This sounds great. Thanks for highlighting it, Caroline!
Doesn't it sound good?