Rediscovering TB: A Review of Discovering Tuberculosis

The single microbe that kills the most humans in 2016 is not Ebola, not Zika, not brain-eating amoebas. It is not an infection that continually grabs headlines. It is Mycobacterium tuberculosis, a profligate killer that has menaced humans since our appearance on the planet. In 2014, tuberculosis felled 1.5 million humans.

There are many books about very aspects of tuberculosis that I have read but none of them have really attempted, in my recollection, to tell the story of tuberculosis with an aim to make the history of our species' battles with disease relevant to the present. That lack of present-centrism is no more with UVA History professor Christian McMillen's Discovering Tuberculosis: A Global History 1900 to the Present.

Discovering Tuberculosis is a scholarly work that takes the reader through several important phases in the control of tuberculosis with attention to the principles at play in each of them. From efforts to control TB on Native American reservations to the global fight against HIV/TB coinfection, McMillen skillfully makes the past not just come alive but completely inform how we presently face this infection.

Some important highlights of the book include the failure of the BCG vaccine and how this vaccine may have stymied vaccine development more generally; the early harbingers of the threat of drug resistant TB in 1960s Kenya; the vicissitudes of the approach to HIV/TB coinfection, and the not often mentioned negative effects of directly observed therapy.

One of the most important aspects of this book is that it relies on Professor McMillen's extensive review of the actual communications between programmatic leaders and health agencies. Such a level of granularity grounds his analysis in the actual medical debates that were occurring, allowing almost direct application to current efforts.

Discovering Tuberculosis allowed me to gain a better understanding of today's global anti-tuberculosis effort and grasp how difficult it will be to rid our race of its most astute infectious disease killer. I highly recommend it.

Dissecting Tuberculosis in the US

Today the CDC released the latest numbers on tuberculosis in the US and it is all good news with a couple of caveats.

Overall, there's been a 2.2% decline in tuberculosis in the US with just 9412 cases reported in 2014. This translates to a rate of 3 cases per 100,000 people which is extremely low but not yet at the goal of 1 case per 1,000,000. Indeed, recent news stories have shown that the risk of tuberculosis still exists with an active case diagnosed in a Pittsburgh school; a similar incident in Kansas caused 27 students becoming skin test positive, indicating they contracted latent TB.

When one dissects the rate of 3 cases per 100,000 there are several important and ominous findings: 

• The rate of tuberculosis is 13.4 times higher in those foreign born when compared to those born in the US; 66.5% of cases are in this group
• Asians are the ethnic group with the highest burden of cases in the US
• Hawaii is the state with the highest rate of tuberculosis in the US
• California, Florida, New York, and Texas account for 50.9% of all US cases in 2014
• 6.3% are HIV-positive
• Just 1.3% of cases (in 2013) were multi-drug resistant

Interpreting these numbers, it becomes clear that tuberculosis is a waning problem in the US when looked at in aggregate. However, looking at the data in all its granularity it becomes clear that the final push for tuberculosis control will be in finding foreign-borne individuals with latent tuberculosis--immigrants are screened for active tuberculosis via culture and chest x-ray in their home country--and placing them on treatment to prevent reactivation. Such an effort is daunting as many of the individuals in these communities are not readily available to public health and medical officials, but placing them on treatment is the means to eliminate tuberculosis from the US. 

Adding Layers to my Understanding of Tuberculosis

When I teach medical students a concept my technique often involves reducing the concept down to the level of simple observation or unsophisticated laboratory or radiographic tests. This approach allows the medical student to not get lost in complexity and lose track of what's actually going on, namely a patient with certain signs or symptoms. 

As an avid attender of myriad infectious disease lectures I, myself, also tend to prefer this type of teaching approach. At a recent meeting of the Baltimore Tropical Medicine Dinner Club, on whose board I serve, I was treated to an exceptional employment of this very technique by an icon in the field of tuberculosis pathology: Johns Hopkins University's Dr. Arthur Dannenberg. 

What Dr. Dannenberg did in this lecture is reduce all the esoteric jargon of tuberculous pathology to literally entities visible to the naked eye (i.e. lesions on rabbit lungs). This lecture deepened my understanding of tuberculosis immensely because it provided me with a new framework to think about tuberculosis, namely as balancing act between two types of T-cell response. One type of response kills infected macrophages, the other activates macrophages to kill the bacteria. 

Using this paradigm it becomes much easier to understand why 90% of people are resistant to tuberculosis and never develop the disease after exposure. The infecting bacilli that survive the initial onslaught by alveolar macrophages are kept in check by a response which kills the cells that harbor them, creating a solid foci of necrosis surrounded by macrophage sentries poised to act. Most human's immune systems are able to keep this foci which, as it liquefies may leech out bacilli, in check (latent TB) but in those whose are unable, macrophages must release firepower on the area, causing the classic destructive lesions of tuberculosis. Aging and immunosuppression are two factor that can lead to loss of control and symptomatology. Similarly the poor population results of the BCG vaccine might be related to the fact that only a small proportion of the population actually needs it.

Such an understanding of tuberculosis provides a green light to think of therapy and vaccines differently. Primarily, tuberculosis therapy involves the prolonged use of antimicrobial therapy to kill bacilli in both the active and the latent stages. Therapies to keep the initial foci of necrosis from liquifying could modify therapy for latent TB. Additionally, immune modulation to dampen inflammation could also play a role (steroids are currently a part of the regimen used in tuberculous meningitis).

A proper conceptualization of a disease is really the only true means to understanding and conquering it.

Control of Tuberculosis: An Agent Carter & Captain America Size Task

The popular culture infectious diseases references continue.

On last night's premiere of ABC's new 1940s-era show, Marvel's Agent Carter a character who sneezes exclaims that she likely has tuberculosis. (For those of who might not know, in the Marvel universe, Agent Carter was an associate of Captain America.) 

In the 1940s tuberculosis was a serious fear in the US and pre-streptomycin (1944) there was no effective treatment available. Despite this, deaths had been declining due to improving socioeconomic and health conditions in the US. However, in 1945 the incidence rate was still was at an alarming 87 per 100,000. For comparison, it was 3 per 100,000 in 2013--a 96% reduction.

Though, as I've written before, there are vulnerabilities in our control of tuberculosis including drug resistance and the fact that the bulk of tuberculosis cases in the US occur in foreign-born individuals, who may present special challenges with respect to case identification, contact tracing, and treatment. 

With those caveats, a 96% reduction in tuberculosis cases in 70 years, in the absence of a vaccine program, was a Captain America seized feat.

Consumption: A Disease For All Seasons, not Just a Winter's Tale

We often talk colloquially about a disease consuming an individual. Examples include AIDS, cancer, or, quite literally flesh-eating bacteria. However, there is one disease that actually has the original claim to that moniker: tuberculosis. 

Consumption was the name of the condition that eventually became known as tuberculosis and its first mentions reach back to the times of Hippocrates and Herodotus. Indeed the Hippocratic corpus distinctively describes consumption (phthisis in Greek) as being nearly always fatal and consisting of symptoms recognizable to a physician practicing over 2000 years later. The disease, in an era without antibiotics and proper nutrition, could be a death sentence and as the infection progress patients would literally waste away as the disease consumed them.

In the developed world, tuberculosis has faded from the mind of the general public and in the US we are now at an all time low with cases falling below 10,000 with 65% of cases occurring in those born outside the US--a statistic often misused by anti-immigration advocates. Because certain types of tuberculosis are transmitted from person-to-person through the air it is one of the instances in which legitimate quarantine orders are issued in the US for non-compliant patients.

A recent movie--in which I had to suspend disbelief about a flying horse, cessation of aging, and Lucifer--reminded me that anti-immigration sentiment over tuberculosis is nothing new. In the supernatural film Winter's Tale a couple arriving in late 19th century America is summarily deported when a "pulmonary" problem is detected on their screening immigration physical examination and later in the film a character dies of it. The pulmonary problem was tuberculosis.

If one reads historical accounts of how immigration and infectious diseases interacted--such as Howard Markel's When Germs Travel--you will learn that fear of tuberculosis led to a very unscientific process of looking for and excluding those with a physical appearance thought to be conducive to tuberculosis infection--ignoring the fact that the disease had stricken many individuals including the famous and the beautiful.

Tuberculosis was, for a time, the reigning king of infectious disease killers before being replaced by HIV and it has not lost its appetite for blood. Now armed with drug resistance genes, tuberculosis control will remain an important task for the foreseeable future.