Tuberculosis

This is Dr. Cal Shipley with a review of tuberculosis, latent infection, reactivation and lung cavitation. Before we get to the animation, let’s take a look at a few facts regarding tuberculosis. Tuberculosis in humans is caused by the Mycobacterium tuberculosis bacillus. Transmission of tuberculosis from one person to another is only possible via droplet infection. All about droplets in a moment. It is estimated that two billion people worldwide are infected, with 1.7 million deaths annually, making it second only to HIV as a cause of infectious human mortality.

Tuberculosis: Incidence and Epidemiology

In the United States, incidence of tuberculosis infection steadily decreased from 1900 to 1950 due to improved nutrition and housing conditions, followed by another steep decrease in incidents between 1950 and 1983 due to the advent of successful drug treatment for the infection. This was followed by a sharp increase in the number of individuals infected with TB between the years of 1985 and 1993. This increase in incidence has been attributed to the spread of the HIV virus, increased numbers of immigrants, a deterioration in the public health system infrastructure, the emergence of strains of TB resistant to drug therapy, and increased numbers of homeless and drug abusers.

This surge in the disease led to a much more aggressive public health effort with the result that since 2004, the overall incidence of tuberculosis in the United States has decreased. Around the world, the highest incidence of tuberculosis infection occurs in India, sub-Saharan Africa and the islands of Southeast Asia and Micronesia with the lowest rates occurring in the United States, Japan, Western Europe, Canada and Australia.

Mycobacterium Tuberculosis characteristics and transmission

Mycobacterium tuberculosis is a member of a genus of bacteria whose defining characteristic is acid fastness, defined as the ability to resist decolorization when an acid alcohol mixture is applied after appropriate staining.

Tuberculosis is an obligate aerobe, and is primarily a pathogen of the mammalian respiratory system. It is an intracellular pathogen. That is, it is capable of surviving within the cells of an infected host. This characteristic is the key to its ability to cause latent infection as we will see. Another defining characteristic of tuberculosis infection in humans is the formation of granulomas and we’ll see how this works in just a moment. As mentioned previously, the transmission of tuberculosis from human to human is only possible via droplet infection. Droplets are particles which are one to five micrometers in size with each droplet containing one to 400 bacilli.

Droplets are expelled by sneezing, laughing, coughing, singing or talking, and may remain suspended in air for several hours. They are then inhaled into the airways of another person. This is the only means by which transmission of tuberculosis may occur from human to human. In many individuals, the inhaled droplets are trapped in the mucus layer lining the epithelium of the upper airways. A microscopic view of an upper airway reveals epithelial cells, and the mucus layer which they secrete. The inhaled bacilli are initially trapped in the mucus layer.

Small hair-like structures called cilia project from the surface of the epithelial cells and move together in a coordinated fashion to sweep the bacilli-bearing mucus up towards the mouth. The bacilli are then expelled by coughing, or swallowed and rendered harmless. However, if as few as 10 bacilli get by the upper airway defenses and reach the alveolus, the individual is considered to have a primary infection. Let’s take a look at the alveolar anatomy.

Alveolar anatomy

The alveolus is the smallest functional unit of the lung and is the point at which oxygen molecule transfer occurs into the bloodstream. An alveolar unit consists of a grape-like cluster of several individual alveoli attached to a small airway called a bronchiole. There are approximately 350 million alveoli in each human lung. Now taking a closer look at a single alveolus, we see the close proximity of a capillary vessel, which allows for the transfer of oxygen molecules from the alveolus into the red blood cells of the capillary during inspiration, and vice versa, the transfer of carbon dioxide molecules from the bloodstream into the alveolus during expiration.

Looking at a cross-sectional view of this anatomy, we can see how the mycobacterium bacillus, after escaping the defenses at the upper airways of the lung, moves down the bronchi, and into a single alveolus.

Tuberculosis: Immune response

Phagocytosis

As mentioned previously, Mycobacterium tuberculosis is an obligate aerobe. That is, it thrives in an oxygen-rich environment. This makes the alveolus of the human lung a very favorable location for the bacillus. Once the bacillus enters the alveolus, it triggers an immune response. Macrophages are the immune system’s first responders.

Macrophages are a type of white blood cell which are one of the three cell types present in a normal alveolus. Through a process known as phagocytosis, macrophages are able to ingest foreign particles, such as dust or carbon, cellular debris, and bacteria. The Mycobacterium bacilli are also ingested by macrophages. The genius of the mycobacterium bacillus is that it contains several variants factors which allow it to resist destruction by immune cells, and permit it to survive in an intracellular state, such as after ingestion by macrophages. Eventually, other cellular immune elements, primarily white blood cells, are attracted to the infected alveolus.

At this stage, the bacillus is contained but not destroyed. Over the course of weeks to months, successive layers of immune cells form around the bacillus containing the macrophages.

Granuloma

This progressive build-up of cell layers forms a structure known as a granuloma. In the 19th century, when Robert Koch first discovered the Mycobacterium bacillus, these granulomas were also known as tubercles. This term lent its name to both the disease and the Mycobacterium species.

Although the granuloma has completely enclosed the infected macrophages, the Mycobacterium bacilli remain intact in a dormant but viable state, and can remain so for decades. This is known as latent infection, and occurs in 90% of individuals infected with the Mycobacterium bacillus. After initial formation, the granuloma may enlarge eroding into adjacent lung tissue and other alveoli. Characteristically, the center of the granuloma often undergoes caseous necrosis, forming a cheese-like consistency. Caseous necrosis does not affect the viability of the dormant Mycobacterium bacilli contained within macrophages at the center of the granuloma.

Reactivation

In time, tubercular granulomas may calcify giving them their characteristic appearance on plan film chest X-ray. In about 10% of those with latent tuberculosis infection, conversion to an active infectious state, also known as reactivation, may occur by a process which is still poorly understood. Reactivation from a latent stage may occur decades after initial infection. What is clear is that reactivation is associated with immunosuppression, or loss of normal immune function. Factors such as HIV infection, cigarette smoking, diabetes mellitus, malignant lymphoma, corticosteroid use, inhibitors of tumor necrosis factor, age, and stage renal disease have all been seen in association with reactivation of latent TB.

Once immune system function has been decreased, or is suppressed, Mycobacterium bacilli begin to replicate and rapidly spread beyond the confines of the granuloma, damaging lung alveoli, airways, lung parenchyma and vascular structures.

Unlike the 10% of individuals infected with tuberculosis who develop active disease immediately without a latent period, most reactivated tuberculosis is confined to the lungs and does not spread to the bloodstream or other organs. The infection has a tendency to spread to the upper lobes where aeration and oxygen content are higher relative to the lower lungs. Unchecked, the infection causes marked inflammation and progressive destruction of lung tissue. Whole lobes may be destroyed and characteristic cavitary lesions, also known as cavitations are common. The characteristic appearance of a cavitation is shown here on the left lung, as if a tunnel was bored through the lung tissue by the Mycobacterium bacillus.

Finally, here is the AP plain film chest x-ray which corresponds to the damage depicted.

Cal Shipley M.D., copyright 2020