Silica dust is inhaled and embeds deep in the lung, where immune cells engulf the silica crystal. This promotes pro-inflammatory responses that induce the production of collagen, which creates a fibrotic node. These nodes spread and grow in time, eventually impairing the lung.
For this context, ‘silica’ or ‘dust’ herein refers to inhalable crystalline silica dust. This dust is usually invisible to the naked eye and smaller than 10 microns in diameter. Silica’s chemical formula is SiO2 and importantly in this context is considered free or ‘unbound’ silica – i.e. not chemically combined with other earth elements to create a ‘silicate’ as opposed to silica. Additionally, ‘silica dust’ is in reference to crystalline silica, not referring to typically nonpathogenic amorphous silica.
Silica dust is associated with a wide variety of diseases, including silicosis, tuberculosis (TB), lung cancer, chronic obstructive pulmonary disease (COPD), scleroderma, systemic lupus erythromatosis, rheumatoid arthritis, and renal diseases1. This report focuses on the physiopathology of silicosis and silicosis-related tuberculosis, as these are the dominant diseases associated with mining.
Host response to silica in the development of silicosis
Silicosis disease pathology is largely dependent on the host’s immune response to the silica dust embedding itself in the depths of the host’s lungs. Thus, silicosis disease is primarily modulated by the interaction between silica dust and the alveolar macrophage. Briefly, alveolar macrophages are recruited and remain intimate with the dust throughout the duration that the dust particles stay in the lung. The silica crystal is phagocytosed by the macrophage, at which point the cell releases a variety of pro-inflammatory responses, typically characterized by leukotriene B4, interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF). This response stimulates fibroblasts, the cell responsible for the excretion of collagen and extracellular matrix2. Collagen forms around the silica particle, promoting the formation of the characteristic nodes found in silicosis.
There are two primary forms of silicosis: chronic (or nodular) silicosis, and accelerated silicosis. Chronic silicosis is the most common form of the disease, where the silica-induced nodules develop in the hilar lymph nodes and upper lung parenchyma approximately 10-20 years after exposure. These nodules are the defining histopathologic hallmark of the disease and are distinguished by a characteristic area of spiraled (whorled) hyalinized collagen fibers, with aggregates of silica-laden macrophages at the periphery. Initially, the nodules reach a size of approximately 3 mm and are located in the upper lobe of both the left and right lung. As the disease progresses, these nodes can spread to other areas of the lung, including the viscera pleura, and eventually become confluent. This confluence results in the lesions growing to greater than thirty times their original size, reaching centimeters in length, and may completely efface the upper lobes. Accelerated silicosis occurs after 3-10 years of exposure, and presents clinical manifestations similar to chronic silicosis. However, the nodes in accelerated silicosis are more cellular than the typically fibrotic nature of chronic silicosis nodes. A third, more rare form of silicosis is termed acute silicosis. In acute silicosis, brief yet intense exposure of high silica containing dust can sometimes lead to the development of features akin to pulmonary alveolar proteinosis; as opposed to interstitial fibrosis of the lung, acute silicosis presents itself as filling the alveolar space with granular lipoporoteinaceous material in the alveolar surfactant1,3,4.
There is no treatment or cure for silicosis. X-ray is used for determining the presence of nodes; silicosis itself does not produce any clinical symptoms. Exertional dyspnoea may present itself if progressive massive fibrosis develops, or if other consequential diseases such as TB or COPD develop.
Importantly, the human lung is unable to eradicate the dust particle. Thus, the elicited effect of the cytokine response from the alveolar macrophage is sustained over time and indicates that all forms of silicosis have a pathological manifestation that is progressive even after exposure ceases. A retrospective cohort study demonstrated that 57% of former South African gold mine workers developed the disease after exposure ceased, with a cumulative risk of silicosis reaching 77%. The average latency period was 7.4 years, though ranged up to 20 years, independent of exposure level5. Moreover, this indicates that silica dust exposure continues to act as a predisposition to tuberculosis and other diseases for the duration of the patient’s lifetime. In 1979, Dr. Edwin Morgan discussed, “The risk of tuberculosis in subjects with silicosis persists for life, and the suggestion is made that chemotherapy should be continued indefinitely6”
TB enters the lungs and normal host immunity barricades the infection in a ‘granuloma.’ Effective sequestering does not produce clinical TB and is termed latent TB. Changes in immune system integrity largely affect the host’s ability to barricade the pathogen, and any compromise in immunity (i.e. HIV, Silicosis) allows the pathogen to exit the granuloma and active (clinical) TB infection occurs.
Chronology of TB infection
Active tuberculosis (TB) is caused by contact with the intracellular parasite Mycobacterium tuberculosis (Mtb). For the context of this report, TB will refer to pulmonary TB unless explicitly stated otherwise. The initial infection of the M. tuberculosis bacterium is by inhalation of contaminated respiratory droplets approximately ≤1-2 µm. Droplets of this size allow for the bacteria to access the lower respiratory tract. Larger droplets are effectively excluded from the lower respiratory tract and remain in the bronchial epithelium, which is impervious to the bacteria and infection is not able to occur7.
After M. tuberculosis successfully enters the lower respiratory tract, the integrity of the host immune response is paramount to the clinical disease outcome. For pulmonary TB, the scientific community generally accepts four distinct outcomes of the organism8:
- I. Eradication: The host immune system orchestrates the successful elimination of all M. tuberculosis mycobacteria. TB infection by this exposure is not viable at any stage in the host’s life.
- II. Primary (clinical or ‘active’ TB) Infection: Immediate reproduction and proliferation of the bacteria can occur, causing clinical TB in the host.
- III. Latent Infection: The bacteria become dormant, remaining in the host but do not cause clinical disease. These cases show a positive Purified Protein Derivative (PPD) test, but are otherwise healthy throughout their lifetime.
- IV. Latent Reactivation: Latent bacteria begin to proliferate and cause clinical disease at a later stage in the host’s life. This occurs in 5-10% of latent TB cases9.
These outcomes are not by chance, and are significantly affected by the competency of the host’s immune system. Thus, this is of particular importance when considering populations with a high prevalence of silicosis HIV/AIDS, as coinfection significantly increases morbidity and mortality in these populations10.
Host response to TB
After Mtb is inhaled, it is primarily phagocytosed by the lung’s alveolar macrophage, as well as secondarily by other antigen presenting cells (APCs) in the lung such as parenchyma macrophages and dendritic cells. The phagocytosis of the bacilli elicits local inflammatory responses that recruit monocytes (white blood cells) from the blood. This subsequently offers additional targets for Mtb infection. Mtb is eventually controlled with the formation of a granuloma, which is the defining histopathologic characteristic of the disease. Granuloma formation begins as an amorphous accumulation of various recruited immune cells (macrophages, neutrophis, and monocytes). This loose accumulation eventually structures itself into a more sophisticated network with the induction of the adaptive immune system11. In a healthy host, a fibrotic wall accompanies immune cells to barricade the granuloma and prevent bacterial spreading, thus allowing the containment of the bacilli for long periods of time (i.e. latent tuberculosis).
If for any reason the protective barrier is depleted, this immune cell death leads to caseous necrosis of the granuloma, a characteristic of tuberculosis in which the diseased tissue forms a firm, dry mass visually having a cheese-like appearance. This allows TB to be released from the host cell and spread and results in active infection12. This is pertinent in HIV positive patients and/or patients with silicosis.
Course of TB if untreated (Natural History)
In a recent analysis of both historical (pre-chemotherapy era) and modern day (HIV-era) reports, researchers can approximate a model for the natural history. For HIV negative individuals with untreated TB, case fatality rates (i.e. percentage of people who die) are estimated at 70% and 20% for smear positive and smear negative individuals, respectively. For HIV infected patients with untreated TB, case fatality rates are 83% and 74% for smear positive and smear negative patients. The remaining patients experience self-cure.13
In regards to duration of disease, untreated tuberculosis in patients without HIV is moderate, with newer models estimating 2 to 3 years until self-cure or death. However, in untreated HIV positive patients, TB strikes with lethal efficiency, with a mean survival time of 6 months13.
Extensively drug resistant TB is generally considered as ‘untreatable’ and responds to an extremely limited number of, if any, medications. However, importantly, XDR-TB is no more virulent than drug susceptible TB (i.e. it is not more ‘dangerous,’ simply more difficult to treat with chemotherapies); thus providing an proxy model to view death rates and duration of disease. Of interest is a recent study in Kwazulu-Natal, South Africa, which showed that 52 of 53 patients with XDR-TB died with a median survival time of only 16 days. Of those, 44 were HIV positive14.
Regardless of HIV status, untreated active tuberculosis has a high fatality rate and a relatively short duration. However, HIV undoubtedly hastens the time to demise and increases the risk of death in untreated TB compared to someone with an intact, functional immune system who develops TB. In the scenario with XDR-TB, an HIV infected patient with drug susceptible TB and an HIV infected patient with drug resistant TB (i.e. XDR) probably has the same risk of death, assuming similar levels of immune system function and competence*.(*Unreferenced. Based on personal experience with patients and discussion with Dr. Ashwin Dharmadhikari, a TB specialist and colleague at Harvard Medical School (8/19/2011)).
A multifarious treatment for TB is needed due to the particularly tenacious and diverse cell wall of Mtb. This highly complex cell wall is unique among prokaryotes and fundamental in the pathogenesis of Mtb, controlling the growth, survival, and the host immunological response. Briefly, it consists of a layer of peptidoglycan surrounding the cell’s basic lipid bilayer. A second layer of arabinogalactin runs parallel to the peptidoglycan layer, surrounding it in an intricate, sugary shell. A third layer extends perpendicular to the arabinogalactin shell and consists of a complex network of mycolic acids. These long and ‘sticky’ mycolic acids are tightly bound in a final exterior layer, rendering the bacilli virtually impermeable and almost entirely waterproof. This complex armor allows Mtb to be resistant to many antibiotics, avoid death by acidic and alkaline compounds, and prevent cellular phagolysosomal fusion, allowing it to successfully evade lysis15,16,17.
These properties make current treatment for active drug-susceptible TB infection particularly arduous; typically a six-month regimen consisting of a two-month ‘intensive’ phase of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) given seven times per week, followed by a four-month continuation phase of RMP and INH given three times a week18.
Multi-drug resistant TB (MDR-TB) is defined as active tuberculosis disease that is resistant in vitro to the two most highly effective drugs to treat TB, rifampicin and isoniazid, with or without resistance to other drugs. Treatment requires the use of several harsh second line drugs, including injectibables such as capreomycin, kanamycin, amikacin, typically lasts 24-27 months, and is 25-50 times more expensive to treat. Extensively drug resistant TB (XDR-TB) can be defined as resistance to INH and RMP in vitro, any of the second line fluoroquinolones, and one or more of the second-line injectable drugs. There is no consensus on treatment regimen and is generally considered untreatable19.
Figure: Outlook for patients that go untreated with TB13.
If your HIV Status is…
And your smear results are…
Then your case fatality rate is…
And your life expectancy is…
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