A large pulmonary cavity replaced by a tuberculosis granuloma and healed during treatment of a patient with tuberculosis

In the early stages of M. tuberculosis infection, lung tuberculosis (TB) granulomas are often formed at sites of infection to constrain the infection and can undergo healing in most cases or enlarge as the disease progresses in some cases. We present here an unusual case of TB in which a large previously existing pulmonary cavity was replaced by a TB granuloma and then healed during treatment of a patient with poly-resistant TB. This case indicates that the disease process from TB granuloma formation to pulmonary cavities and progression or healing is more diverse than previously thought and could be reversed. An in-depth understanding of the disease process from initiation and maintenance of the TB granuloma to pulmonary cavities and progression or healing will provide new ways to combat mycobacterial infections.


Introduction
Tuberculosis (TB) is one of the top ten causes of death and a leading cause of death from infectious diseases in the world.Over 95% of 1.8 million TB deaths occurred in lowand middle-income developing countries in 2015 [1].Latent TB infection affects about one-third of the world's population but only 5-10% of infected people will develop active TB disease over their lifetime, indicating the importance of balanced human immune responses in control of Mycobacterium tuberculosis (Mtb) infection [2,3].In the early stages of Mtb infection, lung TB granulomas are often formed at sites of infection to constrain the infection and disruption of the TB granuloma structure will lead to the formation of pulmonary cavities and the progression to active TB disease [4][5][6][7].It is generally accepted that the disease process from tuberculoma formation to pulmonary cavities and progression or healing usually follows these steps for the vast majority of Mtb cases.However, there is always an exception to every disease process.We report here an unusual case of TB in which a large previously existing pulmonary cavity with a thin wall was replaced by a TB granuloma and healed during treatment of a patient with poly-resistant TB.

Case Report
A 34-year-old Chinese woman with a one-year history of pulmonary TB presented to our hospital with symptoms of cough, blood-streaked sputum, weight loss and fatigue.Her sputum samples revealed the presence of acid-fast bacilli graded as 4+, and pulmonary cavities in the right upper lobe were evident on her previous chest radiography taken three months earlier.Liver function tests were normal and there was no history of alcohol abuse or viral hepatitis.Test results for human immunodeficiency virus (HIV) and fungal infections (Aspergillus and Candida albicans) were negative.
She continued her treatment with four first-line antituberculosis drugs (isoniazid, rifampicin, ethambutol, and pyrazinamide) while waiting for the sputum test results.Sputum culture was confirmed to contain a poly-resistant strain of Mtb resistant to isoniazid, ethambutol and streptomycin.Computed tomography (CT) scan of the chest confirmed the presence of bilateral multiple infiltrative lesions with a few cavities in the right upper lobe.The largest cavity measured 3.1 cm in diameter with a thin wall (Figure 1A, arrow).
A treatment regimen including first-line (rifampicin and pyrazinamide) and second-line anti-tuberculosis drugs (levofloxacin, amikacin, cycloserine and prothionamide) was initiated.A follow-up chest CT scan performed after five months of anti-tuberculosis therapy revealed that the 3.1 cm pulmonary cavity was filled up by a TB granuloma with a size of 2.8×2.7 cm (Figure 1B, arrow).After 12 months of treatment, her chest CT scan showed that the large TB granuloma decreased in size remarkably (Figure 1C, arrow).Six months after the completion of a 15-month treatment (started in January 2015 and ended in April 2016), CT scan of the chest showed that the TB granuloma was absorbed and turned into fibrosis (Figure 1D, arrow).The patient gained 5 kg of weight and her symptoms abated after the treatment.

Discussion
The human TB granuloma, a hallmark of tuberculosis, is an organized structure that plays a key role in the host immune responses to Mtb and pathogen persistence.A TB granuloma has a core of infected macrophages surrounded by foamy macrophages, monocytes and multinucleated giant cells [8].The development of a caseous TB granuloma has been involved in the progression from latent TB to active disease and transmission, and caseation of human TB granulomas has been correlated with elevated host lipid metabolism in cells surrounding the caseum [9].The network of factors that regulates the granulomatous inflammation and the host-pathogen interactions within the TB granuloma is complex and it is still unclear how a balanced response determines a protective rather than a destructive process [10,11].Microarray profiling of caseous TB granulomas showed that many of the genes encoding enzymes involved in the lipid metabolism were differentially upregulated, and some of their encoded proteins were disproportionately abundant in cells surrounding the caseum.Biochemical analysis of the major lipid species within the caseum revealed an abundance of cholesterol esters (CE), cholesterol (CHO), and triacylglycerols (TAG) and also a high level of lactosylceramide (LacCer) [9].
It has been proposed that some Mtb cell wall components could stimulate the host's innate immune response to enhance synthesis and/or sequestration of host lipids in the form of lipid droplets inside macrophages, and accumulated foamy macrophages in the macrophage-rich center of the TB granuloma would ultimately die through either apoptosis or necrosis, leading to the buildup of lipids as caseum and finally to cavitation and release of infectious Mtb bacilli [9].Based on this model, the disease process after the initial Mtb infection is typically started with the formation of a TB granuloma at sites of infection, proceeds to granuloma liquefaction and cavitation caused by accumulation of caseum in the center of the TB granuloma, and ultimately to transmission of Mtb bacilli [11].However, in few unusual cases, a previously existing pulmonary cavity with a thin wall could be replaced by a TB granuloma and then healed completely during treatment of patients with TB, which suggests that the typical disease process is more diverse than previously thought and could be reversed.Among thousands of TB patients treated at our hospital over the last three years, only three such unusual cases of TB have been identified.In this case report, we described one of the three unusual cases of TB due to the lack of complete CT images for the other two cases, even though the disease process and treatment outcomes were very similar.

Conclusions
This case report shows that a large previously existing pulmonary cavity can be replaced by a TB granuloma and healed during the treatment of a patient with poly-resistant TB, indicating that the disease process from TB granuloma formation to pulmonary cavities and progression or healing is more diverse than previously thought and could be reversed.The fact that a large pulmonary cavity in a patient with poly-resistant TB can be cured with appropriate treatment regimens will help physicians and health care providers around the world, especially those who take care of TB patients in 30 high TB burden developing countries [1], to treat TB patients with similar situations.An in-depth understanding of the mechanism from initiation and maintenance of the TB granuloma to pulmonary cavities and progression or healing will provide new ways to combat mycobacterial infections [11,12].

Figure 1 .
Figure 1.Chest CT scan images showing a large pulmonary cavity replaced by a tuberculoma and then healed during treatment of a patient with poly-resistant tuberculosis.(A) A large previously existing pulmonary cavity measured 3.1 cm in diameter (arrow).(B) The large cavity filled up by a large tuberculoma with a size of 2.8×2.7 cm five months after anti-tuberculosis therapy (arrow).(C) A large tuberculoma decreased in size after 12 months of treatment (arrow).(D) A large tuberculoma was absorbed completely and turned into fibrosis six months after the completion of a 15-month treatment (arrow).