1.3 Evolution of tuberculosis infection and disease in humans

When a person inhales infectious droplets containing M. tuberculosis, most of the larger droplets become lodged in the upper respiratory tract (nose and throat) where infection is unlikely to develop. However, smaller droplet nuclei may reach the small air sacs of the lung (the alveoli) where infection can occur.

1.3.1 Primary infection and latent tuberculosis infection

After transmission, M. tuberculosis multiplies slowly, in most cases in the terminal alveoli of the lungs (primary focus) and in the lymph nodes of corresponding drainage areas: this is the primary infection. The primary focus and related hilar lymphadenopathy form the "primary complex".

In one to two months, due to the action of lymphocytes and macrophages (cellular immunity), the primary focus is contained and encapsulated, with a central zone of parenchymal necrosis (caseous lesions). It is not usually detectable on chest x-ray, unless it calcifies or grows substantially. Primary infection is usually asymptomatic. In most cases (90 to 95% of non-HIV infected persons), the pulmonary lesions gradually heal.

During the primary infection, specific immunity develops and a positive skin reaction to tuberculin is observed [1] Citation 1. Ahmad, S. Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol. 2011: p. 814943.
https://doi.org/10.1155/2011/814943 . This immune response may persist without clinical signs of TB. The person is infected, but does not develop the disease. This is referred to as latent tuberculosis infection (LTBI).

Among infected people, on average 5 to 10% will develop active TB over their lifetime [2] Citation 2. World Health Organization WHO consolidated guidelines on tuberculosis. Module 1: prevention – tuberculosis preventive treatment. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.
https://iris.who.int/bitstream/handle/10665/331170/9789240001503-eng.pdf?sequence=1 . For HIV co-infected persons, this risk is much higher.

1.3.2 Active tuberculosis

Before immunity is established, bacilli from the primary complex can be disseminated throughout the body via the lymph system or the bloodstream.
Secondary foci can develop this way, particularly in the lungs, lymph nodes, serous membranes, meninges, bones and kidneys. As soon as an immune response is mounted, most of these foci resolve spontaneously. However, some bacilli may remain dormant in the secondary foci for months and sometimes years.
Different factors can reduce the immune response (e.g. HIV infection) and lead to reactivation of the bacilli and their multiplication in one or more of these foci. This reactivation or progression of the primary or secondary foci results in active TB [3] Citation 3. Ai, JW, et al. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerging Microbes & Infections, 2016. 5: p. e10. 
https://doi.org/10.1038/emi.2016.10 .
An active TB lesion contains actively, slowly or sporadically multiplying bacilli as well as dormant bacilli.
While active TB may occur months or years following primary infection, half of TB cases appear in the year following infection.

1.3.3 Risk factors for developing active tuberculosis

Certain factors increase the risk of developing active TB within the first two years of being infected. These factors include immunodepression, damaged lungs and the intensity and duration of exposure.

Host immune response factors:

• HIV infection
• Children under 5 years [4] Citation 4. Marais, BG, et al. The natural history of childhood intra-thoracic tuberculosis: A critical review of literature from the pre-chemotherapy era. The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease. 2004. 8(4) p. 392-402.
  https://www.ingentaconnect.com/content/iuatld/ijtld/2004/00000008/00000004/art00002;jsessionid=11hrh2bb6hfpv.x-ic-live-03# [5] Citation 5. Erkens, CG., et al. Risk of developing tuberculosis disease among persons diagnosed with latent tuberculosis infection in the Netherlands. Eur Respir J, 2016. 48(5): p. 1420-1428. 
  https://doi.org/10.1183/13993003.01157-2016
• Malnutrition
• Persons over 60 years
• Diabetes mellitus
• Other risk factors: prolonged corticosteroid therapy and other immunosuppressive therapies, severe renal disease, alcohol or substance abuse, certain types of cancer (e.g. leukaemia, Hodgkin's lymphoma, cancer of the head and neck); pregnancy

Conditions that damage the lung:

• Tobacco smoking
• Silicosis
• Chronic obstructive pulmonary disease (COPD)

Intensity of exposure (high number of inhaled bacilli):

• Highly infectious source
• Poorly ventilated environment
• Proximity with infectious source, including residents and employees of institutions such as detention centres, boarding schools or residential care facilities
• Long duration of exposure