Understanding the Basics of Tuberculosis

Tuberculosis (or TB) is said to infect around one-third of the world’s population.  Although it is one of the most widespread transmittable diseases, it manages to go undetected in most of the cases, resulting in fatal consequences.

 It primarily affects the lungs (pulmonary) as well as some other parts of the body (extrapulmonary), and causes damage to the critical organs, disturbing their functions. 

The fact that the diagnosis can get tricky despite of the latest medical advances is what makes this disease dangerous. There has been repeated campaigning done by the governments for quick identification and treatment of TB but challenges continue to remain.

Here is a detailed look at the way this disease affects the human body, the diagnostics presently used as well as which research areas should be focused on for a better future.


Which organism causes TB?  


The Mycobacterium sp.
Mycobacterium tuberculosis affects the humans.

      

 Source: http://www.bio.davidson.edu

It is a rod shaped, aerobic bacillus and has a lipid rich thick cell wall (mainly mycolic acid) which is mostly responsible for its high resistance to the immunity system and medical treatments. It infects intracellularly.


How does the infection spread?

It spreads through the air when a person inhales the aerosol droplets of respiratory fluids released by an affected person’s cough or sneeze.


What are some common symptoms?

• Persistent coughing for many weeks.
  
• Coughing out blood or sputum is a strong symptom.
  
• Sweating at night during sleep.
  
• Weight loss.
  
• Sudden occurrences of high fever.
  
• Fatigue.
  
• Chest pain.
  
• No appetite for food.
  
• Getting chills.
  

Who are prone to TB?

• People exposed to affected patients or to people who are unaware that they have the disease.
  
• People with poor or compromised immunity.
  
• People suffering from malnutrition.
  
• People with HIV or any other disease which affects the immunity system.
  
• People who smoke or suffer from silicosis, diabetes show increased susceptibility to TB.
  
• People who have weakened immunity system due to cancer treatment.
  
• In many patients, a protein which fights the infection, maybe expressed below the normal level because of a hereditary or acquired mutation in its gene.
  

How does M. tuberculosis cause the infection?

• The bacteria reach lungs and enter pulmonary alveoli.
  

• They invade the endosomes of alveolar macrophages and start replicating.
  

• Macrophages identify the pathogens and start phagocytosis but the phagolysosome formation is inhibited by bacteria. Also, the cell wall helps in protection, in the cases when phagolysosome is formed. M. Tuberculosis blocks certain molecules like autoantigens as well, but continues getting access to nutrients for its growth. Hence, the multiplication continues.
  

• CD4+, TH1 T cells secrete cytokines which induce macrophages, T lymphocytes, B lymphocytes, and fibroblasts to aggregate and form granulomas by surrounding the infected macrophages.
  
• Fusions happen when new macrophages attack the infected ones and multinucleated cells form, resulting in palpable nodules.
  
• The tubercle sequesters the infected macrophage and prevents the infection from spreading further.
  
• The immune system gets suppressed as macrophages and dendritic cells present in the granuloma cannot present antigens to the lymphocytes. 
  
• Necrosis happens in the centre of the tubercles because of high amount of lysosomal enzymes. 
  
• Also, the huge number of activated macrophages release lytic enzymes which destroy surrounding healthy cells. This results in circular regions of necrotic tissues which get calcified as the lesions heal. These can then be seen on X-rays.
  
• In many cases, increased lytic acid secretion may cause the lesion or granuloma to rupture, thus releasing the bacteria into blood or lymph vessels, which is dangerous.
  

                                     

                                              Source: http://www.classconnection.s3.amazonaws.com

How is TB diagnosed?


Here are some methods used to identify a TB patient:

•  Chest X-ray: The doctor generally prescribes a Chest PA to check the presence of any calcified lesions and cavities in the lungs. Fibrotic scars, nodules, cloudy appearance of the lung airspace, enlarged lymph nodes in hila, pleural effusion etc. are some of the common findings if the person is affected by TB. 
  

                                            
                                                           Source: http://www.scielo.br
    

•  Sputum culture: Sputum is the coughed up mixture of saliva and mucus of the respiratory tract and may even contain blood.  This would contain the bacteria if the person is infected. Sputum is collected and sent for stain test. The Ziehl-Neelsen stain or auramine-rhodamine staining, can be used to identify M. Tuberculosis.
  

          PCR is followed to confirm the presence of M. Tuberculosis.

•  Mantoux test : A standard dose of Tuberculin units is intradermally injected into the forearm skin of a person and after around 2- 3 days, the forearm is observed. If there is a hard raised area which may cause pain or give an uneasy feeling, the diameter of the area is recorded. If the area is significant, the person is said to have been infected with the M. Tuberculosis because of which his/her immunity system has mounted a hypersensitive defence to the bacteria. The mount is there as the infected person had already been producing sensitised TH1 cells specific for the injected antigen.
  
          
           Source: http://www.tti.library.tcu.edu.tw
  
  

          This test may result in false positive results, mainly because BCG may have been administered earlier to the patient which causes the
           mount to appear.
          Hence, the test not reliable. It is always used in conjunction with any of the above tests.
          Another test known as the Heaf test is no longer in use.

•  The Antibody from Lymphocyte Secretions or ALS Assay method is used to detect active TB rapidly. The plasma B cells release antibody in response to TB antigens. So, an extracted sample of PBMC is cultured and the supernatant is tested against BCG by ELISA to diagnose TB. 
  

• Scientists have developed the T-SPOT.TB ELISPOT Interferon-γ (interferon-gamma) release assays (IGRAs) in which the property of M. tuberculosis antigens to stimulate the host cells to produce interferon gamma is exploited. Large scale use is yet to happen though it is already in use in many developed countries.
  

•  The health parameters of the patient are checked, like any instances of persistent coughing, sputum production, fever, chills, drop in weight etc.  A full blood count test is also recommended. It is advised to contact the doctor when the regular antibiotic medicines don’t seem to heel a persistent respiratory illness.
  

• Although these are the most used tests, there are many other methods followed as well and the tests conducted vary from country to country. 
  

How to prevent TB?

There has not been any guaranteed method to prevent the infection. However, the following are commonly suggested:

•  Bacillus Calmette-Guérin (BCG): It is a vaccine prepared from an attenuated strain of Mycobacetrium bovis and is intermediately effective against TB infection for around 15 years. The effectiveness varies due to geographical locations, genetic difference between populations etc. It helps in preventing the highly serious forms of the disease like childhood tuberculous meningitis and miliary disease.
  
  
•  Adequate public awareness should be raised by the health officials.
  
  
•  Close contact with high risk people and patients should be avoided, if possible.
  
  
•  Patients should minimise their human contact till they are well set on the path of recovery. They should wear masks to prevent others from catching the disease.
  

Is TB curable? If so, what are the popularly used medicines to treat it?


TB is curable if the patient completes the full course (generally 6 to 9 months) of antibiotics, as prescribed by the doctor. This is also followed up with regular check ups.
The drugs prescribed depend on the location of the TB infection.

These medicines are commonly recommended: (the dose strength and drugs vary with time)

• Some first line drugs are: Isoniazid, Rifampicin, Ethambutol, Pyrazinamide etc.
  

Here’s a diagram explaining how these drugs work.


                                

                                                                                Source: http://www.niaid.nih.gov
  

•  Multi drug resistant TB happens when the bacteria is resistant to the first line drugs, mainly Isoniazid and Rifampicin. MDR-TB can happen in a previously unaffected person or after ineffective treatment of a TB patient with first line drugs. This happens due to mutating bacteria, drug efflux systems, secretion of drug inactivating enzymes etc. In many cases, the ineffective drug is identified and suitable second line drugs are given for further treatment.
  

         Second line drugs classes in case the first line doesn’t work: Aminoglycosides, Thioamides, Peptides etc.

         Examples: Kanamycin, Viomycin, Amikacin, Ciproflaxin, Moxifloxacin etc.

         These are more expensive and can take around 2 years for the course to complete.


Here’s a diagram explaining how these drugs work.

                                        

                                      Source: http://www.niaid.nih.gov

• There are third line drugs as well but their efficacy hasn’t been proved yet.
  

What are the focus areas for research regarding combating TB?

• Researchers are trying to find new cell wall proteins which can be sufficient to trigger an immunity response as well as provide a longer protection in comparison to the BCG vaccine. There are many new vaccines like MVA85A which are undergoing trials.
  
  
• Tuberculosis Necrotizing Toxin was discovered recently and is the only known toxin of Mycobacterium tuberculosis. It kills and escapes from the macrophages by hydrolysing NAD+. This is a major discovery and can pave the future of TB drug research.
  

If you prefer videos, here is a fun way to learn about  TB
 
                                                         




There are many institutions advocating TB research and creating awareness about this disease which can often be a silent killer by going undetected.
The TB patients often hesitate in going to the doctors. Many people think that it cannot be cured. Many don’t follow the entire medicine course. Clearly, better awareness amongst people and quick diagnostics with effective drugs are the needs of this hour.

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Websites and Books referred to :  

• Immunology- Kuby
  
•  en.wikipedia.org
  
•  www.niaid.nih.gov   
  

Any mistakes pointed out will be appreciated.
I have tried to keep it simple for both the general public and the students. If the bacterial infection or any other part is not understood, feel free to contact me via the reply box. It is hoped that the article was informative.
Any suggestions are highly welcomed. Thank you for going through this post.