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Understanding the Basics of Tuberculosis
#1
Information  This is post no. 1 under the main topic.
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 be 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.

    [Image: mycoTB_rawmilk.jpg]  

 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.


Formation of granulomatous infection by Delayed Type Hypersensitivity


  • 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.
                                    
[Image: picture81343580775468.png]

                                                                               

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. 
                                            [Image: a06fig1.gif]
                                                                                         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.
[Image: img0024.jpg]
  •                                            
          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.


                                [Image: tb1.jpg]

                                                           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.

                                  [Image: tb2.jpg]      

                                                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.



Websites and Books referred to :   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.
 
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#2
This is post no. 2 under the main topic.
All of us have heard about the DOTS programme run by our Government but do we know what it really stands for?

Here is a brief idea regarding DOTS:

DOTS stands for Directly Observed Treatment, Short-course.

It has 5 main elements:
  •  The willingness of the Governments to address TB related technical and financial requirements.
  •  Use of good quality bacteriology, mainly, the sputum smear microscopy for detecting TB infections.
  •  A standardised treatment for six to nine months should be provided to the patient under direct observation of a health care worker.
  •  The anti-TB drugs should be supplied unhindered, effectively managed and be provided to the poor for free.
  •  Systematic recording and reporting of the progress in treatment should be made.

These have been defined by WHO (World Health Organisation) which has a number of strategies for controlling and decreasing TB infections.

Under the Revised National Tuberculosis Control Program (RNTCP), DOTS was implemented in India on a large scale in the year 1997. From 2006, The Stop TB Strategy of WHO was also incorporated in RNTCP.

DOTS-PLUS is used for MDR-TB.

For enrolling under DOTS, the person should go to a Primary Health Centre to avail free of cost, quality TB drugs.  The patient is asked to visit the centre after a few weeks for monitoring the progress.
Some patients also visit private health centres for treatment.
RNTCP carries out awareness campaigns, mainly about the benefits of availing DOTS as well as motivating patients for completing the entire course.
 
 
 

Here is an excellent video on how the DOTS programme works in India:
                    
                                        


I hope this has helped you in understanding DOTS.
Suggestions are most welcome.
 
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#3
This is post no. 3 under the main topic.
TIDBITS:

Do you know, the X-Ray reports of a person affected by TB mentions the word Koch? A Koch infection is just another way of terming the lesions and tubercles in the lungs. 

Does Koch ring a bell in your mind? Yes you are right! It is named after Robert Koch, the great scientist known for his postulates, who discovered the cause of Tuberculosis amongst his many other notable works.

For his research on TB, he received the Nobel Prize in Medicine in 1905.

[Image: 184px-Robert_Koch_BeW.jpg]

SHARE WITH US IF YOU HAVE ANY SUCH INTERESTING 'TIDBITS'! HAVE A GREAT DAY!
 
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#4
This is post no. 4 under the main topic.
Hello Aparajita how are you?

I wanted to commend you on an informative post on Tuberculosis (TB).  As we both know TB is one of the most common infectious diseases worldwide. Due to its population size India has an additional burden of TB. I wanted to share an article I read with you on the outcome of DOTS with relation to the conversion rate, cure rate and treatment rate.

A three month retrospective study was performed in 2006 on patients who were registered at six DOTS centres located throughout India. Sputum samples of the patients were examined using microscopy at three different phases of their treatment regime – at the end of intensive phase, midway of continuation and at the end of treatment.


It was found that the cure rate for CAT-I was 85.04%.1 The sputum conversion rate for CAT-I and II were 92.5 and 56% respectively. 1
The results from this particular study were compared to results published from previous studies and it was found that these success rates were higher. What caused these higher cure rates?

The higher cure rates for both CAT – I and II were attributed to strict supervision and monitoring of patients. In addition self-motivation of both patients and health professionals assisted to increased cure rates.

DOTS is still is the cornerstone of management of TB in developing countries. In 1993, World Health Organization (WHO) declared TB a global emergency and introduced the DOTS programme. By the year 2005, 187 countries had adopted and started implementing the DOTS programme with 4.9 million cases of TB being treated with the implementation of DOTS.2

China has recorded massive success with DOTS. In 1993, 91% of TB patients who started DOTS treatment was cured.2 Similar results were recorded in Bangladesh. About 72,000 cases of TB are reported in Bangladesh every year with DOTS covering 90% of the population and achieving a treatment success rate of 80%.2

DOTS has proven successful in the treatment of TB. One wonders if this therapy would work for HIV or HIV/TB infections? Share your thoughts.

Maureen.

1. Mishra et al. 2007. A study of effectiveness of DOTS on Tuberculosis patients treated under RNTCP programme. NTI Bulletin 43/3&4 pp47-50. Available from http://www.ntiindia.kar.nic.in
2. Out A.A. 2013. Is the directly observed therapy short course (DOTS) an effective strategy for TB control in a developing country? Asian Pacific Journal of Tropical Disease 3(3):227-231. Available from http://www.ncbi.nlm.nih.gov
 
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#5
This is post no. 5 under the main topic.
Hello Maureen, I am as fit as a fiddle and I hope you are doing fine as well.  Big Grin

You have actually brought up a good and valid point here.

Firstly, I feel that people who suffer from TB and HIV have a certain social stigma. They avoid going for check-ups and almost give up on any hopes of surviving. They hardly want to socialise and turn into recluses. Also, if you see, both HIV and TB cases are really tricky to diagnose. And when an HIV infected patient has TB, the case may turn more complex because of lack of good medical facilities. Hence, why not think about adopting something like DOTS for HIV patients as well?

The only hindrance to a DOTS-like programme for HIV is that TB is actually curable but HIV-AIDS is not.

BUT the later can definitely be controlled.
So, if a similar programme can come up for AIDS, I am sure that it would help the HIV infected patients to keep a check on their health and avoid infections. These programmes can educate them on how to keep small infections at bay, so that even with a compromised immunity system, they can lead a normal life.

I am a big advocate for a strategy that includes some get-togethers and activities, which might motivate the patients to live life to the fullest.

One of the main objectives of DOTS is to provide free of cost medicines to TB patients and if a similar strategy is adopted for AIDS, the patients would benefit hugely from it. But HIV-AIDS drugs can be costly, especially the branded ones and it may not be feasible for them to be provided for free. Generic drugs are much cheaper and can definitely be thought of as safe, low-cost alternatives.

The protocol for diagnosis of HIV needs to be quick, reliable and uniform across the country.

 Also, systematic recording of the patients’ data and keeping them under constant supervision can be effective in bringing down the number of deaths caused by AIDS. This has to be lifelong though, as unlike TB which gets cured in 6 to 9 months, AIDS doesn’t.

And as per HIV-TB infections are concerned, DOTS can be followed to get rid of the mycobacterial infection.

There have been many reports where various AIDS specific strategies are being devised and trials are going on. But none of them are yet to be implemented on a large scale.

I live in India and almost everyday, I see so many advertisements starring big celebrities, informing people about DOTS and I think, if such a programme is launched for AIDS as well, the patients would be happy to get some support, both medically and mentally.

Well, there are some obvious problems with an AIDS strategy but the thought is novel and I hope that a support system for AIDS patients is launched soon; for this world is as much theirs as it is for us!

Have a nice day Maureen!
 
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#6
This is post no. 6 under the main topic.
A NEW DEVELOPMENT  Angel


 
The Indian city of Gurgaon saw the launch of mobile vans which will go around the districts of Haryana in search of active cases of TB.  It is the collaboration of  the Government of Haryana along with Medanta - The Medicity hospital, United States Agency for International Development (USAID), the International Union Against Tuberculosis and Lung Disease, and the Central TB Division of the Ministry of Health & Family Welfare (Government of India).
 
The vans are fitted with X-ray machines and there are facilities for receiving outcomes of the tests instantly. The district doctors would then be approached for further confirmation and thereafter, the patients would be asked to undergo GeneXpert testing which can detect M. tuberculosis DNA. After the confirmations, the patients would be referred to primary health care centres for DOTS.


[Image: hospital-medicity-november-november-hind...59308e.jpg]
 A van to be used in this programme



These vans can screen up to fifty people per day. This is a weekly, three phased programme, spanning across five years.

As discussed earlier in this thread, there is a social stigma attached to this disease and this is definitely a welcome step to curb the fatal cases of TB, which in most cases may go undetected.

 

 References:


http://www.thehindu.com/todays-paper/tp-...901899.ece
http://www.hindustantimes.com/gurgaon/go...Jk6SN.html
http://www.tribuneindia.com/news/haryana...60755.html





A note will follow soon on GeneXpert for TB.
 
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#7
This is post no. 7 under the main topic.
New research shows daily antibiotics may prevent drug-resistant TB and quicken recovery!


A study published recently in the journal BMC Systems Biology claims that the prescriptions advising doses of medicines only once or twice a week may give rise to more cases of drug resistant strains of M. tuberculosis in comparison to the ones which suggest antibiotics on a daily basis. Most probably the considerable gap between the doses gives the bacteria ample time to adapt to the antibiotic induced adverse conditions.

This entire study was based on a computer simulation model fed with information collected from earlier experiments on rabbits and monkeys. They studied the effects of standard drugs like  isoniazid and rifampin with respect to their efficiency at varied doses and future prospects.

The doses comprised of larger doses once or twice a week and small daily doses. Computer simulations showed that that daily treatment was way more effective, though even in this case their was dificulty in wiping off the entire bacterial population due to granulomas or/and passive state of reproduction.  

The team tried to find out the dose frequency which would be most effective in raising antibiotic concentration inside the granuloma and found the daily regime to be more potent. The study shows that nine doses per week (evening and morning doses two days per week and rest of the days having single doses) is the quickest way to get rid of all the bacteria.

The work was done by University of Michigan in collaboration with National Institutes of Health, with computing resources provided by the National Energy Research Computing Center, Open Science Grid, and Extreme Science and Engineering Discovery Environment.


References:

http://timesofindia.indiatimes.com/life-...908816.cms
http://www.ndtv.com/health/daily-antibio...is-1247146
http://www.rdmag.com/news/2015/11/tuberc...nt-strains
http://ns.umich.edu/new/releases/23321-t...nt-strains

[url=http://www.rdmag.com/news/2015/11/tuberculosis-daily-antibiotics-recommended-prevent-resistant-strains][/url]
 
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#8
This is post no. 8 under the main topic.
(11-24-2015, 11:28 PM)APARAJITA AICH Wrote: New research shows daily antibiotics may prevent drug-resistant TB!



Read more here:


http://timesofindia.indiatimes.com/life-...908816.cms

Hi Aparajita,

Really appreciate your posts here. It would be nice if you could post the details of the information than the exit link. It's sort of against the forum rules to post out links (forum is more about giving a platform to discuss and ponder, if people start leaving the forum for out links of info, it will completely loose its meaning).. Hope you understand. Thanks for your co-operation.

Regards,
Editor
 
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#9
This is post no. 9 under the main topic.
Hello everyone! Big Grin As promised earlier, here’s an article on GeneXpert technology which is used as a confirmatory diagnosis test for Tuberculosis. Let us have a look at what it is and how it works.

GeneXpert is a nucleic acid amplification based test. It can not only identify M. tuberculosis DNA but also effectively detects any Rifampicin resistance shown by the bacteria. The name of this test - Xpert MTB/RIF is therefore deduced from the name of the causative organism of TB and Rifampicin.

It’s a cartridge based automated PCR test.

GeneXpert MTB/RIF was developed by Professor David Alland’s lab at University of Medicine and Dentistry of New Jersey in association with the Cepheid Inc. and Foundation for Innovative New Diagnostics(FIND), sponsored by the US National Institutes of Health (NIH).
It was officially launched in 2004.



As described earlier, there are many tests used to confirm TB cases, like Sputum test, Mantoux test, X-rays etc. But GeneXpert holds an edge over the others as it has :

·        Better sensitivity.
·        Highly TB specific testing.
·        Quicker than the traditional mycobacterial culture and drug susceptibility testing.
·        More efficient for detection of MDR-TB and HIV related TB.


Here's a picture of the cartridge loading:
            [Image: Gene_Xpert_USAID.jpg]
Source: http://www.health-e.org.za


Steps of the test:
 
Probable patient’s sputum collected
.
Purification and concentration of M. tuberculosis from sputum
.
Isolation of bacterial genome (Sonication)
.
PCR to amplify genomic DNA
.
 Rifampicin resistant mutations searched by the device
.
Identification and target characterisation by six colour laser detector/beacons.

Here's a diagram showing the steps:


[Image: xpert_mtb_rif_procedure.jpg]
Source: http://www.finddiagnostics.org

The entire process is fairly quick and gives us the result under 2 hours.

A shortcoming of this test is that it detects both live and dead bacteria. Hence, it can’t be used for monitoring on-going treatment. Also, the cost of each test as well as the cartridges and related devices are quite high. The shelf life of the cartridges is low. Moreover, the devices have limited throughput per day.




Cepheid Inc. continues developing new and improved versions of the test device. GeneXpert is being promoted worldwide by WHO in association with MIND.
Let’s hope for the betterment and further globalisation of this technique. Let’s hope for a TB free world!


 
Fun While Learning Visit here for an interactive map by WHO on the GeneXpert roll-out!

http://apps.who.int/tb/laboratory/xpertmap/




References:

www.cepheid.com
https://en.wikipedia.org
www.who.int/tb
www.tbfacts.org
 
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