Tuberculosis is an infectious lung disease that also damages kidneys, brain and spine. Mantoux test can confirm TB symptoms like cough and blood-stained phlegm.

Tuberculosis

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ZAKA CLINIC GULBERG LAHORE

Saad Ullah Siddiqui

Overview

Tuberculosis is defined as a contagious disease caused by the bacteria Mycobacterium tuberculosis<a href="#accordion">[1]</a>. It commonly infects the lungs, but other parts of the body such as the brain, spine, and kidneys can also be affected.

Skeletal remains of prehistoric humans have shown that tuberculosis existed as far back as 4000 BC. While the disease has been called by various names across history, it wasn&#39;t until 1834 that Johann Schonlein, a German physician, coined the term &#39;tuberculosis&#39;. Prior to this, people often called it &#39;the white plague&#39;, &#39;consumption&#39;, and also &#39;captain of all these men of death&#39;.

In 2020, tuberculosis (TB) accounted for 10 million infections and 1.5 million global deaths<a href="#accordion">[2]</a>. The ancient disease is currently the second leading infectious killer after <a href="https://www.merisehat.pk/disease/covid-19" target="_blank">COVID-19</a><a href="#accordion">[2]</a>. Pakistan is currently ranked among the top five high-burden countries accounting for more than two-thirds of new cases. The country reported 573,000 TB infections and 46,000 TB deaths in 2020<a href="#accordion">[3]</a>.&nbsp;

According to the World Health Organization (WHO), the incidence of TB is falling at about 2% per year<a href="#accordion">[2]</a>. Timely diagnosis and effective treatment regimens saved an estimated 66 million lives between 2000 and 2020<a href="#accordion">[2]</a>. However, the increasing levels of multidrug-resistant TB (MDR-TB) pose a threat to public health. As per the global tuberculosis report 2021, MDR-TB had an incidence of 4.2% in new patients and 16% in previously treated patients<a href="#accordion">[4]</a>. A study conducted in a high TB endemic region in Pakistan found a prevalence of 4.9% for MDR-TB<a href="#accordion">[5]</a>.

Human immunodeficiency virus (HIV) has further slowed the decline in TB incidence and increased TB deaths. In 2020, approximately 214,000 TB deaths were reported among HIV-positive people<a href="#accordion">[4]</a>. The WHO African region shares the greatest burden of HIV-associated TB with more than 50% of cases reporting a co-infection of HIV and TB[4]. In Pakistan, the HIV-positive TB incidence was 14,000 in 2020<a href="#accordion">[3]</a>. 
&nbsp;

Tuberculosis can be divided into several types depending on the organs infected.

&nbsp;

<h5>1. Pulmonary TB</h5>

Pulmonary TB accounts for 90% of active infections<a href="#accordion">[6]</a>. It is characterized by an infection of the lungs. A chronic cough, chest pain, and blood-stained sputum are common signs and symptoms of the infection.

<h5 dir="ltr"> 
2. Extra-Pulmonary TB</h5>

This type of TB occurs from an infection of organ systems other than the lungs. It accounts for 15% of all global TB cases. In Pakistan, pleural and lymphatic TB make up approximately 50% of all extra-pulmonary TB cases<a href="#accordion">[7]</a>.&nbsp; Extra-pulmonary TB can be further divided into: 
&nbsp;

<ul>
	<li>Pleural TB:&nbsp;Tuberculosis affects the pleura (lining of the lung), resulting in pleural effusion. The accumulation of fluid within the layers of the lung pleura exerts pressure on the lungs, resulting in breathlessness. In some cases, the fluid can become infected and lead to empyema.&nbsp; 
	&nbsp;</li>
	<li>Lymphatic TB:&nbsp;This is the most common type of extra-pulmonary TB. It involves the lymph nodes; cervical lymph nodes are usually affected. Along with swollen lymph nodes, the disease can also cause night sweats and fever.&nbsp; 
	&nbsp;</li>
	<li>Skeletal TB:&nbsp;Also called Pott&#39;s disease, it&rsquo;s characterized by infection of the spinal column, bones, and joints. The bacteria typically spread to the bones from the lungs or lymph nodes. Back stiffness, muscle spasm, and bone deformities are common symptoms. Moreover, when the joints are affected, TB arthritis can result.&nbsp; 
	&nbsp;</li>
	<li>Gastrointestinal TB:&nbsp;Any part of the gastrointestinal tract can be infected, resulting in varying symptoms, such as an abdominal mass, abdominal pain, altered bowel habits, and weight loss. 
	&nbsp;</li>
	<li>Genitourinary TB:&nbsp;This form of TB often results from a reactivation of the initial infection. The bacteria spread from the lungs to the infected area via the bloodstream or lymph nodes. It can affect any part of the genitals and/or the urinary tract. 
	&nbsp;</li>
	<li>TB Meningitis:&nbsp;Meninges, the membranes surrounding the brain and spinal cord, are infected. As a result, meningitis develops. TB meningitis has a gradual course of progression and can cause an altered mental status in patients. Without adequate treatment, people can go into a coma.&nbsp; 
	&nbsp;</li>
	<li>Miliary TB:&nbsp;This is a disseminated form of TB and results from the bacteria spreading to several organs, such as the lungs, liver, spinal cord, heart, and spleen. The chest X-ray of miliary TB is characteristic of multiple patches on the lungs that resemble millet seeds.&nbsp; 
	&nbsp;</li>
</ul>

Tuberculosis can also be divided into types based on the bacteria&#39;s resistance to common TB drugs. 
&nbsp;

<h5 dir="ltr">3. Multidrug-Resistant TB (MDR-TB)</h5>

MDR-TB results from an M. tuberculosis strain that is resistant to isoniazid and rifampin, the two most potent TB drugs.&nbsp;

&nbsp;

<h5>4. Extensively Drug-Resistant TB (XDR-TB)&nbsp;</h5>

This is a rare type of MDR-TB caused by bacteria resistant to isoniazid and rifampin along with any fluoroquinolone and at least one second-line injectable drug; or infection with bacteria resistant to isoniazid, rifampin, a fluoroquinolone, and bedaquiline or linezolid. 
&nbsp;

Signs And Symptoms

The symptoms of TB typically depend on the organ affected. General symptoms include:

<ul>
	<li>Fever</li>
	<li>Chills</li>
	<li>Night sweats</li>
	<li>Fatigue and weakness</li>
	<li>Unexplained weight loss</li>
	<li>Loss of appetite 
	&nbsp;</li>
</ul>

Pulmonary TB presents with the following symptoms:

<ul>
	<li>A persistent cough (lasting more than 3 weeks)</li>
	<li>Chest pain</li>
	<li>Shortness of breath</li>
	<li>Blood-stained phlegm 
	&nbsp;</li>
</ul>

Extra-pulmonary TB can present with:

<ul>
	<li>Back pain, muscle spasms, paralysis of lower limbs, and tuberculous <a href="https://www.merisehat.pk/disease/arthritis" target="_blank">arthritis </a>in skeletal TB</li>
	<li>Blood in urine, flank pain, and painful and frequent urination in genitourinary TB</li>
	<li>Persistent headaches, confusion, altered mental status, and coma in TB meningitis</li>
	<li>Abdominal pain, ulcers, difficulty swallowing, diarrhea&nbsp;or <a href="https://www.merisehat.pk/disease/constipation" target="_blank">constipation</a>, and poor absorption in gastrointestinal TB</li>
	<li>Enlarged lymph nodes in lymphatic TB</li>
	<li>Joint pains in TB arthritis 
	&nbsp;</li>
</ul>

Causes

Mycobacterium tuberculosis is the causative organism of TB. The rod-shaped bacteria are transmitted via infected air droplets produced from coughing, speaking, sneezing, and even singing. Prolonged close contact with an infected person is required to contract an infection. However, not everyone that has TB is infectious.&nbsp;

 
A TB infection can appear in two forms:

 
Latent TB:&nbsp;Approximately one-quarter of the world&#39;s population has a latent TB infection<a href="#accordion">[2]&nbsp;</a>The inactive stage is characterized by the presence of bacteria in the body and a lack of symptoms. The person cannot transmit the infection to others. However, 10% of these people can develop an active infection later on<a href="#accordion">[2]</a>. Therefore, people with latent TB are often prescribed a treatment regimen to prevent future infections.&nbsp;

 
Active TB:&nbsp;This is also called TB disease. Symptoms are initially mild and may occur weeks or years after infections. A person with active TB can spread the infection to 5-15 people over the course of a year. 
&nbsp;

Screening high-risk individuals for latent TB can significantly reduce the disease burden of TB. The US Centers for Disease Control and Prevention (CDC) recommends screening for people at increased risk of TB, such as those with HIV/AIDS, healthcare workers, and those with a history of exposure.

 
The following tests help screen people for TB:

<ul>
	<li>Mantoux Tuberculin Test:&nbsp;The skin test involves injecting a small amount of PPD tuberculin under the surface of the skin. An allergic reaction to the protein results in a small bump. After 2 or 3 days of the injection, an experienced professional will measure the size of the bump. Swelling of 5 mm or more indicates a positive result in presence of risk factors. In case of a reaction over 15 mm, the results are considered positive regardless of risk factors. However, people who have previously received the Bacille Calmette-Guerin (BCG) vaccine can have false-positive results. Moreover, the test cannot determine if someone has an active infection. Many people, despite having TB, might not respond to the test.&nbsp; 
	&nbsp;</li>
	<li>Interferon-Gamma Release Assay (IGRA):&nbsp;This in-vitro blood test is based on IGRA and can detect M. tuberculosis-specific antigens. Similar to the skin test, it cannot determine a latent infection from an active infection.&nbsp;</li>
</ul>

 
A positive skin test or blood test is often followed by other diagnostic tests, such as a sputum test and chest X-ray.&nbsp;

&nbsp;

Diagnosis

The following tests can help diagnose TB:

<ul>
	<li>Chest X-Ray:&nbsp;A chest X-ray can help diagnose pulmonary TB. People with an active infection present with patchy infiltrates across the lung fields. The pulmonary lesions appear in different lobes of the lungs; they can be dense or calcified, depending on whether the person has latent TB, reactivation, or primary TB. In the case of miliary TB, multiple nodular lesions resembling millet seeds may be seen. Moreover, a chest X-ray can also show an accumulation of pleural fluid in the case of pleuritic TB. 
	&nbsp; &nbsp;</li>
	<li>Sputum Test:&nbsp;Sputum samples are collected in the early morning for 3 consecutive days. The samples are checked for the presence of the bacteria. Moreover, sputum samples can also test for drug-resistant strains and help doctors prescribe an appropriate drug regimen.&nbsp;</li>
</ul>

 
If the doctor suspects extra-pulmonary TB, other tests such as abdominal ultrasound, urine test, CT scan of the brain, and blood tests may also be conducted. 
&nbsp;

Treatment

Treatment for tuberculosis depends on the type of infection (active or latent), the person&#39;s age, the location of the infection, drug resistance of the strain, and the person&#39;s overall health.&nbsp; 
&nbsp;

<h5 dir="ltr">Medications</h5>

First-line medications are considered the most potent anti-TB drugs. They help treat active TB and are typically administered to people who have not received TB drug treatment before. A course of 6 to 9 months is often recommended for the complete elimination of the disease. The first line of drugs are: 
&nbsp;

<ul>
	<li>Isoniazid:&nbsp;The antibiotic prevents the growth of M. tuberculosis bacteria and is most commonly used for treating latent TB. It is typically taken for a period of 9 months. Common side effects include nausea, vomiting, peripheral neuropathy, liver damage, and loss of appetite. The drug is typically administered with pyridoxine (vitamin B6) to prevent peripheral neuropathy. 
	&nbsp;</li>
	<li>Rifampin:&nbsp;Rifampin (also called rifampicin) works by inhibiting DNA-dependent RNA polymerase, which then blocks bacterial RNA transcription. Common side effects include red discoloration of urine and other bodily fluids, elevated liver enzymes, rash, nausea, vomiting, and thrombocytopenia. The drug may decrease the effectiveness of oral contraceptive pills (OCPs). Therefore, people are advised to take additional precautions while taking rifampin.&nbsp; 
	&nbsp;</li>
	<li>Pyrazinamide:&nbsp;Its exact mechanism of action remains unclear. The antibiotic can be routinely administered for the treatment of drug-resistant TB. Common side effects include nausea, vomiting, anorexia, muscle and joint pain, and rash. However, the drug is contraindicated in pregnancy.&nbsp; 
	&nbsp;</li>
	<li>Ethambutol:&nbsp;Ethambutol prevents bacterial wall synthesis. Side effects include fever, abdominal pain, altered liver enzymes, rash, and peripheral neuritis. Due to the risk of optic neuritis, patients are advised monthly eye exams.&nbsp;</li>
</ul>

 
Other medications may also be administered. These include:

<ul>
	<li>Aminoglycosides (Streptomycin, Kanamycin, Amikacin):&nbsp;These drugs inhibit protein synthesis of the mycobacteria. Due to the adverse effects of ototoxicity and nephrotoxicity, they are contraindicated in pregnancy.&nbsp; 
	&nbsp;</li>
	<li>Fluoroquinolones (Levofloxacin, Moxifloxacin):&nbsp;Fluoroquinolones inhibit bacterial DNA synthesis. Common side effects include tendonitis and arthropathy. 
	&nbsp;</li>
	<li>Rifapentine:&nbsp;Also known as rifamycin antibiotic, the drug stops bacterial growth. It is often administered with isoniazid for latent TB. Hyperuricemia is a common side effect of rifapentine.&nbsp; 
	&nbsp;</li>
	<li>Linezolid:&nbsp;The drug belongs to a class of antibacterial called oxazolidinones. It acts on the bacterial DNA and inhibits protein synthesis. Linezolid is part of the treatment regimen for drug-resistant TB. Common side effects include headache, nausea, rash, and diarrhea. Long-term use can cause bone marrow suppression and neuropathy.&nbsp; 
	&nbsp;</li>
	<li>Bedaquiline:&nbsp;This medication is specifically used for treating MDR-TB. It works by preventing mycobacteria ATP synthesis. Common side effects include nausea, headache, joint pain, and chest pain. It can also prolong the QT interval and lead to arrhythmias.&nbsp;</li>
</ul>

 
Treatment Of Active TB - New cases are typically given a 2-month course of 4 drugs (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin). Then, for the next 4 months, patients receive isoniazid and rifampin.&nbsp;

&nbsp;

Treatment Of Latent TB - Since latent TB has a risk of re-activation, doctors prescribe anti-TB medications to these patients. Various regimens exist for the treatment of latent TB. The most common is treatment with isoniazid for 9 months. Another option is a combination of isoniazid and rifampin for 3 months.&nbsp;

&nbsp;

Treatment Of MDR-TB -&nbsp;A combination of fluoroquinolones, an injectable aminoglycoside, and bedaquiline or linezolid is given for a duration of 20 to 30 months.&nbsp;

&nbsp;

Pregnant Women -&nbsp;For pregnant women with active TB, the treatment regimen consists of isoniazid, rifampin, and ethambutol for 2 months. This is followed by 7 months of isoniazid and rifampin. In pregnant women with latent TB, 4-month rifampin monotherapy, 2-month isoniazid monotherapy, or 6- or 9-month isoniazid therapy (with pyridoxine supplementation).

&nbsp;

HIV-Positive Patients -&nbsp;Due to the interaction of anti-TB medications with antiretroviral therapy, rifampin is avoided in patients with HIV. Patients with active TB are administered a 4-month regimen consisting of isoniazid, pyrazinamide, moxifloxacin, and high-dose rifapentine. Another option is the 6- to 9-month RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) regimen. In the case of latent TB, patients with HIV receive 12-week isoniazid and rifapentine therapy.

&nbsp;

Children -&nbsp;Rifampin and isoniazid, for a duration of 6 months, can be administered to most children.&nbsp;Since most anti-TB medications may exert a hepatotoxic effect, regular liver function tests are advised for monitoring liver enzymes. Other than liver tests, blood tests, uric acid levels, and tests for peripheral neuropathy are also routinely conducted.

&nbsp;

<h5 dir="ltr">Surgical Procedures</h5>

In patients with MDR-TB, surgical resection of the infected lung is often recommended. Especially, if there&#39;s a poor response to medical treatment. Other procedures include lobectomy, segmentectomy, and pneumonectomy.&nbsp;

&nbsp;

<h5 dir="ltr">Myrin-P Forte</h5>

Despite multiple efforts at controlling TB, the disease continues to infect millions worldwide. This is largely due to low treatment success rates as a result of poor treatment compliance and the emergence of drug-resistant strains. Moreover, anti-tuberculous regimens often contain a combination of one or more drugs and this pill burden has majorly contributed to poor patient compliance. Therefore, as per WHO&#39;s recommendation, Myrin-P Forte was manufactured for use in the initial phase of antituberculous treatment.&nbsp;

Myrin-P Forte is a fixed combination drug comprising of rifampin, ethambutol, isoniazid, and pyrazinamide. The formulation contains 150 mg rifampin, 75 mg isoniazid, 275 mg ethambutol, and 400 mg pyrazinamide. According to a study conducted at the Pfizer Clinical Research Unit in Singapore, the fixed-dose combination was bioequivalent to single-drug formulations of its components<a href="#accordion">[8]</a>&nbsp;Furthermore, 4 Myrin-P forte tablets equal 15 pills of a free-combination regimen. Thus, significantly reducing the pill burden for chronic disease.&nbsp;

A Russian study demonstrated Myrin-P to have good tolerability and efficacy among 474 patients with drug-resistant and primary TB<a href="#accordion">[9]</a>. However, the drug has several contraindications. It is not advised for use in people weighing less than 30 kg, children, and patients with a history of liver disease or renal insufficiency. Moreover, the combination drug is associated with hypersensitivity reactions and visual disturbances.&nbsp; 
&nbsp;

Most people start to feel better after just a few weeks of starting anti-TB medications. However, it is important to remain compliant with the treatment regimen and complete the whole course of medication. This prevents the development of resistant strains. Therefore, to ensure patient compliance, the WHO recommends a directly-observed treatment, short-course (DOTS) strategy.&nbsp;

Launched in 1995, DOTS involves a healthcare worker or family member administering the medication to the patient. By ensuring that the patient swallows the medication, the strategy reduces the chance of missing a dose. Moreover, it helps patients stick to their treatment regimen. Instead of daily dosing, patients receive 2- or 3-times per week dosing of the medications. 
&nbsp;

Although tuberculosis is a curable disease, it can turn fatal&nbsp;if left untreated. Moreover, it can also lead to complications such as:

<ul>
	<li>Extensive lung damage</li>
	<li><a href="https://www.merisehat.pk/disease/arthritis" target="_blank">Arthritis </a>due to tuberculosis infecting the joints; hip and knee joints are most commonly affected</li>
	<li><a href="https://www.merisehat.pk/disease/pericarditis" target="_blank">Pericarditis </a>from the involvement of the heart</li>
	<li>Meningitis</li>
	<li>Spinal pain and stiffness</li>
	<li>Sepsis 
	&nbsp;</li>
</ul>

The following risk factors increase a person&#39;s chance of contracting M. tuberculosis:

<ul>
	<li>Malnutrition, especially in children, can weaken the immune system and increase the risk of TB</li>
	<li><a href="https://www.merisehat.pk/disease/diabetes-type-1-and-2" target="_blank">Diabetes</a></li>
	<li>Cancers or cancer treatment</li>
	<li><a href="https://www.merisehat.pk/disease/hiv-61" target="_blank">HIV</a>/<a href="https://www.merisehat.pk/disease/aids" target="_blank">AIDS</a></li>
	<li>Drugs for treating <a href="https://www.merisehat.pk/disease/rheumatoid-arthritis" target="_blank">rheumatoid arthritis </a>and Crohn&#39;s disease</li>
	<li>Immunosuppressive medications</li>
	<li>Smoking</li>
	<li>Travelling to or living in an area with a high disease burden (Africa, Asia, or Eastern Europe)</li>
	<li>Substance abuse</li>
	<li>Close contact with an infected individual</li>
	<li>Working in places such as prisons, nursing homes, shelters, or psychiatric hospitals; these facilities have a higher risk due to overcrowding and poor ventilation</li>
	<li>Working in a healthcare setting</li>
</ul>

&nbsp;

A person with active TB can transmit the infection to 10-15 people annually<a href="#accordion">[2]</a>. Therefore, it is essential to take precautions once TB is confirmed. The following steps can help prevent TB transmission:

<ul>
	<li>Staying home during the first few weeks of treatment</li>
	<li>Avoiding crowded places or close contact with other people until no longer contagious</li>
	<li>Wearing a mask around other</li>
	<li>Staying compliant with TB medications</li>
	<li>Ventilating the room</li>
</ul>

&nbsp;

<h4>BCG Vaccine&nbsp;</h4>

In countries with a high prevalence of TB, the BCG (Bacille Calmette-Gu&eacute;rin) vaccine is routinely administered in infants and children. The vaccine is part of the Extended Program of Immunization (EPI) program in Pakistan and is administered at birth or in the first month after birth. In countries such as the United States and Canada, the vaccine is only given to those at high risks, such as healthcare workers who are exposed to a high percentage of TB patients or are in contact with people with active TB. 
&nbsp;

Key Points

<ul>
	<li>Caused by Mycobacterium tuberculosis, TB is a highly infectious disease that commonly affects the lungs (pulmonary TB). However, other organs such as the brain, spine, and kidneys may also be affected (extra-pulmonary TB).</li>
	<li>General symptoms of tuberculosis include fever, chills, sweating, fatigue, unexplained weight loss, and appetite loss. Pulmonary TB can cause a chronic cough, shortness of breath, coughing up blood or sputum, and chest pain.&nbsp;&nbsp;</li>
	<li>A Mantoux tuberculin test is often conducted in high-risk individuals to screen for TB. A positive test is followed by a chest X-ray and a sputum test to confirm the person&#39;s diagnosis.&nbsp;</li>
	<li>Treatment involves a combination of anti-TB medications and depends on the person&#39;s age, overall health, drug resistance to the strain, and location of infection. A combination of the first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) is often recommended for a period of 6 to 9 months.&nbsp;</li>
	<li>Tuberculosis is a notifiable disease and all suspected or confirmed cases should be reported to relevant health authorities. 
	&nbsp;</li>
</ul>

[1] NIH, 2020. Tuberculosis. [Online]

[2] WHO, 2021. Tuberculosis. [Online]

[3] National TB Control Program , n.d. Tuberculosis profile: Pakistan. [Online]

[4] WHO, 2021. Global Tuberculosis Report 2021, Geneva: World Health Organization.

[5] Ali, S. et al., 2020. Prevalence of Multi-Drug Resistant Mycobacterium Tuberculosis in Khyber Pakhtunkhwa – A High Tuberculosis Endemic Area of Pakistan. Polish journal of microbiology, 69(2), pp. 133-137.

[6] Lawn, S. D. & Zumla, A. I., 2011. Tuberculosis. The Lancet, 378(9785), pp. 57-72.

[7] Tahseen, S. et al., 2020. Extrapulmonary tuberculosis in Pakistan- A nation-wide multicenter retrospective study. PLoS ONE, 15(4).

[8] Wang, H. F. et al., 2013. Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination. International Union against Tuberculosis and Lung Disease, 17(12), pp. 1596-1601.