Tuberculosis overview

# Overview
Tuberculosis (abbreviated as TB or Tuberculosis) is a common infectious disease caused by Mycobacterium tuberculosis. Tuberculosis most commonly involves the lungs as the organism thrives in high oxygen environments, but it can also cause disease in the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Over one-third of the world's population has been exposed to M. tuberculosis, and new infections occur at a rate of one per second.  Not all individuals exposed to the bacterium develop clinically overt tuberculosis infection; in fact, asymptomatic, latent TB infection discovered by screening is more common. Approximately, one in ten latent infections progresses to active (symptomatic) TB disease, which, if left untreated, carries mortality rates of up to 50%.  Symptoms include shortness of breath, hemoptysis, fever, chills, night sweats, and weight loss.  Several treatment regimens are available for the latent and active forms of TB. Classically, a prolonged course of 6-9 months of a single agent (rifampin or isoniazid) is administered to patients with latent TB, while a more aggressive course that consists of 4 major anti-tuberculous agents (rifampin, isoniazid, ethambutol, pyrazinamide) is reserved for patients with active disease.

# Historical Perspective
- Tuberculosis has been present in humans for thousands of years.
- The earliest unambiguous detection of Mycobacterium tuberculosis was in the remains of bison, dated 18,000 BC.
- Tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor.
- Tuberculosis has had many names including phthisis and Wasting disease.
- Some hypotheses demonstrate that the origin of the genus,  Mycobacterium tuberculosis, was more than 150 million years ago.
- TB with its different names and presentations throughout its history was detected on skeletal deformities of Ancient Egyptian mummies, dating back to 2400 BC.
- The first written record of TB, found in India and China, dated back to 3300 and 2300 years ago.
- In the Middle Ages as well as during the Renaissance, TB was referenced to as the Kings Evil.
- During this period if time, the contagious nature, pathology and anatomical afflictions were described.
- An English physician named Benjamin Marten, supposed the anticipated origins for this disease by 1720.
- Years later, there were a number of proposed cures but the most significant milestone in the fight against TB was achieved by renowned scientist, Robert Koch.
- Robert Koch discovered the Mycobacterium tuberculosis in 1882.
- In the 19th and early 20th centuries, tuberculosis caused the most widespread public concern, being considered an endemic disease of the urban poor.
- An effective therapy became possible with the development of the antibiotic streptomycin in 1946.
- The drug-resistant strains began to increase in the 1980s.

# Classification
- According to exposure, clinical symptoms, and adjunct diagnostic testing tuberculosis is classified into 6 main classes .
- The classification ranges from Class 0, in people without previous exposure to TB and negative tuberculin skin testing and/or interferon-gamma release assays (2 methods of screening for TB), to Class 3 for active TB and Class 5 for suspected TB based on signs and symptoms of the disease.
- The U.S. Citizenship and Immigration Services also made a special classification for immigrants and refugees according to the risk of infection.

## TB Classification System
- As per CDC (Centers of Disease Control and Prevention), the clinical classification system for TB used in the United States is based on the pathogenesis of the disease.
- This classification system provides clinicians the opportunity to keep an eye on the development of TB in their patients.
- Health care providers should follow with state and local laws and regulations requiring the reporting of TB disease.
- All persons with Class 3 or Class 5 TB should be reported directly to the local or state health department.
- A patient should not have a Class 5 classification for more than 3 months.

# Pathophysiology
- Tuberculosis is a granulomatous infection that is chiefly transmitted through droplets.
- The granuloma encloses mycobacteria and prevents their spreading and facilitates immune immune cell communication.
- Within the granuloma, T lymphocytes (CD4) releases cytokines, such as interferon gamma, that activates local macrophages.
- It is asymptomatic in 90% of immunocompetent individuals.
- In symptomatic patients, it can present as pulmonary or extrapulmonary manifestations. The primary infection may turn into disseminated infection.
- Tuberculosis usually has an impact the progression of HIV if  present together. Depending on the age of the patient, tuberculosis may have different clinical manifestations, progression, and prognosis.

# Causes
- Mycobacterium tuberculosis is the bacterium responsible for tuberculosis.
- It is an aerobic, non-encapsulated, non-motile, acid-fast bacillus.
- M. tuberculosis is one of the Mycobacterium tuberculosis complex, which also includes bacteria, such as M. bovis and M. africanum.
- The bacterium has a very slow rate of replication, and its genetic variations account for the geographical distribution of different strains, and are involved in drug resistance.
- M. tuberculosis has tropism for different kinds of human cells, with preference for cells of the lung.
- It may infect different species, but human beings are its frequent natural reservoir.

# Epidemiology and Demographics
- In 2015, about 10.4 million people developed symptomatic TB and 1.8 million died from the disease.
- There were 9,421 reported cases in the United States in 2014  with an incidence of 3.0 per 100,000 persons.
- Since 1990, the mortality rate was steadily decreasing.
- The prevalence of TB increases with age and it is higher in older men. TB is more prevalent in racial and ethnic minorities than non-Hispanic whites.
- TB is an major cause of death in people coinfected with HIV.
- A third of deaths among these patients is due to TB.
- In 2015, 60% of TB cases worldwide occurred in 6 countries: South Africa, Indonesia, Nigeria, Pakistan, India, and China.
- The WHO has identified 24 other high-burden TB countries including Bangladesh, Congo, Columbia, Lesotho, Cambodia, Korea, Brazil, Ethiopia, Myanmar, Mozambique, Thailand, Angola, Zambia, Vietnam, Kenya, Central Africa, Russia, Liberia, Tanzania, Zimbabwe, Namibia, Philippines,  Sierra Leone, Papua New Guinea.

# Risk Factors
- The risk factors for the development of tuberculosis include:
weakened immune system (patients taking immunosuppressive medication or with immunosuppressive diseases, such as HIV or diabetes
History of contact with infected patients
Bad hygiene conditions
Evidence of previous tuberculosis.
- weakened immune system (patients taking immunosuppressive medication or with immunosuppressive diseases, such as HIV or diabetes
- History of contact with infected patients
- Bad hygiene conditions
- Evidence of previous tuberculosis.
- Risk factors for multidrug-resistant TB include:
Non-adherence to the treatment regimen
Insufficient medication for that strain of bacteria
Contact with patients with multidrug-resistant TB.
- Non-adherence to the treatment regimen
- Insufficient medication for that strain of bacteria
- Contact with patients with multidrug-resistant TB.

# Screening
- Screening for tuberculosis is generally done by using a mantoux tuberculin skin test, also known as a tuberculin skin test or a PPD.
- The test involves injecting a small amount of a purified protein derivative of the tuberculosis bacterium intradermally and watching for a reaction in the following days.

# Natural history, complications and prognosis
- Tuberculosis has been classified as a primary or secondary (post-primary) infection.
- It can have pulmonary and extra pulmonary manifestations as well as severe parenchymal, vascular, pleural, and chest wall complications.
- Pulmonary complications include pleural effusions, cavitations, lymphadenopathy, airway obstruction, pneumonia and bronchiectasis.
- The hematogenous dissemination of infection can lead to miliary tuberculosis.
- The post-primary infection can be due to a recent infection or reactivation of an old infection. Without treatment, 1/3 of patients with active tuberculosis dies within 1 year of the diagnosis, and more than 50% during the first 5 years.
- But with early diagnosis and treatment, it has a good prognosis.

# Diagnosis

## History and Symptoms
- The general symptoms of tuberculosis include weakness, weight loss, fever, and night sweats.
- Symptoms of pulmonary tuberculosis include cough, chest pain, and hemoptysis.
- Tuberculosis is particularly difficult to diagnose in children, as these may not present with common findings.

## Physical Examination
- A physical examination can give an overview about the general condition and other factors that may influence the tuberculosis response to treatment, such as HIV infection or other diseases.
- The most common physical findings include fever, decreased breath sounds, tachypnea and tachycardia.
- Physical findings will depend on the location of the tuberculosis infection.

## Laboratory findings
- Routine laboratory exams are usually in the normal ranges.
- The presence of acid-fast-bacilli (AFB) on a sputum smear or another specimen often indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis.
- Other laboratory tests include peritoneal fluid or CSF analysis, urinalysis, and Interferon-Gamma release assays.

## Electrocardiogram
- Echocardiography or Ultrasound can be helpful in patients who develop pericardial effusion secondary to TB. In rare occasions TB may lead to congestive heart failure, in which case echocardiograph may also help in the diagnosis.
- Common findings in CHF on the echocardiogram include: hypokinesia; valvular insufficiency; and enlargement of all heart chambers.

## Chest X-Ray
- A chest X-ray is one of the important diagnostic tools in tuberculosis.
- A chest radiograph may be used to rule out the possibility of pulmonary TB in a person who are symptomatic or had a positive reaction to a tuberculin test or QFT-G and no symptoms of the disease.
- The findings on chest x-ray can be divided into parenchymal and pleural.
- The early parenchymal findings can be infiltrated, and cavity.
- A healed tuberculotic lesion can present as fibrosis, and calcification.
- Pleural lesions in form of pleural effusion can also be seen.
- An advanced tuberculosis lesion can present a combination of these early lesions and termed fibrocavitary lesions.

## CT
- The majority of patients with pulmonary tuberculosis will have abnormal findings in a chest CT, which include micronodules, interlobular septal thickening, cavitation and consolidation.
- CT scan is more sensitive than an X-ray to detect lymphadenopathies.

## MRI
- MRI is used for the assessment of extrapulmonary tuberculosis, such as CNS tuberculosis, Pott's disease, and parotid gland tuberculosis.

## Echocardiography or Ultrasound
- Echocardiography or Ultrasound can be helpful in patients who develop pericardial effusion secondary to TB.
- In rare occasions TB may lead to congestive heart failure, in which case echocardiograph may also help in the diagnosis.
- Common findings in CHF on the echocardiogram include: hypokinesia; valvular insufficiency; and enlargement of all heart chambers.

## Other Imaging findings
- The abreugraphy is a smaller variant of the chest X-ray that allows the identification of lung abnormalities that may suggest the diagnosis of TB.
- With the decrease of incidence of TB, the abreugraphy is no longer recommended in most countries for low-risk populations.
- However, depending on the screening resources of each country, it may be used for the screening of high-risk groups, such as HIV-positive patients and alcoholics.

## Other Diagnostic Studies
- Because of difficulties with the Tuberculin skin test, many laboratory methods of diagnosis are emerging.

# Treatment

## Medical Therapy
- If there is a high probability of infection, presumptively treat the patient even if the stain is negative, while waiting for the culture results.
- The patient should be brought back in a few weeks.
- Patients usually feel better a few weeks post-treatment.
- Patients must be monitored for adverse effects and treatment failure.
- In the U.S., all TB is tested for drug resistance.

### Special conditions
- Medical therapy for tuberculosis in special conditions include HIV co-infection and extra pulmonary manifestations.
- Different approaches are taken for patients taking ART and those who do not take ART.
- Although WHO recommends the same drug regimen for pulmonary and extrapulmonary manifestations, various stages of skeletal tuberculosis are managed differently.
- For patients with renal or liver diseases, the first line of drugs are substituted with second-line drugs to prevent complications.

### Drug-resistant
- Drug-resistant tuberculosis is caused by M. tuberculosis organisms that are resistant to at least one first-line anti-TB drug.
- Multidrug-resistant TB (MDR TB) is resistant to more than one anti-TB drug and at least isoniazid (INH) and rifampin (RIF).
- Treatment should be started with an empirical treatment of at least 4 drugs based on expert advice as soon as drug-resistant TB disease is suspected.

### Children
- Tuberculosis in children aged 15 years or younger is a public health problem of special significance because it is a marker for recent transmission of TB. *Infants and young children are more likely to develop life-threatening forms of tuberculosis, such as miliary TB or TB meningitis.
- Screening in children is very important, as the clinical manifestations are usually poor or non-specific.
- History of close contact with tuberculosis patients has an important role in the diagnosis of TB in children.
- The treatment is similar to adults, with adjusted dosing according to the child's weight.

## Surgery
- Surgery may be necessary, especially to drain  abscesses , empyema, venticular shunt in tubercular meningitis, surgical resection of tissues affected in abdominal tuberculosis, stabilize the spine in case of Pott's disease, lobectomy, pneumonectomy, pericardiocentesis or surgical repair of pericardium.

## Primary Prevention
- Primary prevention in tuberculosis is targeted to avoid disease transmission and infection of healthy individuals. The BCG vaccine is used in children susceptible to TB infections, such as children living in endemic areas or having close contact with a confirmed case of TB.
- Several preventive measures are used to avoid the transmission of the mycobacteria, such as respiratory isolation, use of respiratory masks among health-care professionals, and advising respiratory hygiene and cough etiquette.

## Secondary Prevention
- Secondary prevention for tuberculosis includes methods for screening and early diagnosis, such as tuberculin skin test (TST) and IGRAs; and to guarantee the correct treatment regimen at the right time to prevent disease progression.

## Cost effectiveness of therapy
- Treatment of tuberculosis must be analyzed for relative cost effectiveness of inpatient and outpatient models of care as it will benefit regions where tuberculosis is highly prevalent.
- Unless there is severe complications it is highly recommended to treat the TB patient in ambulatory care rather than inpatient services.

## Future or investigational therapy
- Since new drug-resistant tuberculosis has been emerging, the role of future therapies is vital in curbing outbreaks.
- The new drugs should be more effective than the current regimen and a few drugs in clinical trials have been showing good results.