Tuberculosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]; João André Alves Silva, M.D. [3]; Ammu Susheela, M.D. [4]
Overview
Tuberculosis (abbreviated as TB for 'Tubercle bacillus' 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.[1] 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.[2] 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 progress 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 izoniazid) is administered to patients with latent TB, while a more aggressive course that consists of 4 major antituberculous agents (rifampin, izoniazid, ethambutol, pyrazinamide) is reserved for patients with active disease.
Historical Perspective
Tuberculosis has been present in humans since ancient times. The earliest unambiguous detection of Mycobacterium tuberculosis was in the remains of bison, dated 18,000 BC.[3] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is unclear.[4] Through history tuberculosis has had many names including phthisis and Wasting disease, which were mostly derived from its symptoms. The Mycobacterium tuberculosis was only identified in 1882 by Robert Koch. In the 19th and early 20th centuries, tuberculosis caused the most widespread public concern, being considered an endemic disease of the urban poor. It was only in 1946, with the development of the antibiotic streptomycin, that effective treatment and cure became possible. Since the rise of drug-resistant strains in the 1980s, hopes that the disease could be completely eliminated have been dashed.
Classification
Tuberculosis may be classified into 6 major classes based on exposure, clinical symptoms, and adjunct diagnostic testing. The classification ranges from Class 0, in individuals with no 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, has also established a special classification for immigrants and refugees based on risk of infection.
Pathophysiology
Tuberculosis is a granulomatous infection which is chiefly transmitted through droplets. The granuloma prevents the dissemination of mycobacteria and provides a pathway for immune cell communication. Within the granuloma, T lymphocytes (CD4) secrete cytokines, such as interferon gamma, which activate local macrophages to kill the bacteria with which they are infected It is asymptomatic in 90% of immunocompetent individuals. In symptomatic patients it can present as pulmonary or extra pulmonary manifestations. The primary infection can progress to certain complications like disseminated infection. Tuberculosis can influence the progression of HIV if concomitantly present. 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 belongs to the Mycobacterium tuberculosis complex, that 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, yet 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. In 2014 there were 9 421 reported cases in the United States, with an incidence of 3.0 per 100 000 persons. Since 1990, the mortality rate of TB has been steadily decreasing. The prevalence of TB increases with age and it is more prevalent in older men. Racial and ethnic minorities have a higher prevalence of TB than non-Hispanic whites. TB is an important cause of death in people who are coinfected with HIV, with approximately a third of deaths among these patients being 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, Cambodia, Korea, Brazil, Ethiopia, Myanmar, Mozambique, Thailand, Angola, Vietnam, Kenya, Central Africa, Russia, Liberia, Zimbabwe, Namibia, Philippines, Tanzania, Sierra Leone, Zambia, Papua New Guinea, Lesotho.[5]
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, and evidence of previous tuberculosis. Risk factors for multidrug-resistant TB include: non-adherence to treatment regimen, inadequate medication for that strain of bacteria, and contact with patients with multidrug-resistant TB.
Screening
Screening for tuberculosis is generally done with 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 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 bronchietasis. 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 provide valuable information about the patient’s overall condition and other factors that may affect how tuberculosis is treated, such as HIV infection or other illnesses. 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 other specimen often indicates TB disease and a positive culture for M. tuberculosis confirms the diagnosis. Other laboratory test 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.[6] 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 disease. The findings on chest x ray can be divided into parenchymal and pleural. The early parenchmal findings can be infiltrates, and cavity. A healed tuberculotic lesion can present as fibrosis, and calcification. Pleural lesions in form of pleral effusion can also be seen. An advanced tuberculosis lesion can present as combination of these early lesions and termed as fibrocavitatory 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.[6] 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 [7] [8].
Treatment
Medical Therapy
If their 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 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 is managed differently. For patients with renal or liver diseases, 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 a 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 the 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 a 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 analysed 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.[9]
Future or investigational therapy
Since new drug resistant tuberculosis have 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.
References
- ↑ Raviglione MC, O'Brien RJ (2004). "Tuberculosis". In Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Isselbacher KJ, eds. Harrison's Principles of Internal Medicine (16th ed. ed.). McGraw-Hill Professional. pp. 953–66. doi:10.1036/0071402357. ISBN 0071402357.
- ↑ World Health Organization (WHO). Tuberculosis Fact sheet N°104 - Global and regional incidence. March 2006, Retrieved on 6 October 2006.
- ↑ Rothschild B, Martin L, Lev G, Bercovier H, Bar-Gal G, Greenblatt C, Donoghue H, Spigelman M, Brittain D (2001). "Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present". Clin Infect Dis. 33 (3): 305–11. PMID 11438894.
- ↑ Pearce-Duvet J (2006). "The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease". Biol Rev Camb Philos Soc. 81 (3): 369–82. PMID 16672105.
- ↑ "WHO 2016 TB Report" (PDF).
- ↑ 6.0 6.1 Kil UH, Jung HO, Koh YS, Park HJ, Park CS, Kim PJ; et al. (2008). "Prognosis of large, symptomatic pericardial effusion treated by echo-guided percutaneous pericardiocentesis". Clin Cardiol. 31 (11): 531–7. doi:10.1002/clc.20305. PMID 19006110.
- ↑ Drobniewski F, Caws M, Gibson A, Young D (2003). "Modern laboratory diagnosis of tuberculosis". Lancet Infect Dis. 3 (3): 141–7. PMID 12614730.
- ↑ Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, Drobniewski F, Lalvani A (2007). "A systematic review of rapid diagnostic tests for the detection of tuberculosis infection". Health Technol Assess. 11 (3): 1–314. PMID 17266837.
- ↑ Fitzpatrick C, Floyd K (2012). "A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis". Pharmacoeconomics. 30 (1): 63–80. doi:10.2165/11595340-000000000-00000. PMID 22070215.