Clinical Update done On Tuberculosis

Tuberculosis is a global healthcare burden. Globally, about 9.6 million new incident cases and 1.5 million deaths were reported due to tuberculosis in 2014 (Sulis, 2016). Though predominantly prevalent in developing countries, the infection is also seen in the developed world. In the developing countries, it affects people with low nutritional status and poor immunity. In the developed world, tuberculosis has become rampant due to the increasing prevalence of AIDS (Gopalan, 2016).

Aetiology and pathogenesis

Transmission of infection: Transmission of infection in tuberculosis occurs through aerosol spread, i.e. through the route of inhalation. Key factors influencing risk of transmission include bacillary load of the patient with tuberculosis, duration of exposure of the contact, and the proximity of the contact with the source. Patients who are sputum smear positive or have cavities in lung are high potential sources of infection (Escombe, 2008).

Course of disease: Most individuals exposed to the tubercular bacilli do not develop an infection. In those who become infected, the following are the possible outcomes (Saenz, 2013):

• Individuals may clear the infection.
• Individuals may harbour the infection for long periods of time (Latent tuberculosis).
• Individuals may develop progressive tubercular disease.

Immune response in tuberculosis: The outcome of an infection with the tuberculosis bacilli is determined by the innate and adaptive immune responses in the body. This immunological army includes several types of cells and mediators, the key ones being macrophages and dendritic cells (Kleinnijenhuis, 2009).

Latent tuberculosis: The presence of immunological response to a previously acquired tubercular infection without any clinically evident signs of active tuberculosis is called latent tuberculosis. This remains an important class of patients and calls for treatment to reduce the burden of tuberculosis.

Clinical features

The most common symptom of tuberculosis is a persistent cough that lasts several weeks to months (Davis, 2014). Other key clinical features include the following (Sulis, 2016):

Presence of at least one of the following four suggestive symptoms should raise a suspicion of tuberculosis:

• Persistent fever
• Persistent cough for 2 weeks or more
• Night sweats
• Weight loss

• History of contact with a case of tuberculosis
• Presence of risk factors for tuberculosis like AIDS, diabetes, malnutrition

Pulmonary tuberculosis: The initial or primary infection with tuberculosis may be mild and may go undetected. In response to the infection, a granuloma, called the primary Gohn complex, is formed in the lower or middle lobes of the lungs. This may be accompanied by enlarged draining lymph nodes and inflammation in the overlying pleura.Typically, this primary granulomatous reaction resolves spontaneously in a few weeks. The resultant fibrosis and calcification can be seen on radiological imaging.

As a part of natural history of tuberculosis, this primary infection may progress or a reinfection may occur. After a period of latency, reactivation of the disease may occur. This is also called post primary tuberculosis. Reactivation is clinically indistinguishable from the primary tuberculosis and usually occurs in immunocompromised conditions like AIDS, severe malnutrition, and in patients who are receiving immunosuppressive therapy. Patients with diabetes and those on haemodialysis are also at risk. Destruction of lung parenchyma may result in cavities filled with pus and necrotic tissue (Figure 1a). In addition to lesions in the lung, there may be foci of infection in the bronchi and in the adjoining lymph nodes. Peri-hilar and paratracheal nodes may be enlarged.

Miliary tuberculosis: The tubercular infection may spread through the haematogenous route and disseminate to the other organs of the body. Miliary granulomas are small (1 to 3 mm) in size and can occur in any visceral organ. Figure 1b shows the typical scattered millet seed appearance in the lungs of a patient with military tuberculosis. A type of extrapulmonary tuberculosis, military turberculosis, can occur after a primary infection, reinfection, or reactivation of tuberculosis.

Extrapulmonary tuberculosis: Tubercular infection may involve the extra-thoracic lymph nodes, pleura, pericardium, spine, or brain (Figure 1c, 1d). Other types of extrapulmonary tuberculosis include genitourinary tuberculosis, gastrointestinal tuberculosis, laryngeal tuberculosis, tubercular arthritis, and others.

Diagnosis

The most definitive diagnosis of tuberculosis is established by isolation of the causative bacterium in the appropriate biological specimen. There are several diagnostic tests for tuberculosis (Sulis, 2016):

Skin test: A subcutaneous injection of purified protein derivative (PPD) tuberculin is given in the flexor aspect of the forearm. After about 48 to 72 hours, the site of the tuberculin test is examined for induration. A firm swelling of 5 to 8 mm is interpreted as a positive tuberculin reaction and is suggestive of tuberculosis. The tuberculin test however is not diagnostic of tuberculosis as the rates of false positive and false negative results are high (Sanduzzi, 2017).

Imaging: Radiological imaging like X-rays and CT scan may reveal changes due to active infection in the organ involved.

Sputum smear microscopy: In this test, samples of sputum are collected and examined under the microscope. Presence of acid fast bacilli through Ziehl–Neelsen staining in the sputum or other biological samples confirms an infection with tuberculosis. According to WHO recommendations, one positive test result on sputum smear microscopy is a mandate for the diagnosis of smear-positive tuberculosis.

Rapid molecular tests: Rapid molecular tests are more accurate than sputum smear microscopy. The WHO recommends the Xpert® MTB/RIF assay (Cepheid, Sunnyvale USA) (WHO guidelines, 2013).

Culture methods: Culture of infectious bacilli is the most definitive test and remains the gold standard for the diagnosis of tuberculosis. Samples of sputum and body fluids like cerebrospinal fluid, pleural effusions and others may be subjected to culture. Culture requires appropriate laboratory conditions and it needs about 12 weeks for results to be obtained.

Treatment

Treatment in tuberculosis aims to eradicate the infection in the patient and minimise the risk of transmission to others. The key objectives of treatment in tuberculosis are as follows (Nahid, 2016):

• Cure infection and minimize risk of death and disability in the patient;
• Reduce bacterial load and hence minimise the risk of transmission of infection; and
• Prevent development of drug resistance.

The treatment of microbiologically confirmed cases of tuberculosis consists of an intensive phase regimen of 2 months of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months of INH and RIF. These pharmacological options are the first line drugs for treatment of tuberculosis. Figure 2 shows the treatment regimens and drug doses in the intensive and continuation phases in accordance with currently available clinical practice guidelines from the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America (Nahid, 2016).

Treatment of latent tuberculosis: In patients with latent tuberculosis, the following are recommended (Nahid, 2016; Getahun, 2015; Gordin 2000):

(1) Decision can be taken to entirely stop treatment if RIF and PZA were included in the initial empiric 4-drug therapy and these were administered for at least 2 months
(2) Decisions for continuation of treatment may include the following options:

• RIF, with or without INH, for a total of 4 months
• INH/rifapentine (RPT) by directly observed treatment (DOT) in 12 weekly doses
• INH for a total of 9 months.

Drug resistant tuberculosis: Tubercular bacilli may be resistant to RIF (Rifampicin-resistant tuberculosis) or to both RIF and INH (Multidrug resistant tuberculosis). Drug susceptibility testing may be used to identify the resistant strains of tuberculosis. Drug resistant tuberculosis is a challenge for treatment and needs introduction of second-line drugs. The WHO recommends the use of various second-line options in tuberculosis. These include fluoroquinolones like levofloxacin, moxifloxacin, and gatifloxacin, injectables like amikacin, capreomycin, kanamycin, and streptomycin, and other agents like ethionamide/prothionamide, cycloserine/terizidone, linezolid, and clofazimine. Other add-on drugs include pyrazinamide, ethambutol, high-dose isoniazid, bedaquiline, delamanid, p-aminosalicylic acid, imipenem–cilastatin, meropenem, amoxicillin-clavulanate, and thioacetazone. The WHO recommends shorter and longer regimens with these drugs in various combinations. Typically, the shorter regimens are administered for 9 to 12 months and the longer regimens are administered over 18 months or longer. These regimens may be tailored according to the response to therapy and prior treatment for tuberculosis. The WHO guidelines also explain the treatment outcomes including relapse, strength and certainty of evidence for recommendations, effect of delay in start of treatment, and possible surgical options for the treatment of drug resistant tuberculosis (WHO guidelines, 2016).

HIV and tuberculosis: Anti-retroviral treatment is recommended in all patients who are positive for HIV, irrespective of the CD4+ counts. Clinical assessments for potential drug reactions and adverse events should be done to minimise adverse events (Gopalan, 2016).

Summary

• Lungs are the commonest site of infection in tuberculosis (pulmonary tuberculosis) though other visceral organs can also be affected (extra pulmonary tuberculosis) and systemic spread of infection may also occur (miliary tuberculosis).
• The underlying pathophysiological mechanisms in tuberculosis involve the innate and adaptive immunity of the body.
• Infections with tuberculosis may be cleared with healing or may result in latent or progressive disease depending upon the immune response of the body. Immunosuppressive states increase the risk of tubercular disease.
• Depending upon the course of disease, infection with tuberculosis may be asymptomatic and may spontaneously resolve, or may manifest in clinical features like persistent non-remitting cough, fever, sweats, and weight loss.
• Laboratory confirmation and isolation of tubercular bacilli from sputum or other biological samples is the most definitive diagnosis of tuberculosis. Skin tests, radiological imaging, rapid molecular tests are other diagnostic approaches in tuberculosis.
• Treatment of tuberculosis aims to reduce the bacillary load in the patient and reduce the potential spread of infection. The key treatment options in tuberculosis include combinations of INH, RIF, PZA, and ethambutol. Latent and resistant tuberculosis are challenging to treat and specific protocols for management of these conditions should be considered.

References

• Barberis, I., Bragazzi, N. L., Galluzzo, L., & Martini, M. 2017. The history of tuberculosis: from the first historical records to the isolation of Koch's bacillus. J Prev Med Hyg., vol. 58(1), pp. E9-E12.
• Davies. P. D. O., Gordon, S. B., Davies, G. R. 2014. Clinical tuberculosis. 5th ed. Boca Raton: CRC Press.
• Escombe, A. R., Moore, D. A., Gilman, R. H., Pan, W., Navincopa, M., Ticona, E., et al. 2008. The infectiousness of tuberculosis patients coinfected with HIV. PLoS Medical, vol. 5(9), pp. e188.
• Heemskerk, D., Caws, M., Marais, B., & Farrar, J. 2015. Tuberculosis in Adults and Children. London: Springer.
• Gopalan, N., Chandrasekaran, P., Swaminathan, S., & Tripathy, S. 2016. Current trends and intricacies in the management of HIV-associated pulmonary tuberculosis. AIDS Res Ther, vol. 26, pp. 13-34.
• Getahun, H., Matteelli, A., Abubakar, I., et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. Eur Respir J., 46, pp. 1563–76.

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