Abstract

Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and a major cause of death world-wide. Tuberculosis continues to be a huge peril disease against the human population and according to WHO, tuberculosis is a major killer of the human population after HIV/AIDS. Tuberculosis is highly prevalent among the low socioeconomic section of the population and marginalized sections of the community. In India, National strategic plan (2017-2025) has a national goal of elimination of tuberculosis by 2025. It requires increased awareness and understanding of Tuberculosis. In this review article history, taxonomy, epidemiology, histology, immunology, pathogenesis and clinical features of both pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (EPTB) has been discussed. A great length of detailed information regarding diagnostic modalities has been explained along with diagnostic algorithm for PTB and EPTB. Treatment regimen for sensitive, drug resistant and extensive drug resistant tuberculosis has been summarized along with newer drugs recommended for multi drug resistant tuberculosis. This review article has been written after extensive literature study in view of better understanding and to increase awareness regarding tuberculosis, as a sincere effort that will help eliminate tuberculosis off the face of the earth in near future.

Keywords

Introduction

       
           
       
    Fig.no 1 Tuberculosis

LITERATURE REVIEW:

Treatment of Tuberculosis

       
           
       
    Fig.no 2 Treatment of Tuberculosis

MANAGEMENT OF TUBERCULOSIS:

       
           
       
    Fig. no 3 Symptoms of Tuberculosis

Pathogenesis

The majority of droplet nuclei containing MTB from infec- tious patients are trapped in upper airway and expelled by ciliated mucosal cells: only a fraction reaches alveoli. The mycobacteria then bind to cell surface of alveolar macro- phages through complement receptors, mannose receptor or type A scavenger receptor. Following phagocytosis, myco- bacteria reduce acidity in phagosome and a cell wall component (i.e. lipoarabinomannan) impairs Ca+/calmod- ulin pathway thus inhibiting phagosome-lysosome fusion. Following successful arrest of phagosome maturation, the multiplication of bacilli begins and the macrophage even- tually ruptures to release its bacilli, which are taken up by macrophages and continues infection cycle further expanding the spread.22 During primary infection, MTB bacilli undergo hematogenous and lymphatic dissemination involving hilar and mediastinal lymph nodes forming pri- mary Ghon's complex. Eventually bacilli enter blood stream and reach various organs. This lympho-hematogenous dissemination results in extrapulmonary tuberculosis dur- ing primary infection or later in life during reactivation of disease. 23 EPTB can involve any site in the body & the most common site is lymph node. However pleural, neurological, synovial, pericardial, abdominal, genitourinary involvement has been described.[15]

1. Tubercular Lymphadenitis

From ancient times, lymph node TB has been called Scrofula or King's evil. It constitutes nearly 35% of EPTB cases. Cervical lymphadenitis is the most common and reported in 60-90% of tuberculous lymphadenitis cases. Involvement of cervical lymph node is due to spread of bacilli from primary focus of infection in Ghon's complex or from tonsils, adenoids, sinonasal/osteomyelitis of the ethmoid bone. Initially, MTB bacilli multiply in lymph node causing marked hyperemia, swelling, necrosis and caseation of involved lymph node. The inflammation, progressive swelling and matting of other nodes around, resulting in adhesion to adjacent skin and rupture into surrounding tissue or through skin forming si- nuses. Mediastinal lymphadenitis can compress major blood vessels, phrenic nerve or recurrent laryngeal nerve or cause erosion of bronchus which is commonly seen in children.

Peripheral tuberculosis of lymph nodes is classified by Jones and Campbell into-

1. STAGE I:-Enlarged, firm, motile discrete nodes.
2. STAGE II:-Large rubbery nodes fixed to surrounding tissue.
3. STAGE III:-Central softening due to abscess formation.
4. STAGE IV:-Collar stud abscess formation.
5. STAGE V:-Sinus tract formation.

2. Pleural TB

The incidence of pleural TB is as high as 30% of all EPTB cases in high burden countries. The patients usually presents with acute febrile illness with nonproductive cough and pleu- ritic chest pain; associated with night sweats, chills, weakness, dyspnea, weight loss. The pathogenesis in pleural TB is pre- sumed to be due to delayed hypersensitivity rather than direct infection of pleural space. This space is infected from initial lung parenchymal lesions and results in immunological response predominated by neutrophils (first 24 hours). This is followed by lymphocyte driven immune response forming pleural granuloma formation and release of Adenosine Deam- inase (ADA). Neutrophils remain the first line of defense for first 24 hours, followed by macrophages which peak at 96 hours and then by lymphocytes. A strong T-helper type-1 (Th 1) response is necessary to contain MTB. Activated CD3+ and CD4+ Th1 cells release interferon ? (IFN- ?) thus activating macrophages to kill MTB. The Th1 immunity in pleural TB is confirmed by the high levels of IFN- ?, interleukin-12 (IL-12) and elevated helper T cells in pleural fluid as compared to serum/peripheral blood. The delayed hypersensitivity reaction to mycobacterial anti- gens affects pleura and increases the permeability of pleural capillaries, and thereby increasing fluid in pleural cavity. The fluid is drained through openings in the parietal pleura called stomata. Since diffuse involvement of parietal pleura with TB and damage to or obstruction of stomata leads to accumulation of pleural fluid. Chronic TB empyema resolve leaving thick- ened, scarred and calcified pleura causing chronic chest pain, dyspnea and impaired lung function. Pleural fibrosis, a well- documented complication has been reported in 5-55% of pleural TB cases.

3. Abdominal TB

The abdominal tuberculosis is diagnosed in 11% of patients with EPTB which was around 55-90% in era before effective ATT. The most common site of gastrointestinal tract involvement is the ileocecal region due to following reasons-

1. More lymphoid tissue (Peyer's patches)
2. Increased physiological stasis
3. Rate of fluid and electrolyte absorption is more
4. Low digestive activity

Other sites of involvement in decreasing order are ascending colon, jejunum, appendix, duodenum, stomach esophagus, sigmoid colon and rectum. Hepatobiliary, splenic and pancreatic TB are rare and associated with miliary tuberculosis; often diagnosed in immunocompromised pa- tients. MTB bacilli gain entry to abdominal organs by two routes and cause disease due to reactivation of dormant focus. As a result of hematogenous spread from primary lung infection in children and as a part of miliary TB. Through ingestion of contaminated food and milk which infect Peyer's patches and are transported to mesenteric lymph node, where they remain dormant. 27,28 esophagus, sigmoid colon and rectum. Hepatobiliary, splenic and pancreatic TB are rare and associated with miliary tuberculosis; often diagnosed in immunocompromised pa- tients. MTB bacilli gain entry to abdominal organs by two routes and cause disease due to reactivation of dormant focus. As a result of hematogenous spread from primary lung infection in children and as a part of miliary TB. Through ingestion of contaminated food and milk which infect Peyer's patches and are transported to mesenteric lymph node, where they remain dormant. 27,28esophagus, sigmoid colon and rectum. Hepatobiliary, splenic and pancreatic TB are rare and associated with miliary tuberculosis; often diagnosed in immunocompromised pa- tients. MTB bacilli gain entry to abdominal organs by two routes and cause disease due to reactivation of dormant focus. As a result of hematogenous spread from primary lung infection in children and as a part of miliary TB. Through ingestion of contaminated food and milk which infect Peyer's patches and are transported to mesenteric lymph node, where they remain dormant.

d.Central Nervous System (CNS) TB

It is serious and often fatal form of EPTB, predominantly affecting young children. CNS TB is difficult to diagnose. It presents in 2 major forms

1. TB meningitis- 0.5-1% of all TB cases
2. Intra-cranial tuberculoma-accounting up to 40% of brain tumors

MTB bacilli reach CNS during dissemination that occurs in active pulmonary disease. These bacilli cross physiological Blood Brain Barrier (BBB) via infected monocytes/neutrophils and cause a caseating focus in brain parenchyma or meninges. These foci are termed as 'Rich foci'. Later, these foci rupture in subarachnoid space triggering inflammatory T cell response with elevated levels of INF y and TNF-a in CSF. The subsequent inflammation leads to production of inflamma- tory infiltrates which obstructs CSF outflow causing hydro- cephalus and vasculitis leads to infarction, causing potentially irreparable neurological damage.

5. Bone and Joint TB

It accounts for 10-15% of all EPTB cases. It arises from reactivation of dormant MTB bacilli lodged in any bone (spine or large joints) during bacteremia of primary lung infection. These bacilli have affinity for spine and large joints because of their rich vascular supply. An extension of initial infection focus from the bone to the joint results in tuberculous arthritis. Rarely the bacilli can reach spine from the lung along the Batson paravertebral venous plexus or by lymphatic drainage to the paraaortic lymph nodes. Non tuberculous mycobacteria (NTM) have been reported to cause osteo- articular TB following a traumatic injury or during surgical procedure like joint arthroplasty. NTM bone infection in pa- tients with AIDS or transpla…

6. Genito-urinary TB (GUTB)

It accounts for 15% of all EPTB cases and 3-4% of all PTB cases. Its occurrence is 20 times more in kidney transplant recipients than in general population. 12 After hematogenous spread of bacilli from active site of infection (usually lungs), bacilli gets lodged in kidney (most common site of GUTB) and form metastatic lesions (tubercles). These foci of infection may heal spontaneously/due to treatment, enlarge and rupture into nephrons or remain dormant for many years. Usually the spread of infection is descending from kidney to other genito-urinary organs. It develops between 2nd and 4th decades of life; usually 5-25 years of inactivity after primary lung infection.

7. Miliary TB

Miliary TB account for less than 2% of all tuberculosis cases and up to 20% of all EPTB cases among immunocompetent adults, however the autopsy studies have shown military TB ranges between 0.3% and 13.3%. TH2 response plays a central role in immunopathogenesis of military TB. It inhibits pro- tective response such as granuloma formation and fencing of the disease activity at the site of infection. The production of interleukin 4 (IL-4) during TH2 response, downregulates nitric oxide synthase (NOS), tall like receptor 2 and macrophage activation; thus sabotaging protective response of TH1 cells. This process favors dissemination of MTB. from host's cell mediated immunity. These tubercles are microscopic to begin with and coalesce to become macro- scopically visible granulomas. The granulomas contain MTB bacilli within macrophages, fibrin rich alveolar exudate, lymphocytes and multinucleated giant cells which are enclosed within fibroblastic rim. These granulomas formed are both caseating and non-caseating granulomas.[16,17]

DIAGNOSIS OF TUBERCULOSIS  :

Hence research on new diagnostic and screening tools and standards has become very necessary in planning to control TB7.9. LTBI is diagnosed with the help of Interferon- gamma release assays (IGRAs) but the tuberculin skin test (TST) is always cost effective for poor peoples. The mechanism behind TST and IGRA is by analyzing the response of immune T cells to the TB antigens.

1. Tuberculin skin test

In the TST test, tuberculin protein derivative from TB is injected intradermally into the patient which caused a delayed hypersensitivity skin reaction (Type 4), if the patient has mycobacteria infection 11. To determine the infection of TB, the size of the skin reaction is measured; the usual standard is between 2 to 3 days and value from 0.74 at 5 mm to 0.40 at 15 mm. However, the TST gives a false report that is positive responses in the patient who are BCG vaccinated and negative in immunosuppressed persons (Table 2: TST Results for Populations at Risk of TB).

2. Interferon-gamma release assays

The IGRAs is a more sensitive and specific diagnostic test for TB (81-88% compared to 70% sensitivity for the TST) 12, but IGRAs are costly and specific technique is used. In IGRAs the release of cytokine IFN-g from T cells that react to antigens not available in the BCG vaccine 12. A blood sample is collected from an individual and the release of cytokine IFN-g is measured. IGRAs have different Guidelines and constantly changing. In Canada and in some European countries, it has even been suggested that IGRAs and the TST be used together to detect LTBI, but these tests are not definitive 11-12. How the disease develops in individuals from a latent to active TB is a heavy task and to improve diagnostic tools we have to identify risk factors associated with high and low burden countries and will improve our understanding of the immune response in  Test for TB: Strength and limitations

3. Chest Radiography

Chest radiography is indicated for all persons being evaluated for LTBI or active ??. Pulmonary TB as a result of endogenous reactivation of latent infection classically presents with infiltrates in the apical and posterior segments of the right upper lobe, the apical-posterior segment of the left upper lobe, and the superior segment of the lower lobe.

4. Smear Microscopy

Smear microscopy for the detection of AFB is the most rapid and cheap method for TB diagnosis 40.[18,19]

SIGNS AND SYMPTOMS

General clinical features of TB

Cough with or without sputum more than 3 weeks, Weight loss, Fever/Pyrexia, Sweating in night Haemoptysis (blood in sputum), Chest ache,Fatigue/Weakness.

Symptoms of tuberculous meningitis

Subtle mental status changes that may progress to coma over a period of days to weeks Low-grade fever.

Symptoms of skeletal TB may include the following

Back pain or stiffness, Lower body paralysis, (50% have Pott disease), Tuberculous arthritis, usually involving the only single joint (most often the hip or knee, followed by the ankle, elbow, wrist, and shoulder).

Symptoms of gastrointestinal TB

Ulcers of the mouth, anus or GIT, Difficulty in swallowing (with the oesophageal disease), Abdominal pain mimicking peptic ulcer disease (with gastric or duodenal infection), Malabsorption (with infection of the small intestine), Pain, diarrhoea, or haematochezia (with infection of the colon).

Signs of extrapulmonary TB

Confusion, Coma, Neurologic deficit, Chorioretinitis, Lymphadenopathy, Cutaneous Lesions.[20]

DRUG

First line

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter Ethambutol is EMB or E, isoniazid is INH or H, pyrazinamide is PZA or Z, rifampicin is RMP First-line anti-tuberculous drug names are often remembered with the mnemonic "RIPE," referring to the use of a rifamycin (like rifampin), isoniazid, pyrazinamide, and ethambutol. The US uses abbreviations and names that are not internationally recognised: rifampicin is called rifampin and abbreviated RIF; streptomycin is abbreviated STM. In the US only, streptomycin is no longer considered a first line drug by ATS/IDSA/CDC because of high rates of resistance. The WHO have made no such recommendation.  Drug regimens are similarly abbreviated in a standardised manner. The drugs are listed using their single letter abbreviations (in the order given above, which is roughly the order of introduction into clinical practice). A prefix denotes the number of months the treatment should be given for; a subscript denotes intermittent dosing (so means three times a week) and no subscript means daily dosing. Most regimens have an initial high-intensity phase, followed by a continuation phase(also called a consolidation phase or eradication phase): the high-intensity phase is given first, thenthe continuation phase, the two phases divided by a slash. So, 2 HREZ/4HR3 means isoniazid, rifampicin, ethambutol, pyrazinamidedaily for two months, followed by four months of isoniazid and rifampicin giventhree times a week.[21]

Isoniazid

General information

Isoniazid, the hydrazide of isonicotinic acid, is highly bactericidal againstreplicating tubercle bacilli. It is rapidly absorbed and diffuses readily into all fluids and tissues. The plasma half-life, which is genetically determined, varies from less than 1 hour in fastacetylators to more than 3 hours in slow acetylators. Isoniazid is largely excreted in the urine within 24 hours, mostly as inactive metabolites. Clinical information Administration and dosage Isoniazid is normally taken orally but may be administered intramuscularly orintravenously to critically ill patients.

Adults:

•           5 mg/kg (4-6 mg/kg) daily, maximum 300 mg

•           10 mg/kg (8-12 mg/kg) three times weekly, maximum 900 mg (1).

Contraindications

•           Known hypersensitivity.

•           Active, unstable hepatic disease (with jaundice)

Adverse effects

Systemic or cutaneous hypersensitivity reactions occasionally occur during the first weeks of treatment. Sleepiness or lethargy can be managed by reassurance or adjustmentof the timing of administration. The risk of peripheral neuropathy is excluded if vulnerable patients receivedaily supplements of pyridoxine. Other less common forms of neurological disturbance, including optic neuritis, toxic psychosis and generalized convulsions, can develop in susceptible individuals, particularly in the later stages of treatment, and occasionally necessitate the withdrawal of isoniazid. Symptomatic hepatitis is an uncommon but potentially serious reaction that canusually be averted by prompt withdrawal of treatment. More often, however, an asymptomatic rise in serum concentrations of hepatic transaminases at the outset of treatment is of no clinical significance and usually resolves spontaneously as treatment continues. A lupus-like syndrome, pellagra, anaemia, and arthralgias are other rare adverse effect[22]

 Drug interactions

Isoniazid inhibits the metabolism of certain drugs, which can increase their plasma concentration to the point of toxicity. Rifampicin, however, has the oppositeeffect for many of these drugs. For example, the available data indicate that administering both rifampicin and isoniazid causes a reduction in plasma levels of phenytoin and diazepam. Isoniazid may increase the toxicity of carbamazepine, benzodiazepines metabolized by oxidation (such as triazolam), acetaminophen, valproate, serotonergicantidepressants, disulfiram, warfarin and theophylline.[23]

Overdose

Gastric lavage may be of value if undertaken within a few hours of ingestion. Very large doses of rifampicin may depress central nervous function. There is no specific antidote and treatment is supportive.

Storage

Capsules and tablets should be kept in tightly closed containers, protected from light Pyrazinamide

General information

Pyrazinamide is a synthetic analogue of nicotinamide that is only weakly bactericidal against M. Tuberculosis but has potent sterilizing activity, particularly inthe relatively acidic intracellular environment of macrophages and in areas of acute inflammation. It is highly effective during the first 2 months of treatment while acuteinflammatory changes persist. Its use has enabled treatment regimens to be shortenedand the risk of relapse to be reduced. It is readily absorbed from the gastrointestinal tract and is rapidly distributed throughout all tissues and fluids. Peak plasma concentrations are attained in 2 hours and the plasma half-life is about 10 hours. It is metabolized mainly in the liver and excreted largely in the urine. Clinical information.[24,25]

Administration and dosage

 Pyrazinamide is administered orally.

Adults (usually for the first 2 or 3 months of TB treatment):

• • 25 mg/kg (20-30 mg/kg) daily
  • 35 mg/kg (30-40 mg/kg) 3 times weekly.
  • Contraindications
  • Known hypersensitivity.
  • Porphyria.
  • Active, unstable hepatic disease (with jaundice)

CONCLUSIONS

Tuberculosis remains one of the most deadly infectious diseases and has claimed millions of lives for many years. While significant progress has been made towards controlling the global burden of TB over the past decade, more efforts are still needed. Emerging issues such as multi drug-resistance threatens to revert the progress made regarding TB care and control. The knowledge base for TB remains a rapidly expanding area and global guidelines are continually being refined for instance to incorporate new anti-tubercular drugs to tackle issues of resistance. Health professionals, policy makers, patients and the general public need to keep up-to-date with current trends in TB management and control. This will be essential for efficient adoption of global guidelines to country-level situation, particularly taking into consideration issues such as disease burden, health system structures and available resources.

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