Tuberculosis: A Clinical Practice Guide

Globally, tuberculosis is one of the top 10 overall causes of death, the leading cause of death from a single infectious agent, and the principal cause of death among subjects living with human immunodeficiency virus infection.

The United Nations and the World Health Organization (WHO) have set very ambitious goals for the period 2020-2035 that include a 95% reduction in the number of deaths and a 90% reduction in TB incidence by 2035 compared with 2015.

The WHO reported in 2018, an estimated 10 million incident cases of TB (global incidence rate: 133 cases per 105 population), and 1.2 million TB deaths, for a case fatality rate of 15.7%. Incidence rates vary widely among regions of the world; geographically, most TB cases in 2018 were in the WHO regions of South-East Asia (44%), Africa (24%) and the Western Pacific (18%).

Rifampin-resistant (RR-TB) or multidrug-resistant TB (MDR-TB) in 2018 occurred in an estimated half a million cases, and accounted for 3.4% of all new cases and 18% of previously treated cases; an estimated 230,000 persons died of either RR or MDR-TB (case fatality rate: 41%).

Almost a quarter of the world population (1.7 billion people or 23%) are estimated to have latent TB infection and therefore are at risk of developing active TB during their lifetime.

Progress toward global TB elimination during 2018 was very modest, as it has occurred in recent years, and if kept at this current pace, the global targets for the period 2020- 2035 will not be accomplished.

Mycobacterium tuberculosis (MTB) is the primary etiological agent of tuberculosis in humans (since the disease may be due to other mycobacteria of the MTB complex such as M. bovis). It belongs to the order of the Actinomycetales and the Mycobacteriaceae family. It is a bacillus that lacks capsule or flagella and does not produce spores or toxins; it measures 0.5 by four microns. Its generation time is prolonged (up to 24 hours). It is an aerobic bacillus that, if necessary, can persist under anaerobic conditions.

It has a cell wall of extremely complex composition, with great strength and thickness, constituted up to 60% by lipids, generally known as mycolic acids that form complexes with polysaccharides such as arabinogalactan and peptidoglycan; these lipids determine their resistance to discoloration by alcohol-acid after they have been stained with carbol fuchsin (hence the term acid-fast bacilli acid or AFB). A distinctive feature of the MTB cell wall is its content of N-glycolimuranic acid instead of N-acetylmuramic acid found in most bacteria.

The unusual cell wall of MTB also allows it to survive initially in the macrophage. The cell wall also constitutes a robust and highly impermeable barrier to harmful compounds and drugs. MTB can sense when the local tissue conditions are inadequate for survival (low oxygen tension and nutrient depletion), as in the macrophages and granulomas, responding by the activation of a dormant state, in which the bacilli stop multiplying, down-regulates its metabolism and activates anaerobic metabolism.

Tuberculosis infection occurs when a subject inhales the Mycobacterium tuberculosis bacilli (MTB). An active case of pulmonary or laryngeal tuberculosis generates infectious particles called droplet nuclei of <5 microns in diameter, when coughing, sneezing or through any other forceful expiratory maneuver. The infectiousness of a patient with TB is directly related to the form of the disease (laryngeal, pulmonary), the presence of cough, cavitary lung disease and the positivity of the sputum smear/culture.

The prevalence of M. tuberculosis infection among household contacts is higher than 50%. Contacts who are <5 years of age or HIV infected have the most significant risk of developing tuberculosis once they acquire the infection.

In latent tuberculous infection, most bacilli are metabolically inactive, and only a few are replicating. In immunocompetent individuals, these bacilli are destroyed by the immune defenses of the host and the development of active disease aborts. When the immunity of the subject fails, the bacilli multiply, and eventually, active tuberculosis ensues. If latent infection tuberculosis is not treated, approximately 5% of infected individuals will develop the active disease within the first two years after infection, and another 5% will develop TB sometime later in life.

HIV infection is the most significant risk factor for the progression of LTBI to active TB disease, with an annual risk of 7-10% for subjects who are not receiving highly active antiretroviral treatment.

Symptoms and signs of active tuberculosis (TB) depend on its anatomical location. Pulmonary disease is the most common presentation of tuberculosis in the adult patient (more than 80% of the cases in the immunocompetent patient). Signs and symptoms can appear after just a few weeks from the primary infection, or many years later due to the reactivation of latent disease anywhere in the body.

Symptoms of pulmonary tuberculosis are nonspecific and may occur in many other pulmonary conditions; however, in high-burden regions, they remain a valuable tool for initial screening.

Signs and symptoms of extrapulmonary tuberculosis (EPTB) are protean, and chest xrays of the chest frequently do not show abnormalities. TB lymphadenitis is the most common form of EPTB, especially in children and young individuals.

Miliary tuberculosis is characterized by the presence of disseminated innumerable small nodules. It is secondary to the hematogenous spread of the bacilli throughout the body after the primary infection or the reactivation of a latent focus.

Although TB can involve any segment of the gastrointestinal tract, the ileocecal region is the most frequently affected. It is due to the ingestion of milk or milk products contaminated with M. bovis, the swallowing of secretions infected with M. tuberculosis, hematogenous dissemination of active TB disease, or from direct spread from contiguous organs.

Central nervous system tuberculosis is a consequence of hematogenous dissemination and the most severe form of the disease, with high morbimortality.

Tuberculosis is an excellent simulator and can mimic virtually any disease. Clinically, it has been divided into primary and post-primary tuberculosis. Primary tuberculosis usually refers to patients not previously exposed to M. tuberculosis. Primary tuberculosis is more frequent in children, with its highest prevalence in children under five years, although the frequency of primary forms in adults is increasing. The primary disease has four main presentations at imaging: chest lymphadenopathy, pneumonia, miliary disease, and pleural effusion. Post-primary TB (also known as reactivation or secondary TB) most commonly involves the lungs in the apical and posterior segments of the upper lobes and the apical segment of the lower lobes. Initially, there are parenchymal consolidations, that if they are not diagnosed and treated, usually progress to necrosis and cavitation. Unilateral lung destruction is a serious complication of pulmonary TB that occurs in chronic advanced cases. Although TB is mostly limited to the lungs, it can happen in any other tissue or organ, especially in the immunocompromised host.

Although sputum microscopy remains the most widely used diagnostic method worldwide, given its low sensitivity (50-80%) and specificity (it does not distinguish M. tuberculosis from nontuberculous mycobacteria), more rapid, sensitive, and specific methods are required nowadays. Culture for mycobacteria continues to be the gold standard due to its higher sensitivity and specificity, and because it also allows the detection of strains resistant to antituberculosis drugs; however, even with liquid culture media, at least one month of processing is required to obtain results. Therefore, rapid genotyping methods (e.g., Xpert and line-probe assays known as LPAs) have replaced phenotypic methods by allowing the identification of species and the presence of mutations associated with resistance in less than 24 hours. The Xpert, an automated real-time PCR system, can identify the presence of mutations associated with rifampin resistance in less than two hours, with a sensitivity higher than 70% in patients with negative microscopy. LPAs allow species identification and the presence of mutations associated with resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectables in less than 24 hours. Progressively, the complete sequencing of the Mycobacterium tuberculosis genome has been integrated into the diagnostic protocol, allowing the identification of all mutations associated with resistance for all antituberculosis drugs. Phenotypic methods (microscopy and cultures) continue to play an essential role in the follow-up of patients who are already under treatment.

Although the underlying general principles of management of tuberculosis are the same for all cases, there are certain special situations in which the treatment regimen must be modified.

Uremia and post-renal transplant are both risk factors for tuberculosis due to the underlying immunodeficiency. Patients undergoing dialysis have a 10-25-fold higher risk of developing the disease than the general population.

Many antituberculosis drugs are hepatotoxic. If aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are increased more than three times the upper limit of normal in the presence of symptoms of hepatitis or >5 times the upper limit of normal, even if the patient is asymptomatic, all hepatotoxic drugs should be discontinued.

First-line drugs (HREZ) are safe during pregnancy, and regimen doses and duration are the same as in non-pregnant individuals. Pyridoxine (50 mg, vitamin B6) should be added to the regimen to prevent neuropathy in the mother and seizures in the fetus.

There is an increased risk of progression to active TB in subjects with latent infection TB and diabetes in comparison with the infected nondiabetic population. Also, outcomes for patients with TB and diabetes are worse than for TB patients without diabetes, and diabetes also increases the risk of drug-resistant TB.

Risk factors for extrapulmonary TB (EPTB) include advanced age, female gender, immunosuppression (including HIV) and chronic comorbidities. Symptoms and signs are usually non-specific, and except for miliary forms, the chest radiograph might be normal; therefore, the diagnosis of EPTB is frequently delayed with the consequent increase in morbidity and mortality.

Traditionally little attention has been paid to pediatric tuberculosis by clinicians, researchers, decision-makers, and even by national tuberculosis programs. According to the World Health Organization (WHO) Global Report for the year 2018, 10 million people developed TB in 2017, with 1 million of those being children under15 years of age. In the same year, there were 1.3 million deaths due to tuberculosis among HIV-negative people; children accounted for 15% of all deaths from TB, a percentage higher than their share of estimated cases.

Clinical presentation of pulmonary TB varies according to the age of the patient. Infants frequently will present with reduced playfulness, fever, dry cough, and dyspnea; children usually have dry cough as the only symptom, whereas in adolescents, the clinical manifestations are very similar to those of adults with fever and productive cough.

Lymphadenopathy is the most common type of extrapulmonary TB in children. The most commonly involved sites are the anterior cervical, posterior cervical triangle, submandibular, and supraclavicular lymph nodes.

BCG is the only vaccine available for clinical use in TB worldwide. Its overall efficacy for preventing tuberculosis is around 50% (range 0-80%). It is especially useful in the prevention of severe forms of the disease in children, including disseminated disease and meningeal tuberculosis. It does not prevent pulmonary tuberculosis effectively.

The lifetime risk of developing active TB in subjects with latent tuberculosis infection without the human immunodeficiency infection (HIV) co-infection is 5-10%; for people living with HIV (PLWHIV), the annual risk is 3-16% per year.

The interaction of these two pathogens is complex: HIV-1 co-infection is the most significant risk factor for developing active tuberculosis, while M. tuberculosis coinfection leads to increased viral replication and disease progression.

Clinical presentation will vary depending on the degree of immunodeficiency. Patients with higher CD4 cell counts can present with the classic symptoms, while the clinical presentation of TB in patients with advanced immunodeficiency (less than 200 cells/mm3) is usually atypical. Extrapulmonary tuberculosis is more frequent among co-infected individuals regardless of the CD4 cell counts, occurring in up to 70% of patients with CD4 counts of ≤100 and about 30% of subjects with counts of >300 cells/mm3.

The diagnostic approach in subjects with TB-HIV-1 co-infection is the same as that of patients without HIV infection, with the goal being the microbiologic confirmation of the diagnosis.

Antiretroviral (ART) should be started in all TB patients living with HIV regardless of their CD4 cell count. Antituberculosis treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment. Unfortunately, the restoration of the immune response sometimes has an undesirable effect known as immune reconstitution inflammatory syndrome (IRIS).

The treatment of susceptible tuberculosis has evolved in the last 70 years, from requiring the use of toxic drugs (PAS, streptomycin by parenteral route) for two years, to exclusively oral treatment, with a combination of more effective and less toxic medications for six months. The cure rate with this regimen that includes isoniazid, rifampicin, ethambutol, and pyrazinamide is higher than 90% when the patient is adherent and completes the treatment. Hence, this indicates the importance of directly observed treatment (DOT), a strategy focused on the patient.

It is essential before starting treatment with first-line drugs to demonstrate that the strain causing the condition is susceptible to isoniazid and rifampin; nowadays, these results can be available in 24-48 hours by molecular methods, avoiding the delay associated with phenotypic methods.

Although the reduction from 24 to 6 months is significant, it is still a very prolonged treatment that favors the loss of follow-up. Unfortunately, attempts to reduce the duration to four months by the addition of fluoroquinolones did not have favorable results, and the recommended length is still six months.

The most recent recommendations of the WHO include the daily administration of the drugs for six months (instead of intermittent administration during the last four months of the regimen) and the administration of the four drugs in a combined fixed dose presentation.

The presence of drug resistance should always be suspected when there are risk factors for it and must be confirmed by bacteriological or molecular tests for standardized drug sensitivity. Any regimen for drug-resistant TB is more likely to be effective if its composition is based on information from reliable drug susceptibility testing.

The presence of drug-resistant tuberculosis should be suspected in patients who are failing treatment, in patients with TB relapse, in subjects coming from regions with a high prevalence of MDR-TB, and in contacts of known cases of MDR-TB. Although there are multiple reasons why treatment may fail, the most frequent is the lack of adherence to the regimen.

The most common causes of relapse include lack of adherence to treatment with the development of acquired drug resistance, treatment with an inadequate therapeutic regimen, malabsorption of drugs, and exogenous reinfection with a different strain of M. tuberculosis.

In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, treatment with rifampicin, ethambutol, pyrazinamide, and levofloxacin is recommended for a duration of 6 months.

One general WHO recommendation is that all patients with rifampin-resistant TB (even those with monoresistance to rifampin) should be treated with an MDR-TB drug regimen. There are three options for the treatment of RR/MDR/XDR TB. Two are recommendations for programmatic management (the short and longer regimens) and one for operational research (the BPaL regimen).

One-third of the world's population is infected with M. tuberculosis. It is from this vast pool of infected people where the new cases of active disease originate. Most of these cases of latent infection are found in low-income countries where national tuberculosis programs concentrate practically all their efforts on the diagnosis and treatment of tuberculosis disease, neglecting the diagnosis and treatment of latent tuberculosis in contacts of an active case. Each case of pulmonary tuberculosis infects an average of 20 contacts, and of these, 10% of immunocompetent subjects will develop the active disease if the latent infection is not detected and treated, which means that each case of active TB will generate two new cases of TB; this explains, at least in part, the difficulty that high burden countries have in controlling the epidemic. These figures are even higher for subjects with some state of immunosuppression (for example, people living with HIV, patients receiving immunosuppressive treatment, malnourished, etc.).

For the diagnosis of latent TB, we currently have in vitro tests to determine the release of interferon-γ (IGRA´s), with higher specificity than the traditional tuberculin test, an essential point in subjects vaccinated with BCG.

Also, now there is a regimen (isoniazid and rifapentine) that requires only 12 doses of medication instead of 180-270 doses of isoniazid, which facilitates adherence to the regimen, with the same effectiveness and less toxicity.

The WHO has recommended the treatment of infected cases of MDR-TB (specifically children and people living with HIV) with a fluoroquinolone.

Despite recent advances in the pharmacologic treatment of tuberculosis, some patients are left with residual or persistent sequels that could benefit from surgical intervention.

Most experts believe that surgical treatment is rarely necessary in patients with pansensitive tuberculosis, and is only necessary in case of complications, such as massive hemoptysis, empyema, bronchopleural fistula, etc.

The main indication for surgical treatment is MDR/XDR-TB. Surgical treatment in pulmonary MDR-TB is usually indicated in patients with inadequate response to medical therapy and localized lung lesions.

Indications for surgical treatment in tuberculosis can be classified as emergency surgery, urgent surgery, and elective surgery. It is recommended, when possible, that chemotherapy should be administered for at least three months before surgery to reduce the bacillary load and reduce the risk of complications.

There are four essential criteria that a patient must fulfill to be considered as a candidate for surgery in MDR-TB:

1. The patient must have localized disease and adequate respiratory function (forced expiratory volume in one second [FEV-1] ≥1.5 L in cases of lobectomy and ≥2.0 L for pneumonectomy) that will allow the surgical removal of the lesion.

2. The mycobacterial strain causing the disease must have a complex resistant profile, a characteristic associated with a high risk of treatment failure or relapse.

3. Lung tissue, including the airway around the resection margins, should be free of disease to reduce the risk of fistula at the bronchial stump.

4. The availability of enough efficient second-line drugs for treatment after surgery.

The BCG vaccine is derived from the Bacillus Calmette-Guérin (BCG) and is the most utilized vaccine in the history of humankind. Calmette and Guérin developed it in the Pasteur Institute from an original strain of Mycobacterium bovis.

The use of BCG vaccine is limited to the prevention of disseminated and meningeal TB, the most severe forms of the disease in children. BCG vaccination is recommended in countries or settings with a high incidence of TB. A single dose of BCG vaccine should be given to all healthy neonates at birth. The standard dose of BCG vaccine is 0.05 mL for infants aged less than one year and 0.1 mL for those aged one year and older. Studies have shown minimal or no evidence of additional benefits of repeat BCG vaccination against TB.

BCG vaccination is not recommended during pregnancy and it is contraindicated for individuals with immunodeficiency. HIV-infected children, when vaccinated with BCG at birth, are at increased risk of developing disseminated BCG disease.

An effective vaccine preventing pulmonary TB in adults is urgently needed but has long been considered by the TB community as an elusive goal. The slight decrease in the global incidence of TB and the rise in multidrug-resistant TB (MDR-TB) are elements that show the critical state of the TB epidemic and emphasize the need for the development of new tools, including candidates for an effective vaccine.

One of the main components of the End TB Strategy is the need for infection prevention and control (IPC) in health facilities and other settings where the risk of transmission is high. The strategy has three components that should be implemented as an integrated package of IPC interventions to prevent M. tuberculosis transmission. The main components of the policy are a) administrative controls, b) environmental controls, and c) respiratory protection. The administrative controls include the triage of patients with signs or symptoms or with known TB disease, the isolation of patients with presumed or demonstrated TB, and the prompt initiation of effective antituberculosis treatment for patients diagnosed with tuberculosis. The environmental controls include the use of upper-room germicidal ultraviolet (GUV) and natural o mechanical ventilation systems to reduce the concentration of infectious particles in the air. Finally, the respiratory protection strategy recommends using particulate respirators integrated as a part of a respiratory protection protocol.

Another essential component of the strategy is the periodic screening of all health workers with a risk of exposure to tuberculosis patients.

The treatment of tuberculosis requires the use of multiple drugs for prolonged periods, and most patients will, at some time, experience some difficulty tolerating them. In general, it is considered that there is an underestimation of the frequency of adverse effects during the treatment of tuberculosis. Although treatment of drug-sensitive disease with first-line drugs is usually well-tolerated, treatment of multidrug-resistant disease (MDR-TB) requires the use of drugs known as “secondline” drugs, which are associated with a higher frequency and severity of adverse reactions to antituberculosis drugs.

Since it is impossible to predict the response of a given patient, the use of a drug should not be avoided in advance, for fear of an adverse reaction. There are factors that influence the development of adverse reactions, including errors in the dosage of medications, genetic factors, the age of the subject (more frequent in patients older than 60 years), consumption of alcohol and illicit substances, renal failure or hepatic disease, and co-infection with HIV.

Everything possible must be done to facilitate tolerance to medicines; patients must be assured that, while side effects are inevitable, they will be treated as vigorously as possible.

This chapter discusses the adverse effects of antituberculosis drugs on different body systems and organs.