Tuberculosis

Worldwide, most cases of active TB presents soon after infection, and disease rarely manifests more than two years after infection, and most cases do not result in major disease outbreaks.

If untreated mortality rate is about 70% in smear positive patients.

The leading cause of death in adults infected with the HIV.

Worlwide an approximately 1000 people with HIV virus infection die from tuberculosis each day.

In 2013 1.1 million people were estimated to have tuberculosis-HIV co-infection, 13% of the global caseload.

About 80% of tuberculosis-HIV associated disease occurred in Africa and this association accounted for about 25% of the total number of tuberculosis related deaths.

Mycobacteria efficiently transmitted by aerosolized droplets during cough.

Has killed roughly 1,000,000,000 people in the past two centuries.

Ranks among the top 10 causes of death worldwide.

After inhalation of M tuberculosis immune response involves the alveolar macrophages and granulocytes to combat the infection.

In some individuals the bacilli are cleared whereas in others infection is established and replication of bacilli and macrophages and regional lymph nodes leads to lymphatic and hematogenous dissemination with seeding of multiple organs and may give rise to extra pulmonary disease.

The bacilli are contained within macrophages and extracellularly within granulomas limits their replication and controls tissue destruction, resulting in a balance between pathogen and host.

Key risk factors include poverty, overcrowding, undernutrition, alcohol misuse, HIV, silicosis, chronic renal failure with dialysis, fibro-apical radiographic changes, diabetes, tobacco smoking , and immune suppressant therapy.

Disease development is a function of the patients immunocompetence.

Organism transmitted from person to person, among animals or between animals and people.

Isolation of organisms indicates the presence of disease.

Transmission occurs when the organism is aerosolized by the cough of infected patient and inhaled into the alceoli of the new host.

Likelihood of transmission related to the number of organisms being expelled, the frequency of expelled bacteria, and the time of exposure and susceptibility of a potential host.

In some cases transmission is highest within families, but outbreaks can occur in schools, factories public transportation facilities, etc.

Tuberculosis does not always settle in the lungs, and if the involvement in the brain, organs, kidneys, joints, or others areas, the patient may have active tuberculosis for an extended period of time before discovering that they have active disease.

Depending on ventilation and other factors, these tiny respiratory droplets from the person who has active tuberculosis can remain suspended in the air for several hours.

Should another person inhale them, he or she may become infected with TB.

The probability of transmission will be related to the infectiousness of the person with TB, the environment where the exposure occurred, the duration of the exposure, and the susceptibility of the host.

A large fraction of cases are the result of recent transmission rather than reactivation of latent disease.

10,521 cases reported in the US in 2011, for a rate of 3.4 per 100,000 ppopulation-the lowest rate since reporting began in 1953, and 6.4% lower than the 2010 rate.

9421 cases reported in US in 2014.

TB rate among foreign born individuals 11 times that of US born individuals (2010).

In the US TB rates for Hispanics, blacks, Asians 7, 8, and 25 times greater than whites.

In 2010 four states reported more than 500 cases, accounting for 50% of all cases reported in 2011.

Estimated that a third of the world’s population is infected with Mycobacterium tuberculosis.

Second leading cause of death from infectious disease is globally.

Leading cause of death in patients with HIV.

Affects more than 9 million people worldwide and causes more than one and half million Deaths each year.

In 2013 estimated 9 million incident cases reported, equivalent to 126 cases per 100,000 population with more than 60% of the burden concentrated in 22 high burden countries.

Case detection rate about 64%.

Mortality has declined from almost 30 per 100,000 20 years ago to around 16 per

100,000 in 2013.

Global incidence of 122 persons per hundred thousand population and 1.3 million people died in 2012.

Incidence varies from high of 550 per hundred thousand population in southern Africa to fewer than 10 per hundred thousand patients in Western societies.

Global prevalence of multidrug resistant tuberculosis is estimated 3.6% of the newly diagnosed cases and 20.2% of previously treated cases.

In sub-Saharan Africa tuberculosis epidemic is driven by a HIV through increased reactivation of latent TB, and increased risk of rapid development of disease soon after exposure to Mycobacterium tuberculosis because of HIV induced immunodeficiency.

Without effective treatment it is associated with substantial morbidity and mortality.

Among sputum smear positive cases in HIV negative patients the estimated 10 year case fatality rate is 70%.

HIV patients have a 20-30 times more likely to develop active disease.

Approximately 3.9 million cases worldwide have positive sputum smears, the most infectious form of the disease.

Estimated 8.7 million new cases in 2011 and 1.4 million people died from TB

Globally 9.4 million incident cases , 14 million prevalent cases, and 1.7 million deaths in 2009 (WHO).

There is between 500,000 and 1 million new cases of childhood tuberculosis diagnosed worldwide annually.

Most cases in adults are diagnosed through detection of acid-fast bacilli on microscopic examination of sputum specimens.

Newer diagnostic techniques can provide greater sensitivity, particularly among children and individuals with HIV infection since sputum smears are often negative, and can also identify rifampin resistance.

Early and accurate diagnosis results in earlier treatment and decreased transmission rates.

In the majority of childhood cases of Tbc, smears and cultures are negative for Mycobacterium tuberculosis and the diagnosis is made usually on clinical grounds.

Primary TB manifested by lymphadenopathy, lung infiltrates and pleural effusion.

Clinical diagnosis of Tbc in children is unreliable and is responsible for over and under diagnosis.

Diagnosis of childhood tuberculosis microbiologically usually requires hospital admission to obtain gastric lavage fluids with saline induced sputum.

Miliary tuberculosis results from lymphohematogenous spread of Mycobacterium TB, and accounts for 1-2% of all cases of TB.

Miliary TB accounts for about 8% of all forms of extrapulmonary TB.

Miliary TB associated with 100% mortality rate if untreated.

Microbiological confirmation of tuberculosis in children is achieved in only a small portion of patients because of the paucity of bacilli in childhood Tbc and the characteristic extrapulmonary presentation.

Miliary TB typically affects children less than 3 years.

Miliary TB associated with HIV, diabetes, ESRD, or immunosuppression.

Miliary tuberculosis may be the result of a primary infection or reactivation of a latent infection.

Miliary TB can present as an acute, subacute and chronic presentation.

Miliary TB acute presentation is rapidly progressive, leading to sepsis, acute respiratory distress syndrome and multiple organ failure.

Miliary TB subacute and chronic disease presentation are usually characterized by fevers, malaise and weight loss.

Miliary TB diagnosis is based on clinical, microbiological and histopathological evidence.

Miliary TB imaging hallmark is milary pattern on chest x-Ray, but it is seen only in 28%,

Miliary TB findings on examination may reveal hepatosplenomegaly, lymphadenopathy, and choroidal tubercles on fundoscopic exam.

Miliary TB treated with standard treatment with 6 months of anti-TB medications: 2 months of rifampin, INH, ethambutol, and pyrazinamide, followed by 4 months of INH and rifampin.

X-ray findings in childhood tuberculosis are often nonspecific.

In childhood tuberculosis, tuberculin skin test and interferon-Gama-release assay (IGRA) cannot differentiate active disease from latent infection.

The CDC estimates they may be up to 14 million persons with latent TB infection in the US.

The risk of developing active TB in persons with latent TB can range from 5-15%.

It usually takes 8 to 10 weeks after exposure before the TB test is positive. would show if someone had become infected.

An estimated 1.32 million people who were not infected with the human immunodeficiency virus died of tuberculosis in 2007, as did an estimated 456,000 people who were HIV positive.

1.7 million people die each year of tuberculosis and nearly 250,000 have HIV (2008).

Estimated that 700,00 new cases of tuberculosis occur in HIV infected individuals each year (2008).

Africa has 29% of global burden of tuberculosis related deaths.

Average incidence in African countries more than doubled between 1990 and 2005 from 149 to 343 per 100,000 population.

Increases in disease attributable to the HIV epidemic and is the most common coexisting condition in people who die from AIDS.

Diabetes increases the risk of developing tuberculosis by three fold.

death from tuberculosis is greater in diabetic patients.

500,000 cases of multidrug resistant tuberculosis in 2007.

Autopsy results show 30-40% of HIV infected patients die from tuberculosis.

Trials have shown preventive treatment of HIV infected patients with INH for 6-12 months or a combination of INH and rifampin for 3 months reduces the risk of tuberculosis by 32-64%.

Primary isoniazid prophylaxis does not improve tuberculosis disease free survival among HIV infected children or tuberculosis infection free survival among HIV uninfected children immunized with BCG vaccine (Madhi SA et al).

A trial to prevent tuberculosis in HIV patients comparing 12 weeks of rifapentine plus INH, rifampin plus INH, INH daily for 6 years or INH for 6 months: all regimens were effective, but no regimen was superior to 6 months of INH (Martinson NA et al).

Despite effective therapies for tuberculosis, mortality is very high in patients with severe immune depression, and mortality among HIV-infected patients is approximately 30% within the first two months of tuberculosis treatment if antiretroviral therapy is withheld (Lawn SD et al).

Among HIV infected adults with CD4+ T cell counts of 200 per cubic millimeter or lower initiating antiretroviral therapy two weeks after the start of tuberculosis treatment significantly improves survival compared with individuals treated later, at eight weeks (Blanc FX e al).

The most common opportunistic disease, and most common cause of death in patients with HIV infection in developing countries (Mukadi YD).

Among HIV infected children tuberculosis accounts for up to one in five of all deaths.

The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial determined that the initiation of antiretroviral therapy during tuberculosis therapy signficantly improved survival (Abdool Karim, SS).

95% of cases occur in developing countries where the disease accounts for 25% of avoidable adult deaths.

5-10% of people exposed to tuberculosis experience primary tuberculosis with symptoms that last about 2 years and these individuals are infectious following recovery.

About 90% of individuals exposed to tuberculosis develop a chronic latent state without clinical disease and who are not infectious.

Latent tuberculosis refers to a period is asymptomatic disease with persistent bacterial viability, immune control, and no evidence of clinically manifested active disease.

It is not possible to clinically diagnose latent M tuberculosis and its diagnosis depends on response to in vivo or in vitro stimulation of M tuberculosis antigens with a tuberculin skin test or interferon-gamma release assay

Patients with chronic latent disease have a positive skin test for tuberculosis and have viable bacilli in lung granulomas.

Latent tuberculosis will develop into active disease in approximately 5-15% of patients during their lifetime and in a higher percentage if the person is immuno compromised.

5.8 cases per 100,000 inhabitants in the U.S. in the year 2000.

About 4% of the US population has latent tubercuosis

Risk factors in the U.S. include incarceration, immunodeficiency, homelessness, travel to endemic areas, exposure to individuals with active disease, drug abuse, alcohol abuse and being a health care worker.

Active smoking and passive exposure to secondhand tobacco smoke in households predisposes to the development of tuberculosis (Leung CC).

Most cases in Africa and Southeast Asia with an annual incidence of 350 and 182 cases per 100,000 population, respectively.

Majority of patients with the disease live in the most populous countries of Asia: Bangladesh, China, India, Indonesia and Pakistan, accounting for 48% of all new cases annually.

Of all newly diagnosed cases each year 80% come from 22 of the most populous countries.

Causes 6.7% of deaths in developing counties.

Accounts for 18.5% of all deaths in persons aged 15-59 years.

Therapy with tumor necrosis factor inhibitors increases the risk of active disease.

Primary infection usually associated with lymphadenopathy, parenchymal infiltrate, pleural effusion, or military disease.

Right paratracheal adenopathy and right hilar adenopathy common in primary infection.

Commonly affected lung is the middle lobe, lower lobes and the anterior segments of upper lobes, although any lobe can be involved.

Latent infection refers to individuals with a positive skin tests but no evidence of active disease.

Latent M. tuberculosis infection is a continuim host-microbe interactions, characterized by clinical latency when host responses predominate and by disease when bacterial replication exceeds the threshold to cause symptoms.

Post inflammatory responses, especially interleukin-one beta may enhance mycobacterial replication demonstrating immune responses may be present in latent infection.

Latent M. tuberculosis infection is estimated to be present in approximately one third of the world’s population.

Annual rates of tuberculosis infection range from 4.2% in South Africa and 1.7% Vietnam to 0,03% in the US.

M. Tuberculosis infection has declined the many places do to improved living conditions.

Anergy seen in as many as 25% of patients with active pulmonary disease.

The prevention of reactivation tuberculosis through the treatment of latent infection is the major goal of eliminating tuberculosis in the U.S.

Can exist as a latent infection for years and in 90% of such patients the disease does not manifest itself.

The recommended treatment of latent infection is nine months of antibiotic therapy.

The completion rate for treatment of latent infection ranges from 3-60% with rates of 20-30% most common.

The lifetime risk for reactivation tuberculosis is 5-10%

The lifetime risk for reactivation tuberculosis is 20% or more among patients with tuberculin skin test induration of 10 mm or more, have HIV infection or have evidence of old, healed tuberculosis.

The lifetime risk is 10-20% for patients with recent skin test conversion.

Risk 10-20% for children of 5 year or younger with a skin test induration of 10 mm or more.

The risk of reactivating tuberculosis decreases 10% per decade as 10% of adults lose tuberculin reactivity each decade.

A consequence of HIV epidemic is the increased incidence of tuberculosis.

Primary prevention treatment for tuberculosis in patients with HIV and no history of the disease results in a reduced incidence of tuberculosis.

Isoniazid preventative therapy reduces the incidence of tuberculosis in HIV infected patients overall by 42% and by 60% in those with tuberculin positive skin tests.

Advanced HIV infection increases the risk of reactivation of tuberculosis 10 times that of persons without HIV.

A third of the 40 million patients with HIV/AIDS are infected with tuberculosis.

In 2003 tuberculosis was the major cause of death in HIV positive patients with about 674,000 of such patients developing tuberculosis.

Relative risk for developing tuberculosis is 2.4 for patients with chronic renal failure.

Majority of cases that occur in the U.S. are in foreign-born individuals.

Foreign born cases account for more than half of cases in the U.S., a rate nine times that of those born in America.

Meningitis is the severest form of infection, resulting in death or severe neurological defects in greater than half of those affected, despite treatment.

Estimated that infectious tuberculosis patients spreads the infection to 12 susceptible persons.

Early spinal disease is frequently asymptomatic.

Has a predilection to destroy the anterior aspect of vertebral bodies with absence of osteophyte spurring or involvement of the spinous processes.

Most common form of skeletal tuberculosis involves the spine.

About 25% of spinal disease involves the thoracic region, 20% in the lumbar and lumbosacral region and 5% in the cervical area.

Involves the bone in 3-5% of cases but in HIV positive patients this percentage increases to 60%.

Bone and joint involvement occurs in 2% of TB infections (Watts HG).

Pott diseases in indolent course but back discomfort is reported in approximately 80% of patients and may be only initial symptom.

Fewer than half of the patients with Pott disease have signs of fever night sweats or weight loss, delaying diagnosis.

Adjacent lower thoracic or lumbar vertebrae involvement or common. The cervical and upper thoracic spine are involved in fewer than 10% of patients.

Radiologic sparing of the disc is characteristic of Pott disease.

A paraspinal mass lacking erythema, tenderness and warmth can occur in about 50% of patients, but the paraspinal mask can impinge on the spinal cord and could be associated with neurologic deficit is 40% of patients.

Involvement of the skeleton results from hematogenous spread usually from the lung and spares the intervertebral disc which is avascular.Can lead the skeletal abscess formation.

Patients with skeletal involvement typically resent with fever, night sweats, weight loss and pain on percussion of the vertebral body.

MRI is the most sensitive imaging procedure for identifying bone destruction that is characteristic of M tuberculosis, articularly in early disease.

Treatment of spinal disease 3 or 4 of the following drugs: isoniazid, rifampin, pyrazinamide and ethambutol.

Drug therapy for skeletal tuberculosis should be for at least 6 months.

Surgery for spinal disease may be needed for patients with neurological deficits, spinal instability, spinal deformities and for patients unresponsive to medical management.

Cervical spine lesions may present with upper extremity weakness and progress to quadriplegia.

Lesions of the neck may present with retropharyngeal abscesses, dysphagia, neck masses and mediastinal disease.

Mycobacterium tuberculosis can be contained in a latent state in a granuloma which is a stable structure.

Within a granuloma the Mycobacterium organism lives inside macrophages and dendritic cells and is maintained in a stable state by TNF-alpha

In 2004 14,517 cases reported in the U.S., with 6-7% of cases occurring among children under the age of 14 years.

Children are more likely to have disseminated disease than adults.

Children with infection more likely to be foreign born or belong to a racial or ethnic minority group.

In general children with infection have had contact with an infected adult or adolescent.

9-14 million people in the U.S. have latent infection and this number is growing as immigration from high prevalence areas occurs.

Treatment of latent infection reduces the risk of active tuberculosis, especially in high risk groups such as patients with HIV infection.

Individuals with radiographic evidence of inactive tuberculosis, close contacts with patients with active disease, patients treated with infliximab and other immunosuppressive treatments, and children under age 5 years could benefit from treatment of latent disease.

Emergence of drug resistance occurs with widespread use of antimicrobial agents.

Wild isolates of M tuberculosis in absence of exposure to antituberculosis agents are almost never resistant to such drugs.

Multidrug resistant (MDR) disease associated with cure rate of 6-59%.

Multidrug resistant tuberculosis indicates resistance to both isoniazid and rifampin.

Multidrug resistant tuberculosis accounts for 110,000 deaths worldwide each year.

Multidrug resistant tuberculosis required extended treatment with second line agents that are less effective and are associated with more adverse effects than isoniazid and rifampin based drugs.

Multidrug resistant tuberculosis defined as a disease caused by strains of the Mycobacterium tuberculosis are resistant to isoniazid and rifampicin.

Extensively drug-resistant tuberculosis refers to disease caused by multi-drug resistant strains that are also resistant to treatment with fluoroquinolone and injectable drugs used as second line therapy.

Turnaround time between identification of the specimen positive for tuberculosis with the smear microscopy or molecular diagnostics should not be longer than 24 hours.

TREATMENT

Completion of the six-month course of multi drug therapy leads to cure, with less than a 5-8% chance of relapse.

If relapse occurs, it usually happens within 12 months after completion of therapy, indicating the disease has been incompletely treated.

Standard treatment consists of two months induction treatment with at least isoniazid, rifampin, and pyrazinamide, followed by a four-month consolidation phase with at least isoniazid and rifampin.

TB is usually treated with a six month rifampin-based regimen.

During first two months of treatment, viable bacteria in sputum undergo a biphasic kill curve with at least two bacterial subpopulations: one subpopulation is rapidly killed, the other responds more slowly.

The second group is classified as persistent bacteria in a metabolic state making them less susceptible to killing by antimicrobials because of micro environmental factors or phenotypic variants.

Some anti-mycobacterial agents rapidly kill multiplying bacteria and others have the ability to kill persistent or nonreplicating bacteria.

Four months of anti-tuberculous treatment was noninferior to six months of treatment in children with drug susceptible, non-severe, smear negative tuberculosis (SHINE trial team).

Initial treatment with an eight week bedaquiline-linezolid regimen was non-inferior to standard treatment for tuberculosis with respect to clinical outcomes (TRUNCATE-TB trial team).